Analysis of 6,515 exomes reveals a recent origin of most human protein-coding variants

By Wenqing Fu, T. O’Connor, Goo Jun, Hyun Min Kang, Gonçalo R. Abecasis, Suzanne M. Leal, Stacey Gabriel, D. Altshuler, Jay Shendure, Deborah A. Nickerson and 4 more. 2012

970 citations recorded by the source corpus.

Establishing the age of each mutation segregating in contemporary human populations is important to fully understand our evolutionary history and will help to facilitate the development of new approaches for disease-gene discovery. Large-scale surveys of human genetic variation have reported signatures of recent explosive population growth, notable for an excess of rare genetic variants, suggesting that many mutations arose recently. To more quantitatively assess the distribution of mutation ages, we resequenced 15,336 genes in 6,515 individuals of European American and African American ancestry and inferred the age of 1,146,401 autosomal single nucleotide variants (SNVs). We estimate that approximately 73% of all protein-coding SNVs and approximately 86% of SNVs predicted to be deleterious arose in the past 5,000–10,000 years. The average age of deleterious SNVs varied significantly across molecular pathways, and disease genes contained a significantly higher proportion of recently arisen deleterious SNVs than other genes. Furthermore, European Americans had an excess of deleterious variants in essential and Mendelian disease genes compared to African Americans, consistent with weaker purifying selection due to the Out-of-Africa dispersal. Our results better delimit the historical details of human protein-coding variation, show the profound effect of recent human history on the burden of deleterious SNVs segregating in contemporary populations, and provide important practical information that can be used to prioritize variants in disease-gene discovery.

Subfields: Genetics, Molecular Biology

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Citations in the corpus

dbNSFP v2.0: A Database of Human Non-synonymous SNVs and Their Functional Predictions and Annotations (2013, methodology): “To facilitate filtering common SNVs observed in human populations, allele frequencies from the 1000 Genomes Project phase 1 data (Abecasis et al. 2012) and the NHLBI Exome Sequencing Project data (Fu et al. 2013) were added.”
Ensembl 2014 (2013, methodology): “Additional human data are imported directly from the 1000 Genomes Project (19), the Exome Sequencing Project (20) and from 14 individual genomes that provide genotype information.”
dbNSFP v3.0: A One-Stop Database of Functional Predictions and Annotations for Human Non-synonymous and Splice Site SNVs (2016, background): “…GERP++ [Davydov et al., 2010] and SiPhy C© 2015 WILEY PERIODICALS, INC. [Garber et al., 2009; Lindblad-Toh et al., 2011]; and allele frequencies from the 1000 Genomes Project phase 1 data [The 1000 Genomes Project Consortium, 2012]; and the NHLBI Exome Sequencing Project data [Fu et al., 2013].”
Variation Interpretation Predictors: Principles, Types, Performance, and Choice (2016, neutral): “and European-American populations [Fu et al., 2013].”
Neutral and weakly nonneutral sequence variants may define individuality (2013, background): “…variants to be ﬁ xed (become common) quickly, ( ii ) neutrals and weak nonneutrals are normally ﬁ xed at about the same rate via genetic drift (31), and ( iii ) in the presence of an evolutionary bottleneck, weakly nonneutral variants contribute to species ﬁ tness (chance of survival) (30).”
A proteome-wide fission yeast interactome reveals network evolution principles from yeasts to human (2016, neutral): “…on three examples: two (legend continued on next page) Mendelian disease variants (Stenson et al., 2014) that disrupt the human NMNAT1-NMNAT1 and PCBD1-PCBD1 interactions and one population variant from the Exome Sequencing project (Fu et al., 2013) that disrupts the human SNW1-PPIL1 interaction.”
Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program (2019, positive): “Our study extends previous efforts by identifying and characterizing the rare variants that comprise the majority of human genomic variation 7,10–12 .”