Variation in germline mutagenesis in humans and other great apes

Abstract

All heritable variation begins with damage or copying mistakes affecting the DNA of germline, eggs, or embryos. Different DNA motifs and loci can have different mutation rates, and these rates can vary or change over time and genomic space. Here, I present work documenting how the spectrum of mutability of three-base-pair motifs has evolved rapidly during great ape diversification. I show that even as ape mutation spectra diverged from each other, there exists spatial mutation spectrum variation between different genomic regions that is largely conserved across all species. The mutational process can be deconvoluted into a mixture of fast-evolving signatures with uniform spatial distributions and conserved signatures that target specific regions. I also present work showing variation in de novo mutagenesis at short tandem repeats in different human families. Short tandem repeats are genomic elements with an elevated mutation rate thought to largely result from polymerase slippage during replication. However, I find evidence that short tandem repeat mutation rates are associated with both paternal and maternal age at the birth of a proband. Because the maternal germline does not replicate after birth, the latter association supports a new possible damage-associated mutational pathway for these loci. Furthermore, I find that African genetic ancestry corresponds to a significantly higher short tandem repeat mutation rate, particularly at loci with high diversity. My findings may ultimately help determine the factors, either genetic or environmental, that contribute to temporal and spatial variation in germline mutagenesis.