Abstract
BackgroundRecent studies have shown that human populations have experienced a complex demographic history, including a recent epoch of rapid population growth that led to an excess in the proportion of rare genetic variants in humans today. This excess can impact the burden of private mutations for each individual, defined here as the proportion of heterozygous variants in each newly sequenced individual that are novel compared to another large sample of sequenced individuals.ResultsWe calculated the burden of private mutations predicted by different demographic models, and compared with empirical estimates based on data from the NHLBI Exome Sequencing Project and data from the Neutral Regions (NR) dataset. We observed a significant excess in the proportion of private mutations in the empirical data compared with models of demographic history without a recent epoch of population growth. Incorporating recent growth into the model provides a much improved fit to empirical observations. This phenomenon becomes more marked for larger sample sizes, e.g. extrapolating to a scenario in which 10,000 individuals from the same population have been sequenced with perfect accuracy, still about 1 in 400 heterozygous sites (or about 6,000 variants) at the 10,001st individual are predicted to be novel, 18-times as predicted in the absence of recent population growth. The proportion of private mutations is additionally increased by purifying selection, which differentially affect mutations of different functional annotations.ConclusionsThe burden of private mutations for each individual, which are singletons (i.e. appearing in a single copy) in a larger sample that includes this individual, is predicted to be greatly increased by recent population growth, as well as by purifying selection. Comparison with empirical data supports that European populations have experienced recent rapid population growth, consistent with previous studies. These results have important implications to the design and analysis of sequencing-based association studies of complex human disease as they pertain to private and very rare variants. They also imply that personalized genomics will indeed have to be very personal in accounting for the large number of private mutations.
Highlights
Recent studies have shown that human populations have experienced a complex demographic history, including a recent epoch of rapid population growth that led to an excess in the proportion of rare genetic variants in humans today
Comparison with empirical data supports that European populations have experienced recent rapid population growth, consistent with previous studies
Comparison of site frequency spectra As the burden of private mutations is a function of the site frequency spectrum, we first contrasted the site frequency spectra between three demographic models, the Neutral Regions (NR) data [3], and the Exome Sequencing Project (ESP) data [1,7] (Figure 1)
Summary
Recent studies have shown that human populations have experienced a complex demographic history, including a recent epoch of rapid population growth that led to an excess in the proportion of rare genetic variants in humans today This excess can impact the burden of private mutations for each individual, defined here as the proportion of heterozygous variants in each newly sequenced individual that are novel compared to another large sample of sequenced individuals. A predicted consequence of the skew in the SFS due to population growth is an increase in the burden of private mutations for each individual We recently defined this quantity as the proportion of heterozygous positions in each newly sequenced individual that are novel, i.e., completely absent from a previously sequenced sample from the same population [9]. Empirical estimates in that paper were based on a small sample size of less than 100 individuals, while the contribution of recent rapid growth is expected to be more pronounced for larger sample sizes [1,2,3,4,5,6,9]
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