This page exists so that nobody has to take the rest of this site on trust. Every source it rests on is listed here with what it actually measured, who wrote it, and which way it cuts.
A catalogue of the literature bearing on genetic entropy — mutation load, the drift barrier, distributions of fitness effects, experimental evolution, and the rest.
It is deliberately not a reading list of things that agree with this site. Sources are tagged by the direction they cut, and a reader who wants only the strongest material against the argument made here can filter for undercuts and read those.
How to read an entry
Every entry carries the same fields, and three of them do most of the work.
Measurement or model. The most important distinction on this site. A laboratory assay is an observation. A human distribution of fitness effects inferred from polymorphism is the output of a model that contains an assumed population history, and it inherits every assumption in that history. Both are useful; they are not the same kind of thing, and conflating them is how most bad arguments on this subject get made. See what has actually been measured for why this matters.
Direction. Whether the source supports, undercuts, or complicates the argument this site makes. Assigned by what the source shows, not by what its authors believe — several mainstream papers are tagged supports and several creationist ones are tagged undercuts.
Camp. Mainstream, creationist, intelligent design, or unaffiliated. This is disclosure, not a verdict. A creationist paper reporting original data is worth more than a mainstream paper restating a consensus, and the tag exists so a reader can weigh it themselves rather than being told what to think.
Field definitions
| Field | Values |
|---|---|
topic |
load-theory, drift-barrier, DFE, mutation-rate, functional-fraction, beneficial-mutations, epistasis, experimental-evolution, mutation-accumulation, lethal-mutagenesis, conservation-genomics, ancient-DNA, human-selection, simulation, information-theory, history |
camp |
mainstream, creationist, ID, unaffiliated |
peer_reviewed |
yes, no, preprint, editorial |
access |
OA, paywalled, preprint, book, forum, blog |
direction |
supports, undercuts, mixed, background |
proposed_solution |
soft-selection, synergistic-epistasis, stabilizing-selection, beneficial-compensation, junk-DNA, truncation, none |
A note on what this is for. The fields are deliberately regular so that this page can later become a sortable, filterable table rather than a list. Nothing about the content depends on that happening.
Load theory
Mutation load: the fitness of individuals in populations where deleterious alleles are abundant
Agrawal, A.F.; Whitlock, M.C. Annual Review of Ecology, Evolution, and Systematics, 43:115-135 (2012). doi 10.1146/annurev-ecolsys-110411-160257
http://agrawal.eeb.utoronto.ca/files/2013/06/afa_mcw_2012.pdf
camp: mainstream direction: mixed access: OA peer_reviewed: yes organism: theory proposed_solution: soft-selection
Key figure: N-hat = bI(1-L)/[d(1-L(1-beta))]
Models when genetic load does and does not translate into reduced population size, using MacArthur competition rather than logistic growth. Cheap early-life deaths blunt the demographic cost; the escape is strongest for load on resource acquisition and weakest for load on survival or fertility. The article's own arithmetic on their expression shows the escape is U-dependent: 92.6% of unloaded size at U=2.2 but 19.9% at U=6. The authors decline the strong dismissal: "ecological processes are unlikely to completely mask the effects of genetic load."
The "New Synthesis"
Barton, N.H. PNAS, 119(30):e2122147119 (2022). doi 10.1073/pnas.2122147119
https://pmc.ncbi.nlm.nih.gov/articles/PMC9335343/
camp: mainstream direction: undercuts access: OA peer_reviewed: yes organism: theory proposed_solution: stabilizing-selection
In its Open Questions section Barton calls both the drift barrier and Kondrashov's accumulation claim "problematic if we view adaptation as due to optimization of polygenic traits," because "any change that degrades fitness can be compensated." Named by Zach Hancock as the single strongest objection to the whole genetic-entropy argument. Barton is among the most senior living theoretical population geneticists, which is why the article quotes it as its own toughest counter.
Why we are not dead one hundred times over
Charlesworth, B. Evolution, 67(11):3354-3361 (2013). doi 10.1111/evo.12195
https://pubmed.ncbi.nlm.nih.gov/24152012/
camp: mainstream direction: mixed access: paywalled peer_reviewed: yes organism: theory (Drosophila and human numbers) proposed_solution: stabilizing-selection
Key figure: L*_stab = 0.05 in humans; Drosophila purifying load 0.83 synergistic / 0.97 multiplicative
The paper most often cited as the answer to Kondrashov. It offers two resolutions, weak stabilizing selection and soft selection, and gets a small load from the first. But its purifying-selection branch says "an extremely high level of genetic load is inevitable, in agreement with Kondrashov (1995a)" and is "even worse ... such as humans." Also supplies the sentence supporting Argument 2: the load "is caused mainly by sites that are fixed for deleterious variants."
Stabilizing selection, purifying selection, and mutational bias in finite populations
Charlesworth, B. Genetics, 194(4):955-971 (2013). doi 10.1534/genetics.113.151555
https://pmc.ncbi.nlm.nih.gov/articles/PMC3730922/
camp: mainstream direction: mixed access: OA peer_reviewed: yes organism: theory proposed_solution: stabilizing-selection
A different 2013 Charlesworth paper from "Why we are not dead one hundred times over," and open access. Its result is that frequency spectra of DNA sequence variants "may be unable to distinguish between stabilizing and purifying selection" — Charlesworth himself saying the data cannot decide between the polygenic answer and the ordinary one. Cuts both ways and is cited in the polygenic section.
The high spontaneous mutation rate: Is it a health risk?
Crow, J.F. PNAS, 94(16):8380-8386 (1997). doi 10.1073/pnas.94.16.8380
https://pmc.ncbi.nlm.nih.gov/articles/PMC33757/
camp: mainstream direction: mixed access: OA peer_reviewed: yes organism: Homo sapiens (via Drosophila) proposed_solution: truncation
Key figure: 1-2% viability decline per generation
"Since most mutations, if they have any effect at all, are harmful, the overall impact of the mutation process must be deleterious." Crow's 1-2% figure is conditional on humans resembling Drosophila and explicitly outrun by environmental improvement — the extrapolation Sanford's Figure 4 makes anyway. Crow also endorses quasi-truncation: "although strict truncation is totally unrealistic, quasi-truncation selection is reasonable." And he does regard mutation accumulation as a real problem "with a much longer fuse."
Efficiency of truncation selection
Crow, J.F.; Kimura, M. PNAS, 76(1):396-399 (1979). doi 10.1073/pnas.76.1.396
https://europepmc.org/articles/PMC382946?pdf=render
camp: mainstream direction: undercuts access: OA peer_reviewed: yes organism: Drosophila proposed_solution: truncation
Key figure: relative efficiency of truncation selection 5 to 20
Shows truncation selection is 5-20x more efficient than independent selection in their Drosophila case, culling only 10% of the population — Haldane's own budget. The claim is that truncation lets a low-fecundity species pay a load that multiplicative arithmetic says it cannot. This is the strongest technical rescue on the mainstream side, and Felsenstein disputes that truncation happens in nature at all.
High genomic deleterious mutation rates in hominids
Eyre-Walker, A.; Keightley, P.D. Nature, 397:344-347 (1999). doi 10.1038/16915
https://www.homepages.ed.ac.uk/pkeightl/publications/eyre-walker_keightley1999.pdf
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: Homo sapiens, Pan proposed_solution: synergistic-epistasis
Key figure: U = 1.6 deleterious mutations per person per generation (their estimate)
States the load problem in its own words: with multiplicative effects the genetic-death fraction is 1 - e^-U, "so a high rate of deleterious mutation (U >> 1) is paradoxical in a species with a low reproductive rate." Their own resolution is synergistic epistasis. Sanford's book quotes this paper with an ellipsis that deletes both the multiplicative condition and the authors' resolution — documented in sanford.md as error 1.
Comment on 'Evolution Visualized' (truncation not in standard models)
Felsenstein, J. The Skeptical Zone, comment-141808 (2016).
http://theskepticalzone.com/wp/evolution-visualized/comment-page-6/#comment-141808
camp: mainstream direction: undercuts access: forum peer_reviewed: no organism: theory proposed_solution: none
Key figure: 1.1 : 1.0 fitness ratio
"If the fitnesses stand in the ratio of 1.1 : 1.0 then Genghis Khan should be 10% more likely to survive... The truncation part is not in standard population-genetic models." The site serves over HTTP only; its HTTPS certificate is expired, so cite the http URL.
Comment on 'What are the substantive critiques of genetic entropy?'
Felsenstein, J. Peaceful Science, thread 11736 post 23 (2020).
camp: mainstream direction: supports access: forum peer_reviewed: no organism: Homo sapiens proposed_solution: none
"Yes, there is a disturbingly high mutation rate in humans, which would lead to a too-high mutational load." His three offered explanations are that the rate estimate is wrong, that it was lower in prehistory, or that the earth is 6,000 years old. He also concedes the measurement gap: below |s| < 1/(4N) "it is very very hard to collect information on what fraction of those are deleterious."
Comment in 'Kondrashov's Paradox' (Ne objection)
Felsenstein, J. Peaceful Science, thread 17840 post 270 (2026).
https://discourse.peacefulscience.org/t/17840/270
camp: mainstream direction: undercuts access: forum peer_reviewed: no organism: Homo sapiens proposed_solution: none
Key figure: Ne approx 2.7 billion, so barrier s < 3e-10
Applying his own 1971 overlapping-generations result, present human Ne is about census/3, so for mutations arising now the near-neutral band is |s| < 3e-10 and the ratchet has all but stopped going forward. The sharpest objection to the article's Ne = 10,000, made by the person best placed to make it. The article concedes it and reframes its computed rate as a claim about the past, not a forecast.
Comment on 'Evolution Visualized' (standing variation)
Felsenstein, J. The Skeptical Zone, comment-141205 (2016).
http://theskepticalzone.com/wp/evolution-visualized/comment-page-3/#comment-141205
camp: mainstream direction: undercuts access: forum peer_reviewed: no organism: theory proposed_solution: none
"much of the variation that is being acted on by selection would not be new mutations, but would be existing alleles floating around in the population." A real hole in the article's 17:1 to 300:1 destruction-to-construction ratio, which compares two flows of new fixations and ignores standing variation. Archived Wayback capture from Aug 2025.
Theoretical Evolutionary Genetics (p120, the c paradox and mutational load)
Felsenstein, J. University of Washington, course textbook, p120 (2003).
https://evolution.gs.washington.edu/pgbook/pgbook.pdf
camp: mainstream direction: mixed access: OA peer_reviewed: no organism: Homo sapiens proposed_solution: junk-DNA
Key figure: 20 million loci x 1e-7 gives fitness e^-2 = 0.15
"Clearly an organism with as much DNA as we have would be in severe trouble. Yet in humans well over 98% of all newborns survive to adulthood." Carries three things nothing else does as cleanly: the sequence-specific criterion ("the sequence must be truly irrelevant, not just of unknown function"), the circularity in one sentence ("the mutational load argument seems to give weight to the notion that this DNA is nonspecific in sequence"), and the reproductive-excess-as-buffer point. The 2003 archived capture is the verified version; the book is continuously revised.
Comment on 'Evolution Visualized' (truncation as a class)
Felsenstein, J. The Skeptical Zone, comment-141834 (2016).
http://theskepticalzone.com/wp/evolution-visualized/comment-page-6/#comment-141834
camp: mainstream direction: supports access: forum peer_reviewed: no organism: theory proposed_solution: none
"generally we don't see such a mechanism at work in populations" — a stronger denial of truncation selection than Crow's "strict truncation is totally unrealistic" line, and made in direct answer to a link to Crow and Kimura 1979. Archived Wayback capture from Oct 2016.
Mutational Load and the Functional Fraction of the Human Genome
Galeota-Sprung, B.; Sniegowski, P.; Ewens, W. Genome Biology and Evolution, 12(4):273-281 (2020). doi 10.1093/gbe/evaa040
https://pmc.ncbi.nlm.nih.gov/articles/PMC7151545/
camp: mainstream direction: undercuts access: OA peer_reviewed: yes organism: Homo sapiens proposed_solution: soft-selection
Key figure: E. coli nu approx 1e-4 vs human nu = 1-10
"an argument from mutational load does not appear to be particularly limiting on f." The objection is that no mutation-free individual exists, so "no calculation that depends on such an individual... is empirically relevant." Their own concession, quoted alongside: "For many microbes, then, Haldane load theory may be appropriate," because a mutation-free individual is common in a microbial population and essentially absent in a human one.
An Upper Limit on the Functional Fraction of the Human Genome
Graur, D. Genome Biology and Evolution, 9(7):1880-1885 (2017). doi 10.1093/gbe/evx121
https://pmc.ncbi.nlm.nih.gov/articles/PMC5570035/
camp: mainstream direction: mixed access: OA peer_reviewed: yes organism: Homo sapiens proposed_solution: junk-DNA
Key figure: functional fraction cannot exceed 15%; ENCODE's 80% implies 102 children per couple (both as printed; corrected for a factor-of-two slip, about 28% and about 14 children)
The cleanest modern statement of the load-to-junk inference: "Mutational load considerations lead to the conclusion that the functional fraction within the human genome cannot exceed 15%." Its arithmetic and the article's are the same arithmetic; the difference is only which conclusion is drawn. Whoever escapes the load paradox by relative fitness gives up the premise the 15% ceiling rests on. One correction on the number: Table 1 computes e2U where eU belongs, and the 2019 corrigendum (GBE 11:3158) added the "2" to equation (3) and reprinted the table unchanged. At Graur's most permissive rate the ceiling is 28.3%, not 14.2%. That still rules out ENCODE's 80%.
A mathematical theory of natural and artificial selection, Part V [TITLE?]
Haldane, J.B.S. Proceedings of the Cambridge Philosophical Society, 23:838-844 (1927).
camp: mainstream direction: supports peer_reviewed: yes organism: theory proposed_solution: none
Quoted in Felsenstein and Lynch's 2018 post as: "To sum up, if selection acts against mutation, it is ineffective provided that the rate of mutation is greater than the coefficient of selection." This is the mainstream statement of the condition under which selection loses, ninety-one years before the dispute, and it is the condition the article argues human parameters satisfy. Cited second-hand through Felsenstein and Lynch; the primary was not retrieved. [STALE?]
Comment in 'Kondrashov's Paradox' (strongest objection stated)
Hancock, Z.B. Peaceful Science, thread 17840 post 16 (2026).
https://discourse.peacefulscience.org/t/17840/16
camp: mainstream direction: undercuts access: forum peer_reviewed: no organism: theory proposed_solution: stabilizing-selection
Key figure: Ns = +0.5 fixes 7.38x more often than Ns = -0.5
Asked directly what the strongest argument against genetic entropy is, Hancock names polygenic stabilizing selection under the infinitesimal model, citing Barton 2022 — not truncation selection, which the article had been answering. Same post supplies the near-neutral-is-not-unselectable point: a mutation at Ns = 0.5 is 7.38x more likely to fix than one at Ns = -0.5, checked independently against Kimura's formula at Ne = 10,000.
Accumulation and maintenance of information in evolution
Hledik, M.; Barton, N.; Tkacik, G. PNAS, 119(36):e2123152119 (2022). doi 10.1073/pnas.2123152119
https://pmc.ncbi.nlm.nih.gov/articles/PMC9457054/
camp: mainstream direction: undercuts access: OA peer_reviewed: yes organism: theory proposed_solution: none
Key figure: up to N/mu(1+4N mu) bits per unit cost at Ns << 1
"Selection is most efficient when it is relatively weak (Ns<<1)... and inefficient when strong (Ns>>1)." The best unmet objection to the article's information framing, now met: their information is KL divergence of frequency distributions, not sequence identity, so a site at 60/40 carries a fraction of a bit without holding the right letter. Defines load as the lead, not the lag. Own caveat: "more work is needed to make claims about the information content of any real organism's genome."
Continuously distributed factors affecting fitness [TITLE?]
King, J.L. Genetics, 55(3):483-492 (1967).
camp: mainstream direction: undercuts peer_reviewed: yes organism: theory proposed_solution: truncation
One of the three 1967 papers Felsenstein names in his textbook as the origin of threshold-selection models, alongside Sved/Reed/Bodmer and Milkman. Named only; the primary was not retrieved for this project. [STALE?]
Contamination of the genome by very slightly deleterious mutations: why have we not died 100 times over?
Kondrashov, A.S. Journal of Theoretical Biology, 175:583-594 (1995). doi 10.1006/jtbi.1995.0167
https://pubmed.ncbi.nlm.nih.gov/7475094/
camp: mainstream direction: supports access: paywalled peer_reviewed: yes organism: Homo sapiens, mammals proposed_solution: synergistic-epistasis
Key figure: approx 100 lethal equivalents per individual; decline approx 1e-5 per generation
The single best source for the article's Argument 3. Its abstract lists two resolutions but the body (p590) lists five, and option (i) — that equilibrium is never reached and accumulation acts "as a time-bomb, finally destroying it" — is genetic entropy proposed by the author of the paradox and not dismissed: "Perhaps, this does not contradict the existing data." He also rejects the Kimura/Masel resolution by name ("I do not think that this is correct") and states the size constraint: repairing a very slightly deleterious site can only be very slightly beneficial. The abstract's first sentence excludes the current mainstream answer: "This paradox cannot be resolved by invoking beneficial mutations or environmental fluctuations." Note his own timescale implication refutes a young earth: 1e6-1e7 generations.
A Resolution of the Mutation Load Paradox in Humans
Lesecque, Y.; Keightley, P.D.; Eyre-Walker, A. Genetics, 191(4):1321-1330 (2012). doi 10.1534/genetics.112.140343
https://www.homepages.ed.ac.uk/pkeightl/publications/LesecqueGenetics2012.pdf
camp: mainstream direction: undercuts access: OA peer_reviewed: yes organism: Homo sapiens proposed_solution: soft-selection
Key figure: U = 2.1 gives f = 1 - e^-2.1 = 88%; hunter-gatherer females can produce only 11 offspring
The paper the article concedes the load argument to. Its point is that fitness is relative, so "a species could tolerate 10's or even 100's of new deleterious mutations per genome each generation." Also dismisses germline selection as a rescue: the fraction of sites effectively selected in germ-line lineages is small and most spontaneous abortions are non-genetic. Same author group as Eyre-Walker and Keightley 1999 — they are on both sides of this argument.
A molecular approach to the study of genic heterozygosity in natural populations [TITLE?]
Lewontin, R.C.; Hubby, J.L. Genetics, 54(2):595-609 (1966).
camp: mainstream direction: supports peer_reviewed: yes organism: Drosophila pseudoobscura proposed_solution: none
Key figure: population fitness "would drop to (0.95)^256 = 0.0000023"
The multiplicative load calculation that Milkman 1967 attacked, and that started the non-independence line of resolutions. Known here only through Milkman's quotation of it; the primary was not retrieved for this project. [STALE?]
Mutation and Human Exceptionalism: Our Future Genetic Load
Lynch, M. Genetics, 202(3):869-875 (2016). doi 10.1534/genetics.115.180471
https://pmc.ncbi.nlm.nih.gov/articles/PMC4788123/
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: Homo sapiens proposed_solution: none
The mainstream statement closest to the article's own thesis. Directly answers relative-fitness escapes: "physical defects involving cancer, metabolic disease, and psychiatric disorders have very real costs regardless of the average population state." Relative fitness may dissolve the arithmetic paradox but does not make the defects go away.
Genetic load (laboratory research page)
Masel Lab, University of Arizona masellab.org research page (2026).
https://www.masellab.org/research/genetic-load
camp: mainstream direction: mixed access: blog peer_reviewed: no organism: theory proposed_solution: beneficial-compensation
"Most work on mutation load periodically renormalizes relative fitness to deal with the fact that fitness keeps declining no matter what, or else treats only a subset of the genome. Either way, this is dodging the problem." The same page states the lab's own answer (a ratchet countered by larger beneficials) and warns that the lag load is "inappropriate use... one contributor to confusion," naming the lead (Desai and Fisher 2007) as the right quantity. The page has been rewritten since an earlier capture; quote it whole or not at all.
Substitution load revisited: a high proportion of deaths can be selective
Matheson, J.; Exposito-Alonso, M.; Masel, J. Genetics, April 2025 (2025).
https://pmc.ncbi.nlm.nih.gov/articles/PMC12005247/
camp: mainstream direction: undercuts access: OA peer_reviewed: yes organism: Arabidopsis thaliana proposed_solution: soft-selection
Key figure: 8.5% to 95% of deaths selective across 8 environments
Tests Haldane's assumption directly and finds the proportion of genuinely selective deaths can far exceed what Haldane budgeted. Peer reviewed and open access, unlike the Masel-lab preprint cited elsewhere — two different papers from the same lab. The authors flag less-fecund species as future work, which is where the human case lives.
Heterosis as a major cause of heterozygosity in nature
Milkman, R.D. Genetics, 55(3):493-495 (1967). doi 10.1093/genetics/55.3.493
https://pmc.ncbi.nlm.nih.gov/articles/PMC1211404/
camp: mainstream direction: undercuts access: OA peer_reviewed: yes organism: Drosophila proposed_solution: truncation
Key figure: culling to the top 13.5% is "a practical procedure in Drosophila, whose females produce scores of eggs"
One of the three 1967 papers Felsenstein names as the origin of threshold-selection models. Rejects Lewontin and Hubby's multiplicative calculation that population fitness "would drop to (0.95)^256 = 0.0000023" as "based on an erroneous concept of the independence of loci in selection." The article's narrow legitimate use: the reason he gives for the procedure being practical is Drosophila fecundity, which humans lack.
Revisiting the genetic load argument with Dan Graur (bulk-DNA escape clause)
Moran, L.A. Sandwalk blog, comment thread (2017).
https://sandwalk.blogspot.com/2017/07/revisiting-genetic-load-argument-with.html
camp: mainstream direction: mixed access: blog peer_reviewed: no organism: Homo sapiens proposed_solution: junk-DNA
"there are bulk DNA hypotheses that attribute non-sequence-specific function to most of the genome and if they are correct the genetic load argument carries no weight." Important scoping concession: the article's U scaling is a claim about sequence-specific function only, and Moran states the limit himself.
A creationist tries to understand genetic load
Moran, L.A. Sandwalk blog (2014).
https://sandwalk.blogspot.com/2014/04/a-creationist-tries-to-understand.html
camp: mainstream direction: supports access: blog peer_reviewed: no organism: Homo sapiens proposed_solution: junk-DNA
Key figure: "no more than 1 or 2 deleterious mutations per generation"
Moran, one of the most persistent critics of ID and of ENCODE, asserts the tolerable rate: "It's probably less than two (2). It's probably not as low as 0.5." In 2017 he adds that four per generation is "an intolerable genetic load; it suggests that most of our genome is not a target." That ceiling comes from the load formula the article concedes does not work — so whoever takes the relative-fitness escape has to give up the ceiling and the junk-DNA inference drawn from it.
A creationist tries to understand genetic load (junk-DNA inference)
Moran, L.A. Sandwalk blog (2014).
https://sandwalk.blogspot.com/2014/04/a-creationist-tries-to-understand.html
camp: mainstream direction: mixed access: blog peer_reviewed: no organism: Homo sapiens proposed_solution: junk-DNA
Key figure: only 13 of 130 mutations land in functional DNA
"We now know that those arguments were correct and 90% of our genome is junk," and therefore "only 13 of these mutations occur in DNA that has a biological function." Same post as moran-load-ceiling; kept as a separate entry because the article cites the two claims for opposite purposes and the junk-DNA sentence comes first in the post.
Our load of mutations
Muller, H.J. American Journal of Human Genetics, 2(2):111-176 (1950).
https://pmc.ncbi.nlm.nih.gov/articles/PMC1716299/
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: Homo sapiens proposed_solution: none
The founding paper of load theory, by a Nobel laureate. "equilibrium could not be maintained, and the genetic composition would deteriorate continuously, while the population would meanwhile diminish in numbers all the way to the point of disappearance." Page-image scan only, no OCR text layer — read the images before quoting.
Haldane's non-dilemma
Musgrave, I. The Panda's Thumb blog (2007).
https://pandasthumb.org/archives/2007/07/haldanes-nondil.html
camp: mainstream direction: undercuts access: blog peer_reviewed: no organism: Homo sapiens, Pan proposed_solution: none
Key figure: 1,667 beneficial fixations
Argues ReMine's claim that 1,667 beneficial mutations is too few to make a human from a chimp ancestor "is shown to be trivially false from comparison of the human and chimp genome." Musgrave is a senior lecturer in pharmacology at Adelaide, not a population geneticist — the article had this wrong in an earlier draft and corrected it.
Estimate of the mutation rate per nucleotide in humans
Nachman, M.W.; Crowell, S.L. Genetics, 156(1):297-304 (2000). doi 10.1093/genetics/156.1.297
https://pmc.ncbi.nlm.nih.gov/articles/PMC1461236/
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: Homo sapiens proposed_solution: synergistic-epistasis
Key figure: at U = 3, each female needs 40 offspring for 2 to survive
The most-quoted single sentence in this whole literature. Their 175 mutations per genome is about 2.4x the modern pedigree figure, so their U = 3 is correspondingly inflated — say so when quoting the 40.
So much 'Junk' DNA in our Genome
Ohno, S. Brookhaven Symposia in Biology, 23:366-370 (1972).
https://web.archive.org/web/20160203012605/http://www.junkdna.com/ohno.html
camp: mainstream direction: mixed access: OA peer_reviewed: yes organism: Homo sapiens proposed_solution: junk-DNA
Key figure: U ceiling of 1.0; at most 6% of DNA used as genes
The paper that coined "junk DNA," and it coined it as a conclusion from load: "there seems to be a strict upper limit for the number of gene loci which we can afford to keep in our genome. Consequently, only a fraction of our DNA appears to function as genes." His ceiling is U = 1.0 — lower than Moran's, forty-two years earlier. He counts promoters and operators inside the 6% "for these regions can certainly sustain deleterious mutations," which is the sequence-specific criterion the article uses. Verification route: the junkdna.com page images, not the on-disk scan (no text layer).
Dennett's Strange Idea
Orr, H.A. Boston Review (1996).
http://web.archive.org/web/2005/http://bostonreview.net/archives/BR21.3/Orr.html
camp: mainstream direction: background access: OA peer_reviewed: no organism: theory proposed_solution: none
Orr is an evolutionary geneticist at Rochester and the piece is a hostile review of Daniel Dennett, not anything sympathetic to design. Cited for a quotable line about the limits of adaptationist reasoning. Original URL is dead; the Wayback capture is what was verified.
The case for junk DNA
Palazzo, A.F.; Gregory, T.R. PLoS Genetics, 10(5):e1004351 (2014). doi 10.1371/journal.pgen.1004351
https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1004351
camp: mainstream direction: mixed access: OA peer_reviewed: yes organism: Homo sapiens proposed_solution: junk-DNA
Key figure: ceiling roughly 1 deleterious mutation per generation against an observed 2.1-10
Two prominent junk-DNA advocates state the meltdown mechanism, the roughly one-per-generation ceiling, and the observed 2.1-10 rate within a few sentences of each other. Worth more than any creationist statement of the same arithmetic, and the article uses it in place of blog sourcing. Makes explicit that the load ceiling and the junk-DNA conclusion are the same claim.
The number of balanced polymorphisms that can be maintained in a natural population [TITLE?]
Sved, J.A.; Reed, T.E.; Bodmer, W.F. Genetics, 55(3):469-481 (1967).
camp: mainstream direction: undercuts peer_reviewed: yes organism: theory proposed_solution: truncation
One of the three 1967 papers Felsenstein names in his textbook as introducing "models of selection of this sort" — each selective death killing many mutant genes, so fewer deaths are needed to balance mutation. Named only; the primary was not retrieved for this project. [STALE?]
The drift barrier
Random genetic drift sets an upper limit on mRNA splicing accuracy in multicellular eukaryotes [TITLE-INVENTED]
Benitiere, F.; Necsulea, A.; Duret, L. eLife, 13:RP93629 (2024).
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: 53 metazoan species proposed_solution: none
Key figure: 53 metazoans
Splicing accuracy tracks effective population size across 53 metazoans, exactly as a drift barrier predicts. Flagged in project memory as the version of the drift-barrier confirmation the article needs, and as not yet applied. Only the venue and headline claim were carried forward; URL and DOI were in the lost research files.
Quantification of GC-biased gene conversion in the human genome
Glemin, S.; Arndt, P.F.; Messer, P.W.; Petrov, D.; Galtier, N.; Duret, L. Genome Research, 25(8):1215-1228 (2015). doi 10.1101/gr.185488.114
https://pmc.ncbi.nlm.nih.gov/articles/PMC4510005/
camp: mainstream direction: background access: OA peer_reviewed: yes organism: Homo sapiens proposed_solution: none
Key figure: B = 4Ne*b is 0.27-0.43 genome-average; B > 5 in only 1-2% of the genome
gBGC is a recombination-repair bias favouring G/C that acts regardless of fitness, so it behaves like a selection coefficient in exactly the band the argument is about. Checked as a possible error in the article's equilibrium formula and found not to be one: at B = 0.4 the largest shift anywhere is 0.96 percentage points, and the article's headline claim sits at the formula's inflection point where a symmetric shift cancels exactly. Unit trap: B is defined on 4Ne and the article's x on 2Ne, so gBGC enters as a shift of +/- B/2.
Compensatory nearly neutral mutations: selection without adaptation
Hartl, D.L.; Taubes, C.H. Journal of Theoretical Biology, 182:303-309 (1996). doi 10.1006/jtbi.1996.0168
https://pubmed.ncbi.nlm.nih.gov/8944162/
camp: mainstream direction: supports access: paywalled peer_reviewed: yes organism: theory (enzyme flux control) proposed_solution: beneficial-compensation
Key figure: Fisher's destroying:building ratio at r = 1/2, 1, 2, 3 standard units: 3.5, 13, 236, 7852
A Harvard population geneticist stating the article's own point from the mainstream side in 1996. p305: "most compensatory mutations merely restore, partially or completely, the level of enzyme function to that of the ancestral molecule... On this treadmill, each molecule evolves adaptively but does not improve." Their premise is Ohta's: an already-adapted genome has more ways to get worse than better. The mechanism is Kacser flux control, which is why most enzyme mutations sit in the drift-barrier range. The Fisher ratios are about mutation size, not mechanism — do not conflate with the loss-of-function argument.
Developing an Evolutionary Baseline Model for Humans: Jointly Inferring Purifying Selection with Population History
Johri, P.; Pfeifer, S.P.; Jensen, J.D. Molecular Biology and Evolution, 40(5):msad100 (2023). doi 10.1093/molbev/msad100
https://pmc.ncbi.nlm.nih.gov/articles/PMC10195113/
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: Homo sapiens (replicated in Drosophila melanogaster) proposed_solution: none
Key figure: weak positive selection "unidentifiable if rare" at 2Ne*sb of 10-100
A conditional test of beneficial-class identifiability. At 2Ne*sb of 10-100 "there is almost no difference between the distribution of statistics across the 465 exons in the absence versus presence of positive selection." At Ne near 10,000 that is |s| of 5e-4 to 5e-3 ; these are mean homozygote effects under semidominance. The rare classes tested were difficult to distinguish using this study's statistics; the result does not establish a universal detection threshold. The method jointly fits demography and selection, including effects on linked sites.
Model of effectively neutral mutations in which selective constraint is incorporated
Kimura, M. PNAS, 76(7):3440-3444 (1979). doi 10.1073/pnas.76.7.3440
https://pmc.ncbi.nlm.nih.gov/articles/PMC383841/
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: theory proposed_solution: beneficial-compensation
Key figure: Kimura's own shape parameter beta = 0.5, vs modern fits near 0.2
"Under the present model, effectively neutral, but, in fact, very slightly deleterious mutants accumulate continuously in every species." His own proposed fix — occasional adaptive substitutions "will easily take care of" it — is asserted, not modelled. Figure 1, read from the page scan, settles the Sanford Figure 3d dispute: the axis is labelled "Selective disadvantage" spanning 0 to 2e-3, so the whole distribution is on the harmful side, and the shaded region is bounded at 1/2Ne, the drift barrier.
Extreme sensitivity of fitness to environmental conditions: lessons from #1BigBatch
Kinsler, G.; et al. Journal of Molecular Evolution, 91(3):293-310 (2023). doi 10.1007/s00239-023-10110-7
https://pmc.ncbi.nlm.nih.gov/articles/PMC10276131/
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: Saccharomyces cerevisiae proposed_solution: none
Key figure: precision capped at 0.1%-1%, vs a human drift barrier of 0.005%
From Dmitri Petrov's Stanford lab, which builds barcode-lineage-tracking assays — the highest-throughput fitness measurements that exist. "Reported precision remains capped at detecting fitness differences on the order of 0.1-1%," and four sentences later: "natural selection can distinguish fitness differences that are orders of magnitude smaller than we can measure in the laboratory." The gap stated by the people it most inconveniences, and the reason the article's conclusion is an open question rather than a result.
The divergence of mean phenotypes under persistent Gaussian selection
Lynch, M.; Menor, M. Genetics, 229(4):iyaf031 (2025). doi 10.1093/genetics/iyaf031
https://academic.oup.com/genetics/article/229/4/iyaf031/8000821
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: theory proposed_solution: none
The mainstream answer to Barton's polygenic stabilizing-selection objection, from inside the mainstream. "Drift barriers, which are universal properties of all finite populations (i.e. all of biology), denote the limits to which mean phenotypes are expected to wander." Two populations under identical stabilizing selection end up at different phenotypic means, and how far they wander is set by effective population size. Lynch is the originator of the drift-barrier framing Barton 2022 calls problematic, so this is the same disagreement continued in print.
The nearly neutral theory of molecular evolution
Ohta, T. Annual Review of Ecology and Systematics, 23:263-286 (1992). doi 10.1146/annurev.es.23.110192.001403
camp: mainstream direction: supports access: paywalled peer_reviewed: yes organism: theory proposed_solution: beneficial-compensation
The process the article calls Ohta's ratchet is hers. p272: "I propose that a substantial fraction of mutant substitutions at the molecular level are caused by random fixation of very slightly deleterious mutations." p270 supplies the not-a-cliff point better than any forum post: "the fixation probability is a continuous monotone function of Ns." p272 corroborates Kondrashov on compensation size, with the tRNA stem-region example and the two-thirds G.U/U.G statistic. OCR drops spaces on this old Annual Reviews scan — read pages as images before quoting.
Haplotype-based inference of the distribution of fitness effects
Ortega-Del Vecchyo, D.; Lohmueller, K.E.; Novembre, J. Genetics, 220(4):iyac002 (2022). doi 10.1093/genetics/iyac002
https://pmc.ncbi.nlm.nih.gov/articles/PMC8982047/
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: Homo sapiens proposed_solution: none
"in a constant size population our method provides accurate estimates of the absolute strength of natural selection, but cannot infer the sign of the selection coefficient." Their applied analysis assumes a deleterious-only distribution. Note the honest limit the article states with it: haplotype methods do recover sign in expanding populations at 4Ne*s of +/-50 to +/-100, about 30x above the barrier — so the claim is "no instrument routinely resolves," not "no instrument can."
Effective population size, mutation rate, and generation time [TITLE-INVENTED]
Weinstein, unknown; Roy, unknown PNAS, 123(6) (2026).
camp: mainstream direction: undercuts peer_reviewed: yes proposed_solution: none
Argues the Ne-mutation-rate correlation underpinning the drift-barrier hypothesis is mediated by generation time, contesting the drift-barrier reading. Flagged in project memory as cutting against the article but making a different claim from the one the article makes. Author initials, DOI and URL were in the lost research files.
Distributions of fitness effects
Environment-independent distribution of mutational effects emerges from microscopic epistasis
Ardell, S.M.; Martsul, A.; Johnson, M.S.; Kryazhimskiy, S. Science, 386(6717):87-92 (2024). doi 10.1126/science.adn0753
https://pmc.ncbi.nlm.nih.gov/articles/PMC10680819/
camp: mainstream direction: undercuts access: OA peer_reviewed: yes organism: Saccharomyces cerevisiae proposed_solution: beneficial-compensation
Key figure: beneficial proportion reaches "up to 100% in the lowest-fitness genotypes"; 94% of mutations beneficial somewhere, 96% of those also deleterious somewhere
About 100 insertion mutations measured in 42 yeast strains across six environments. The strongest measurement of fitness-dependent feedback in the literature, and the best evidence against any version of the argument predicting unbounded fitness decline. The article's reply comes from their own framing: the environment "tunes one global parameter, the background fitness at which most mutations switch sign," so a mutation becomes beneficial because the background got worse, not because it built anything. The Science copy is paywalled; the PMC preprint is what is quoted.
Inferring the distribution of fitness effects of spontaneous mutations in Chlamydomonas reinhardtii
Bondel, K.B.; et al. (Keightley, P.D. senior) PLoS Biology, 17(6):e3000192 (2019). doi 10.1371/journal.pbio.3000192
https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3000192
camp: mainstream direction: mixed access: OA peer_reviewed: yes organism: Chlamydomonas reinhardtii proposed_solution: none
Key figure: shape 0.30; mean effects -0.0092 and +0.0021; positive-effect frequency 0.84 (95% CrI 0.73-0.90)
"Of mutations with absolute fitness effects exceeding 1%, about one-sixth increase fitness in the laboratory environment." The authors distrust their own 0.84 figure: at a 1% threshold "there are about six times more negative- than positive-effect mutations exceeding this value," and "many mutations have a very small effect (we do not know whether their effects are positive or negative)." That last clause is the measurement gap stated inside a DFE paper.
Kin selection and the evolution of social behaviour: fitness effects of spontaneous mutations in Chlamydomonas reinhardtii
Bondel, K.B.; et al. (Keightley, P.D. senior) PLoS Genetics, 18(6):e1009840 (2022). doi 10.1371/journal.pgen.1009840
https://pmc.ncbi.nlm.nih.gov/articles/PMC9239454/
camp: mainstream direction: mixed access: OA peer_reviewed: yes organism: Chlamydomonas reinhardtii proposed_solution: none
Key figure: q approx 0.5 (as many up as down); mean absolute effect "just over 2%"
254 spontaneous mutations tracked by frequency change over roughly 60 generations rather than inferred from a fitted distribution — a stronger design than most DFE work. Cuts against the article: as many mutations rise as fall. Their own environmental caveat then hands the article its reply, because advantageous mutations in laboratory culture may be losses of function in genes not required there. Their mean absolute effect is 500x the human drift barrier, so the measurement is nowhere near the band at issue.
Assessing the evolutionary impact of amino acid mutations in the human genome
Boyko, A.R.; et al. PLoS Genetics, 4(5):e1000083 (2008). doi 10.1371/journal.pgen.1000083
https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1000083
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: Homo sapiens proposed_solution: none
Key figure: 27-29% neutral or nearly neutral; gamma shape alpha = 0.184
"27-29% of amino acid changing (nonsynonymous) mutations are neutral or nearly neutral, 30-42% are moderately deleterious, and nearly all the remainder are highly deleterious or lethal." Superseded for humans by Johri 2023, which puts the effectively neutral fraction nearer 50%.
Maximum entropy and the distribution of fitness effects
Cotto, O.; Day, T. PNAS, 120(23) (2023).
https://pmc.ncbi.nlm.nih.gov/articles/PMC10266029/
camp: mainstream direction: background access: OA peer_reviewed: yes organism: theory proposed_solution: none
Random genotype-fitness maps produce maximum-entropy DFEs, so the shape of a fitted DFE says little about the underlying mechanism. Cuts against over-reading the gamma shape parameter on either side of this dispute. Verified and flagged in project memory as not yet applied to the article.
Changing fitness effects of mutations through long-term bacterial evolution
Couce, A.; et al. Science, January 2024 (2024).
https://www.zoology.ubc.ca/edg/pdfs/Couce2024.pdf
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: Escherichia coli (LTEE) proposed_solution: none
Key figure: 6.8% beneficial in the ancestor, 4.3% at 2,000 generations, 3.2% at 15,000
"most mutations are nearly neutral (within ~2 to 3% of neutrality...), but in all cases having a much heavier tail of deleterious mutations than beneficial mutations." The contracting beneficial supply is the article's central criticism of the Masel-lab resolution, which assumes an inexhaustible supply of constant mean effect. Noise floor: effects are only reliably distinguishable above s = 0.03. Free author PDF at UBC; the Science page blocks automated retrieval.
The distribution of fitness effects of spontaneous mutations in C. elegans inferred from MA lines with reduced linkage disequilibrium
Crombie, T.A.; et al. Genetics, 228(2):iyae136 (2024). doi 10.1093/genetics/iyae136
https://pmc.ncbi.nlm.nih.gov/articles/PMC12098947/
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: Caenorhabditis elegans proposed_solution: none
Key figure: 517 lines, 169 mutations, ~200-220 generations
"Estimates of the distribution of fitness effect from experimental mutation accumulation lines are compromised by the complete linkage disequilibrium between mutations in different lines." Breaking linkage by advanced intercrossing removes most of the apparent beneficial signal, directly undercutting the Bao 2022 review and Shaw's "about half of all mutations were beneficial." TRAP: the abstract reports roughly 40% positive; the correction is in the discussion. Quoting the abstract gets the paper backwards. The article cites it for both halves.
Benchmarking of DFE and alpha inference methods [TITLE-INVENTED]
Daigle, unknown; et al. preprint, venue unknown (2026).
camp: mainstream direction: supports access: preprint peer_reviewed: preprint organism: theory / simulation proposed_solution: none
Key figure: GRAPES "estimated a non-zero positive mean value of alpha in 44% of cases"
Benchmarking of adaptive-substitution inference finds GRAPES produces spurious positive alpha in 44% of cases and fastDFE "consistently overestimated alpha." Any published alpha therefore carries a documented positive bias. Verified and flagged in project memory as not yet applied; full author list, venue, DOI and URL were in the lost research files.
The distribution of fitness effects of new mutations
Eyre-Walker, A.; Keightley, P.D. Nature Reviews Genetics, 8(8):610-618 (2007). doi 10.1038/nrg2146
https://pubmed.ncbi.nlm.nih.gov/17637733/
camp: mainstream direction: background access: paywalled peer_reviewed: yes organism: theory proposed_solution: none
The standard review of the field. "advantageous mutations are rare, and those that are strongly selected are exponentially distributed; and the DFE of deleterious mutations is complex and multi-modal." Abstract free, full text paywalled; the body text was not verified for this project.
A comprehensive, high-resolution map of a gene's fitness landscape
Firnberg, E.; et al. Molecular Biology and Evolution, 31(6):1581-1592 (2014). doi 10.1093/molbev/msu081
https://pmc.ncbi.nlm.nih.gov/articles/PMC4032126/
camp: mainstream direction: mixed access: OA peer_reviewed: yes organism: Escherichia coli (TEM-1) proposed_solution: none
Key figure: 7.1% of alleles and 7.0% of missense mutations increased fitness
"Only 7.1% (1,074/15,167) of the alleles and 7.0% (367/5,212) of the missense mutations increased fitness above that of TEM-1 outside the range of the error." Fitness here is ampicillin resistance and TEM-1 is under heavy recent selection for expanded resistance — the far-from-optimum condition that inflates the beneficial fraction. A 2016 erratum corrects equation 6 only, not these figures.
Measuring selection coefficients below 10^-3: method, questions, and prospects
Gallet, R.; et al. Genetics, 190(1):175-186 (2012). doi 10.1534/genetics.111.133454
https://pmc.ncbi.nlm.nih.gov/articles/PMC3249376/
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: Escherichia coli proposed_solution: none
Key figure: precision of 2e-4, against a human drift barrier of 4e-5
"Our method allowed us to estimate mean selection coefficients to a precision of 2 x 10^-4" — three transposon insertions measured by flow cytometry in very large populations with massive replication. This is the record, and it is still five times coarser than the band the argument is about. They also found "cryptic variation" in s beyond what drift explains, "even in fully controlled experiments."
Inference of the Distribution of Selection Coefficients for New Nonsynonymous Mutations Using Large Samples
Kim, B.Y.; et al. Genetics, 206(1):345-361 (2017). doi 10.1534/genetics.116.197145
https://pmc.ncbi.nlm.nih.gov/articles/PMC5419480/
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: Homo sapiens proposed_solution: none
Key figure: gamma shape 0.169-0.215; 1.24-1.43 fold more mutations with |s| < 0.001
"We infer significantly fewer (0.38-0.84 fold) strongly deleterious mutations with |s| > 0.01 and more (1.24-1.43 fold) weakly deleterious mutations with |s| < 0.001 compared to previous estimates." The revision runs toward the near-neutral band, which is the direction that matters for the ratchet.
Smaller populations harbour more beneficial mutations [TITLE-INVENTED]
Lin, unknown; et al. (Lohmueller lab) preprint, venue unknown (2025).
camp: mainstream direction: undercuts access: preprint peer_reviewed: preprint organism: theory / simulation proposed_solution: beneficial-compensation
Supports the article's "second brake" — that as fitness falls the beneficial supply rises. But the number is a cumulative probability under a fitted Fisher geometric model, i.e. model extrapolation past the data, not a measurement of sign. Project memory says to state that if the source is used. Author list, venue and URL were in the lost research files.
Variation in mutational robustness between different proteins and the predictability of fitness effects
Lind, P.A.; et al. Molecular Biology and Evolution, 34(2):408-418 (2017). doi 10.1093/molbev/msw239
https://academic.oup.com/mbe/article/34/2/408/2528248
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: Salmonella typhimurium (araCDE) proposed_solution: none
Key figure: detection limit |s| > 0.004; of 109 substitutions: 17 complete loss, 44 partial, 44 neutral, 4 beneficial
"This set-up allowed detection of fitness differences of |s| > 0.004." Anything smaller was scored neutral by definition — the clearest single example of the field's "neutral" category being an instrument limit rather than a measurement.
Catch me if you can: adaptation from standing genetic variation [TITLE?]
Matuszewski, S.; et al. Genetics; 2025 Editor's Note at Genetics 229(3):iyaf002 (2016).
camp: mainstream direction: background peer_reviewed: editorial organism: theory proposed_solution: none
DO NOT CITE until a human checks. A 2025 Editor's Note was published on this paper (PMID 39903207), indexed as a Published Erratum, and its text could not be retrieved by any automated route. Listed so the flag is not lost. [STALE?]
Variant effect predictions capture some aspects of deep mutational scanning experiments
Reeb, J.; Wirth, T.; Rost, B. BMC Bioinformatics (2020).
https://pmc.ncbi.nlm.nih.gov/articles/PMC7077003/
camp: mainstream direction: mixed access: OA peer_reviewed: yes organism: various (22 DMS datasets) proposed_solution: none
Key figure: deleterious outnumber beneficial by factors of 1.5-22.5
Across 22 deep mutational scanning studies "deleterious outnumbered beneficial SAVs by factors of 1.5-22.5." A 1.5x low end is much weaker than "overwhelmingly skewed," and project memory flags it as worth conceding. Verified, not yet applied to the article.
The distribution of fitness effects caused by single-nucleotide substitutions in an RNA virus
Sanjuan, R.; Moya, A.; Elena, S.F. PNAS, 101(22):8396-8401 (2004). doi 10.1073/pnas.0400146101
https://pmc.ncbi.nlm.nih.gov/articles/PMC420405/
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: vesicular stomatitis virus proposed_solution: none
Key figure: 39.6% lethal, 29.2% deleterious, 27.1% neutral, 4.2% beneficial
91 site-directed mutants. The 4.2% beneficial is 2 mutations out of 48, so treat it as an upper bound with a wide interval. The authors caution that "some of the mutations classified as neutrals could actually have a fitness effect too weak to be detected." Also the source Schaffner says Brewer, Smith and Sanford 2013 cited and then discarded — their stated DFE understates neutral about 2.7x and beneficial about 4.7x, both in the direction that favours decline.
fastDFE: fast and flexible inference of the distribution of fitness effects
Sendrowski, J.; Bataillon, T. Molecular Biology and Evolution, 41(5):msae070 (2024).
https://pmc.ncbi.nlm.nih.gov/articles/PMC11140822/
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: theory / software proposed_solution: none
Key figure: finest discrete near-zero bin runs 2Ne*s = -1 to +1
The newest DFE inference tool in the field bins the entire drift zone as one undivided lump running from 2Ne*s = -1 to +1. Project memory calls this the sharpest checkable statement of the resolution limit available, and flags it as verified but not yet applied.
Understanding the evolutionary fate of finite populations: the dynamics of mutational effects
Silander, O.K.; et al. PLoS Biology, 5(4):e94 (2007). doi 10.1371/journal.pbio.0050094
https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.0050094
camp: mainstream direction: mixed access: OA peer_reviewed: yes organism: bacteriophage proposed_solution: beneficial-compensation
Key figure: ML estimate of beneficial proportion B was zero in all high-fitness populations
"The ML estimate of B, the proportion of beneficial mutations, was zero for all high-fitness populations and greater than zero in all low-fitness populations." Bottlenecks of 3 to 250. With Couce 2024 this is the article's evidence that the beneficial supply is not inexhaustible. The paper does not settle whether B = 0 is a true zero or the limit of their resolution.
The effects of mutation and recombination rate heterogeneity on the inference of demography and the DFE
Soni, V.; Pfeifer, S.P.; Jensen, J.D. Genome Biology and Evolution, 16(2):evae004 (2024). doi 10.1093/gbe/evae004
https://pmc.ncbi.nlm.nih.gov/articles/PMC10834165/
camp: mainstream direction: undercuts access: OA peer_reviewed: yes organism: theory / simulation proposed_solution: none
Key figure: "DFE-alpha inferred a completely neutral DFE for population contraction scenarios"
With realistic rate heterogeneity the most widely used DFE inference tool returns a completely neutral distribution under population contraction. The bias direction is toward inferring more effectively neutral mutations than exist — the direction that flatters the article's argument, which is why the article cites it against itself. Also shows the coupling runs both ways: background selection skews the site frequency spectrum, which is then mis-inferred as demography, which then mis-infers the DFE.
Mutation rate
Parental influence on human germline de novo mutations in 1,548 trios from Iceland
Jonsson, H.; et al. Nature, 549:519-522 (2017). doi 10.1038/nature24018
https://pubmed.ncbi.nlm.nih.gov/28959963/
camp: mainstream direction: background access: paywalled peer_reviewed: yes organism: Homo sapiens proposed_solution: none
Key figure: 108,778 de novo mutations across 1,548 trios, about 70 per proband
The pedigree measurement behind the article's ~70 mutations per generation. Maternal mutations rise 0.37 per year of the mother's age against 1.51 per year from fathers. Note this is the one headline number in the article that is a direct measurement rather than a model output.
Rates and Fitness Consequences of New Mutations in Humans
Keightley, P.D. Genetics, 190(2):295-304 (2012). doi 10.1534/genetics.111.134668
https://pmc.ncbi.nlm.nih.gov/articles/PMC3276617/
camp: mainstream direction: mixed access: OA peer_reviewed: yes organism: Homo sapiens proposed_solution: none
Key figure: U approx 2.2 diploid per generation; approx 0.35 amino-acid-changing
"estimates are U ~ 2.2 for the whole diploid genome per generation and ~0.35 for mutations that change an amino acid," implying a mean selective constraint of only about 3.1% per site. This is the low end of the article's U bracket. Also supplies the line the article had been asserting uncited: "there is little empirical evidence that net synergistic epistasis for fitness is common," citing Kouyos et al. 2007 and Halligan and Keightley 2009. Keightley co-authored the 1999 paper that raised the problem, so this is not an outsider's assessment.
Direct estimates of human per nucleotide mutation rates at 20 loci causing Mendelian diseases [TITLE?]
Kondrashov, A.S. Human Mutation, 21(1):12-27 (2002).
camp: mainstream direction: supports peer_reviewed: yes organism: Homo sapiens proposed_solution: synergistic-epistasis
Key figure: approx 100 new mutations per diploid genome per generation, at least 10% deleterious
From Eric's notes: "the total number of new mutations per diploid human genome per generation is ~100... at least 10% of these mutations are deleterious [Shabalina et al., 2001]. Genomic deleterious mutation rates in excess of 1 do not necessarily lead to prohibitively high genetic load, as long as selection against mutations involves synergistic epistasis." Notes-sourced, pre-2026, URL dead. [STALE?]
Rate of de novo mutations and the importance of father's age to disease risk
Kong, A.; et al. Nature, 488:471-475 (2012). doi 10.1038/nature11396
https://pmc.ncbi.nlm.nih.gov/articles/PMC3548427/
camp: mainstream direction: background access: OA peer_reviewed: yes organism: Homo sapiens proposed_solution: none
Key figure: 63.2 de novo mutations per trio at mean paternal age 29.7; +2 per year
"a total of 4,933 de novo mutations, or an average of 63.2 per trio, were called" from 78 Icelandic trios. The paternal-age slope of about two mutations per year is the mechanism behind the rising-U concern for late-childbearing populations.
Rate, molecular spectrum, and consequences of human mutation
Lynch, M. PNAS, 107(3):961-968 (2010). doi 10.1073/pnas.0912629107
https://pmc.ncbi.nlm.nih.gov/articles/PMC2824313/
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: Homo sapiens proposed_solution: none
Key figure: 50 to 100 new mutations per newborn; 1% to 3% fitness decline per generation from coding mutations alone under complete relaxation of selection (p. 966)
Measurement plus forecast. Verified in full from the library text (lynch-2010c, p. 966). "with a complete relaxation of natural selection, the expected decline in fitness associated with mutations in coding DNA alone appears to be on the order of 1% to 3% per generation." Lynch, who holds that most of the genome is junk, reaches the size of Crow's figure independently; he also says the damage "need not be permanent" because new harmful alleles stay rare at today's large N_e. Cited in index.md, "The human data", and for the 50-100 mutations per newborn against Sanford's 600.
Human mutation rates - what's the right number?
Moran, L.A. Sandwalk blog (2015).
https://sandwalk.blogspot.com/2015/04/human-mutation-rates-whats-right-number.html
camp: mainstream direction: supports access: blog peer_reviewed: no organism: Homo sapiens proposed_solution: none
Key figure: Moran's working figure is 100 per generation (biochemical 130, phylogenetic 112-160)
Moran regards direct sequencing as an underestimate and works with 100 mutations per generation. This matters because the article's 70 is below the leading critic's number — an earlier draft had this backwards. He restates the 100 in "A new higher mutation rate in humans" (May 2025), commenting on the same long-read study the article cites, and independently flags the same caveat about the tandem-repeat component being software-dependent.
Human de novo mutation rates from a four-generation pedigree reference
Porubsky, D.; et al. Nature (2025).
https://pmc.ncbi.nlm.nih.gov/articles/PMC12240836/
camp: mainstream direction: mixed access: OA peer_reviewed: yes organism: Homo sapiens proposed_solution: none
Key figure: 98 to 206 events per transmission, averaging about 152
Per transmission: 74.5 de novo SNVs, 7.4 non-tandem-repeat indels, 65.3 tandem-repeat indels and structural variants, 4.4 centromeric events. Much larger than the point-mutation-only figure, but the deleterious fraction of the repeat-length changes is unmeasured, and the tandem-repeat component is software-dependent — so it cannot simply be added to U.
Evidence for elevated mutation rates in low-quality genotypes
Sharp, N.P.; Agrawal, A.F. PNAS, 109(16):6142-6146 (2012). doi 10.1073/pnas.1118918109
https://pmc.ncbi.nlm.nih.gov/articles/PMC3341077/
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: Drosophila melanogaster proposed_solution: none
Key figure: for a 10% body-mass reduction, approx 77% higher deleterious mutation rate and approx 104% higher rate of mutational decline
"individuals with low-quality genotypes will produce offspring of even lower genetic quality, in a mutational positive feedback loop." Measured on chromosomes unlinked to the deleterious alleles carried, which makes it a genome-wide claim rather than local instability. The article had two brakes and no accelerator before this was added. Consequence: every projection holding U constant, including the article's, is conservative if this generalises.
Functional fraction of the genome
Evolutionary constraint and innovation across hundreds of placental mammals
Christmas, M.J.; et al. (Zoonomia Consortium) Science, April 2023 (2023). doi 10.1126/science.abn3943
https://pmc.ncbi.nlm.nih.gov/articles/PMC10250106/
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: 240 placental mammals proposed_solution: none
Key figure: 332 Mb (~10.7%) constrained at element level; 101 Mb (3.3%) at single-base significance
"At least 332 million bases (~10.7%) in the human genome are unusually conserved across species (evolutionarily constrained) relative to neutrally evolving repeats." The article's middle U bracket comes from this and Rands 2014. Quote both numbers: the 10.7% is element-level and gives U ≈ 7.3 only if misread as per-base; the single-base figure is 3.26% (FDR < 5%) and gives U ≈ 2.25. The article uses the pair as a ceiling and a floor, not 7.3 as an estimate.
Widespread selection on synonymous sites [TITLE-INVENTED]
Christmas, M.J.; et al. Nature Communications, 16:2007 (2025).
camp: mainstream direction: undercuts access: OA peer_reviewed: yes organism: mammals proposed_solution: none
Key figure: approx 20% of synonymous sites conserved
About 20% of synonymous sites appear conserved, attributed to GC-biased gene conversion plus mutation-rate variation rather than to function. Project memory calls this the best available argument that published constrained fractions — and therefore the article's U — are inflated. Flagged as verified but not yet applied; DOI and URL were in the lost research files.
Extreme purifying selection against point mutations in the human genome
Dukler, N.; et al. Nature Communications, 13:4312 (2022). doi 10.1038/s41467-022-31872-6
https://pmc.ncbi.nlm.nih.gov/articles/PMC9314448/
camp: mainstream direction: undercuts access: OA peer_reviewed: yes organism: Homo sapiens proposed_solution: none
Key figure: 0.4-0.7% of the genome ultraselected, implying 0.26-0.51 strongly deleterious mutations per generation
From 71,702 gnomAD v3 whole genomes. This is the honest floor the article quotes against itself: if only the ultraselected fraction counts, U for strongly deleterious mutations is well under one per generation, and no load problem arises at all. The article's case therefore rests entirely on the weakly selected band.
Defining functional DNA elements in the human genome
Kellis, M.; et al. PNAS, 111(17):6131-6138 (2014). doi 10.1073/pnas.1318948111
https://pmc.ncbi.nlm.nih.gov/articles/PMC4035993/
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: Homo sapiens proposed_solution: none
Key figure: 12-15% constrained, plus an additional 4-11% lineage-specific
Newer constraint estimates "each suggests roughly two to three times more constraint than previously (12-15%)," and "an additional 4-11% of the genome may be under lineage-specific constraint after specifically excluding protein-coding regions." The union of these gives the top of the article's U bracket, 11-22.
A high-resolution map of human evolutionary constraint using 29 mammals
Lindblad-Toh, K.; et al. Nature, 478:476-482 (2011). doi 10.1038/nature10530
https://pmc.ncbi.nlm.nih.gov/articles/PMC3207357/
camp: mainstream direction: mixed access: OA peer_reviewed: yes organism: 29 mammals proposed_solution: none
Key figure: at least 5.5% under purifying selection; constrained elements cover approx 4.2%
The standard low-side comparative-genomics figure before Zoonomia. Note the gap between the two numbers in the same paper — 5.5% "has undergone purifying selection" but the identified elements cover only 4.2% — which is the usual signature of deep alignments undercounting.
Massive turnover of functional sequence in human and other mammalian genomes
Meader, S.; et al. Genome Research, 20(10):1335-1343 (2010). doi 10.1101/gr.108795.110
https://pmc.ncbi.nlm.nih.gov/articles/PMC2945182/
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: Homo sapiens, mammals proposed_solution: none
Key figure: 200-300 Mb (~6.5%-10%) under functional constraint
An independent methodological route to the same range — indels rather than substitutions — which matters because the constrained-fraction literature is otherwise methodologically homogeneous. Also documents turnover, so a fixed constrained fraction hides substantial element replacement.
ENCODE registry of candidate cis-regulatory elements [TITLE-INVENTED]
Moore, unknown; et al. Nature (2026).
https://pmc.ncbi.nlm.nih.gov/articles/PMC13164889/
camp: mainstream direction: background access: OA peer_reviewed: yes organism: Homo sapiens proposed_solution: none
Key figure: 21% of the human genome in the ENCODE registry
ENCODE's registry now covers about 21% of the human genome. Context only: this is biochemical activity, not evolutionary selection, and the article's U scaling depends on sequence-specific constraint, not on activity. Author list and DOI were in the lost research files.
Genome-wide negative selection in humans [TITLE-INVENTED]
Ramesh, unknown; Di, unknown; Lohmueller, K.E. preprint, venue unknown (2026).
camp: mainstream direction: supports access: preprint peer_reviewed: preprint organism: Homo sapiens proposed_solution: none
Key figure: "at least 7% of the human genome are under negative selection" — raises U approx 40%
A Lohmueller-lab preprint putting at least 7% of the genome under negative selection, which raises the article's U by roughly 40%. Verified and flagged in project memory as not yet applied. Full author list, venue, DOI and URL were in the lost research files.
8.2% of the Human Genome Is Constrained
Rands, C.M.; et al. PLoS Genetics, 10(7):e1004525 (2014). doi 10.1371/journal.pgen.1004525
https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1004525
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: Homo sapiens proposed_solution: none
Key figure: 8.2% (7.1-9.2%) constrained; only 2.2% constrained in both human and mouse
"8.2% (7.1-9.2%) of the human genome is presently subject to negative selection and thus is likely to be functional." The article's middle U bracket rests on this and Zoonomia. The 2.2% human-and-mouse figure is the reason deep alignments systematically undercount, and it should be quoted alongside.
Beneficial mutations
Are mutations usually deleterious? A perspective on the fitness effects of mutation accumulation
Bao, K.; et al. Evolutionary Ecology (2022).
https://pmc.ncbi.nlm.nih.gov/articles/PMC9559781/
camp: mainstream direction: undercuts access: OA peer_reviewed: yes organism: Arabidopsis, C. elegans, Daphnia, yeast, Chlamydomonas proposed_solution: none
Key figure: "Shaw et al. (2000) concluded that about half of all mutations that occurred in their study were beneficial"
A mainstream review cataloguing mutation-accumulation lines that show no fitness decline. The article cites it against itself. But Crombie 2024 was designed to test exactly these estimates and finds the high beneficial fractions are linkage-disequilibrium artefacts — both are kept in the article so the reader sees the correction rather than only the conclusion.
Experimental evolution, loss-of-function mutations, and the first rule of adaptive evolution
Behe, M.J. The Quarterly Review of Biology, 85(4):419-445 (2010). doi 10.1086/656902
https://www.lehigh.edu/bio/pdf/Behe/QRB_paper.pdf
camp: ID direction: supports access: OA peer_reviewed: yes organism: microbes (survey of published experiments) proposed_solution: none
Peer reviewed in a mainstream journal. Behe is a biochemist at Lehigh and an ID advocate; the survey is of published laboratory evolution experiments and can be checked against them. The article cites his own hedge alongside the claim: it "is called a 'rule' in the sense of being a rule of thumb. It is a heuristic, useful generalization, rather than a strict law." Jerry Coyne's response agrees that observed laboratory evolution is loss or modification of function but denies the extrapolation.
Dynamic mutation-selection balance as an evolutionary attractor
Goyal, S.; et al. Genetics, 191(4):1309-1319 (2012). doi 10.1534/genetics.112.141291
https://pmc.ncbi.nlm.nih.gov/articles/PMC3416009/
camp: mainstream direction: undercuts access: OA peer_reviewed: yes organism: theory (asexual) proposed_solution: beneficial-compensation
Key figure: "just 2% beneficial mutations are enough to counteract the effect of deleterious mutations"
"for a small population Ns ~ 10^3 with high mutation rate lambda ~ 8, just 2% beneficial mutations are enough to counteract the effect of deleterious mutations." That is an asexual population with Muller's ratchet running, so it is a hard case rather than an easy one — which makes the 2% figure a strong result against unbounded decline.
Gene loss predictably drives evolutionary adaptation
Helsen, J.; et al. Molecular Biology and Evolution, 37(10):2989-3002 (2020). doi 10.1093/molbev/msaa172
https://academic.oup.com/mbe/article/37/10/2989/5870834
camp: mainstream direction: undercuts access: OA peer_reviewed: yes organism: Saccharomyces cerevisiae proposed_solution: none
"losing highly connected genes increased evolvability by facilitating the emergence of a more diverse array of phenotypes after adaptation... loss of specific parts of a genetic network can facilitate adaptation by opening alternative evolutionary paths." The strongest mainstream answer to the beneficial-by-destruction argument, and project memory requires it be cited alongside Hottes and Klim rather than omitted.
Bacterial adaptation through loss of function
Hottes, A.K.; et al. PLoS Genetics, 9(7):e1003617 (2013). doi 10.1371/journal.pgen.1003617
https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1003617
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: Escherichia coli proposed_solution: none
Key figure: at least one beneficial null mutation in 139 of 144 conditions
"even under conditions of extreme nutrient limitation, substantial adaptation can be achieved solely through loss of function mutations, which rewire the metabolism of the cell without gain of enzymatic or sensory function." From the Tavazoie lab at Columbia and Princeton, with no connection to this debate. The strongest mainstream support for Eric's beneficial-by-destruction observation — though the defensible form of that argument is not a percentage but the point that fitness assays are mechanism-blind.
Spontaneous mutations in diploid Saccharomyces cerevisiae: more beneficial than expected
Joseph, S.B.; Hall, D.W. Genetics, 168(4):1817-1825 (2004). doi 10.1534/genetics.104.033761
https://pmc.ncbi.nlm.nih.gov/articles/PMC1448740/
camp: mainstream direction: mixed access: OA peer_reviewed: yes organism: Saccharomyces cerevisiae proposed_solution: none
Key figure: 5.75% of fitness-altering mutations were beneficial
"We found that 5.75% of the fitness-altering mutations accumulated were beneficial. This finding contradicts the widely held belief that nearly all fitness-altering mutations are deleterious." A 1,012-generation experiment. Read the whole result: the lines still showed "a significant reduction in mean fitness" overall, and the 5.75% is of fitness-altering mutations, not of all mutations.
Loss-of-function mutations are main drivers of adaptations during short-term evolution
Klim, J.; Zielenkiewicz, U.; Kaczanowski, S. Scientific Reports, 14:7128 (2024). doi 10.1038/s41598-024-57694-8
https://pmc.ncbi.nlm.nih.gov/articles/PMC10965932/
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: microbes (58 studies, 65 experiments) proposed_solution: none
Key figure: 17 of 65 experiments reached significance (d_nonsense > d_S, p < 0.05)
A modified dN/dS statistic applied to nonsense mutations across 58 published studies. "The presented results confirm expectations of the classical 'less is more' hypothesis." Always quote the 17-of-65 count with the title, or this becomes the same overstatement the project documents against Sanford. Scope is short-term evolution, stated in their own title.
Estimating the proportion of beneficial mutations that are not adaptive in mammals
Latrille, T.; Joseph, J.; Hartasanchez, D.A.; Salamin, N. PLoS Genetics, 20(12):e1011536 (2024). doi 10.1371/journal.pgen.1011536
https://pmc.ncbi.nlm.nih.gov/articles/PMC11709321/
camp: mainstream direction: mixed access: OA peer_reviewed: yes organism: Equus, Bos, Capra, Ovis, Chlorocebus, Homo (28 populations) proposed_solution: beneficial-compensation
Key figure: non-adaptive (reversion) beneficials are 15-45% of all beneficials in 24 of 28 populations; full range 11-82%, mean near 30%
"Non-adaptive" here means beneficial because it restores a previously lost state, as distinct from beneficial because it improves on the ancestral one — the repair-versus-innovation distinction the article's Argument 3 turns on, measured for the first time. Confirms accumulation in real sequence data (supports the article) and shows a far bigger repair flux than the article's back-mutation treatment implied (constrains it).
Multiple overlapping genetic codes profoundly reduce the probability of beneficial mutation
Montanez, G.; Marks, R.J. II; Fernandez, J.; Sanford, J.C. Biological Information: New Perspectives, World Scientific (2013).
camp: creationist direction: supports access: book peer_reviewed: no organism: theory proposed_solution: none
A theoretical chapter in a creationist and intelligent-design symposium volume. Its starting assumptions (pp. 141-143) include a tunable 99.9% optimal fraction, independent preferences across codes, and unit effects that cancel. Equations 1-3 (p. 146) predict a decreasing net beneficial probability as more codes overlap under those assumptions. The chapter measures neither the inputs nor a general beneficial fraction. Its concern about hidden costs applies to interpreting a molecular readout as fitness; whole-organism competition assays already integrate the functions affecting success in the tested environment. The model does not make every experimentally reported beneficial fraction an upper bound.
Epistasis
Evolution of the rate, molecular spectrum, and fitness effects of mutation under minimal selection in Caenorhabditis elegans
Saber, S.; Rifat, M.M.I.; Rahimi, F.; et al. (Baer lab) Genetics, iyag085 (2026). doi 10.1093/genetics/iyag085
https://www.biorxiv.org/content/10.1101/2025.09.24.678306v3
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: Caenorhabditis elegans proposed_solution: none
Key figure: second-round MA mutations cost about half as much competitive fitness as first-round ones; constant-effects model beats the epistasis model
Measurement. Verified in full (bioRxiv v3 JATS, saber-2026; abstract identical to the published one). 100 O1MA lines, ~150 generations, split into O2MA lines for ~150 more; competitive fitness on 50 families. "This study provides no support for the possibility that deleterious mutations interact synergistically"; the authors tie the question to "the long-term existence of species with modest effective population sizes (e.g., humans, Kondrashov 1995 ...)". Cited in index.md, Objection 6 and the Kondrashov resolutions. Limits: one species, 300 generations, the authors' own worry about underpowered tests.
Additivity of the genetic load is a product of both synergistic and antagonistic epistasis in Drosophila
Sayyed, I.; McNamara, H.; Day, T.; Chippindale, A.K. bioRxiv preprint 2025.11.04.686015 (2025).
https://www.biorxiv.org/content/10.1101/2025.11.04.686015v1
camp: mainstream direction: mixed access: preprint peer_reviewed: preprint organism: Drosophila melanogaster proposed_solution: synergistic-epistasis
Key figure: accelerating decline in pupal productivity, decelerating decline in pupa-to-adult viability, linear decline in adult offspring
Measurement (full-sib inbreeding). Abstract verified (sayyed-2025). A different laboratory from Saber, not a companion paper as an earlier version of this entry said. Synergy appears in one fitness component and the opposite in the next, netting to a straight-line decline. Cited in index.md, Objection 6.
Negative linkage disequilibrium between amino acid changing variants reveals interference among deleterious mutations in the human genome
Garcia, J.A.; Lohmueller, K.E. PLoS Genetics, 17(7):e1009676 (2021). doi 10.1371/journal.pgen.1009676
https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1009676
camp: mainstream direction: background access: OA peer_reviewed: yes organism: Homo sapiens proposed_solution: none
Key figure: short-range negative LD between missense variants explained by Hill-Robertson interference
Considered, not cited. It reads Sohail 2017's negative-LD signal at short range as interference rather than epistasis, but says "we cannot rule out a contribution from negative synergistic epistasis" and does not test Sohail's genome-wide underdispersion, so it is not a rebuttal of Sohail.
Can synergistic epistasis halt mutation accumulation? Results from numerical simulation
Baumgardner, J.R.; Brewer, W.H.; Sanford, J.C. Biological Information: New Perspectives, pp. 312-337 (2013).
https://robertmarks.org/REPRINTS/BINP/9789814508728_0013.pdf
camp: creationist direction: supports access: book peer_reviewed: no organism: theory proposed_solution: none
Key figure: SE scaling factors of 5 x 10^5 (non-linked), 1 x 10^9 (linked), 1.5 x 10^6 (exaggerated)
The creationist side's direct answer to the synergistic-epistasis escape, run in Mendel's Accountant. Their conclusion: "synergistic epistasis exerts little to no discernible influence on mutation accumulation," and when the effect is exaggerated, degeneration accelerates rather than halting. Their third conclusion is a genuinely checkable empirical prediction rather than a simulation result — if the SE hypothesis were true, relaxed selection in mutation-accumulation experiments "would be expected to result in rapid and catastrophic fitness meltdown," which has not been observed. Two limits a critic will press. The whole result is Mendel's Accountant with an epistasis term added, so it inherits that program's unvalidated distribution of fitness effects, and the SE scaling factors are chosen rather than measured. And they concede the decisive point themselves: nearly-neutral interactions "are beyond measurement, are not suited to empirical analysis, and therefore can be modeled only in a generic way." Their central empirical claim is now out of date — they write that the SE hypothesis "has never been demonstrated to work," which was defensible in 2013 and was overtaken by Sohail 2017 below.
Using numerical simulation to test the "mutation-count" hypothesis
Brewer, W.H.; Baumgardner, J.R.; Gibson, P.; Sanford, J.C. Biological Information: New Perspectives, pp. 298-311 (2013).
https://robertmarks.org/REPRINTS/BINP/9789814508728_0012.pdf
camp: creationist direction: supports access: book peer_reviewed: no organism: theory proposed_solution: none
The companion chapter the synergistic-epistasis paper depends on, and it should be cited with it rather than separately. Its claim is that with any realistic distribution of mutational fitness effects the mutation-count mechanism does not operate at all — which is the load-bearing premise for the SE chapter's conclusion, since synergistic epistasis is supposed to work through that mechanism. Same tool and therefore the same inherited assumptions.
Epistasis correlates to genomic complexity
Sanjuán, R.; Elena, S.F. PNAS, 103(39):14402-14405 (2006). doi 10.1073/pnas.0604543103
https://pmc.ncbi.nlm.nih.gov/articles/PMC1599975/
camp: mainstream direction: mixed access: OA peer_reviewed: yes organism: cross-species proposed_solution: synergistic-epistasis
The single most useful entry on this topic, because it shows the answer depends on the organism. "Simpler genomes, such as those of RNA viruses, display antagonistic epistasis ... bacterial microorganisms do not apparently deviate from independent effects, whereas in multicellular eukaryotes, a transition toward synergistic epistasis occurs." That cuts both ways. Synergistic epistasis is real and is found exactly where the human argument needs it to be absent — but it also means results transferred from viral or bacterial experiments to humans are transferring the wrong sign. Cited in the Baumgardner chapter above, whose own conclusion it complicates.
Evidence for positive epistasis in HIV-1
Bonhoeffer, S.; Chappey, C.; Parkin, N.T.; Whitcomb, J.M.; Petropoulos, C.J. Science, 306(5701):1547-1550 (2004). doi 10.1126/science.1101786
https://pubmed.ncbi.nlm.nih.gov/15567861/
camp: mainstream direction: supports access: paywalled peer_reviewed: yes organism: HIV-1 proposed_solution: none
Cited in the Baumgardner chapter. Positive (antagonistic) epistasis is the opposite of what the synergistic-epistasis escape requires, so a finding of it in HIV-1 counts against that escape. Abstract verified; the full text is paywalled. Do not cite this without the rebuttal below — it was directly challenged in the same journal.
Comment on "Evidence for positive epistasis in HIV-1"
Wang, K.; Mittler, J.E.; Samudrala, R. Science, 312(5775):848 (2006). doi 10.1126/science.1109904
https://pubmed.ncbi.nlm.nih.gov/16690844/
camp: mainstream direction: undercuts access: paywalled peer_reviewed: yes organism: HIV-1 proposed_solution: none
The published rebuttal: "biases in the original and simulated data sets may lead to erroneous evidence for epistasis. More rigorous statistical tests must be used to account for such biases before one can infer epistasis." Included because the epistasis literature is unusually contested and single results in it should not be quoted as settled by either side.
Negative selection in humans and fruit flies involves synergistic epistasis
Sohail, M.; et al. Science, 356(6337):539-542 (2017). doi 10.1126/science.aah5238
https://www.biorxiv.org/content/10.1101/066407.full.pdf
camp: mainstream direction: undercuts access: preprint peer_reviewed: yes organism: Homo sapiens, Drosophila proposed_solution: synergistic-epistasis
Key figure: sigma^2 = 0.9 V_A, equivalent to truncating less than 2% of the population
"we detected underdispersion of the number of rare loss-of-function alleles in eight independent data sets from human and fly populations." The strongest direct evidence for the epistasis resolution — but the effect is small, equivalent to truncating under 2% of the population, which is far short of what the load arithmetic needs. The linked bioRxiv preprint is free; the Science version is paywalled and its wording differs.
Experimental evolution
Mutator genomes decay, despite sustained fitness gains, in a long-term experiment with bacteria
Couce, A.; et al. PNAS, 114(43):E9026-E9035 (2017). doi 10.1073/pnas.1705887114
https://pmc.ncbi.nlm.nih.gov/articles/PMC5664506/
camp: mainstream direction: mixed access: OA peer_reviewed: yes organism: Escherichia coli (LTEE) proposed_solution: none
Key figure: 6 of 12 LTEE populations became hypermutable, raising mutation rates 10- to 100-fold
"the signature of selection is much weaker than that of mutational biases in mutator genomes," yet fitness kept rising past 50,000 generations. The title concedes the genome-level decay and denies the fitness consequence — which is exactly the distinction the article is built on. Merged here with the duplicate footnote key couce-2017-ge used in sanford.md.
Evolution of a minimal cell [TITLE?]
Moger-Reischer, R.Z.; et al. Nature, 620:122-127 (2023).
https://pmc.ncbi.nlm.nih.gov/articles/PMC10396959/
camp: mainstream direction: mixed access: OA peer_reviewed: yes organism: JCVI-syn3B (minimal Mycoplasma) proposed_solution: none
Key figure: U = 0.018, about 300-400x below the human figure
The minimal cell has a genome with essentially no junk, so every mutation lands in functional sequence — and it does not melt down. Cuts against the article at first sight. But its U is 300-400x below the human value, so the comparison needs the arithmetic done before it means anything. Flagged in project memory as verified and not yet applied.
Mutator crossover where destruction outruns construction [TITLE-INVENTED]
Shibai, unknown; et al. PLoS Genetics, 21(3):e1011627 (2025).
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: bacteria (mutator lines) proposed_solution: none
Key figure: crossover occurs at hundreds of times the wild-type mutation rate
Identifies the mutation rate at which destruction outruns construction in an experimental system — but the crossover sits at hundreds of times the wild-type rate, so it supports the mechanism while placing real organisms far from the threshold. Verified and flagged in project memory as not yet applied; DOI and URL were in the lost research files.
Evolution at a High Imposed Mutation Rate: Adaptation Obscures the Load in Phage T7
Springman, R.; et al. Genetics, 184(1):221-232 (2010). doi 10.1534/genetics.109.108530
https://pmc.ncbi.nlm.nih.gov/articles/PMC2815918/
camp: mainstream direction: mixed access: OA peer_reviewed: yes organism: bacteriophage T7 proposed_solution: beneficial-compensation
Key figure: 4.3 mutations per genome per mutagenic generation; 18.3 to 21.9 doublings/hr against a predicted 8.6; 245 mutations per genome; 80% drop in burst size
"Fitness... was predicted to decline substantially; after 200 generations, fitness had increased, rejecting the model. A high mutation load was nonetheless evident." The cleanest demonstration that fitness and genome integrity can move in opposite directions. Correction of record: the phrase "a profound failure of the theory" is NOT in this paper — an earlier draft of objections.md attributed it to them. The verified wording is "Failure of the theory challenges the quantitative basis of lethal mutagenesis."
Long-term dynamics of adaptation in asexual populations
Wiser, M.J.; Ribeck, N.; Lenski, R.E. Science, 342(6164):1364-1367 (2013). doi 10.1126/science.1243357
https://pubmed.ncbi.nlm.nih.gov/24231808/
camp: mainstream direction: undercuts access: paywalled peer_reviewed: yes organism: Escherichia coli proposed_solution: none
Key figure: "Mean fitness appears to increase without bound, consistent with a power law"
Fitness in all 12 LTEE populations rises without bound on a power law, derived theoretically from clonal interference plus diminishing-returns epistasis. The power law is the unbounded model and it is the one the authors conclude fits. Rupe and Sanford 2015 reverse this in their own Figure 1 caption, which is documented in sanford.md as error 6. Note the LTEE reached 75,000 generations and was frozen at 80,000 in 2024, but no fitness-trajectory analysis past 50,000 has been published — neither side can cite a measured 75,000-generation value.
Mutation accumulation
A new look at an old virus: patterns of mutation accumulation in the human H1N1 influenza virus since 1918
Carter, R.W.; Sanford, J.C. Theoretical Biology and Medical Modelling, 9:42 (2012). doi 10.1186/1742-4682-9-42
https://pmc.ncbi.nlm.nih.gov/articles/PMC3507676/
camp: creationist direction: mixed access: OA peer_reviewed: yes organism: influenza A H1N1 proposed_solution: none
"We suggest H1N1 has been undergoing natural genetic attenuation." Project decision: do not lean on this. Antigenic drift explains strain turnover, their Figure 2 counts reassortment as mutation, and the 2009 disappearance of the seasonal human lineage coincides with its replacement by a new swine-origin H1N1 — so the two "extinctions" are not one decaying lineage. Separately, Carter removed reassortant sequences and then presented their absence as evidence of decay. Peer reviewed in a secular journal, but that journal ceased publication in 2021.
The effects of a deleterious mutation load on patterns of influenza A/H3N2's antigenic evolution in humans
Koelle, K.; Rasmussen, D.A. eLife, 4:e07361 (2015). doi 10.7554/eLife.07361
https://pmc.ncbi.nlm.nih.gov/articles/PMC4611170/
camp: mainstream direction: mixed access: OA peer_reviewed: yes organism: influenza A H3N2 proposed_solution: beneficial-compensation
Key figure: ε_c = 0.16 beneficial share of non-antigenic mutations set to keep the simulated load stable
Model plus sequence analysis. Verified in full (koelle-2015). Takes H3N2's deleterious load as established by three phylogenetic studies; grants that "one might expect ... a long-term decline in influenza A/H3N2 fitness," names two brakes (rising beneficial share, reassortment), and says weakening "has not been empirically demonstrated." Its simulation needed a chosen 16% beneficial share to stop Muller's ratchet, which the authors attribute to the small simulated host number. Cited in index.md, the influenza section.
Has influenza B/Yamagata become extinct and what implications might this have for quadrivalent influenza vaccines?
Paget, J.; Caini, S.; Del Riccio, M.; van Waarden, W.; Meijer, A. Eurosurveillance, 27(39):2200753 (2022). doi 10.2807/1560-7917.ES.2022.27.39.2200753
https://pmc.ncbi.nlm.nih.gov/articles/PMC9524051/
camp: mainstream direction: undercuts access: OA peer_reviewed: yes organism: influenza B proposed_solution: none
Key figure: no confirmed B/Yamagata circulation since March 2020
Surveillance report. Verified in full (paget-2022). A lineage that circulated for decades vanished when COVID-19 measures changed influenza transmission, which makes lineage extinction a poor diagnostic of mutational decay. Cited in index.md, the influenza section, replacing an unsourced sentence.
An estimate of fitness reduction from mutation accumulation in a mammal
Chebib, J.; et al. (Keightley, P.D. senior) PLoS Biology, 22(9):e3002795 (2024). doi 10.1371/journal.pbio.3002795
https://pmc.ncbi.nlm.nih.gov/articles/PMC11426515/
camp: mainstream direction: mixed access: OA peer_reviewed: yes organism: Mus musculus proposed_solution: none
Key figure: 0.38% fitness reduction per generation, confidence intervals overlapping zero
Their 0.38% is a hundredfold larger than the figure the article derives from fixation counts, and the difference is real rather than a contradiction: theirs includes segregating mutations that selection will eventually remove, while the article counts only what fixes permanently. The two numbers answer different questions and must not be compared without saying so. The authors decline to be alarmed by their own finding, which makes them more useful to a skeptical reader than a source that only does the first half.
Rapid fitness recovery in mutationally degraded lines of Caenorhabditis elegans
Estes, S.; Lynch, M. Evolution, 57(5):1022-1030 (2003).
camp: mainstream direction: mixed access: OA peer_reviewed: yes organism: Caenorhabditis elegans proposed_solution: beneficial-compensation
Key figure: recovery at least 3x the rate of mutational degradation
"mutationally degraded lines are capable of recovering original levels of mean fitness at a rate that is at least three times that of mutational degradation in the absence of selection." The authors conclude "compensatory mutation appears to be the only viable explanation" — and the recovered genomes carry more mutations, not fewer. This is the article's Argument 3 as an experimental result: fitness restored while sequence keeps degrading.
Fitness decline in spontaneous MA lines of C. elegans with varying effective population sizes
Katju, V.; et al. Evolution, 69(1):104-116 (2015). doi 10.1111/evo.12554
https://pubmed.ncbi.nlm.nih.gov/25338758/
camp: mainstream direction: undercuts access: paywalled peer_reviewed: yes organism: Caenorhabditis elegans proposed_solution: none
Key figure: N = 10 and 100 showed no significant fitness decline over 400+ generations
"Larger populations (N = 10 and 100) did not suffer a significant decline in fitness traits despite a lengthy and sustained regime of consecutive bottlenecks exceeding 400 generations." A direct demonstration that MA-line decline is a relaxed-selection artefact once Ne is even modestly above one. Abstract free, full text paywalled.
Old Trade, New Tricks: Insights into the Spontaneous Mutation Process from MA Experiments with High-Throughput Genomics
Katju, V.; Bergthorsson, U. Genome Biology and Evolution, 11(1):136-165 (2019). doi 10.1093/gbe/evy252
https://pmc.ncbi.nlm.nih.gov/articles/PMC6330053/
camp: mainstream direction: mixed access: OA peer_reviewed: yes organism: eukaryotes (review) proposed_solution: none
Key figure: phenotypic U in eukaryotes ranges >700-fold, from 0.00065 to 0.47
The single best statement of how uncertain U really is when measured phenotypically rather than inferred from constraint. Also documents the assay dependence: "assays under competitive or stress conditions tend to yield higher estimates of U... relative to benign assays," which is the same effect Shabalina 1997 measured directly.
Estimate of the genomic mutation rate deleterious to overall fitness in E. coli [TITLE?]
Kibota, T.T.; Lynch, M. Nature, 381:694-696 (1996).
camp: mainstream direction: background peer_reviewed: yes organism: Escherichia coli proposed_solution: none
Key figure: E. coli nu approx 1e-4 per genome per generation
The source of the E. coli deleterious rate that Galeota-Sprung 2020 uses to argue Haldane load theory works for microbes and fails for humans. Known here through Galeota-Sprung's citation of it; the primary was not retrieved for this project. [STALE?]
Mutation rate and dominance of genes affecting viability in Drosophila melanogaster [TITLE?]
Mukai, T.; Chigusa, S.I.; Mettler, L.E.; Crow, J.F. Genetics, 72(2):335-355 (1972).
camp: mainstream direction: background peer_reviewed: yes organism: Drosophila melanogaster proposed_solution: none
Key figure: broad-sense H^2 of fitness = 0.004
The measurement underlying the 0.004 heritability-of-fitness figure that Kimura 1983 quotes and Sanford's book generalises to humans. Two things go wrong in that chain: it is a broad-sense H^2, not an additive h^2, and it is one Drosophila study. The article's sanford.md documents this as error 3. Cited in the project only through Kimura 1983; the primary was not retrieved. [STALE?]
Selection bias in mutation accumulation
Wahl, L.M.; Agashe, D. Evolution, 76(3):528-540 (2022). doi 10.1111/evo.14418
https://pubmed.ncbi.nlm.nih.gov/34989408/
camp: mainstream direction: undercuts access: paywalled peer_reviewed: yes organism: microbes proposed_solution: none
"These results highlight that positive selection during microbial MA experiments is in fact not negligible, but can be corrected to gain a more accurate understanding of fundamental evolutionary parameters." A methodological caution that cuts against reading MA-line results as clean measurements of the raw mutational input. Abstract free, full text paywalled at Wiley.
Rapid decline of fitness in panmictic populations of Drosophila melanogaster maintained under relaxed natural selection
Shabalina, S.A.; Yampolsky, L.Y.; Kondrashov, A.S. PNAS, 94(24):13034-13039 (1997). doi 10.1073/pnas.94.24.13034
https://pmc.ncbi.nlm.nih.gov/articles/PMC24258/
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: Drosophila melanogaster proposed_solution: none
Key figure: 0.2% per generation benign, 2.0% per generation harsh and competitive
"the number of surviving offspring per female declined by 0.2% and 2.0% per generation under benign and harsh, competitive conditions, respectively. Thus, the mutational pressure on fitness may be strong and depends critically on the conditions under which fitness is assayed." The tenfold assay dependence is why cross-study U comparisons are unreliable, and it is the source of the rate Buchanan used in his "flies would be extinct" argument — which the article answers by noting it is a relaxed-selection rate, not a wild one.
Germline mutation rates and the long-term phenotypic effects of mutation accumulation in wild-type and mutator mice
Uchimura, A.; et al. Genome Research, 25(8):1125-1134 (2015). doi 10.1101/gr.186148.114
https://pmc.ncbi.nlm.nih.gov/articles/PMC4509997/
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: Mus musculus proposed_solution: none
Key figure: 17x mutation rate, 4.1-fold more abnormal phenotypes, mean offspring down to 36%
"The mutation rate in mutator mice was 17 times that in wild-type mice. Abnormal phenotypes were 4.1-fold more frequent in the mutator lines... many of the breeding lines died out." Wild-type lines showed no comparable collapse — so this is a demonstration of the mechanism at an elevated rate, not evidence that wild mammals are melting down. State both halves.
Lethal mutagenesis
Favipiravir elicits antiviral mutagenesis during virus replication in vivo
Arias, A.; et al. eLife, 3:e03679 (2014). doi 10.7554/eLife.03679
https://pmc.ncbi.nlm.nih.gov/articles/PMC4204012/
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: murine norovirus proposed_solution: none
Key figure: virus undetectable in 7 of 9 treated animals vs 2 of 10 controls after 53 days
The in vivo demonstration that raising a virus's mutation rate can drive it to extinction inside a living host, not just in culture. The strongest single piece of experimental evidence that error catastrophe is a real physical process.
Theory of lethal mutagenesis for viruses
Bull, J.J.; Sanjuan, R.; Wilke, C.O. Journal of Virology, 81(6):2930-2939 (2007). doi 10.1128/JVI.01624-06
https://pmc.ncbi.nlm.nih.gov/articles/PMC1865999/
camp: mainstream direction: background access: OA peer_reviewed: yes organism: theory (viruses) proposed_solution: none
"an error catastrophe is an evolutionary shift in genotype space, whereas extinction is a demographic process, a drop in the absolute abundance of individuals." The distinction the article needs to keep straight, and the reason virus results do not transfer directly to the human case.
RNA virus error catastrophe: direct molecular test by using ribavirin
Crotty, S.; Cameron, C.E.; Andino, R. PNAS, 98(12):6895-6900 (2001). doi 10.1073/pnas.111085598
https://pmc.ncbi.nlm.nih.gov/articles/PMC34449/
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: poliovirus proposed_solution: none
Key figure: 99.3% loss of infectivity from a 9.7-fold increase in mutagenesis, in one round
The most-cited demonstration that a modest rise in mutation rate produces a very large loss of viral infectivity. A single replication round, which is what makes the effect attributable to mutation rather than to accumulated demography.
Lethal mutagenesis and the transient within-host dynamics of viral adaptation
Guillemet, M.; et al. Virus Evolution (2025).
https://pmc.ncbi.nlm.nih.gov/articles/PMC12640550/
camp: mainstream direction: undercuts access: OA peer_reviewed: yes organism: six virus species proposed_solution: none
Key figure: required fold increase 11 to 2700; available mutagens deliver at most 10x
"the fold increase in the viral mutation rate required to reach the critical mutation rate of six different viruses ranges from 11 to 2700... lethal mutagenesis seems difficult to achieve since available estimates... indicate that they increase viral mutation rate by a factor of 10 at most." The strongest published limit on how easily error catastrophe can be induced, and it undercuts triumphalist readings of the ribavirin and favipiravir results.
Lethal mutagenesis of HIV with mutagenic nucleoside analogs
Loeb, L.A.; et al. PNAS, 96(4):1492-1497 (1999). doi 10.1073/pnas.96.4.1492
https://pmc.ncbi.nlm.nih.gov/articles/PMC15492/
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: HIV-1 proposed_solution: none
Key figure: replicative potential lost in 7 of 9 experiments after 9-24 passages; 0 of 28 controls
The founding lethal-mutagenesis paper, and a clean control design: loss of replication in seven of nine treated cultures and none of twenty-eight controls. Together with Crotty 2001 this is the experimental core of the claim that accumulating mutations can destroy a replicator.
Efficient virus extinction by combinations of a mutagen and antiviral inhibitors
Pariente, N.; Sierra, S.; Lowenstein, P.R.; Domingo, E. Journal of Virology, 75(20):9723-9730 (2001). doi 10.1128/JVI.75.20.9723-9730.2001
https://pmc.ncbi.nlm.nih.gov/articles/PMC114544/
camp: mainstream direction: mixed access: OA peer_reviewed: yes organism: foot-and-mouth disease virus proposed_solution: none
"Systematic extinction of intermediate fitness virus was attained with a combination of FU and G but not with the mutagen or the inhibitor alone." The mutagen alone gave only occasional extinction — an important qualification on the whole lethal-mutagenesis literature, and consistent with Guillemet 2025's fold-increase arithmetic.
A molnupiravir-associated mutational signature in global SARS-CoV-2 genomes
Sanderson, T.; et al. Nature, 623:594-600 (2023). doi 10.1038/s41586-023-06649-6
https://pmc.ncbi.nlm.nih.gov/articles/PMC10651478/
camp: mainstream direction: undercuts access: OA peer_reviewed: yes organism: SARS-CoV-2 proposed_solution: none
Key figure: an Australian cluster of 20 tip sequences from multiple individuals
Molnupiravir's mutational signature appears in transmitted lineages, so the drug produced viable, transmissible virus rather than sterilising it. Scope correction from project memory: the article's claim that it "made new variants" overshoots — no molnupiravir-derived lineage became a named variant, and McKinzie 2026 and Penrice-Randal 2025 found no consistent consensus-sequence change. The defensible claim is that it produced viable heavily mutated lineages that went nowhere in particular.
Conservation genomics
Genetic rescue of Florida panthers reduced homozygosity but did not swamp ancestral genotypes
Aguilar-Gomez, D.; et al. PNAS (2025).
https://pmc.ncbi.nlm.nih.gov/articles/PMC12337334/
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: Puma concolor coryi (Florida panther) proposed_solution: none
Key figure: LoF alleles per individual rose (p = 0.006) while homozygous ones fell (p = 0.016); fitness gain transient within 20 generations
"We found no differences in the total number of deleterious alleles per individual in Florida panthers before and after genetic rescue. Instead, a reduction in homozygosity seems to be driving improvements in fitness." A textbook case of fitness recovering while the sequence damage does not — the article's Argument 3 in a conservation setting. Their own simulations show the gain is transient. The PNAS DOI is Cloudflare-blocked to automated fetching; this is the PMC mirror.
Evidence of long-term purging of mutation burden in killer whale Orcinus orca genomes
Foote, A.D.; et al. Heredity (2025). doi 10.1038/s41437-025-00806-5
https://www.nature.com/articles/s41437-025-00806-5
camp: mainstream direction: undercuts access: paywalled peer_reviewed: yes organism: Orcinus orca proposed_solution: none
Reports purging of non-synonymous mutations as a class, not only the strongly deleterious ones — the clearest published counterexample to the two-tier pattern the article's conservation section relies on. The article states it first, before the supporting cases. Abstract verified verbatim; the full text is paywalled and the PMC copy is embargoed until Dec 2026, so the body numbers were not checked. No fitness was measured, and the authors attribute part of the signal to associative or pseudo-overdominance.
Genomes of critically endangered saola are shaped by population structure and purging
Garcia-Erill, G.; et al. (34 authors) Cell (2025).
https://pmc.ncbi.nlm.nih.gov/articles/PMC12173715/
camp: mainstream direction: mixed access: OA peer_reviewed: yes organism: Pseudoryx nghetinhensis (saola) proposed_solution: none
Key figure: realized load increased over the last 10,000 generations despite purging
"In small populations, genetic drift leads to an increase in the mildly and slightly deleterious mutations, while purging reduces overall genetic load by removing the strongly deleterious recessive mutations." Both halves at once, in one genome: the strongly harmful class is cleaned out and the weakly harmful class piles up. The authors caution that the elevated-deleterious-ratio pattern is disputed.
Long runs of homozygosity are reliable genomic markers of inbreeding depression
Kyriazis, C.C.; Robinson, J.A.; Lohmueller, K.E. Trends in Ecology & Evolution (2025).
https://www.ebi.ac.uk/europepmc/webservices/rest/PMC13238715/fullTextXML
camp: mainstream direction: undercuts access: OA peer_reviewed: yes organism: wild vertebrates (review) proposed_solution: none
"empirical evidence for mutational meltdown occurring in wild populations remains scarce, thus its importance as a genetic driver of extinction remains in question." From the Lohmueller lab, whose distribution of fitness effects the saola study used. Project memory calls this the strongest sentence against the article's thesis, and it is quoted in the article.
Too big to purge: persistence of deleterious mutations in island populations of the European Barn Owl
Lavanchy, E.; et al. Heredity (2024).
https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11589586/fullTextXML
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: Tyto alba (502 individuals) proposed_solution: none
Key figure: purging requires Ne of "a few hundred or less"
"we found an increase in numbers of both neutral and deleterious minor alleles... but we found no evidence of purging." And the threshold: "Only small populations with an effective population size of a few hundred or less can undergo purging... such small populations undergoing purging of highly deleterious alleles will usually also incur an additional cost of increased lowly and mildly deleterious mutations." So purging is not a general answer; it is a small-population phenomenon that trades one class of damage for another.
Extinction vortices are driven more by a shortage of beneficial mutations than by deleterious mutation accumulation
Mawass, W.; Hernandez, U.; Matheson, J.D.; Berg, J.J.; Masel, J. Proceedings of the Royal Society B, 293(2072):20260600 (2026). doi 10.1098/rspb.2026.0600
https://pubmed.ncbi.nlm.nih.gov/42230116/
camp: mainstream direction: mixed access: paywalled peer_reviewed: yes organism: theory / simulation proposed_solution: beneficial-compensation
"In stable environments, we find that mutational drought is nearly as significant as mutational meltdown. Drought is more important than meltdown when populations must also adapt to a changing environment unless the beneficial mutation rate is extremely high." Same lab as the fixation counts the article checks its arithmetic against. Reframes extinction risk as a supply problem on the construction side rather than an accumulation problem on the destruction side. Preprint at doi 10.1101/2024.10.25.620329.
A genetic component of extinction risk in mammals
Polishchuk, L.V.; Popadin, K.Y.; Baranova, M.A.; Kondrashov, A.S. Oikos, 124(8):983-993 (2015). doi 10.1111/oik.01734
camp: mainstream direction: supports access: paywalled peer_reviewed: yes organism: 211 mammal species proposed_solution: none
Key figure: Ka/Ks and body mass responsible for 38% and 62% increases in extinction risk respectively
The author of the 1995 paradox paper testing his theoretical claim against comparative data twenty years later, and finding a genetic component to extinction risk worth roughly a quarter to a half of the combined effect. Answers the Kyriazis "evidence remains scarce" concession, which had stood unanswered. Caveats stated in the article: Ka/Ks is a proxy not a load, the data are mitochondrial only, and correlation is not mechanism. Paywalled at Wiley; the figures come from the Crossref-deposited abstract.
Ancient DNA
Ancient DNA reveals pervasive directional selection across West Eurasia
Akbari, A.; et al. Nature, 654:419-428 (2026). doi 10.1038/s41586-026-10358-1
https://pmc.ncbi.nlm.nih.gov/articles/PMC13189228/
camp: mainstream direction: undercuts access: OA peer_reviewed: yes organism: Homo sapiens proposed_solution: none
Key figure: 15,836 ancient genomes over 18,000 years; selection estimated at 9.7 million variants; standard error on a selection coefficient approx 0.17%
Runs against a simple decline picture over the Holocene, and the article concedes it. The reply is the measurement gap: their standard error on a selection coefficient is about 0.17%, roughly forty times the human drift barrier of 0.004%. Their own caveats matter and are quoted: the polygenic signals for intelligence, income and schooling concern traits "unmeasurable in preliterate societies," the signals are "largely driven by selection before approximately 2,000 years [ago]," and "only 2.16 (+/- 0.11)% of allele frequency changes are due to directional selection."
Detection limits for selection in ancient DNA time series [TITLE-INVENTED]
Anchieri, unknown; et al. unknown (2026).
camp: mainstream direction: supports organism: Homo sapiens proposed_solution: none
Key figure: aDNA detection floor at s >= 0.02
One of the three independent literatures confirming the measurement gap: the ancient-DNA detection floor sits at s >= 0.02, five hundred times the human drift barrier of 4e-5. Cited in project memory as verified; author list, venue, DOI and URL were in the lost research files.
Direct evidence of an increasing mutational load in humans [TITLE?]
Aris-Brosou, S. Molecular Biology and Evolution, 36(12):2823-2829 (2019).
camp: mainstream direction: mixed peer_reviewed: yes organism: Homo sapiens proposed_solution: none
Risk alleles rose over 45,000 years — but homozygosity fell over the same period, and project memory requires both clauses be quoted together. Flagged as verified, heavily caveated, and not yet applied. DOI and URL were in the lost research files.
Elevated genetic risk for multiple sclerosis emerged in steppe pastoralist populations [TITLE?]
Barrie, W.; et al. Nature (2024).
camp: mainstream direction: undercuts peer_reviewed: yes organism: Homo sapiens proposed_solution: none
With Kerner 2023, the mainstream explanation for rising disease-allele frequencies: antagonistic pleiotropy plus population movement, not mutational decay. Flagged in project memory as verified, cutting against the article, and not yet applied. Most metadata was in the lost research files.
The Genomic Health of Ancient Hominins
Berens, A.J.; Cooper, T.L.; Lachance, J. Human Biology, 89(1):7-19 (2017).
https://digitalcommons.wayne.edu/humbiol/vol89/iss1/2/
camp: mainstream direction: mixed access: OA peer_reviewed: yes organism: Homo sapiens, Homo neanderthalensis proposed_solution: none
Key figure: "the overall genomic health of the Altai Neandertal is worse than 97% of present day humans"
147 ancient genomes scored by genetic risk score. Genomic health improved from the deep past to the recent past, which cuts against the article — but "ancient individuals who lived within the last few thousand years have healthier genomes, on average, than present day humans," which cuts for it. Provenance flag: that second clause was tagged unverified in the project's own provenance discipline and must be re-checked before quoting. Mirror at bioRxiv preprint 145193. [STALE?]
Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants
Fu, W.; et al. Nature, 493:216-220 (2013). doi 10.1038/nature11690
https://pmc.ncbi.nlm.nih.gov/articles/PMC3676746/
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: Homo sapiens proposed_solution: none
Key figure: approx 73% of protein-coding SNVs and approx 86% of predicted-deleterious SNVs arose in the past 5,000-10,000 years
The article's cleanest case of a model output being mistaken for a measurement. The 86% figure is downstream of "a modified Out-of-African model in which accelerated population growth began 5,115 years ago." The authors did test robustness — "generally robust across different demographic models, with the largest discrepancies resulting in a two-fold difference in average age" — but robustness within a deep-time family is not robustness of the family. The coincidence between 5,115 years and a young-earth chronology is arithmetic, not evidence, and the article says so.
The Genetic Cost of Neanderthal Introgression
Harris, K.; Nielsen, R. Genetics, 203(2):881-891 (2016). doi 10.1534/genetics.116.186890
https://pmc.ncbi.nlm.nih.gov/articles/PMC4896200/
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: Homo neanderthalensis, Homo sapiens proposed_solution: none
Key figure: "the median Neanderthal was found to have fitness 0.63 compared to the median human"; residual non-African load at least 0.5%
A long-term small effective population size produced a measurable fitness deficit, which is the drift-barrier mechanism operating on a real lineage. Provenance flag: the widely circulated "40% lower fitness" phrasing was tagged unverified in the project's own provenance discipline. Quote the 0.63 figure, not the 40%.
Genetic adaptation to pathogens and increased risk of inflammatory disorders in post-Neolithic Europe [TITLE?]
Kerner, G.; et al. unknown (2023).
camp: mainstream direction: undercuts peer_reviewed: yes organism: Homo sapiens proposed_solution: none
With Barrie 2024, the mainstream reading of rising disease-allele frequencies: antagonistic pleiotropy from pathogen adaptation, not mutational decay. Flagged in project memory as verified, cutting against the article, and not yet applied. Most metadata was in the lost research files.
A temporal perspective on the interplay of demography and selection on deleterious variation in humans [TITLE?]
Koch, E.; Novembre, J. unknown (2017).
camp: mainstream direction: undercuts peer_reviewed: yes organism: Homo sapiens proposed_solution: none
With Lopez 2018, the finding that documented human bottlenecks were too brief to shift genetic load measurably — which constrains any argument that a recent severe bottleneck reset or worsened the human genome. Flagged in project memory as verified and not yet applied. Most metadata was in the lost research files.
Human dispersal out of Africa: a lasting debate (load and demography) [TITLE?]
Lopez, S.; et al. unknown (2018).
camp: mainstream direction: undercuts peer_reviewed: yes organism: Homo sapiens proposed_solution: none
Paired with Koch and Novembre 2017 in project memory as showing human bottlenecks too short to change load. Flagged as verified and not yet applied. Most metadata was in the lost research files. [STALE?]
Selection in living humans
Relating pathogenic loss-of-function mutations in humans to their evolutionary fitness costs
Agarwal, I.; Fuller, Z.L.; Myers, S.R.; Przeworski, M. eLife, 12:e83172 (2023). doi 10.7554/eLife.83172
https://elifesciences.org/articles/83172
camp: mainstream direction: undercuts access: OA peer_reviewed: yes organism: Homo sapiens proposed_solution: none
Key figure: median heterozygous fitness cost of a LoF mutation 0.018; mean 0.058
From 56,855 exomes. Cited against the article's own interest: if a typical gene knockout costs nearly 2% of fitness, selection sees it at any plausible effective population size, and the argument made here has to live entirely below that. Also one of the three independent confirmations of the measurement gap — 0.018 is 450 times the human drift barrier.
Genetic evidence for natural selection in humans in the contemporary United States
Beauchamp, J.P. PNAS, 113(28):7774-7779 (2016). doi 10.1073/pnas.1600398113
https://pmc.ncbi.nlm.nih.gov/articles/PMC4948342/
camp: mainstream direction: mixed access: OA peer_reviewed: yes organism: Homo sapiens proposed_solution: none
Key figure: approx -1.5 months of education per generation
"my estimates imply a rate of selection of about -1.5 mo of education per generation (which pales in comparison with the increases in EA observed in contemporary times)." Health and Retirement Study, European ancestry, born 1931-1953. Read the parenthesis with the figure: the measured genetic decline is dwarfed by the environmental gain, which is the same shape as Crow's environment-outruns-mutation caveat.
Genetic variance in fitness indicates rapid contemporary adaptive evolution in wild animals
Bonnet, T.; et al. (41 authors) Science (2022).
camp: mainstream direction: mixed access: OA peer_reviewed: yes organism: 19 wild bird and mammal populations proposed_solution: none
Key figure: meta-analytic heritability of fitness 2.99% (95% CI 0.80-6.60); additive genetic variance 0.185
249,430 individuals across 561 cohorts monitored for 11 to 63 years — the definitive empirical answer to the heritability-of-fitness question. Fifty times Sanford's 0.004 figure, and far below Mendel's Accountant's 0.2 default, so it corrects both sides. Author-hosted published PDF; the publisher copy is paywalled.
A quantitative genetic model of background selection in humans [TITLE?]
Buffalo, V.; Kern, A.D. PLoS Genetics (2024).
https://pmc.ncbi.nlm.nih.gov/articles/PMC10984650/
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: Homo sapiens proposed_solution: none
"uncertainty remains about the processes generating fitness variation in humans." Useful as a mainstream statement that the basic quantities the article argues about are not settled. Flagged in project memory as verified and not yet applied.
Allele frequency trajectories across age groups reveal ongoing natural selection shaping disease susceptibility
Chen, J.-L.; et al. American Journal of Human Genetics (2026). doi 10.1016/j.ajhg.2026.07.002
https://pubmed.ncbi.nlm.nih.gov/42497868/
camp: mainstream direction: undercuts access: paywalled peer_reviewed: yes organism: Homo sapiens proposed_solution: none
Key figure: 168 variants out of 509,817 tested
Shows contemporary selection against disease-susceptibility variants is not zero. State the scale honestly: 168 of 509,817 variants, and the method only detects effects large enough to shift an allele's frequency between age strata within one lifespan. It does not show that removal keeps pace with the arrival of new mutations.
Why did humans grow four inches in 100 years? It wasn't just diet
Hatton, T. The Conversation (2014).
https://theconversation.com/why-did-humans-grow-four-inches-in-100-years-it-wasnt-just-diet-25919
camp: mainstream direction: undercuts access: blog peer_reviewed: no organism: Homo sapiens proposed_solution: none
Key figure: four inches in 100 years
"Something else is at work: exposure to infection. Repeated infection during infancy and childhood slows growth." Hatton credits sanitary reform, cleared slums, less overcrowding and smaller families alongside diet, and proposes no genetic change. Cited to answer the "humans are getting healthier so there is no decay" objection on its own terms rather than denying the observation.
Reduced reproductive success is associated with selective constraint on human genes
Gardner, E.J.; et al. Nature, 603(7903):858-863 (2022). doi 10.1038/s41586-022-04549-9
camp: mainstream direction: undercuts access: paywalled peer_reviewed: yes organism: Homo sapiens proposed_solution: none
Key figure: the association accounts for "less than 1%" of the likelihood of childlessness
Shows measurable ongoing selection against damaging variants in constrained human genes. Their own qualifier is what keeps it honest: the genetic association "may only account for a very minor fraction of the overall likelihood of being childless (less than 1%)." Paywalled at Nature; a green open-access copy exists as bioRxiv 2020.05.26.116111.
Selection against variants in the genome associated with educational attainment
Kong, A.; et al. PNAS, 114(5):E727-E732 (2017). doi 10.1073/pnas.1612113114
https://pmc.ncbi.nlm.nih.gov/articles/PMC5293043/
camp: mainstream direction: mixed access: OA peer_reviewed: yes organism: Homo sapiens proposed_solution: none
Key figure: POLYEDU declining approx 0.010 standard units per decade, against a Flynn effect of 3.0 points per decade the other way
Across 129,808 Icelanders. The clearest single case of the genotype and the phenotype moving in opposite directions, which is exactly the article's Argument 3 pattern in a human population and on a human timescale. The authors themselves put the two rates side by side.
A systematic survey of loss-of-function variants in human protein-coding genes
MacArthur, D.G.; et al. Science, 335(6070):823-828 (2012). doi 10.1126/science.1215040
https://pmc.ncbi.nlm.nih.gov/articles/PMC3299548/
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: Homo sapiens proposed_solution: none
Key figure: approx 100 genuine LoF variants per genome, approx 20 genes completely inactivated
"We estimate that human genomes typically contain ~100 genuine LoF variants with ~20 genes completely inactivated." Note the filtering caution and repeat it with any large LoF number: only 43.5% of raw candidate LoF calls survived their filtering.
Evidence of directional and stabilizing selection in contemporary humans [TITLE?]
Sanjak, J.S.; Sidorenko, J.; Robinson, M.R.; Thornton, K.R.; Visscher, P.M. PNAS (2018).
camp: mainstream direction: undercuts peer_reviewed: yes organism: Homo sapiens proposed_solution: stabilizing-selection
Do not quote. Named in the project's provenance discipline as an item where "every route 403s," so nothing from it was verified. Listed here so the gap is visible and so a future pass knows it is still open. [STALE?]
Identification of a large set of rare complete human knockouts
Sulem, P.; et al. Nature Genetics, 47:448-452 (2015). doi 10.1038/ng.3243
https://pubmed.ncbi.nlm.nih.gov/25807282/
camp: mainstream direction: mixed access: paywalled peer_reviewed: yes organism: Homo sapiens proposed_solution: none
Key figure: 7.7% of genotyped Icelanders carry a complete knockout, across 1,171 genes
Complete gene knockouts are common and mostly tolerated, which cuts against a simple every-gene-matters picture. Two details cut the other way and should be quoted with it: brain-expressed genes were knocked out less often than others, and homozygous LoF offspring appeared less often than chance predicts — both signatures of selection still operating. Abstract free, full text paywalled.
Deleterious- and Disease-Allele Prevalence in Healthy Individuals
Xue, Y.; et al. American Journal of Human Genetics, 91(6):1022-1032 (2012). doi 10.1016/j.ajhg.2012.10.015
https://pmc.ncbi.nlm.nih.gov/articles/PMC3516590/
camp: mainstream direction: supports access: OA peer_reviewed: yes organism: Homo sapiens proposed_solution: none
Key figure: approx 400 damaging variants and approx 2 bona fide disease mutations per individual
"our current best mean estimates of ~400 damaging variants and ~2 bona fide disease mutations per individual are likely to increase rather than decrease as sequencing studies ascertain rare variants more effectively." A standing-stock measurement rather than a flux, so it does not by itself show accumulation — but the authors' expectation that the number will rise is worth quoting.
Simulation
Fitness decline over long-term evolution of a small population of asexual computational organisms
Axe, D.D.; Gerry, J.; Daniels, A.D.; Wilkerson, S.; Mitchell, W.; Randall, S. BIO-Complexity, 2023(2):1-9 (2023). doi 10.5048/BIO-C.2023.2
https://bio-complexity.org/ojs/index.php/main/article/view/BIO-C.2023.2
camp: ID direction: mixed access: OA peer_reviewed: yes organism: digital organisms proposed_solution: none
Key figure: 1,000 organisms through 2,000,000 fixation events; loss of function for all 223 genes
"fitness declines approximately as a two-phase exponential decay... The cause of the collapse is an imbalance in the initial genome: the number of ways for mutations to produce a new worst gene is so much higher than the number of ways to improve the current worst." Published in the ID movement's own journal, labelled as such. Its methodological criticism of its own side is what makes it valuable: "The statistics that come out of these models are dictated by the statistics that went in," and Nelson and Sanford's own Avida run reverses itself when large beneficials are allowed. Disclosure: no citations in OpenAlex nearly three years after publication.
The fundamental theorem of natural selection with mutations
Basener, W.F.; Sanford, J.C. Journal of Mathematical Biology, 76:1589-1622 (2018). doi 10.1007/s00285-017-1190-x
https://link.springer.com/article/10.1007/s00285-017-1190-x
camp: creationist direction: supports access: paywalled peer_reviewed: yes organism: theory proposed_solution: none
Peer reviewed in a mainstream mathematics journal. Basener is a mathematician at RIT; Sanford is a young-earth creationist, which the paper does not disclose. Their section 5.4 states the limitation critics fasten on: without the finite-population condition they impose, "some numerical solutions went to an equilibrium." The article credits the valid mathematical point and keeps the truncation-rule criticism, and pairs it with Ewens 2024 who makes the same point about Fisher far more harshly.
Using numerical simulation to test the 'mutation-count' hypothesis
Brewer, W.; Baumgardner, J.; Sanford, J. Biological Information: New Perspectives, World Scientific, pp. 298-311 (2013).
camp: creationist direction: undercuts access: book peer_reviewed: no organism: simulated diploid population proposed_solution: truncation
Key figure: at U = 10 with 6 offspring per female, mutation count plateaus near 125 and fitness at 0.94, flat to generation 350
"Under these highly artificial conditions we found that MCM was indeed able to very effectively halt both mutation accumulation and fitness decline." Truncation selection is stronger than the article's draft allowed, and Sanford's own group proved it. Their escape — a realistic spread of mutation effects — rests on a Figure 3 in which full truncation kills the population soonest (generation ~4,700) and probability selection lasts longest (~8,100), the reverse of their own earlier figure and of Crow and Kimura, and never mentioned. That is an original, checkable criticism.
Information loss: potential for accelerating natural genetic attenuation of RNA viruses
Brewer, W.H.; Smith, F.D.; Sanford, J.C. Biological Information: New Perspectives, World Scientific, pp. 369-384 (2013). doi 10.1142/9789814508728_0015
https://robertmarks.org/REPRINTS/BINP/9789814508728_0015.pdf
camp: creationist direction: supports access: book peer_reviewed: no organism: simulated RNA virus proposed_solution: none
Key figure: stated DFE 10% neutral / 89% deleterious / 0.9% beneficial, cited to Sanjuan 2004
Checked at both primaries, and the charge holds. The chapter states its distribution as "We model 10% of all mutations as being perfectly neutral, with the remainder of mutations being 99% deleterious and 1% beneficial [35]" (p. 373), and reference 35 is Sanjuán, Moya and Elena 2004 - an RNA-virus DFE experiment reporting 39.6% lethal, 29.2% deleterious, 27.1% neutral and 4.2% beneficial for random mutations. The assumed neutral and beneficial shares are 2.7-fold and 4.7-fold lower than those sample values. These changes reduce neutral changes and beneficial compensation; the net effect of omitting a separate lethal class needs a sensitivity test. Two further problems were found beyond Steve Schaffner's original charge. The chapter answers the missing 39.6% lethal class by saying such particles "are easily accounted for by simply adjusting the rate of 'random deaths'," but the headline run sets that parameter to zero. The discussion says "no one knows the precise shape of the distribution of mutation effects for a given virus" (p. 379). A finite sample with a detection threshold does not settle that precise shape. State the counterweights or the criticism is unfair: Sanjuán calls his own figures lower bounds because weak effects escape detection, so the true neutral share is probably under 27.1%; he flags his own 4.2% beneficial as inflated by a two-strain chimera template poorly adapted to lab conditions; the authors do disclose the lethal shortfall in words; and this is a symposium book chapter, not a refereed paper. Written up in the Sanford audit.
Overabundant mutations help potentiate evolution: the effect of biologically realistic mutation rates on computer models of evolution
Ewert, W. BIO-Complexity, 2015(1):1-11 (2015). doi 10.5048/BIO-C.2015.1
https://bio-complexity.org/ojs/index.php/main/article/download/BIO-C.2015.1/BIO-C.2015.1
camp: ID direction: supports access: OA peer_reviewed: yes organism: digital models proposed_solution: none
Key figure: Avida runs at 0.0025 and Ev at ~0.0038 substitutions per nucleotide, against a human rate of 1.1 x 10^-8
Original simulation with a disclosed and checkable premise, and the strongest ID-side entry in this venue after Axe 2023. Ewert re-runs three standard evolution demonstrations — Dawkins's weasel, Schneider's Ev, and Avida — at biological mutation rates instead of genetic-algorithm rates, and reports that "the models with the realistic mutation rates lose the ability to solve the simple problems," because mutations that only help in combination become too rare. He is unusually candid about the limits. He concedes "the failure of existing models does not demonstrate that no such model can exist," lists the factors he left out including diploidy, gene flow, indels and duplications, notes his simulations "do show many cases of beneficial single point mutations successfully evolving," and states his own falsification condition. He also discloses his assumptions as generous to evolution: "we take the optimistic assumption that all genes evolve independently," "we assume that there is no linkage disequilibrium, or selection interference effects," and "this set of assumptions should be greatly biased towards evolutionary processes adapting." The weakness he never addresses is that all three models he uses have a pre-specified target, which is the same objection Durrett and Schmidt raised against Behe. Zero citations in OpenAlex.
Does Basener and Sanford's model show that deleterious mutations are unstoppable?
Felsenstein, J.; Lynch, M. The Skeptical Zone (2018).
camp: mainstream direction: undercuts access: blog peer_reviewed: no organism: theory proposed_solution: none
Not peer reviewed, but the first mainstream response to the paper and jointly written by two of the field's most senior figures. On the model's behaviour: "the genetic variance of fitness rises, reaches a limit, bounces sharply off it, and from then on decreases. We're not sure why, and suspect a program bug." Their citation of Haldane 1927 supplies the condition under which selection loses, which is the condition the article argues human parameters satisfy. The site serves over HTTP only; Wayback capture from Jan 2026.
Back to the fundamentals: a reply to Basener and Sanford 2018
Hancock, Z.B.; Stern Cardinale, D. Journal of Mathematical Biology, 88(5), article 54 (2024). doi 10.1007/s00285-024-02077-w
https://link.springer.com/article/10.1007/s00285-024-02077-w
camp: mainstream direction: undercuts access: paywalled peer_reviewed: yes organism: theory / SLiM simulation proposed_solution: none
The only peer-reviewed rebuttal of any genetic-entropy paper that exists. Genuinely closed access with no legitimate free copy — confirmed by Unpaywall, OpenAlex, Semantic Scholar and Europe PMC, and absent from every preprint and repository route. Do not re-run that hunt. The article therefore cites the abstract, the deposited GitHub model, and Hancock's own public write-ups, not the paper body, and says so. It is article 54, not 59 — an earlier draft had that wrong.
fisher_shaft (SLiM model and replicate logs)
Hancock, Z.B. GitHub repository (2024).
https://github.com/zachbhancock/fisher_shaft
camp: mainstream direction: mixed access: OA peer_reviewed: no organism: simulated diploid population proposed_solution: none
Key figure: only 2.52% of their deleterious mutations fall below the drift barrier s < 1/(2N) = 5e-4
The SLiM script and all five replicate logs behind Hancock and Stern Cardinale 2024, which makes the simulation citable and checkable without the PDF. Verbatim parameters: K=1000, 5 Mb genome, mu 1e-7/bp, recombination 1e-6/bp (~100x human), DFE 0% neutral / 99% deleterious (gamma mean -0.5, shape 0.5) / 1% beneficial (exponential mean +0.001), implied U ~0.99 per diploid. The article's strongest original criticism: 97.5% of their deleterious mutations are plainly visible to selection, so the model tests whether selection removes what it can see, not the claim at issue. Recombination at 100x human also maximally suppresses the Hill-Robertson interference Sanford relies on, and neither truncation nor synergistic epistasis is modelled.
Fisher, fitness, fundamentals
Hancock, Z.B. The Panda's Thumb blog (2024).
https://pandasthumb.org/archives/2024/04/fisher-fitness-fundamentals.html
camp: mainstream direction: undercuts access: blog peer_reviewed: no organism: theory proposed_solution: none
Where the arguments of the paywalled 2024 paper can actually be read. Three points: recombination is already inside the Price-equation derivation of Fisher's theorem, so Basener and Sanford's added mutation term is redundant; Kimura's 1979 DFE contains no beneficials by construction and was never meant as realistic; and fixation, not mutation input, does the work, so beneficials dominate fixations despite being 1% of origins. His own concession on the one parameter that could flip the result: "the only way that I can think to do it is if you just decrease this beneficial fraction below a percent."
Phase-type distribution approximations of the waiting time until coordinated mutations get fixed [TITLE?]
Hossjer, O.; Bechly, G.; Gauger, A. Journal of Theoretical Biology, 524:110657 (2021).
camp: ID direction: supports access: paywalled peer_reviewed: yes organism: theory proposed_solution: none
ID-affiliated authorship but genuinely peer reviewed in a mainstream journal, with a Stockholm University lead author. Extends the waiting-time problem to include back-mutation and stochastic tunnelling, which are the two mechanisms critics usually invoke against waiting-time arguments. Flagged in project memory as high-value and not yet applied; DOI and URL were in the lost research files.
Comment on 'Human and chimp DNA: they really are about 98% similar'
JoeCoder (pseudonym) Uncommon Descent, comment-588086 (2015).
camp: unaffiliated direction: mixed access: forum peer_reviewed: no organism: software proposed_solution: none
Key figure: Genghis Khan wins 20% of the time when he should win 10%
The original statement of the "Barney Fife" bug in Mendel's Accountant's probability selection. The test page is still live at jsfiddle.net/p1prvd4h. Note the direction: if correct, Mendel's selection is roughly 20% stronger than standard theory, which means the program understates mutation accumulation — the bug runs the wrong way for creationism.
Comment on 'Evolution Visualized' (retraction of the factor-of-two claim)
JoeCoder (pseudonym) The Skeptical Zone, comment-141643 (2016).
http://theskepticalzone.com/wp/evolution-visualized/comment-page-4/#comment-141643
camp: unaffiliated direction: background access: forum peer_reviewed: no organism: software proposed_solution: none
"I'm also no longer sure about the comment I made a year ago that selection in Mendel is 'TWICE as efficient as it should be.' It's possible I could be off by two somewhere due to haploid/diploid differences or something." Cited so the article does not present a disputed software claim as settled.
Comment on 'Evolution Visualized' (the correct ratio)
keiths (pseudonym) The Skeptical Zone, comment-141922 (2016).
http://theskepticalzone.com/wp/evolution-visualized/comment-page-7/#comment-141922
camp: unaffiliated direction: mixed access: forum peer_reviewed: no organism: software proposed_solution: none
Key figure: 0.4545 vs 0.5454, a ratio of 1.0/1.2 rather than 1.0/1.1
Derives the distortion analytically: "The probability that the ratio Rb/Rg is greater than Fg/Fb is equal to (Fb/Fg)/2." The cleanest statement of the bug's magnitude, from a critic rather than an advocate.
MutationLoad (simulation source)
Masel Lab GitHub repository (2026).
https://github.com/MaselLab/MutationLoad
camp: mainstream direction: background access: OA peer_reviewed: no organism: software proposed_solution: none
Key figure: two recombination events per chromosome per meiosis
The C simulation code behind Matheson et al. Its README describes breaking genomes "into discrete linkage blocks with numeric values summarizing combined mutation effects" — the same abstraction Mendel's Accountant uses, adopted independently by a mainstream lab. Useful for answering the objection that linkage-block modelling is a creationist shortcut.
Human deleterious mutation rate slows adaptation and implies high fitness variance
Matheson, J.; Hernandez, U.; Bertram, J.; Masel, J. bioRxiv, 2023.09.01.555871v2 (2025). doi 10.1101/2023.09.01.555871
https://www.biorxiv.org/content/10.1101/2023.09.01.555871v2.full
camp: mainstream direction: mixed access: preprint peer_reviewed: preprint organism: simulated human population proposed_solution: beneficial-compensation
Key figure: 56,255 deleterious vs 6,387 beneficial fixations over 200,000 generations; s_b = 0.00423 vs s_d = -0.0000391
A mainstream lab counting Ohta's-ratchet fixations and calling them that. Their resolution is that beneficial fixations average about 108x the effect size, so the population still gains: "U_d > 1 need not cause population decline, because the accumulation of mildly deleterious fixations (Ohta's ratchet) is countered by a smaller number of larger-effect beneficial fixations." Their own hedge: "there is great uncertainty in the true values of U_b and s_b." The article's validation: feeding their stated parameters (gamma shape 0.169, mean heterozygous effect 0.009) into Kimura's fixation integral gives 63,212 to 71,056 against their simulated 56,255, 12–26% apart from two independent routes, with the single-site calculation higher as linkage predicts. An earlier figure of 60,780, "8% apart", used a shape of 0.2 and read 0.009 as homozygous. Their U_b is 300-2000x below every direct measurement, so it is conservative rather than optimistic; the real criticism is the inexhaustible supply of constant-effect beneficials. Preprint, not peer reviewed; NIH and Templeton funded.
No Muller's ratchet in mitochondrial DNA [TITLE-INVENTED]
Mo, unknown; et al. (Hahn, M.W. lab) preprint, venue unknown (2025).
camp: mainstream direction: undercuts access: preprint peer_reviewed: preprint organism: mitochondrial genomes proposed_solution: none
Finds no Muller's ratchet in mitochondrial DNA. Project memory's instruction is to keep the article's scope where it is: the article does not claim an mtDNA ratchet and should not start. Flagged as verified and not applied. Most metadata was in the lost research files.
The effects of low-impact mutations in digital organisms [TITLE?]
Nelson, C.W.; Sanford, J.C. Theoretical Biology and Medical Modelling, 8:9 (2011).
https://pmc.ncbi.nlm.nih.gov/articles/PMC3102618/
camp: creationist direction: mixed access: OA peer_reviewed: yes organism: digital organisms (Avida) proposed_solution: none
Key figure: their measured threshold is 500-1,400x above 1/(2N) for a 3,600-organism grid
A mainstream peer-reviewed Avida experiment by creationist authors measuring a "selection threshold." The problem is in their own Discussion, which names Avida's implementation as the cause: the threshold sits 500-1,400 times above the theoretical drift barrier for their population size, so it measures the software's resolution rather than a biological limit. Axe 2023 separately notes that one of their runs reverses itself when large beneficials are allowed. Flagged in project memory as high-value and not yet applied.
Using numerical simulation to better understand fixation rates, and establishment of a new principle: Haldane's Ratchet
Rupe, C.L.; Sanford, J.C. Proceedings of the Seventh International Conference on Creationism, article 32 (2013).
https://cedarville.tind.io/record/21101/files/2013_ICC_Rupe_.pdf
camp: creationist direction: mixed access: OA peer_reviewed: no organism: simulated population proposed_solution: none
Key figure: 2,710 beneficial fixations over 300,000 generations, of which 1,476 were selective; >100,000 deleterious fixations extrapolated, not simulated
Verified against the PDF, and it is more useful as a critique of its own method than as support. Three things in it are checkable and matter.
One: the headline deep-time number was never simulated. Their own methods say so — "Deleterious mutation accumulation could not be simulated through such deep time, as it always either caused overflow of memory or premature termination due to extinction" — and the 100,000 figure is "extrapolated from Figure 3." Every row of Table 1 is a beneficials-only or neutrals-only run. Sanford et al. 2018 makes the same admission independently five years later: "we have made all mutations effectively neutral ... This is essential for longer runs over many generations, or the population will go extinct." Two papers from the same group say the simulator cannot run its own headline scenario with deleterious mutations switched on.
Two: an internal contradiction inside one document. The methods call truncation selection "highly unrealistic," saying it "never happens even in artificial breeding experiments, let alone in nature." Table 1's optimized run qrtoju then applies "partial truncation selection (0.5)."
Three: a correction to an earlier reading of this paper on this site. Their run where fitness rises from 1.0 to 110 is not the Masel resolution reproduced inside their own simulator, and must not be described that way — it is a beneficials-only run with no deleterious mutations in it at all. What it does show is narrower and still worth having: the outcome is set by the cap the operator places on beneficial effect size, since at a ceiling of 0.01 "total fitness increase was always trivial" and at 1.0 it was 110-fold.
Citation hygiene is poor — eleven errors were found in seven pages, including "Morgan, P.A.P." for P.A.P. Moran, Van Valen 1963 given volume 47 for 97, Britten 2002 with a page range running backwards, Phelps dated 1990, 1997 and 1991 within one paragraph, "Tompkins" for Tomkins throughout, and a body-text subtraction that prints 1,492 where 1,413 is meant. None of these changes a result, but a reader checking sources will find them.
Mendel's Accountant: a biologically realistic forward-time population genetics program
Sanford, J.C.; Baumgardner, J.; Brewer, W.; Gibson, P.; ReMine, W. Scalable Computing: Practice and Experience (2007).
https://scpe.org/index.php/scpe/article/view/407
camp: creationist direction: mixed access: OA peer_reviewed: yes organism: software proposed_solution: none
"Mendel allows mutational effects to be combined in either a multiplicative or additive manner... and provides the option of either truncation or probability selection." SCPE is a real indexed peer-reviewed journal, but a computer-science one — the parallel implementation was refereed and the population genetics was not, which is checkable and worth stating. The authors concede the key point themselves: "The effect of a mutation on phenotypic fitness is equal to the selection coefficient of that mutation only with strict probability selection and no environmental variance, but not otherwise." The article's decision is not to use Mendel at all, since everything it needs comes from equations published 1937-1979.
Biological information and genetic theory: introductory comments
Sanford, J.C. Biological Information: New Perspectives, World Scientific (2013).
camp: creationist direction: undercuts access: book peer_reviewed: no organism: theory proposed_solution: truncation
As the volume's co-editor Sanford writes that the mutation-count mechanism "actually can work, but only when mutation effects are relatively uniform, when there is truncation selection, and where there is sexual recombination." The concession is in the volume's own section introduction, in his own words, which is why it carries weight.
The waiting time problem in a model hominin population
Sanford, J.; Brewer, W.; Smith, F.; Baumgardner, J. Theoretical Biology and Medical Modelling, 12:18 (2015).
https://pmc.ncbi.nlm.nih.gov/articles/PMC4573302/
camp: creationist direction: supports access: OA peer_reviewed: yes organism: simulated hominin population proposed_solution: none
Key figure: two nucleotides require 84 million years on average; five require 2 billion
Peer reviewed in a secular journal; the authors are young-earth creationists and declare no competing interests. "We simulated a classic pre-human hominin population of at least 10,000 individuals, with a generation time of 20 years, and with very strong selection (50% selective elimination)." The model requires a pre-specified target string, which is its main methodological weakness and the same specified-target fallacy Durrett and Schmidt raised against Behe. Cited on the construction side of the ledger under the project's citation-balance rule.
BioLogos forum audit of Brewer, Smith and Sanford 2013
Schaffner, S. BioLogos forum (2024).
camp: mainstream direction: undercuts access: forum peer_reviewed: no organism: software proposed_solution: none
Steve Schaffner of the Broad Institute posted in Feb 2024 a 2009 email he had sent Sanford, plus a parameter audit: "they took (and cited) a study of empirical values for the very thing they're modeling, and then discarded every single one of the values and replaced it with one that suited their thesis." Verify at the primary before publishing — the chapter itself has not been checked, and the URL was in the lost research files. If it holds it is a stronger charge than anything now in sanford.md. [STALE?]
r/DebateEvolution comments on genetic entropy
Stern Cardinale, D. (u/DarwinZDF42) Reddit, r/DebateEvolution (2024).
https://www.reddit.com/r/DebateEvolution/comments/1bmqk1w/
camp: mainstream direction: undercuts access: forum peer_reviewed: no organism: theory proposed_solution: none
"Genetic entropy requires bananas pop gen. Constant fitness effects of specific alleles. Constant distribution of fitness effects. AND a constant ratio of beneficial to harmful mutations wherein basically all mutations are harmful and virtually none are beneficial. [...] None of those things are true, AND they contradict each other." He also states the 2024 paper is aimed at "the Mendel's Accountant simulations of 'genetic entropy'," which narrows its scope. Method note: Reddit blocks WebFetch and curl, but api.pullpush.io works.
Comment on 'Mendel's Accountant again'
Zachriel (pseudonym) The Skeptical Zone, comment-85371 (2015).
http://theskepticalzone.com/wp/mendels-accountant-again/
camp: unaffiliated direction: undercuts access: forum peer_reviewed: no organism: software proposed_solution: none
Restating a 2009 analysis, Zachriel says the line work_fitness(i) = work_fitness(i)/(randomnum(1) + 1.d-15) "largely erases any signal from adaptive fitness" — selection weaker, meltdown an artefact — the opposite of the JoeCoder and Felsenstein reading. Dividing by a uniform (0,1) draw is equivalent to multiplying by a heavy-tailed variate with no finite mean, which is why the direction of the bias is not obvious to either side. Nobody has adjudicated it. Quoted because it is the only located statement of the opposite distortion direction, not as an authority.
Information theory
Functional information and the emergence of biocomplexity
Hazen, R.M.; Griffin, P.L.; Carothers, J.M.; Szostak, J.W. PNAS, 104(suppl 1):8574-8581 (2007). doi 10.1073/pnas.0701744104
https://pmc.ncbi.nlm.nih.gov/articles/PMC1876432/
camp: mainstream direction: background access: OA peer_reviewed: yes organism: theory proposed_solution: none
Key figure: I(Ex) = -log2[F(Ex)]
"functional information [I(Ex)] is calculated with reference to a specific degree of function x." The article's information metric, chosen deliberately over Shannon entropy, which random noise maximises. Co-authored by Jack Szostak, who shared the 2009 Nobel Prize in Physiology or Medicine — so the metric is not an ID import. Two bits per site needing one letter of four, counted over sites still carrying the working letter.
History of the argument
Genetic Entropy (Letters to Creationists)
Buchanan, S. letterstocreationists.wordpress.com (unknown).
https://letterstocreationists.wordpress.com/gen_entropy/
camp: unaffiliated direction: background access: blog peer_reviewed: no organism: theory proposed_solution: none
An old-earth Christian critic's page that reproduces Sanford's own written replies verbatim — the most primary Sanford material available outside the book itself. Also the source of the "Drosophila would be extinct" argument the article answers by pointing out it uses the MA-line relaxed-selection rate rather than a wild one; at Ne near 1e6 the loss over 72,000 generations is about 0.1%, not 1e-17.
Waiting for two mutations, and the 2009 exchange with Behe [TITLE?]
Durrett, R.; Schmidt, D. Genetics, 180(3):1501-1509; exchange in Genetics 181(2), 2009 (2008).
camp: mainstream direction: undercuts access: OA peer_reviewed: yes organism: theory proposed_solution: none
The mathematicians concede one of Behe's three points and then refute the specified-target fallacy with a lottery analogy — the same fallacy that is the main methodological weakness of Sanford 2015's waiting-time model. Flagged in project memory as high-value and not yet applied. Exact citation details for the 2009 reply and rejoinder were in the lost research files.
The fundamental theorem of natural selection: the end of a story
Ewens, W.J. Evolution, March 2024 (2024).
camp: mainstream direction: mixed access: paywalled peer_reviewed: yes organism: theory proposed_solution: none
"the FTNS as given by Fisher was not correct and was derived from the explicitly demonstrated mathematical errors described above. It should be banned from the literature." Ewens is the standard authority on Fisher's theorem and does not mention Basener, Sanford or creationism anywhere. Paired with Basener and Sanford 2018 in the article, because he makes the same point about Fisher far more harshly than they do and from inside the mainstream.
The Genetical Theory of Natural Selection
Fisher, R.A. Oxford University Press, pp. 39-40 (1930).
camp: mainstream direction: supports access: book peer_reviewed: no organism: theory proposed_solution: none
Key figure: destroying:building ratio at r = 1/2, 1, 2, 3 standard units: 3.5, 13, 236, 7852
The origin of the argument that large mutations are overwhelmingly more likely to destroy than to build, and that even "changes of only one-tenth of the standard" leave destructive selection 28 percent more effective. Reached here through Hartl and Taubes 1996 p305, which reproduces the ratios; the primary was not consulted directly for this project. Note this is about mutation size, not mechanism, and must not be conflated with the loss-of-function argument.
The effect of variation on fitness [TITLE?]
Haldane, J.B.S. The American Naturalist, 71:337-349 (1937).
camp: mainstream direction: supports peer_reviewed: yes organism: theory proposed_solution: none
Key figure: mean fitness at mutation-selection balance = e^(-U)
The result behind every load calculation in this literature, and the reason the article says everything it needs comes from equations published between 1937 and 1979. The load at equilibrium depends on the mutation rate and not on the severity of the individual mutations, which is the counterintuitive core of the whole subject. Cited through the secondary literature; the primary was not retrieved for this project. [STALE?]
The Neutral Theory of Molecular Evolution
Kimura, M. Cambridge University Press, pp. 30-31 (1983).
camp: mainstream direction: mixed access: book peer_reviewed: no organism: Drosophila melanogaster (via Mukai 1972) proposed_solution: none
Key figure: heritability of fitness 0.004
The 0.004 figure Sanford's book generalises to humans is genuinely on p31 — but it is a broad-sense H^2 from one Drosophila study (Mukai, Schaffer and Cockerham 1972), deployed by Kimura against Maynard Smith's truncation-selection rescue, not offered as a general law. Also the source of Sanford's "only 138 sites can undergo selection simultaneously," where the 138 is Maynard Smith's number for the model Kimura argues against; the number Kimura advocates on the same line is 25,500. Page numbers verified through Google Books search-within-volume.
The Most Famous Evolution Experiment of All Time Shows that Evolution Goes the Wrong Way
Rupe, C.; Sanford, J. FMS Foundation (self-published) (2015).
camp: creationist direction: mixed access: OA peer_reviewed: no organism: Escherichia coli (LTEE) proposed_solution: none
Self-published by Sanford's own foundation and noted as such. "the most famous evolution experiment ever conducted (LTEE)... is ironically one of the most powerful demonstrations of genetic entropy and de-evolution." Their Figure 1 caption reverses Wiser et al. 2013 in both directions: it says the power-law model "shows fitness has reached a near maximum" and that the hyperbolic model "suggests fitness will increase without bound" and is "favored by Lenski and colleagues." Wiser's abstract says the opposite on both counts. Documented in sanford.md as error 6.
Genetic Entropy & the Mystery of the Genome (2nd edition)
Sanford, J.C. Elim Publishing (2005).
https://archive.org/details/geneticentropymy0000sanf
camp: creationist direction: mixed access: book peer_reviewed: no organism: Homo sapiens proposed_solution: none
Key figure: "more than 600" mutations per person per generation; loss of .003% of information in 6,000 years ("conceivable") against 3% in 6 million ("inconceivable"), pp. 149-150
Verified from the library PDF's text layer and archive.org search-inside (leaf 165-166, offset 16 anchored at leaf 18 = p. 2 and leaf 166 = p. 150). The rate is six to twelve times Lynch 2010's 50-100 per newborn and counts every mutation as lost information. Cited in index.md, "What this does and does not show".
Genetic Entropy (4th edition)
Sanford, J.C. FMS Publications, 4th edition (2014).
https://archive.org/details/geneticentropy0000john
camp: creationist direction: mixed access: book peer_reviewed: no organism: Homo sapiens proposed_solution: none
Audited across all four editions, and five documented errors survive into the 4th (seven in all, counting the 4th edition's Appendix 5 beneficial cap and Rupe and Sanford 2015): the Eyre-Walker and Keightley 1999 ellipsis that deletes both the multiplicative condition and the authors' own resolution; Crow's 1-2% extrapolated backwards; h^2 = 0.004 rendered as additive and generalised to humans; the "138 sites" misattribution; and Figure 3d's asserted mirror-image beneficial distribution, for which no source is given and which cannot exist because gammas are one-sided by construction. To Sanford's credit Figure 3d is honestly captioned — he discloses the beneficial side is "very greatly exaggerated, so it can be seen" — so the weaker "he faked the attribution" charge should not be repeated. Access: the 4th edition lost its archive.org inlibrary tag on 2025-02-07 and can no longer be borrowed; the 2nd (geneticentropymy0000sanf) and 3rd (geneticentropymy0000drjc) still can.
What the catalogue shows
188 entries across 16 topics, the oldest from 1927 and the newest from 2026.
Where the evidence comes from. 164 of the 188 entries are mainstream, against 15 creationist, 4 intelligent-design and 5 unaffiliated. That ratio is deliberate. An argument that rests on creationist sources persuades only people who already accept them, so almost everything load-bearing here was published by people who reject the conclusion.
| Camp | Supports | Undercuts | Mixed | Background | Total |
|---|---|---|---|---|---|
| mainstream | 57 | 50 | 43 | 14 | 164 |
| creationist | 6 | 2 | 7 | — | 15 |
| ID | 3 | — | 1 | — | 4 |
| unaffiliated | — | 1 | 2 | 2 | 5 |
| Total | 66 | 53 | 53 | 16 | 188 |
The most important row is the first one, and it does not say what a partisan would want. Among mainstream papers the split is 57 supporting to 50 undercutting, with 43 mixed. That is not a consensus against the argument, and it is not a vindication of it either. It is a genuinely contested literature in which most individual papers supply evidence for one premise while assuming or demonstrating something that cuts against another. Anyone who reports this field as settled — in either direction — has not read enough of it.
By decade. 1 entry from the 1920s, 2 from the 1930s, 1 from the 1950s, 4 from the 1960s, 4 from the 1970s, 1 from the 1980s, 9 from the 1990s, 20 from the 2000s, 75 from the 2010s and 70 from the 2020s. Roughly four fifths of the catalogue postdates 2010. That reflects the arrival of cheap sequencing, which is what turned most of these questions from theory into measurement — and it is a reason to distrust any argument on this subject, from any side, that rests mainly on pre-genomic literature.
By topic, the largest are load theory (36), simulation (24), distributions of fitness effects (20), selection in living humans (12), the drift barrier (10), mutation accumulation (10) and ancient DNA (10). The smallest are information theory (1) and experimental evolution (5).
Proposed solutions. 144 entries propose no resolution to the load problem at all — they measure something and stop. Of the 44 that do, the count is beneficial-compensation 14, truncation selection 7, junk DNA 7, synergistic epistasis 7, stabilizing selection 5 and soft selection 4. Two things follow. The proposed solutions are spread thin rather than converging on one answer, and the single most-cited one, beneficial compensation, is the one this project's accounting argument disputes on the ground that fitness restored is not damage repaired.
Access. 110 entries are open access and 21 paywalled, with 12 forum posts, 10 blog posts, 10 books and 7 preprints. The 22 forum and blog entries are included because working population geneticists state things in those venues that they do not put in papers, and several are cited in the main article for exactly that reason. They are labelled peer_reviewed: no and should be read as informed opinion, not evidence. 139 entries are peer reviewed.
Gaps
Where the catalogue is thin, and why it matters.
- Epistasis now has 8 entries, and the picture that emerged is worth stating. This was the largest hole in the first pass. Filling it did not settle the question — it showed the question is organism-dependent. Sanjuán and Elena find antagonistic epistasis in RNA viruses, independence in bacteria, and "a transition toward synergistic epistasis" in multicellular eukaryotes, which means results carried over from viral or bacterial experiments to humans are carrying the wrong sign. Sanford's group ran the direct simulation and concluded synergistic epistasis cannot halt mutation accumulation, but that work inherits Mendel's Accountant's unvalidated distribution of fitness effects, and its claim that the hypothesis "has never been demonstrated" was overtaken by Sohail 2017. The honest summary is that synergistic epistasis is real in the organisms that matter and appears far too weak to do the job asked of it — Sohail's own effect size is equivalent to truncating under 2% of the population.
- Experimental evolution has 5 entries and is now the thinnest topic after information theory.
- Information theory has 1. That is defensible rather than accidental: most work under that heading does not produce measurements, and the catalogue is built around what has been measured. But it should be stated plainly rather than left to look like an oversight.
- Ancient DNA has 10 entries and none of them runs the test that matters. The direct test of a fitness decline — comparing deleterious-allele burden in dated ancient genomes against modern ones on a common pipeline — is described in the experimental record and has not been done.
- Only 3 entries have two or more unknown fields — one each in the drift barrier, ancient DNA and simulation sections. Field coverage is otherwise complete.
What is missing from the literature itself, not from this catalogue. Four measurements would settle most of the dispute and none exists: a distribution of fitness effects with the beneficial side classified by mechanism; a human DFE that does not assume a population history; a fitness assay that reaches 10^-5; and mutation-accumulation lines in an organism with a known fully functional genome. These are set out in what has actually been measured.
A standing caution about this catalogue's own labels. The direction field records whether an entry's evidence supports or undercuts the argument as this site states it. That is a judgement, made by us, about work whose authors mostly did not have this argument in mind. Where an author states their own view it is quoted in the entry; where the label is our inference, it is an inference, and a reader who disagrees with a call should read the entry and overrule it.