Distribution of fitness effects of mutations?

By Razib Khan | May 31, 2008 2:47 pm

Haven’t had a time to check this paper out, but looks real interesting, Assessing the Evolutionary Impact of Amino Acid Mutations in the Human Genome:

Although mutations are known to cause varying degrees of harmful effects, it is difficult to quantify the distribution that best describes the variation of fitness effects of these mutations. Here we present a new method for inferring this distribution and inferring population history using Single Nucleotide Polymorphism (SNP) data from human populations. Using 47,576 SNPs discovered in 11,404 genes from sequencing 35 individuals (20 European Americans and 15 African Americans), we find evidence of an ancient population expansion in the sample with African ancestry and a relatively recent bottleneck in the sample with European ancestry. In both populations, the patterns of variation are consistent with a leptokurtic distribution of selection coefficients (e.g., gamma or log-normal) peaked near neutrality. Specifically, we predict 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. Furthermore, we infer that 10-20% of amino acid differences between humans and chimpanzees were fixed by positive selection, with the remainder of differences being neutral or nearly neutral.

Leptokurtosis describes a more acute peak around the mean.

CATEGORIZED UNDER: Genetics
  • http://leherensuge.blogspot.com/ Luis

    I also browsed it casually only first and now I’ve re-read it with more care, even if it’s a little too dense and arithmetic for my level.
    What most called my attention was the “Inference on Demography” section of the discussion and the related table S1.
    According to that Africans have been expanding regularly since 6809 generations ago, what I translate into some 170,000 years (at 25 years per gen.) That is roughly coincident with estimates of the formation of H. sapiens as separate species but it also means that all that literature about many small groups separated by massive droughts and the like suddenly seem to make little sense: African humans, at least those represented in the sample (probably Khoisan are not, for instance) have been expanding steadily since the very beginning of the species (or shortly after). The lack of bottlenecks in Africans (or their American descendants) is not something new anyhow.
    I’m not sure how to read the European results. The authors state that the best-fitting model is that of two expansions with an intermediate bottleneck but that the other two models (not the stationary one) are also reasonably fit to results.
    So we have three models that more or less agree with the results:
    1. Model “Expansion”: Europeans have expanded since some 6500 years ago (Neolithic).
    2. Model “Bottleneck”: Europeans have been expanding since some 21,850 years ago (LGM). The bottleneck lasted for c.192,000 years before that.
    3. Model “Bottleneck + 2 step recovery”: first expansion c. 130,000 years ago (an early OOA?), a second expansion c. 14,400 years ago (post-LGM) and a bottleneck lasting some 2100 years only (when? before the first or second expansion?).
    Model 3 is the best model but while it does fit well with what we know of post-LGM expansion it also seems to suggest another earlier expansion c. 130,000 BP. That seems to suggest that the OOA event happened a lot earlier than usually acknowledged. That it has nothing to do with Toba nor the massive African droughts that preceded it but that people was in Eurasia since about that date. Certainly Indian late Middle Paleolithic does suggest pre and post Toba continuity and there is no good reason to think that H. sapiens only arrived in the traiditionally considered transition to UP, specially as blade tools are known since c. 100 BP.
    In fact, I have been driven to this same conclusion recently by just counting haplogroup SNPs: unless there’s been not an acceleration but a deceleration of mutation rates (what makes little sense, IMO) there is no way that best studied Y-DNA branches, like R1b or O3 fit with their TMRCA estimated ages. A much older OOA than the usual c. 60-70,000 years ago seems a realistic consideration to me. In fact an OOA of c. 130,000 BP was precisely what I was “finding” with my amauterish logic (but logic after all). So I’m somehow glad to see that others with better qualifications and different methods seem to reach to the same conclusions, even if they shyly express them in generations (and not more impacting terms of years).

  • henry harpending

    Have a look at:
    Genetics, Vol. 178, 1571-1578, March 2008,
    Synergistic Fitness Interactions and a High Frequency of Beneficial Changes Among Mutations Accumulated Under Relaxed Selection in Saccharomyces cerevisiae, W. Joseph Dickinson
    Estimate is that 25% of mutations in yeast are favorable.
    Henry

  • http://www.pandasthumb.org RBH

    I’m a confused. Everything I know about evolution tells me that “fitness” is not a property of traits per se, but of the intersection of traits and selective environment. What sense does it make to construct a distribution of the fitness effects of mutations in the absence of a careful description of the selective context?

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This blog is about evolution, genetics, genomics and their interstices. Please beware that comments are aggressively moderated. Uncivil or churlish comments will likely get you banned immediately, so make any contribution count!

About Razib Khan

I have degrees in biology and biochemistry, a passion for genetics, history, and philosophy, and shrimp is my favorite food. In relation to nationality I'm a American Northwesterner, in politics I'm a reactionary, and as for religion I have none (I'm an atheist). If you want to know more, see the links at http://www.razib.com

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