An abundance of rare functional variants in 202 drug target genes sequenced in 14,002 people

By Matthew R. Nelson, Daniel Wegmann, Margaret G. Ehm, Darren Kessner, P. S. St Jean, Claudio J. Verzilli, Judong Shen, Zhengzheng Tang, S. Bacanu, D. Fraser and 21 more. Science, 2012

717 citations recorded by the source corpus.

A Deep Look Into Our Genes Recent debates have focused on the degree of genetic variation and its impact upon health at the genomic level in humans (see the Perspective by Casals and Bertranpetit). Tennessen et al. (p. 64, published online 17 May), looking at all of the protein-coding genes in the human genome, and Nelson et al. (p. 100, published online 17 May), looking at genes that encode drug targets, address this question through deep sequencing efforts on samples from multiple individuals. The findings suggest that most human variation is rare, not shared between populations, and that rare variants are likely to play a role in human health. A pharmacogenomics analysis shows how challenging it will be to associate rare variants with phenotypes. Rare genetic variants contribute to complex disease risk; however, the abundance of rare variants in human populations remains unknown. We explored this spectrum of variation by sequencing 202 genes encoding drug targets in 14,002 individuals. We find rare variants are abundant (1 every 17 bases) and geographically localized, so that even with large sample sizes, rare variant catalogs will be largely incomplete. We used the observed patterns of variation to estimate population growth parameters, the proportion of variants in a given frequency class that are putatively deleterious, and mutation rates for each gene. We conclude that because of rapid population growth and weak purifying selection, human populations harbor an abundance of rare variants, many of which are deleterious and have relevance to understanding disease risk.

Subfields: Genetics

View Paper: https://www.semanticscholar.org/paper/859c7e6d91fe69c0946ad33c0c346509b2efeb31

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In Genetics

Citations in the corpus

An integrated map of genetic variation from 1,092 human genomes (2012, background): “…individuals from diverse, Recent efforts to map human 2–4 admixed, populations. origin, they exhibit increased levels of population differentiation 6– Characterizing such variants, for both point mutations and structural many variants of functional importance and is crucial for interpreting…”
Structure and dynamics of molecular networks: A novel paradigm of drug discovery: A comprehensive review (2012, background): “A more equal coverage is also required by the geographic clustering of rare genetic variants affecting drug efficacy (Nelson et al., 2012).”
Estimating the Unseen (2013, background): “A better understanding of these distributions of rare mutations would shed light on our evolutionary process and selective pressures [25, 29, 38].”
The Next-Generation Sequencing Revolution and Its Impact on Genomics (2013, neutral): “In any single gene, there are a large number of rare variants due to recent human population growth (Coventry et al., 2010; Nelson et al., 2012; Tennessen et al., 2012), and there may be many nonassociated variants in a gene.”
Low concordance of multiple variant-calling pipelines: practical implications for exome and genome sequencing (2013, methodology): “Recent studies have substantiated the prevalence of rare mutations in the human genome [1,2].”