The Case for Junk DNA

T. Ryan Gregory and Alexander Palazzo,PLOS Genetics, 2014
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T. Ryan Gregory is an evolutionary and genome biologist. In 2014 he and biochemist Alexander Palazzo, argued in favor of large amounts of junk DNA, pulling in nearly every argument previously used by others:

Neutral Theory

Several analyses of sequence conservation between humans and other mammals have found that about 5% of the genome is conserved. It is possible that an additional 4% of the human genome is under lineage-specific selection pressure ... the idea that 9% of the human genome shows signs of functionality is actually consistent with the results of ENCODE and other large-scale genome analyses...

Kimura, Ohta, King, and Jukes... demonstrated that alleles that were slightly beneficial or deleterious behaved like neutral alleles, provided that the absolute value of their selection coefficient was smaller than the inverse of the “effective” population size...For humans it has been estimated that the historical effective population size is approximately 10,000...Given the overall low figures for multicellular organisms in general, we would expect that natural selection would be powerless to stop the accumulation of certain genomic alterations over the entirety of metazoan [meaning animal] evolution.

In other words, any mutation that has an effect on fitness less than 10^-5 (1/10,000) will become fixed in the population, regardless of whether it's beneficial or deleterious--which would likely be the majority of mutations. Otherwise we would see stronger effects from the 100 or so we get per human generation. And because so little DNA is shared with other mammals, neutral evolution could not have generated large amounts of functional difference.

Genetic Load

It has long been appreciated that there is a limit to the number of deleterious mutations that an organism can sustain per generation. The presence of these mutations is usually not harmful, because diploid organisms generally require only one functional copy of any given gene. However, if the rate at which these mutations are generated is higher than the rate at which natural selection can weed them out, then the collective genomes of the organisms in the species will suffer a meltdown as the total number of deleterious alleles increases with each generation. This rate is approximately one deleterious mutation per generation. In this context it becomes clear that the overall mutation rate would place an upper limit to the amount of functional DNA. Currently, the rate of mutation in humans is estimated to be anywhere from 70–150 mutations per generation. By this line of reasoning, we would estimate that, at most, only 1% of the nucleotides in the genome are essential for viability in a strict sequence-specific way. However, more recent computational models [Keightley's A resolution of the Mutational Load Paradox, 2012] have demonstrated that genomes could sustain multiple slightly deleterious mutations per generation. Using statistical methods, it has been estimated that humans sustain 2.1–10 deleterious mutations per generation. These data would suggest that at most 10% of the human genome exhibits detectable organism-level function and conversely that at least 90% of the genome consists of junk DNA. These figures agree with measurements of genome conservation (~9%, see above) and are incompatible with the view that 80% of the genome is functional in the sense implied by ENCODE.

Selfish Genes

Because of their capacity to increase in copy number, transposable elements have long been described as “parasitic” or “selfish”. However, the vast majority of these elements are inactive in humans, due to a very large fraction being highly degraded by mutation. Due to this degeneracy, estimates of the proportion of the human genome occupied by TEs [transposable elements] has varied widely, between one-half and two-thirds... there is evidence of organism-level function for only a tiny minority of TE sequences. It is therefore not obvious that functional explanations can be extrapolated from a small number of specific examples to all TEs within the genome.

C-Value Paradox

Although elsewhere Gregory has preferred the term "C-value enigma"

genome size varies enormously among species: at least 7,000-fold among animals and 350-fold even within vertebrates... a human genome contains eight times more DNA than that of a pufferfish but is 40 times smaller than that of a lungfish. Third, organisms that have very large genomes are not few in number or outliers—for example, of the >200 salamander genomes analyzed thus far, all are between four and 35 times larger than the human genome. Fourth, even closely related species with very similar biological properties and the same ploidy level can differ significantly in genome size... the notion that the majority of eukaryotic noncoding DNA is functional is very difficult to reconcile with the massive diversity in genome size observed among species, including among some closely related taxa.

Appears to not do anything

The majority of human DNA consists of repetitive, mutationally degraded sequences. There are unambiguous examples of nonprotein-coding sequences of various types having been co-opted for organism-level functions in gene regulation, chromosome structure, and other roles, but at present evidence from the published literature suggests that these represent a small minority of the human genome.