SMBE 2014: Evidence for different mutation rates across human populations

Evidence for different mutation rates across human populations

Ron Do, David Reich
Department of Genetics, Harvard Medical School, Boston, USA

Although mutation rates (per base pair) have clearly changed across primate evolution, many analyses continue to assume that all present-day human populations have the same mutation rates. Recently, William Amos analyzed 1000 Genomes Project and Complete Genomics sequences and found evidence of significantly higher divergence rates on African than on non-African lineages since separation (W. Amos, PLoS One 4, e63048). The detected pattern was strongest in genomic regions of high polymorphism rate, a pattern that the author hypothesized was due to ‘heterozygote instability’, whereby gene conversion events surrounding heterozygous sites increase the mutation rate. To further test this observation, we measured the relative accumulation of mutations in lineages drawn from two different populations, using 25 deep genome sequences generated according to the same experimental protocol using the Illumina technology. We carried out pairwise comparisons of five sub-Saharan African (Dinka, Mandenka, Mbuti, San, Yoruba) and eight Non-African populations (Australian, Dai, French, Han, Karitiana, Mixe, Papuan, Sardinian) on all divergent sites.  We observed statistically significant differences in the relative accumulation of mutations for many pairs of African and Non-African populations. Among the strongest differences is significantly more lineage-specific mutations in Mbuti than in Han Chinese (R=1.044, standard error (SE) =0.0015).  On average, we observed about 1% more mutations on African lineages compared to Non-African lineages. We also observed some significant differences across non-African populations, with the Han Chinese who have experienced extreme expansions in population size associated with agriculture having more mutations than the Karitiana, a hunter-gatherer population from Amazonia who did not experience such expansions (R=1.015, SE=0.0014).  The results are consistent across both European and African segments of the human reference sequence, so are not an artifact of reference sequence bias. Taken together, these results support the view that per-base pair mutation rates may be dynamically and substantially changing across humans.

Identification of mutation rate polymorphism from genome-wide haplotype data

Cathal Seoighe
National University of Ireland Galway, Galway, Connaught, Ireland

The rate of germline mutation is known to vary significantly between species, but, as yet there are few examples of intra-specific mutation rate polymorphisms. Recent advances in sequencing technologies have enabled direct measurement of the human germline mutation rate for the first time from parent-offspring trios and one large-scale study in the Icelandic population reported that most of the variance in the rate of de novo mutation was the result of paternal age. Here we devise a strategy to infer mutation rate polymorphisms from derived allele profiles and apply this approach to human haplotype data from the one thousand genomes project. We demonstrate using coalescent simulations that a mutation that increases the rate of germline mutation is likely to result in a distinctive pattern of derived alleles in the genomic region in linkage disequilibrium with the affected locus. This signature is characterized by a number of haplotypes with a locally high proportion of derived alleles, against a background in which most of the haplotypes have a typical proportion of derived alleles. We searched for this signature in the one thousand genomes haplotype data and found a striking candidate close to a human histone deacetylase (HDAC2), which has been reported to be involved in the DNA damage response. The signature was found only in haplotypes of African or African-American origin and is consistent with the presence of a low-frequency allele with a significant impact on the germline mutation rate that has persisted for a large number of generations.