  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. We 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. The proportion of
private mutations is additionally increased by purifying selection, which
differentially affect mutations of different functional annotations. 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.
