Malaria Resistance Alleles

Behe, Michael J.  “A Response to My Lehigh Colleagues, Part 1.”  Evolution News.  2019.  Library copy of the page, with a local text extraction.  Evolution News is the Discovery Institute's publication and is now at scienceandculture.com;  the old addresses redirect.  No printed pages;  locators are sections.

1. 1a.

   Section Reply on non-laboratory evolution:  “Except for the sickle mutation (which itself is a desperate remedy), all mutations selected in the wild in humans for resistance to malaria are degradative.” ↩

Allison, A. C.  “Protection afforded by sickle-cell trait against subtertian malareal infection.”  British Medical Journal 1(4857):290–294.  Feb 6, 1954.  Allison was working at the Radcliffe Infirmary, Oxford, on material collected in Uganda and Kenya.  Read as the scanned PDF fetched from PMC.  The journal's own misspelling "malareal" is in the printed title.  The volunteer challenge experiment would not be approved today.  Mirror:  PMC2093356

1. 2a.

   Page 293:  “The incidence of parasitaemia in 43 Ganda children with the sickle-cell trait was significantly lower than in a comparable group of 247 children without the trait.  An infection with P. falciparum was established in 14 out of 15”.  Page 294:  “Africans without the sickle-cell trait, whereas in a comparable group of 15 Africans with the trait only 2 developed parasites.”  The sentence breaks across the page turn;  both halves are given with the page each sits on.  Folios read from the printed running heads, which put p. 290 on PDF page 1 and p. 294 on PDF page 5. ↩ ↩ ↩

2. 2b.

   Table I, page 292:  “With Parasitaemia 12 (27-9%) 113 (45-7%)”.  “It is apparent that the incidence of parasitaemia is lower in the sickle-cell group than in the group without sickle cells.”  Table I gives 43 sicklers and 247 non-sicklers as the totals.  The percentages print with a hyphen for the decimal point in the scan. ↩

Malaria Genomic Epidemiology Network.  “Reappraisal of known malaria resistance loci in a large multicenter study.”  Nature Genetics 46(11):1197–1204.  2014.  Read as the PMC author manuscript, fetched with bin/pmcget.py after Europe PMC's full-text service returned an empty record.  The manuscript has no printed folios, so locators are sections.  Results are adjusted for gender, ethnicity and, except at rs334 itself, for sickle-cell trait.  Mirror:  PMC4617542

1. 3a.

   Section Abstract:  “We collected data on 11,890 cases of severe malaria due to Plasmodium falciparum and 17,441 controls from 12 locations in Africa, Asia and Oceania.  There was strong evidence of association with the HBB, ABO, ATP2B4, G6PD and CD40LG loci but previously reported associations at 22 other loci did not replicate in the multi-centre analysis.” ↩ ↩

2. 3b.

   Section Results, HBB:  “The SNP responsible for HbS, rs334, was present at all the African sites with heterozygote frequencies in controls ranging from 0.05 (Malawi) to 0.22 (Nigeria).  Heterozygotes had a reduced risk of severe malaria (odds ratio (OR) 0.14, P = 1.6 × 10−225), cerebral malaria (OR 0.11, P = 4.7 × 10−88) and severe malarial anaemia (OR 0.11, P = 9.3 × 10−65)”. ↩ ↩

3. 3c.

   Section Results:  “HbS confers a remarkably fixed level of protection against cerebral malaria and severe malarial anaemia, with heterozygotes showing 89% reduced risk for both conditions when averaged across sites (Table 2).” ↩

4. 3d.

   Section Results, HBB:  “As shown in Table 2, each copy of the derived allele reduced the risk of severe malaria by 29% (OR 0.71, P = 6.9 × 10−9), of cerebral malaria by 28% (OR 0.72, P = 0.01) and of severe malarial anaemia by 26% (OR 0.74, P = 2.1 × 10−3).” ↩

5. 3e.

   Section Results, HBB:  “The SNP responsible for HbE, rs33950507, was found at a derived allele frequency of 0.4 in the S’tieng ethnic group in Vietnam but was rare or absent in other ethnic groups, such that the sample was too small to estimate association with severe malaria.” ↩

6. 3f.

   Section Results:  “If males and females are combined in an additive model, the G6PD+202 T allele confers reduced risk of cerebral malaria (OR 0.91, P= 6.1×10−3) but increased risk of severe malarial anaemia (OR 1.19, P=2.6 × 10−5) and the overall effect on severe malaria is close to neutral (OR 1.02, P=0.15)”. ↩ ↩ ↩ ↩

7. 3g.

   Section Discussion:  “The main force for evolutionary selection is widely assumed to be severe malaria due to P. falciparum but this is called into question by the present findings which show that G6PD deficiency has little effect on the overall risk of severe malaria.” ↩ ↩

8. 3h.

   Section Discussion:  “In a region of Thailand where both species are endemic, G6PD deficiency has been observed to suppress P. vivax more effectively than P. falciparum infection.  An important biological difference from P. falciparum is that P. vivax preferentially infects reticulocytes (i.e. young erythrocytes) which have higher levels of G6PD enzyme activity than older erythrocytes, and it is conceivable that in these circumstances G6PD deficiency might exert a stronger protective effect.” ↩ ↩

Miller, Louis H. et al.  “The resistance factor to Plasmodium vivax in blacks.  The Duffy-blood-group genotype, FyFy.”  New England Journal of Medicine 295(6):302–304.  1976.  Abstract only.  The full text is behind the publisher's wall;  the abstract was taken from the Europe PMC record (PMID 778616) and saved to the library.  No page-level locators inside the paper are claimed.  Like Allison 1954, the study deliberately exposed volunteers to infection.

1. 4a.

   Section Abstract:  “To determine if the FyFy genotype is the vivax resistance factor, we performed blood typing on 11 black and six white volunteers who had been exposed to the bites of P. vivax-infected mosquitoes.  Only the five FyFy blacks were resistant to erythrocytic infection; the remaining six blacks and all whites had the Duffy-positive determinants (Fya or Fyb or both) and had contracted malaria.” ↩ ↩ ↩ ↩

Hedrick, Philip W.  “Population genetics of malaria resistance in humans.”  Heredity 107:283–304.  2011.  A review by a population geneticist at Arizona State University.  Library PDF.  PDF page N = printed page 282 + N, and every page prints its folio in the running head, which is how each locator below was fixed.  Two-column;  extracted a page at a time with pdftotext without -layout.  Where a number comes from a study Hedrick reviews rather than from his own work, the primary is named in the quotation.

1. 5a.

   Page 286:  “It appears that many of the genetic variants that provide resistance to severe malaria that have been dated are recent, not ancient, polymorphisms and that they have arisen in the last 5000–10 000 years or less (see Table 2).”  The sentence begins at the foot of p. 285;  the quoted words are on p. 286. ↩ ↩ ↩

2. 5b.

   Page 287:  “The S allele differs from the normal A allele at one nucleotide at codon position 6 in the b-globin molecule, which translates into a change from the amino acid glutamic acid to valine”.  The PDF text layer renders the Greek beta as "b" throughout. ↩

3. 5c.

   Page 287:  “There appears to be five independent origins, or mutations, of the S allele from the A allele, based on their existence in nearly non-overlapping geographical regions, four in Africa, Bantu (Central Africa Republic, CAR), Benin, Cameroon and Senegal, and another one in both India and Saudi Arabia, and the extensive differences in linked variants resulting in association with different classical haplotypes.” ↩ ↩

4. 5d.

   Page 287:  “On the other hand, it has been proposed that a plausible explanation for much of the haplotype diversity around S alleles is that it reflects past recombination and gene conversion (Flint et al., 1998).” ↩

5. 5e.

   Page 288:  “The selection coefficient (s) for genotype AS can be estimated as s ¼ mð1  ORÞ”.  “For example, for the AS genotype if OR ¼ 0.082 as above and m ¼ 0.1 (see below), then s ¼ 0.092.”  The PDF text layer renders "=" as "¼" and the minus sign as a space.  The formula is s = m(1 − OR), where m is the mortality given severe malaria.  Hedrick notes that Hill 1991 suggested m = 0.07 and that WHO 1998 and Carter and Mendis 2002 support at least 0.1, and cautions on the same page that the historical value "may actually have been significantly higher." ↩ ↩

6. 5f.

   Page 288:  “the relative fitness levels of genotypes AA, AS and SS become 0.908, 1 and 0.  From these values, the expected equilibrium frequency of allele S (Hedrick, 2011a, p. 136) is 0.092/(0.092 þ 1.0) ¼ 0.084, not unlike that observed in many sub-Saharan populations.”  “First, heterozygotes AS do not appear to have symptoms of anemia or other effects (costs) of carrying the S allele in nonmalarial environments (Sheng et al., 2010)”.  "þ" and "¼" are the text layer's renderings of "+" and "=". ↩

7. 5g.

   Table 2, page 289:  “Also given is the estimated selection coefficient where — indicates no selection (neutrality) is assumed in the estimation and the selection coefficients with an * are assumed, not estimated, values.”  The S row from Currat et al. 2002, s = 0.152, carries the asterisk. ↩ ↩

8. 5h.

   Page 288:  “Using a selective advantage of 0.152 for AS genotypes over AA, they estimated that the age of S Senegal alleles was between 45 and 70 generations (1125 and 1750 years using 25 years per generation; see Table 2).”  “They estimated that the age of the mutation was very recent and between 10 and 28 generations (250–700 years).”  The first sentence is Currat et al. 2002 on the Senegal haplotype, from linkage disequilibrium;  the second is Modiano et al. 2008 on the Benin haplotype, from the decay of linkage disequilibrium. ↩

9. 5i.

   Table 2, page 289:  Rows as printed.  S:  Currat et al. 2002, 45–70 generations, 1125–1750 years, s 0.152*;  Modiano et al. 2008, 10–28 generations, 250–700 years.  C:  Wood et al. 2005, 75–150 generations, 1875–3750 years, s 0.04–0.09;  Modiano et al. 2008, 38–120 generations, 950–3000 years.  E:  Ohashi et al. 2004, 100.3 (62–222) generations, 2508 (1550–5550) years, s 0.079 (0.035–0.099).  G6PD A−:  Tishkoff et al. 2001, 254.3 generations, 6357 (3840–11 760) years, s 0.044;  Sabeti et al. 2002, 93 generations, 2325 (1200–3862) years;  Verrelli et al. 2002, 1800 generations, 45 000 (25 000–65 000) years;  Slatkin 2008, 40 generations, 1000 years, s 0.25.  G6PD Med:  Tishkoff et al. 2001, 133.2 generations, 3330 (1600–6640) years, s 0.034;  Verrelli et al. 2002, 400 generations, 10 000 (0–35 000) years.  G6PD Mahidol:  Louicharoen et al. 2009, 63 generations, 1575 years, s 0.23.  Duffy ES:  Hamblin and Di Rienzo 2000, 1323 generations, 33 075 (6500–97 200) years;  Seixas et al. 2002, 310 and 490 generations, 7750 (3625–13 125) and 12 250 (4250–26 500) years.  Ages in years assume 25 years per generation. ↩ ↩ ↩ ↩

10. 5j.

    Page 289:  “The change in the b-globin molecule for C is at the same amino-acid position as for S, but results in a change from glutamic acid to lysine rather than to valine”. ↩

11. 5k.

    Page 289:  “The protective effect of C may result from increased immune clearance of infected erythrocytes.” ↩

12. 5l.

    Page 289:  “There does not appear to be any cost from anemia or other traits to either the heterozygote AC or the homozygote CC, although CC homozygotes have symptoms comparable with a mild form of thalassemia.” ↩

13. 5m.

    Page 289:  “From examination of haplotypes and from its geographic distribution, there appears to be a single origin of C in Africa (Flint et al., 1998).  The C variant has also been found in Thailand on a different, non-African haplotype, indicating a second, independent origin (Sanchaisuriya et al., 2001).” ↩

14. 5n.

    Page 290:  “Wood et al. (2005) used a coalescent-based approach to jointly estimate the time since the C allele began to increase in frequency because of strong selection and the selection coefficient utilizing data on the present allele frequency (0.15), effective population size and recombination rate.  They estimated that the age of the allele was between 75 and 150 generations (1875 and 3750 years) and that the selection coefficient s was between 0.04 and 0.09”. ↩

15. 5o.

    Page 290:  “Modiano et al. (2008) calculated the age of the C haplotype in Burkina Faso by estimating the number of generations taken for linkage disequilibrium to decay to the observed level from the maximum expected when the C mutation occurred.  They estimated that the age of the mutation was between 38 and 120 generations (950–3000 years), at the lower range of the estimate of Wood et al. (2005).” ↩

16. 5p.

    Table 7, page 293:  Hedrick's own fitted values for the C allele, s = 0.166 with dominance h = 0.518, used in his Figure 2 simulation in which C entering a monomorphic A population reaches fixation in "slightly over 100 generations" and, entering an A/S polymorphic population, in about 200 generations. ↩

17. 5q.

    Page 290:  “It results from the substitution of lysine for glutamic acid in codon 26 (b26 Glu-Lys and GAG-AAG).  Besides being a structural variant, the E variant also causes the production of an abnormal mRNA with less b-globin being synthesized.  As a result, there is a mild thalassemia phenotype in EE homozygotes, but it does not appear to have an effect in AE heterozygotes (however, there is a much lower fitness of compound heterozygotes with both the E and the a- and b-thalassemia haplotypes; Fucharoen, 2001).” ↩ ↩ ↩ ↩ ↩ ↩

18. 5r.

    Page 290:  “From forward simulations, which used the amount of linkage disequilibrium close to the variant and the observed allele frequency, the age of the E allele was estimated to be about 100.3 generations (Ohashi et al., 2004), or 2508 years, and the estimated selection coefficient between genotypes AA and AE was 0.079.” ↩

19. 5s.

    Page 290:  “Although extensive sequence analysis has not been carried out, from examination of the haplotypic backgrounds for E alleles in northeast Thailand, more than one mutational origin (Fucharoen et al., 2002) is suggested.  However, the E allele found in China is on the same haplotype as that found in Thailand (Ohashi et al., 2005), suggesting that it does not have a different origin.” ↩

20. 5t.

    Page 290:  “Hemoglobin E is the most common structural hemoglobin variant in Southeast Asia and has reached an allele frequency of up to 70% in some areas of northern Thailand and Cambodia.” ↩

21. 5u.

    Page 290:  “The deleted forms appear to be generated at a relatively high rate by unequal crossing over and Lam and Jeffreys (2006) estimated the rate of deletion generation in sperm from two men as 0.42  104.”  “In a large case–control study in Kenya (Williams et al., 2005b), the OR values, standardized to the normal aa/aa genotype, for a þ heterozygotes and homozygotes in Kenya are 0.623 and 0.522 for severe malaria, respectively”.  The printed rate is 0.42 × 10^-4;  the multiplication sign and the exponent are lost in the text layer and recovered from the sentence.  "a þ" is the text layer's rendering of alpha-plus. ↩

22. 5v.

    Page 293:  “Ruwende et al. (1995) found in Gambia and Kenya that the reduction in risk (1—OR) of severe malaria in male hemizygotes (A-) was 58% and that the reduction in risk for heterozygous females (BA-) was 46%.  On the other hand, Guindo et al. (2007) found that in two populations in Mali, the reduction in risk of severe malaria in male hemizygotes (A-) was also 58%, but in female heterozygotes (BA-) there was no reduction in risk.”  “In addition, Johnson et al. (2009) found no protective effect for either male hemizygotes (A-) or female heterozygotes (BA-) in a Uganda population, but did find a protective effect for females that were found to be G6PD deficient.” ↩

23. 5w.

    Page 293:  “Tishkoff et al. (2001) jointly estimated the age and selection for both A- and Med alleles using forward simulations and found that the estimated age of A- was 6357 years (254 generations) and the selection coefficient was 0.044, and that the estimated age of Med was 3330 years (132 generations) and the analogous selection coefficient was 0.034.”  “From joint estimations using Bayesian methods, Slatkin (2008) estimated that the age of A- was only 1000 years (40 generations) and the selection coefficient was 0.25 and Louicharoen et al. (2009) estimated that the age of allele Mahidol was 1575 years (63 generations) and the selection coefficient was 0.23.”  The first sentence is printed continuously on the page but Figure 1 and its caption fall between its halves in the PDF text layer, so a plain string search for the whole sentence fails.  Both halves were checked against the page. ↩ ↩ ↩ ↩

24. 5x.

    Page 293:  “The difference in these estimates may be because they were based on different data, with that of Tishkoff et al. (2001) based on microsatellite data and that of Slatkin (2008) based on sequence data.” ↩

25. 5y.

    Page 293:  “Recently, evidence has suggested that G6PD deficiency caused by the Mahidol mutation in Southeast Asians provides parasite resistance to infection by P. vivax, but not to that by P. falciparum.  Further, G6PD deficiency Med in Pakistan has been shown to provide protection from P. vivax malaria (Leslie et al., 2010).” ↩

26. 5z.

    Page 294:  “The ES allele in Africa differs from FY*B with a T to C SNP mutation, 33 nucleotides upstream from the transcription starting point (33).  This mutation disrupts a binding site for transcription factor GATA-1 on the gene promoter and blocks expression of the gene in erythrocytes.”  The printed position is −33;  the minus sign is lost in the text layer. ↩ ↩ ↩

27. 5aa.

    Page 294:  “This allele, FY*BES, now termed erythrocyte silent (ES), is near fixation in sub-Saharan Africa (it is not a true null allele because it is expressed on cell types besides erythrocytes).” ↩

28. 5ab.

    Page 294:  “Several experiments showed that Duffy ES homozygotes (FYBES/FYBES) were resistant to infection by two malarial species, P. knowlesi and P. vivax, but were susceptible to infection by P. falciparum (Miller et al., 1976).” ↩

29. 5ac.

    Page 294:  “There does not appear to be any cost (or disease) associated with the presence of FY*BES homozygotes or heterozygotes.” ↩

30. 5ad.

    Page 294:  “Surprisingly, a Duffy ES allele found in low frequency (0.022) in Papua New Guinea, differed from FYA in exactly the same way at the 33 nucleotide in the promoter region as does the FYBES allele found in Africa (Zimmerman et al., 1999) and is now called FY*AES.” ↩

31. 5ae.

    Page 285:  “For example, the two known independent Duffy ‘null’ variants in African and Papua New Guinea are at the exact same nucleotide position, 33”.  The printed position is −33. ↩

32. 5af.

    Page 295:  “In the sample examined of 476 asymptomatic Duffy-negative individuals from eight locations, P. vivax was found in 8.8%.  However, they still found a substantial reduction in clinical P. vivax malaria among Duffy-negative individuals compared with Duffy-positive individuals.”  The sentence begins on p. 294 and the quoted words are on p. 295. ↩

33. 5ag.

    Page 295:  “It appears that this population with both Duffy-negative and -positive individuals provided an environment for strains of P. vivax to evolve the ability to invade Duffynegative individuals, giving an example of evolution for utilization of an alternate receptor besides the Duffy antigen for erythrocyte invasion.” ↩

34. 5ah.

    Page 295:  “One mutation in this gene, found in Papua New Guinea and Malaysia, is due to a 27-nucleotide (9-amino-acid) deletion in a region that is highly conserved throughout species (Jarolim et al., 1991).”  “The homozygote appears to be lethal because it has never been observed even in progeny from heterozygous matings (Genton et al., 1995).”  “For example, the frequency of the deletion was 0.146 in a sample of healthy Papua New Guinea children whereas it was not present in any of the children with cerebral malaria”. ↩ ↩

Behe, Michael J.  “Experimental evolution, loss-of-function mutations, and 'the first rule of adaptive evolution'.”  Quarterly Review of Biology 85(4):419–445.  Dec 2010.  Library copy is the Wayback capture of the author's Lehigh PDF.  PDF page N = printed page 418 + N, and the folio is printed in every running head.  Two-column;  extracted with pdftotext without -layout so the columns stay apart.

1. 6a.

   Page 422:  “This is an example of an adaptive gain-of-FCT mutation because a codon helping to specify a new, albeit weak—with Kd ~ 1 mM (Behe and Englander 1979)— protein binding site has appeared.”  The tilde and the Kd subscript are recovered from the two-column extraction;  the printed text sets Kd with a subscript d. ↩ ↩ ↩

2. 6b.

   Page 422:  “When the red blood cell is invaded by the malarial parasite, the mutant, hydrophobic valine residue allows hemoglobin molecules to aggregate with each other into long microtubular structures.  This polymerization is associated with a measure of resistance to malaria (Friedman 1978), although the exact mechanism for resistance in vivo is still a matter of debate (Verra et al. 2007).” ↩

3. 6c.

   Page 422:  “Although the altered hemoglobin (HbC) does not aggregate as sickle hemoglobin does, it confers resistance to malaria for reasons that are unclear.  Because apparently no new, discrete, coded molecular feature has been developed, this is categorized as a “modification-of-function” adaptive mutation;  no FCT has been lost or gained.” ↩ ↩

4. 6d.

   Page 423:  “Any one of hundreds of separate known mutations in the coding and control regions of the gene has eliminated the functional enzyme, or has significantly decreased its catalytic activity.” ↩ ↩ ↩

5. 6e.

   Page 423:  “Other loss-of-FCT mutations include the deletion of a gene for Band 3 protein, and the loss of a promoter site for expression of Duffy antigen in red blood cells.”  The band 3 variant under malaria selection is a 27-base in-frame deletion inside SLC4A1, not a deletion of the gene;  see Hedrick 2011 p. 295. ↩

6. 6f.

   Page 421:  “A “gain-of-FCT” adaptive mutation is a mutation that produces a specific, new, functional coded element while adapting an organism to its environment.  The construction by mutation of a new promoter, intron/exon splice site, or protein processing site are gain-of-FCT mutations.”  Folio 421, on PDF page 3 of the library copy.  The paper prints "intron/extron" in its list of FCT examples on p. 420 and "intron/exon" here;  the misprint recorded in the Measuring Biological Information notes belongs to the p. 420 list, not to this sentence. ↩

7. 6g.

   Table 1, page 422:  Eight rows, headed "Human mutations selected for resistance to malaria."  Hb S is marked G;  Hb C and Hb E are marked M;  hereditary persistence of fetal hemoglobin, thalassemia, G6PD deficiency, loss of Duffy antigen in red blood cells and Band 3 protein deficiency are marked L.  The Hb E row gives the underlying mutation as beta-26 glu to lys and cites Weatherall et al. 2002.  No reason is given in the text for the Hb E score. ↩ ↩

Leffler, Ellen M. et al.  “Resistance to malaria through structural variation of red blood cell invasion receptors.”  Science 356(6343).  2017.  Read as the PMC author manuscript.  The published article carries the eLocation ID eaam6393 rather than page numbers, so locators are sections.  The Europe PMC abstract record prints "has recently increased in frequency" where the manuscript prints "has recently risen in frequency";  the manuscript wording is quoted here because it is the copy read.  Mirror:  PMC5575826

1. 7a.

   Section Abstract:  “We find that a nearby association with severe malaria is explained by a complex structural rearrangement involving the loss of GYPB and gain of two GYPB-A hybrid genes, which encode a serologically distinct blood group antigen known as Dantu.  This variant reduces the risk of severe malaria by 40% and has recently risen in frequency in parts of Kenya, yet it appears to be absent from west Africa.”  Section Results:  “One of the imputed CNVs, DUP4, is associated with decreased risk of severe malaria (odds ratio, OR=0.60; 95% CI 0.50-0.72; Padditive = 9.9x10-8; computed under an additive model of association using fixed-effect meta-analysis; Fig. 3A).”  The 40% is 1 − 0.60 from the additive model.  The homozygous relative risk is given as 0.31 (95% CI 0.09–1.06) on 24 homozygotes, so the homozygote effect is not resolved in this paper. ↩ ↩ ↩

2. 7b.

   Section The physical structure of DUP4:  “The copy number profile of DUP4 is complex, with a total of six copy number changes that cannot have arisen by a single unequal crossover event from reference-like sequences (Figs. 1B, 4B).  At the gene level, this copy number profile corresponds to duplication of GYPE, deletion of the 3’ end of GYPB, duplication of the 5’ end of GYPB and triplication of the 3’ end of GYPA.” ↩

3. 7c.

   Section The physical structure of DUP4:  “These data localize the breakpoint to a 184 bp section of GYPA and GYPB where the two genes have identical sequence (Fig. S19).  If translated, the encoded protein would join the extracellular domain of GYPB to the transmembrane and intracellular domains of GYPA, creating a peptide sequence at their junction that is characteristic of the Dantu antigen in the MNS blood group system”. ↩ ↩ ↩

4. 7d.

   Section The physical structure of DUP4:  “Either complex mutational events or a series of at least four unequal crossover events are needed to account for the formation of this variant (confirmed by simulation; Fig. S20).  However, we find no potential intermediates and no obvious relationship between DUP4 and other structural variant haplotypes in the present dataset”. ↩

5. 7e.

   Section Discussion:  “One possibility for why DUP4 is not more widespread, given its strong protective effect against malaria, is that it has arisen recently without time for gene flow to facilitate its dispersion.  Alternatively, this frequency distribution could be consistent with balancing selection, for example if it protects only against certain strains of P. falciparum that are specific to east Africa.”  Section Results:  “Computation of haplotype homozygosity provides evidence that DUP4 is carried on an extended haplotype (P=0.012 for iHS”.  The Methods give the exact empirical value as P = 0.0119, from 996 of 83,419 variants in the matched frequency bin. ↩

Kariuki, Silvia N. et al.  “Red blood cell tension protects against severe malaria in the Dantu blood group.”  Nature 585(7826):579–583.  2020.  Read as the PMC author manuscript, fetched as Europe PMC full-text XML.  The manuscript has no printed page numbers, so locators are sections.  The 74% figure is quoted by these authors from earlier work, not measured here.  Mirror:  PMC7116803

1. 8a.

   Section Abstract:  “Recently, it was shown that the blood group variant Dantu provides 74% protection against all forms of severe malaria in homozygous individuals.  This is a similar degree of protection to sickle cell trait and considerably greater than the best malaria vaccine, but until now the protective mechanism has been unknown.”  “By following invasion using video microscopy, we found a strong link between RBC tension and merozoite invasion and identified a tension threshold above which invasion rarely occurred, even in non-Dantu RBCs.  Dantu RBCs had higher average tension, meaning that a greater proportion resisted invasion.” ↩ ↩ ↩

2. 8b.

   Section Results:  “Despite the fact that Dantu leaves an intact copy of GYPA within the genome, the surface expression level of GYPA in Dantu RBCs was significantly reduced when measured by flow cytometry”. ↩

3. 8c.

   Section Results:  “To investigate the specific step at which invasion was impaired, we used time-lapse video microscopy to study the invasion process by 3D7 strain parasites.” ↩

Mitchell, Elizabeth.  “Link Between Sickle-Cell and Malaria Resolved.”  Answers in Genesis.  Nov 19, 2011.  Retrieved Sep 27, 2026.  A "News to Know" item reporting Michael Lanzer's work on the actin cytoskeleton.  Web copy fetched with curl and tags stripped locally;  locators are sections.

1. 9a.

   Section Conclusion:  “However, despite claims by evolutionists that the “beneficial” sickle-mutation is proof of Darwinian evolution, no information acquisition is involved.  Darwinian evolution—production of a different kind of organism as the result of accumulated mutations—would require acquisition of new genetic information.  Yet the sickle-mutation is a defect.”  “Thus, no evolutionary advantage accrues to the population.  Carriers do not pass improved genetic information on to their children.” ↩ ↩

Shriner, Daniel, and Charles N. Rotimi.  “Whole-Genome-Sequence-Based Haplotypes Reveal Single Origin of the Sickle Allele during the Holocene Wet Phase.”  American Journal of Human Genetics 102(4):547–556.  2018.  CC BY-NC-ND 4.0.  The publisher copy at cell.com answers 403 to a plain request;  PMC serves it.  Both authors are at the National Human Genome Research Institute.  Read as Europe PMC full-text XML, so locators are sections rather than pages.  Their own stated limitation is that the sample lacks northern, central and southern Africa.  Mirror:  Cell.com

1. 10a.

   Section Abstract:  “Modeling of balancing selection indicated that the heterozygote advantage was 15.2%, an equilibrium frequency of 12.0% was reached after 87 generations, and the selective environment predated the mutation.”  The Results give the fitted value as s = 0.158.  The abstract's 15.2% is the figure Currat et al. 2002 assumed.  Both are printed here rather than reconciled. ↩

2. 10b.

   Section Results, balancing selection:  “We modeled balancing selection assuming that the relative fitness of the βA/βA homozygote was 1, the relative fitness of the βS/βS homozygote was 0, and the relative fitness of the βA/βS heterozygote was 1+s.  On the basis of the 504 continental Africans from the 1000 Genomes Project, we estimated that s=0.158, which was in agreement with previous estimates.” ↩ ↩

3. 10c.

   Section Results, balancing selection:  “We found that the mutant allele was lost 74.6% of the time and, conditional on reaching equilibrium, reached a frequency of 12.0% after an average of 87 (95% confidence interval [68,124]) generations, or approximately 2,400 (95% confidence interval from 1,900 to 3,500) years.  We stress that this value is not the age of the sickle mutation nor the age since the onset of balancing selection but rather the time to reach a frequency of 12.0%.” ↩ ↩

4. 10d.

   Section Results, balancing selection:  “To determine the fate of the mutant allele in the absence of heterozygote advantage, we repeated the simulation while assuming s=0.  We found that the mutant allele was lost after an average of 12 generations (95% confidence interval [1,92]), with a median of two generations.” ↩ ↩

5. 10e.

   Section Abstract:  “Each haplotype is thought to represent an independent occurrence of the sickle mutation rs334 (c.20A>T [p.Glu7Val] in HBB).” ↩

6. 10f.

   Section Discussion:  “By molecularly mapping restriction sites to the sequence data, we found that the restriction sites correlated poorly with rs334, such that none of the canonical sites were included in our sequence-based haplotypes.  This discrepancy can be explained by the fact that the RFLP-defining markers circulate on both βS- and βA-carrying chromosomes, even though the restriction sites were originally used for defining types of βS-carrying chromosomes.” ↩ ↩ ↩

7. 10g.

   Section Results:  “The network revealed that the sickle mutation occurred once in the background of the ancestral haplotype and gave rise to HAP1, which is associated predominantly with the CAR haplotype.”  “Two additional clusters were derived from this haplotype and not from the ancestral haplotype.” ↩

8. 10h.

   Section Results, ancestral recombination graph:  “We estimated the age of the sickle mutation as 259 (95% credible interval [123,395]) generations, or approximately 7,300 years (95% credible interval from 3,400 to 11,100 years).”  From ARGweaver, with a mutation rate of 0.97 × 10^-8 and a recombination rate of 1.5 × 10^-8 per site per generation selected as the best fit over a grid of 15 pairs.  The implied generation length is about 28 years. ↩ ↩

McManus, Kimberly F. et al.  “Population genetic analysis of the DARC locus (Duffy) reveals adaptation from standing variation associated with malaria resistance in humans.”  PLoS Genetics 13(3):e1006560.  2017.  Open access, CC BY 4.0.  Read as Europe PMC full-text XML.  No printed folios, so locators are sections.  Mirror:  PMC5365118

1. 11a.

   Section Abstract:  “We estimate the time to most recent common ancestor (TMRCA) of the most common FYO haplotype to be 42 kya (95% CI: 34–49 kya).  We infer the FYO null mutation swept to fixation in Africa from standing variation with very low initial frequency (0.1%) and a selection coefficient of 0.043 (95% CI:0.011–0.18), which is among the strongest estimated in the human genome.” ↩ ↩

2. 11b.

   Section Results, Inference of TMRCA:  “For FYO, we initially estimate the time to most recent common ancestor (TMRCA) over all FYO haplotypes to be 230,779 years (95% CI: 169,790–291,039 years), which would imply very old selection under the assumption of a de novo sweep model.”  “We estimate the major FY*O haplotype class to be 42,183 years old (95% CI: 34,100–49,030) and the minor haplotype class to be 56,052 years old (95% CI: 38,927–75,073)”. ↩ ↩

3. 11c.

   Section Results, Mode and magnitude:  “Utilizing a multinomial logistic regression method, we observed strong support for the 0.1% initial frequency model and low support all other models (posterior probabilities: de novo 0.0002; 0.1% 0.9167; 1% 0.0827; 10% 0.0000; 25% 0.0004)”.  “We conclude selection on FY*O occurred on standing variation with a very low (0.1%) allele frequency at selection onset.” ↩

4. 11d.

   Section Results:  “We find that the FYO mutation is at or near fixation in western and central African populations, but almost absent from European and Asian samples.  All sampled sub-Saharan African populations show frequencies of >99% for FYO, with the exception of the southern African Zulu and ≠Khomani San populations that contain all three of”. ↩

5. 11e.

   Section Results, Evidence of positive selection:  “We find that FY*O has the largest population differentiation, as measured by FST, of any SNP in the genome among the 1000 Genomes populations.”  “Accordingly, we find the DARC promoter region is not an outlier in the genome with respect to segregating sites, average number of pairwise differences nor Tajima’s D”. ↩

Williams, Thomas N. et al.  “Sickle cell trait and the risk of Plasmodium falciparum malaria and other childhood diseases.”  Journal of Infectious Diseases 192(1):178–186.  2005.  Read as the PMC author manuscript, fetched with bin/pmcget.py.  The manuscript has no printed folios, so locators are sections.  Two prospective cohorts at Kilifi on the Kenyan coast.  Mirror:  PMC3545189

1. 12a.

   Section Abstract:  “HbAS had no effect on the prevalence of symptomless parasitemia but was 50% protective against mild clinical malaria, 75% protective against admission to the hospital for malaria, and almost 90% protective against severe or complicated malaria.” ↩

2. 12b.

   Table 2:  “All severe malaria”.  The birth-cohort row gives 191 episodes in HbAA children at an incidence of 21.53 per 1,000 child-years, reference category 1, against 6 episodes in HbAS children at 3.98 per 1,000 child-years, incidence rate ratio 0.17 with a 95% confidence interval of 0.07 to 0.40 and P < .0001.  The table's own note states that the sickle-cell-trait data were collected from 384 children during 1509.9 child-years of follow-up and the HbAA data from 2271 children during 8871.4 child-years. ↩ ↩ ↩

3. 12c.

   Section Abstract:  “The protective effect of HbAS was remarkably specific for falciparum malaria, having no significant impact on any other disease.”  Section Results:  “We found no significant associations between HbAS and the incidence of any other diseases, whether detected at the outpatient clinic or on hospital admission (tables 1 and 2).” ↩ ↩

Behe, Michael J.  The Edge of Evolution: The Search for the Limits of Darwinism.  Free Press.  2007.  Behe is a biochemist at Lehigh University and a senior fellow of the Discovery Institute.  Wording read from the library e-book;  printed pages pinned on the archive.org scan of the 2007 hardback, item isbn_9780743296205, via bin/iapdsearch.py with printed page = leaf − 14.  The offset was anchored twice:  on the item's own page map from BookReaderJSIA.php (leaf 40 = p. 26, leaf 52 = p. 38, leaf 83 = p. 69, leaf 124 = p. 110) and against the independent anchoring recorded for the Plasmodium falciparum article.

1. 13a.

   Page 37:  “Junking G6PD makes the red blood cell more fragile, which as we have seen can be a net plus during an invasion by malaria.”  “Hundreds of mutations are known that alter the amino acid sequence of G6PD, and either destroy or greatly diminish its effectiveness.” ↩

2. 13b.

   Page 38:  “Turning off Duffy antigen in red cells has little noticeable ill effect, although it may be associated with an increased risk of prostate cancer.”  Reich et al. 2009 later identified the same variant as the cause of benign ethnic neutropenia. ↩

3. 13c.

   Page 69:  “For example, in human history a new sickle mutation (not one that was just inherited from a parent who had it) has freshly arisen at most only a few times, perhaps just once.  Yet thalassemia has popped up hundreds of times.” ↩ ↩

4. 13d.

   Page 69:  “To get sickle, one particular nucleotide has to be substituted.  To get thalassemia (which breaks a hemoglobin gene), on the other hand, any of hundreds of nucleotides can be substituted or deleted and the gene will no longer produce a working protein.” ↩

5. 13e.

   Page 68:  “Any one particular nucleotide (like, say, the one that will give the sickle mutation) is freshly substituted about once every hundred million births.” ↩

6. 13f.

   Page 110:  “Put another way, only one out of every hundred million babies is born with a new mutation that gives it sickle hemoglobin.  Over a hundred generations in a population of a million people, we would expect the mutation to occur once by chance.” ↩

7. 13g.

   Page 110:  “The odds of getting the second mutation in exactly the right spot are again about one in a hundred million.  So the odds of getting both mutations right, to give hemoglobin C-Harlem in one generation in an individual whose parents have normal hemoglobin, are about a hundred million times a hundred million”.  The printed text gives the product as 10 to the 16th;  the superscript is destroyed by the search-inside OCR and by the e-book extraction, and is recovered here from the surrounding prose. ↩

8. 13h.

   Chapter 2:  “So far, the C-Harlem gene doesn’t seem to have spread much.  Its antimalarial properties aren’t much help in contemporary New York.”  “In Africa the C-Harlem gene would be a boon, but the C-Harlem mutation apparently hasn’t turned up there yet.”  Read from the e-book, in the section following the description of C-Harlem's second substitution at position 73.  The printed page was not pinned, so the locator is the chapter. ↩ ↩

9. 13i.

   Chapter 2:  “We aren’t quite sure why, but experiments indicate that HbC is less sturdy than normal hemoglobin.”  Read from the e-book;  printed page not pinned. ↩

10. 13j.

    Chapter 2:  “However, since the hemoglobin C gene needs two copies to be effective, and gives only a small amount or malaria resistance in single copy, then C-Eve was no better off than her fellow villagers.”  "or" for "of" is the e-book's typo.  Read from the e-book;  printed page not pinned. ↩

11. 13k.

    Chapter 2:  “HPFH helps sickle disease sufferers, apparently by diluting the sickle hemoglobin in their red blood cells.”  “In the case of HPFH some of these control elements are broken.”  Read from the e-book;  printed page not pinned. ↩

Modiano, David et al.  “Haemoglobin C protects against clinical Plasmodium falciparum malaria.”  Nature 414(6861):305–308.  2001.  Abstract only.  The full text is behind the publisher's wall;  Wayback copies of the publisher PDF returned the site wrapper rather than the file.  The abstract was taken from the Europe PMC record (PMID 11713529) and saved to the library.  No page-level locators inside the paper are claimed.

1. 14a.

   Section Abstract:  “Here we show, in a large case-control study performed in Burkina Faso on 4,348 Mossi subjects, that HbC is associated with a 29% reduction in risk of clinical malaria in HbAC heterozygotes (P = 0.0008) and of 93% in HbCC homozygotes (P = 0.0011).”  “These findings, together with the limited pathology of HbAC and HbCC compared to the severely disadvantaged HbSS and HbSC genotypes and the low betaS gene frequency in the geographic epicentre of betaC, support the hypothesis that, in the long term and in the absence of malaria control, HbC would replace HbS in central West Africa.” ↩ ↩

Chotivanich, Kesinee et al.  “Hemoglobin E: a balanced polymorphism protective against high parasitemias and thus severe P falciparum malaria.”  Blood 100(4):1172–1176.  2002.  Abstract only.  The full text is behind the publisher's wall;  the abstract was taken from the Europe PMC record (PMID 12149194) and saved to the library.  No page-level locators inside the paper are claimed.

1. 15a.

   Section Abstract:  “In vitro, starting at 1% parasitemia, Plasmodium falciparum preferentially invaded normal (HbAA) compared to abnormal hemoglobin (HbH, AE, EE, HCS, beta-thalassemia E) red cells (HRBCs).”  “The heterozygote AE cells differed markedly from all the other cells tested with invasion restricted to approximately 25% of the RBCs”. ↩ ↩

2. 15b.

   Section Abstract:  “This would not protect from uncomplicated malaria infections but would prevent the development of heavy parasite burdens and is consistent with the "Haldane" hypothesis of heterozygote protection against severe malaria for hemoglobin E.” ↩

3. 15c.

   Section Abstract:  “These findings suggest that HbAE erythrocytes have an unidentified membrane abnormality that renders the majority of the RBC population relatively resistant to invasion by P falciparum.” ↩ ↩

Ruwende, C. et al.  “Natural selection of hemi- and heterozygotes for G6PD deficiency in Africa by resistance to severe malaria.”  Nature 376(6537):246–249.  1995.  Abstract only.  The full text is behind the publisher's wall;  the abstract was taken from the Europe PMC record (PMID 7617034) and saved to the library.  No page-level locators inside the paper are claimed.

1. 16a.

   Section Abstract:  “Glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common enzymopathy of humans, affects over 400 million people.”  “Here we report that, in two large case-control studies of over 2,000 African children, the common African form of G6PD deficiency (G6PD A-) is associated with a 46-58% reduction in risk of severe malaria for both female heterozygotes and male hemizygotes.” ↩ ↩

2. 16b.

   Section Abstract:  “A mathematical model incorporating the measured selective advantage against malaria suggests that a counterbalancing selective disadvantage, associated with this enzyme deficiency, has retarded its rise in frequency in malaria-endemic regions.  Although G6PD deficiency is now regarded as a generally benign disorder, in earlier environmental conditions it could have been significantly disadvantageous.” ↩

Tishkoff, Sarah A. et al.  “Haplotype diversity and linkage disequilibrium at human G6PD: recent origin of alleles that confer malarial resistance.”  Science 293(5529):455–462.  2001.  Abstract only.  The full text is behind the publisher's wall;  three Wayback routes to the publisher PDF returned the site's HTML wrapper rather than the file.  The abstract was taken from the Europe PMC record (PMID 11423617) and saved to the library.  Point estimates quoted in this article come from Hedrick 2011's Table 2, which reports them.  No page-level locators inside the paper are claimed.

1. 17a.

   Section Abstract:  “Haplotype analysis of "A-" and "Med" mutations at this locus indicates that they have evolved independently and have increased in frequency at a rate that is too rapid to be explained by random genetic drift.  Statistical modeling indicates that the A- allele arose within the past 3840 to 11,760 years and the Med allele arose within the past 1600 to 6640 years.  These results support the hypothesis that malaria has had a major impact on humans only since the introduction of agriculture within the past 10,000 years”. ↩ ↩ ↩

Reich, David et al.  “Reduced neutrophil count in people of African descent is due to a regulatory variant in the Duffy antigen receptor for chemokines gene.”  PLoS Genetics 5(1):e1000360.  2009.  The paper carries the Creative Commons public-domain declaration.  Read as Europe PMC full-text XML.  No printed folios, so locators are sections.  6,005 African Americans from the Jackson Heart Study, Health ABC and ARIC.  Mirror:  PMC2628742

1. 18a.

   Section Abstract:  “An excellent candidate is the Duffy Null polymorphism (SNP rs2814778 at chromosome 1q23.2), which is the only polymorphism in the region known to be so differentiated in frequency and is already known to protect against Plasmodium vivax malaria.  We confirm that rs2814778 is predictive of WBC and neutrophil count in African Americans above beyond the previously described admixture association (P = 3.8×10−5), establishing a novel phenotype for this genetic variant.”  "above beyond" is the manuscript's wording. ↩

2. 18b.

   Section Introduction:  “This condition, called “benign ethnic neutropenia”, can have important effects on medical decision-making, since WBC is a valuable indicator of immunocompetence, infection, and inflammation.”  Section Author summary:  “The African, or “null,” form of this variant abolishes expression of the “Duffy Antigen Receptor for Chemokines” on red blood cells, perhaps altering the concentrations and distribution of chemokines that regulate neutrophil production or migration.” ↩

Batten, Don.  “Clarity and confusion.”  Journal of Creation 22(1):28–33.  Apr 2008.  Creation Ministries International's review of The Edge of Evolution.  Batten is a plant physiologist.  Library copy of the web version;  locators are sections, since the web copy carries no page breaks.

1. 19a.

   Section Protein-protein binding sites:  “A typical cell might have some 10,000 protein-binding sites, but in all the cases surveyed, perhaps one protein-protein binding site has arisen by mutation: the sickle cell condition in humans, which is quite non-specific and actually destroys the normal structure of the hemoglobin tetrad and causes disease not evolutionary advancement.  So Behe is being generous in granting one example.” ↩

2. 19b.

   Section What mutations can do:  “Sickle cell trait, which requires a specific nucleotide change (mutation), has arisen de novo only a few times in human history.  However, thalassemia, which merely requires the breaking of a hemoglobin gene, for which there are many ways to achieve this, has arisen hundreds of times.  Again these frequencies are consistent with the probabilities of mutations in a human-like population.  ‘Evolution’ (mutations and natural selection) is quite able to do this sort of thing.” ↩

Konotey-Ahulu, Felix.  “Sickle-cell anemia does not prove evolution!”  Creation 16(2):40–41.  Mar 1994.  Creation Ministries International.  Konotey-Ahulu is a physician and clinical geneticist who practised in Ghana and London and wrote the 643-page The Sickle Cell Disease Patient (Macmillan, 1991).  Web copy fetched with curl and tags stripped locally;  locators are sections, since the web copy carries no page breaks.

1. 20a.

   Section Sickle-cell disease:  “This is good evidence that natural selection plays a part in maintaining a higher frequency of this carrier state.  If you are resistant to malaria, you are more likely to survive to pass on your genes.  Nevertheless, it is a defect, not an increase in complexity or an improvement in function which is being selected for, and having more carriers in the population means that there will be more people suffering from this terrible disease.” ↩

Menton, David.  “Sickle Cell Anemia and Other "Good" Mutations of Evolution.”  Answers in Genesis.  Aug 12, 2017 (edition of 1994).  Retrieved Sep 27, 2026.  Menton was an anatomist at Washington University before joining Answers in Genesis.  The page's editor's note says it first appeared in St. Louis MetroVoice 4, no. 3 (March 1994).  Web copy fetched with curl and tags stripped locally;  locators are sections.

1. 21a.

   Section Are there any known examples of unquestionably "beneficial" mutations?:  “Ironically, the primary textbook example of a “good” mutation is one that causes the disease sickle cell anemia.  This mutation of blood hemoglobin is considered “good” because people who have it (and survive it) are more resistant to the disease malaria.  The symptoms of this “good” mutation include acute attacks of abdominal and joint pain, ulcers on the legs, defective red blood cells, and severe anemia—often leading to death.” ↩

Sherwin, Frank.  “Evolution and Malaria.”  Acts & Facts 34(4).  2005.  Institute for Creation Research.  Sherwin is a zoologist on ICR's science staff.  Web copy fetched with curl and tags stripped locally;  locators are sections.  ICR's slug-form URLs return an empty page shell;  the numeric-ID form returns the article.  The page prints its own citation line.

1. 22a.

   Section Body:  “People homozygous for sickle-cell anemia (both parents provide the mutant gene to the offspring) usually die before adolescence.  But those offspring that are heterozygous (receiving a mutant gene from just one parent) can lead normal lives.”  “Those with sickle-cell anemia in the same area are quite resistant to a deadly strain of malaria because their atypical blood cells collapse or "sickle," destroying the developing parasite.”  The second sentence attributes the protection to the disease genotype.  The measured protection is in heterozygotes;  Hedrick 2011 p. 288 assigns SS a relative fitness of 0 without modern care. ↩

Sanford, John C.  Genetic Entropy.  FMS Publications.  4th edition.  2014.  Sanford is a plant geneticist, formerly of Cornell, and co-inventor of the gene gun.  Library EPUB.  The EPUB carries printed-page anchors (id="page_N"), each at the start of that printed page, checked by reading the text following page_148, page_150 and page_151.  Searching both the 4th-edition EPUB and the OCR of the 2005 first edition finds no mention of sickle haemoglobin or of any other human malaria-resistance allele.

1. 23a.

   Page 150:  “Behe shows that while these organisms rapidly adapt to new external conditions, they do not innovate any new internal functions.  Even within these “ideal evolutionary systems”, the type of change being documented only represents “fine-tuning”, not true innovation.”  From the book's 2008 Update section, discussing The Edge of Evolution.  The claim is about HIV, the malaria parasite and E. coli, not about the human alleles. ↩

Kong, Augustine et al.  “Rate of de novo mutations and the importance of father's age to disease risk.”  Nature 488(7412):471–475.  2012.  Library copy is the NIH author manuscript PDF, which carries no printed folios, so locators are sections.  4,933 de novo mutations in 78 Icelandic trios over an effective 2.63 billion base pairs.  Mirror:  PMC3548427

1. 24a.

   Section Abstract:  “novo mutation rate is 1.20×10−8 per nucleotide per generation.”  Section Results:  “From that, 4933 mutations correspond to a germline mutation rate of 1.20×10−8 per”.  The abstract sentence begins "the de" on the preceding line of the manuscript.  The Results sentence continues "nucleotide per generation, falling within the range between 1.1×10−8 and 3.8×10−8 previously reported". ↩ ↩

Chance that one particular child carries one particular new substitution at one particular site.  Kong's rate is 1.20 × 10⁻⁸ per nucleotide per generation for the transmitted haploid genome.²⁴  A child inherits two copies of each site, so the per-child rate for a mutation of any kind at that site is 2 × 1.20 × 10⁻⁸ = 2.4 × 10⁻⁸.  A given base can change to three others, and treating those as equally likely gives 2.4 × 10⁻⁸ ÷ 3 = 8 × 10⁻⁹ per child, or one in 125 million.  The three substitutions are not in fact equally likely, so the figure for any particular one is accurate only to a factor of about two.  This is the same convention used in the ledger of the Plasmodium falciparum article, so the two sets of figures can be compared. ↩ ↩

World Health Organization.  Malaria.  Dec 4, 2025.  Retrieved Sep 27, 2026.  Fact sheet.  The counts are for all malaria species.  Library copy of the page with a local text extraction.

1. 26a.

   Section Key facts:  “Globally in 2024, there were an estimated 282 million malaria cases and 610 000 malaria deaths in 80 countries.”  “In 2024, the WHO African Region was home to 95% of malaria cases (265 million) and 95% (579 000) of malaria deaths.” ↩ ↩

The exposed-birth ledger, and every figure in the table.  Births = assumed average exposed population × generations, taking one birth per person per generation, which is the replacement assumption and is conservative in a growing population.  Generations = years ÷ 25;  300 generations is 7,500 years and 400 is 10,000 years, chosen to bracket the period in which most of these variants are dated.⁵  Expected arrivals over the whole period = births × 8 × 10⁻⁹.²⁵  Row by row:  10⁶ × 300 = 3 × 10⁸ births, and 3 × 10⁸ × 8 × 10⁻⁹ = 2.4;  10⁷ × 300 = 3 × 10⁹ births, 24 arrivals;  10⁸ × 300 = 3 × 10¹⁰ births, 240 arrivals;  10⁸ × 400 = 4 × 10¹⁰ births, 320 arrivals.  No historical census of malarious regions was obtained, so the three population values are assumptions, chosen two orders of magnitude apart to show that the conclusion does not turn on the choice.  The modern anchor is the WHO's 282 million cases a year, 95% of them in Africa, which puts today's exposed population at 10⁸ to 10⁹, above the top of this range;  earlier millennia were smaller.²⁶  The arrival counts are for the whole period, not per generation, and they count mutational events rather than surviving lineages. ↩

The parasite column is taken from the ledger of the Plasmodium falciparum article, which derives it from White 2004's census of about 10¹⁷ parasites alive at once and fewer than 10²⁰ born a year, Hamilton 2017's substitution rate of 2.45 × 10⁻¹⁰ per base per 48-hour cycle, and a 75-year drug era:  1.5 to 7.5 × 10²¹ parasites born, about 10¹⁹ substitutions, and one specific substitution arising 1.6 to 8 billion times a year.  The chloroquine figure of about one origin per 10²⁰ parasites is White's, and is a rate of successful emergence rather than a mutation rate.  The human column is this article's, from the note above.  The two columns are not the same kind of quantity in one respect:  the human figure counts births, each of which is one meiosis, while the parasite figure counts individuals, each of which is one mitotic replication. ↩