Wednesday, 11 September 2013

Chapter 3: 'Human Genome Decay': Kondrashov and Sandford

Selective use of Kondrashov

Sarfati cites the evolutionary geneticist Alexey Kondrashov in support of the claim that the human genome is accumulating harmful mutations at such a rate that the human race cannot be tens of thousands of years old.
[B]ad neutral mutations accumulate till the point of damage. These mutations are accumulating much faster than previously thought—at least 100 nucleotide substitutions (single-letter 'typos') per person per generation, according to geneticist Kondrashov—and the rate might be as high as 300....Evolutionist Kondrashov himself asked, "Why aren't we dead 100 times over?" (p 57)

Sarfati's selective use of Kondrashov suggests he is citing Kondrashov for rhetorical effect ("This presents such a challenge to evolution that even a prominent evolutionist is expressing doubts!").

A look at the Kondrashov papers cited by Sarfati presents a different picture. Kondrashov's question ("Why have we not died 100 times over?") is part of the title of his 1995 paper[1], which sets out to answer that question. The paper outlines several possible resolutions, including soft selection[2] and synergistic epistasis (discussed below).

Sarfati also cites a 2002 paper[3] by Kondrashov, which has the figure of 100 new mutations per human genome per generation. Sarfati presents this in a way that gives the impression all 100 of these mutations are harmful. Howevever, Kondrashov's article states that the ratio of harmful mutations is around 10 percent of the 100 ("Comparison of human and murine [mouse] orthologous intergenic regions suggests that at least 10% of these mutations are deleterious"). He then adds that "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"[4].

Theoretical models and synergistic epistasis

The following paragraphs are from an extensive review of Genetic Entropy and the Mystery of the Genome (the book by plant geneticist John Sanford, which Sarfati is summarising in this section of The Greatest Hoax on Earth) by chemical engineer Scott Buchanan[5].
Much of the confusion in Sanford's book is due to his failure to distinguish models from reality.  He seizes on the predictions of oversimplified models when they suit his case, and ignores the fact that these models obviously do not represent the real world.
There is general agreement among geneticists that a simple model of mutations, with high rate of deleterious mutations operating independently, would predict that a population's fitness and genome will deteriorate fairly rapidly. The cost of eliminating each mutation would be too high for the population to bear.
There is also general agreement that if mutations interact such that several mutations together decrease fitness more than predicted by the sum of their individual effects, then the genome will not deteriorate.[6]
The effect is that individuals with say four or five mutations have a much higher probability of dying young or otherwise producing few offspring, compared to the individuals with just one or two mutations. This reduces the cost to the population of eliminating the bad mutations. This is known as "synergistic epistasis". The opposite trend is "antagonistic epistasis", where just one mutation can have a large effect, and additional mutations have diminishing effects[....]
Sanford addresses the experimental evidence for synergistic epistasis with a single sentence on page 110: "At least one paper provides experimental evidence that the concept is not valid (Elena and Lenski, 1997)."  As we have come to expect from Sanford, this statement is formally true, but grossly misleading for the general reader. Sanford claims to be most concerned about the genomes of higher organisms like animals and humans, yet he ignores the studies which show synergistic epistasis in multi-cellular eukaryotes[7] and cites only a single study on the bacteria E. coli.[8]
We have already noted that prokaryotes like bacteria are likely to show no epistasis. Further, this particular study used artificial insertion mutations rather than random natural mutations. Dickinson has pointed out that these insertion mutations are unlikely to show epistasis.[9] So again Sanford has cherry-picked one study which is largely inappropriate yet shows the results he wants, and ignored the body of evidence that points in the opposite direction.
Buchanan's review is worth reading in full to see all of the problems in Sandford's approach. Here are a few other good points made by Buchanan that are relevant to Sarfati's use of Sandford.
For all Sanford's hand-wringing over the inescapable declines in genomes everywhere, his lack of concrete examples shows that the scientific facts are not on his side. Microbes have existed for untold millions of generations, and even small mammals like mice and rabbits which reproduce one or more times a year have existed with humans for thousands of generations in historic times, and many more thousands of generations in prehistoric times. If genomes of these rodents were declining by say 0.1% per year, then in 3000 years since 1000 BC, they should be down to 5% of their original fitness (0.999 raised to 3000 power = 0.05) So where is the evidence of super-rabbits in 1000 BC or even 1000 AD?
Humans carry around 100-200 new mutations per generation[10]. That seems like a lot, but that is only about one mutation in each 15 to 30 million nucleotides. While a few of these mutations can have devastating health effects, most of these mutations have no apparent physical impact. Most of these mutations fall in regions of the genome with no known function, and many mutations in protein coding regions are "silent" mutations which do not alter the protein which is ultimately formed. Even within the coding for proteins, many of amino acids can be altered without appreciable harm to the individual[11].


[1] Alexey Kondrashov, 'Contamination of the genome by very slightly deleterious mutations: why have we not died 100 times over?', Journal of Theoretical Biology, Vol 175, No 4 (1995), pp 583-94 [only the abstract is available free online]
[2] For a definition, see here:

[3] Alexey Kondrashov, 'Direct Estimates of Human per Nucleotide Mutation Rates at 20 Loci Causing Mendelian Diseases', Human Mutation, Vol 21, Issue 1 (2002), pp 12-27; available in full online at:
[4] Kondrashov (2002), p 22.

[5] Scott Buchanan, 'Assessing Limits to Evolution and to Natural Selection: Reviews of Michael Behe's Edge of Evolution and John Sanford's Genetic Entropy' (2010)

[6] James Crow,'The high spontaneous mutation rate: Is it a health risk?', PNAS, Vol 94 (1997), pp 8380-6; Kondrashov (1995); M W Nachman and S L Crowell, 'Estimate of the mutation rate per nucleotide in humans', Genetics, Vol 15, No 6 (2000), pp 297-304.

[7] Rafael Sanjuán and Santiago Elena, 'Epistasis correlates to genomic complexity', PNAS, Vol 103, No 39 (2006), pp 14402-5; W C Whitlock and D Bourguet, 'Factors affecting the genetic load in Drosophila: synergistic epistasis and correlations among fitness components', Evolution, Vol 54, No 5 (2000), pp 1654-60;
 Victoria Ávila, et al, 'Increase of the Spontaneous Mutation Rate in a Long-Term Experiment With Drosophila melanogaster', Genetics, Vol 173 (2006), pp 267-77; Gregory Kryukov, Steffen Schmidt and Shamil Sunyaev, 'Small fitness effect of mutations in highly conserved non-coding regions', Molecular Genetics, Vol 14, No 15 (2005), pp 2221-9; W Joseph Dickinson, 'Synergistic Fitness Interactions and a High Frequency of Beneficial Changes Among Mutations Accumulated Under Relaxed Selection in Saccharomyces cerevisiae', Genetics, Vol 178 (2008), pp 1571-8

[8] S F Elena and R E Lenski, 'Test of synergistic interactions among deleterious mutations in bacteria', Nature, Vol 390 (1997), pp 395-8

[9] See Dickinson (2008) in reference 7.

[10] Wellcome Trust Sanger Institute, 'We are all mutants: measurement of mutation rate in humans by direct sequencing' (2009) 

[11] Michael Lynch, 'Simple evolutionary pathways to complex proteins', Protein Science, Vol 14 (2005), pp 2217-25

1 comment:

  1. A bit disingenuous. Did Kondrashov recognize the enigma of accumulating non-beneficial mutations (which are genetic ERRORS, by the way)? Of course he did.
    "[B]ad neutral mutations accumulate till the point of damage. These mutations are accumulating much faster than previously thought—at least 100 nucleotide substitutions (single-letter 'typos') per person per generation"
    Did Kondrashov find a verifiable solution to this enigma? No, only "possibilities" (maybe's, could have's, might have's). Therefore, the enigma still has no answer. We are STILL accumulating more & more genetic copying errors per generation.