Comparative analyses of somatic mutational processes in primates across lifespans

Project Summary Abstract The vast diversity in lifespans among organisms provides a remarkable natural experiment in which to explore the evolutionary innovations that have shaped the extensive variation of this phenotype. Non-human primates represent a critical taxon for understanding the evolution of human lifespan due to their close phylogenetic proximity and broad

range of lifespans. One key hallmark of aging is genomic instability and the accumulation of somatic mutations. Only recent improvements in the accuracy of genome sequencing have enabled the study of these mutations in aging tissues. A subset of these mutations confer growth advantages driving carcinogenesis, however emerging evidence

also highlights their role in several other age-associated diseases and potentially aging itself. We recently demonstrated that somatic mutation rates are inversely correlated with lifespan in mammals, consistent with a potential causal role in aging. Furthermore, comparative genomics analyses we and others have performed across

species with diverse lifespans have determined that DNA repair genes are key players in adaptations to long life. Here, we propose to characterize somatic mutational landscapes of aging in primate species spanning 70 million years of evolution. These maps will be generated across 10 tissue types from a collection of marmosets, macaques, baboons,

chimpanzees and humans of diverse ages and both sexes using ultra-accurate NanoSeq mutation profiling. For a subset of tissues we will also perform PacBio long read sequencing to assess somatic structural variants. These data will be supplemented with NanoSeq profiling of several cell types from 17 additional primate species. Together, these maps

will allow us to ascertain how somatic mutational processes, including mutation rates and signatures, vary with age

across primate species with diverse life spans and life histories. As a result of these somatic mutations as we age many tissues also become colonized by clonal expansions of positively selected mutant cells. To determine how these clonal dynamics relate to species lifespan we will next perform deep targeted-NanoSeq on 250 genes, known to drive clonal

expansions in humans, across individuals of different ages from 8 of the aforementioned species. These analyses will

permit identification of the mutations driving clonal expansions, the rate at which these expansions occur during aging, and spatial clonal dynamics across the lifespan in diverse species and tissues, informing our understanding of how they contribute to aging. Finally, we will seek to identify the species-specific genetic determinants of these somatic

mutation phenotypes. We will perform a phylo-GWAS analysis to identify the genes associated with differences in mutational patterns among species using both general phenotypes (e.g. lifespan, body size) as well as the molecular mutational phenotypes identified in aims 1 and 2 (e.g. mutation rates, spectra, and clonal dynamics). These

comparative genomics approaches will allow us to link both broad primate phenotypes and quantified molecular phenotypes to the evolutionary innovations that have impacted lifespan in the primate clade. Together these multi-

scale evolutionary comparisons will reveal factors that contribute to the diversity of life spans across primates and to ultimately identify novel targets for interventions to extend human health span.