Nonsense SNPs introduce premature termination codons into genes and can
result in the absence of a gene product or in a truncated and
potentially harmful protein, so they are often considered
disadvantageous and are associated with disease susceptibility. As
such, we might expect the disrupted allele to be rare and, in healthy
people, observed only in a heterozygous state. However, some, like
those in the CASP12 and ACTN3 genes, are known to be
present at high frequencies and to occur often in a homozygous state
and seem to have been advantageous in recent human evolution. To
evaluate the selective forces acting on nonsense SNPs as a class, we
have carried out a large-scale experimental survey of nonsense SNPs in
the human genome by genotyping 805 of them (plus control synonymous
SNPs) in 1,151 individuals from 56 worldwide populations. We identified
169 genes containing nonsense SNPs that were variable in our samples,
of which 99 were found with both copies inactivated in at least one
individual. We found that the sampled humans differ on average by 24
genes (out of about 20,000) because of these nonsense SNPs alone. As
might be expected, nonsense SNPs as a class were found to be slightly
disadvantageous over evolutionary timescales, but a few nevertheless
showed signs of being possibly advantageous, as indicated by unusually
high levels of population differentiation, long haplotypes, and/or high
frequencies of derived alleles. This study underlines the extent of
variation in gene content within humans and emphasizes the importance
of understanding this type of variation.
