Assessing the evolutionary impact of amino acid mutations in the human genome.

PLoS Genet 2008 May 30;4(5):e1000083. Epub 2008 May 30.

Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, USA.

Quantifying the distribution of fitness effects among newly arising mutations in the human genome is key to resolving important debates in medical and evolutionary genetics. Here, we present a method for inferring this distribution using Single Nucleotide Polymorphism (SNP) data from a population with non-stationary demographic history (such as that of modern humans). Application of our method to 47,576 coding SNPs found by direct resequencing of 11,404 protein coding-genes in 35 individuals (20 European Americans and 15 African Americans) allows us to assess the relative contribution of demographic and selective effects to patterning amino acid variation in the human genome. 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. After accounting for these demographic effects, we find strong evidence for great variability in the selective effects of new amino acid replacing mutations. 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 (|s|<0.01%), 30-42% are moderately deleterious (0.01%<|s|<1%), and nearly all the remainder are highly deleterious or lethal (|s|>1%). Our results are consistent with 10-20% of amino acid differences between humans and chimpanzees having been fixed by positive selection with the remainder of differences being neutral or nearly neutral. Our analysis also predicts that many of the alleles identified via whole-genome association mapping may be selectively neutral or (formerly) positively selected, implying that deleterious genetic variation affecting disease phenotype may be missed by this widely used approach for mapping genes underlying complex traits.

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1000083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2377339PMC
May 2008
15 Reads
265 Citations

Publication Analysis

Top Keywords

amino acid
16
human genome
12
selective effects
8
mutations human
8
find evidence
4
variation human
4
effects patterning
4
patterning amino
4
acid variation
4
genome find
4
ancient population
4
ancestry bottleneck
4
bottleneck sample
4
sample european
4
african ancestry
4
sample african
4
population expansion
4
expansion sample
4
evidence ancient
4
relative contribution
4

Similar Publications