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Recent studies have shown that human populations have experienced a complexdemographic history, including a recent epoch of rapid population growth thatled 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 sequencedindividual that are novel compared to another large sample of sequencedindividuals. We calculated the burden of private mutations predicted bydifferent demographic models, and compared with empirical estimates based ondata from the NHLBI Exome Sequencing Project and data from the Neutral Regions(NR) dataset. We observed a significant excess in the proportion of privatemutations in the empirical data compared with models of demographic historywithout a recent epoch of population growth. Incorporating recent growth intothe model provides a much improved fit to empirical observations. Thisphenomenon becomes more marked for larger sample sizes. The proportion ofprivate mutations is additionally increased by purifying selection, whichdifferentially affect mutations of different functional annotations. Theseresults have important implications to the design and analysis ofsequencing-based association studies of complex human disease as they pertainto private and very rare variants.

High burden of private mutations due to explosive human population growth and purifying selection