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

Abstract

Establishing the age of each mutation segregating in contemporary human populations is important to fully understand our evolutionary history1,2 and will help facilitate the development of new approaches for disease gene discovery3. Large-scale surveys of human genetic variation have reported signatures of recent explosive population growth4-6, notable for an excess of rare genetic variants, qualitatively 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 (n=4,298) and African (n=2,217) American ancestry and inferred the age of 1,146,401 autosomal single nucleotide variants (SNVs). We estimate that ~73% of all protein-coding SNVs and ~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 compared to 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, illustrate the profound effect recent human history has had on the burden of deleterious SNVs segregating in contemporary populations, and provides important practical information that can be used to prioritize variants in disease gene discovery.

Homozygous missense variant in the human CNGA3 channel causes cone-rod dystrophy

“…No carriers of the c.955T4C variant were found among 552 ancestry-matched control chromosomes, in the 1000 Genomes database or in the 6500 individuals who are listed in the NHLBI-ESP variant database. 21,22 Segregation analysis confirmed biparental transmission of the variant (Figure 1). A statistically significant two-point LOD score of 3.14 at recombination fraction y ¼ 0 was observed for CNGA3-linked STR marker D2S2222, further supporting the linkage between the CRD phenotype and CNGA3 on chromosome 2q11.2 in family PKAB157.…”

“…(2) Known SNPs (db135 version) and variants recurring in the 1000 Human Genomes or NHLBI exome databases with a minor allele frequency of 40.01 underwent bioinformatic filtration. 21,22 (3) Non-conserved deep intronic changes, other than those present in predicted regulatory/promoter regions or at splice junctions, were filtered out. (4) Synonymous changes, other than those present at splice junctions, were also filtered out.…”

Pathway analysis with next-generation sequencing data

“…Genotype calling and quality control were described as previously. 33 After quality control of the data (Supplementary Information), a total of 18 737 genes with 575 259 SNPs were included in the analysis. We assembled 249 pathways from KEGG 34 and 308 pathways from Biocarta (http://www.biocarta.com).…”

PI4K2A deficiency in an intellectual disability, epilepsy, myoclonus, akathisia syndrome

“…One was a nonsense variant in exon 1 of PI4K2A , which would lead to protein truncation at amino acid 22 (chr10: 99400564C>A (hg19); c.65C>A; p.Ser22* (NM_018425)). This variant has not been observed in population databases 7, 8, 9, 10. Review of the WES data revealed that the variant had been missed by WES due to there being no coverage of this exon, likely due to high GC content.…”

“…The probability of loss of function intolerance (pLI) score for PI4K2A according to the Exome Aggregation Consortium (ExAC) is 0.98, indicating high probability that the gene is intolerant to loss‐of‐function variants, even in heterozygous state 7. There are no homozygous loss of function variants reported in PI4K2A in population databases7, 8, 9, 10 or in over 10,500 individuals of Pakistani origin from a study of myocardial infarction 11. Sanger sequencing confirmed the variant and showed that it segregates in homozygous state with the disease (Fig.…”