The impact of sample size and population history on observed mutational spectra: a case study in human and chimpanzee populations.

Recent studies have highlighted variation in the mutational spectra among human populations as well as closely related hominoids - yet little remains known about the genetic and non-genetic factors driving these rate changes across the genome. Pinpointing the root causes of these differences is an important endeavour that requires careful comparative analyses of population-specific mutational landscapes at both broad and fine genomic scales. However, several factors can confound such analyses. Although previous studies have shown that technical artefacts, such as sequencing errors and batch effects, can contribute to observed mutational shifts, other potentially confounding parameters have received less attention thus far. Using population genetic simulations of human and chimpanzee populations as an illustrative example, we here show that the sample size required for robust inference of mutational spectra depends on the population-specific demographic history. As a consequence, the power to detect rate changes is high in certain hominoid populations while, for others, currently available sample sizes preclude analyses at fine genomic scales.