UC Berkeley

Nucleic acids are the medium of biology, transmitted over space and time. The biology of an organism manifests from the information encoded in its genome, resulting in the diversity of life we observe in the natural world. Mutations in an organism’s genome can thus fundamentally change how its biology is constructed. Most changes are expected to be neutral to slightly deleterious in nature and are usually mitigated by genome repair mechanisms. Genome repair is highly effective in healthy, young individuals, yet damage accumulates through aging. Unresolved mutations can destabilize the genome, resulting in aging-associated signatures of cellular dysfunction and disease [72]. Globally, the average human life expectancy has risen consistently as a function of industrialization, modernization, and improved public health [60]. Consequently, population structure has shifted towards larger, older populations, increasing the global burden of aging-associated disease and the urgency of understanding genomic mechanisms underlying aging processes [175]. The Human Genome Project, established in 1990 and completed in 2003, heralded the rise of sequencing and genomics. In the two decades following the project, further advances in sequencing technologies and human genetic resources have massively improved our understanding of the biology of genomes – however, the genetic basis of aging remains elusive. Increased lifespan and resistance to the molecular and physiological symptoms of aging (e.g. improved DNA repair) have evolved repeatedly across the tree of life, suggesting that longevity and robustness are not fixed. These changes arise from mutations and their propagation in response to their effect on fitness, as well as random fixation through drift, mediated by an organism’s environment and life history. Modern sequencing technologies now enable investigation of these processes across multiple timescales, from evolutionary comparisons among species to direct detection of mutations in individual cells. In my doctoral research, I characterize the mutation and evolution of genomes throughout aging using these technological advances to study aging across evolutionary, population, and somatic timescales.I begin by establishing the evolutionary framework for understanding aging, integrating theory with modern genomic approaches that are enabled by high-quality sequencing technologies. In First, in Chapter 1, I review the evolutionary theories of aging and provide an overview of key genes identified through comparative genomics, highlighting the relationship between genetics, life history, and environment in modulating lifespan and aging. Subsequently, I discuss the population genetics of aging, presenting findings from studies of vertebrate populations and highlighting notable results from studies of human population genetics and genomic instability in aging. Finally, I describe how comprehensive sequencing and functional genomic approaches have transformed our ability to study aging mechanisms. This work underscores the importance of approaching aging from both evolutionary and molecular perspectives, and establishes the methodological foundation for studying genetic mechanisms of longevity in natural populations.Next, in Chapter II, I demonstrate the application of advanced sequencing technologies to create genomic resources for studying longevity mechanisms in natural systems. I present a complete, haplotype-resolved genome assembly for Sebastes paucispinis. S. paucispinis (maximum lifespan: 70 years), also known as bocaccio rockfish, is an ecologically important and critically endangered rockfish species native to the western coast of the United States. Rockfish (genus Sebastes) are a richly diverse clade of teleost fishes that exhibit highly variable lifespans, ranging from as little as 11 years to over 200 years [99]. The longevity of species like S. paucispinis emerges from genetic mechanisms that confer resistance to aging processes, shaped by the interplay between genetics, environment, and life history over long periods of evolutionary time. Bocaccio, once plentiful in the early 20th century, were federally declared overfished following depletion from the 1980s through the early 2000s. Overfishing, in combination with the species’ relatively long generation time (20 years), has driven a severe population collapse of bocaccio populations over the last 20 years. This high-quality genome assembly, created as part of the California Conservation Genomics Project (CCGP), enables comparative genomic analyses and supports near and long term studies of how genetic mechanisms underlying longevity respond to anthropogenic stressors and population bottlenecks.Finally, in Chapter III, I present my analyses of germline mobile element insertions, directly identified from long-read sequencing of human sperm cells to understand how aging affects mutation accumulation in individual gametes. Human germline tissues accumulate far fewer mutations than somatic tissues. However, the germline mutation rate rises steadily with age, increasing the risks of developmental and neurological disease to children conceived in advanced age. This trend is especially pronounced in the paternal germline, evidenced by both a decline in sperm quality (e.g. motility, count) and an increased burden of de novo mutations in children born to older fathers. By leveraging trio or pedigree information, these mutations can be phased to the parental gamete of origin and distinguished from inherited genetic variation. However, isolation of de novo mutations is significantly more difficult without parental reference information. To address this challenge, I employ highly accurate long-read sequencing to sequence sperm genomes and directly identify mutations, specifically de novo mobile element insertions, by developing a novel approach that uses personal reference genome assemblies rather than requiring parental genomes.In summary, my work demonstrates how advances in sequencing technology enable joint experimental and computational approaches to characterize the mutation and evolution of genomes across evolutionary, population, and somatic timescales. These technological capabilities allow us to study aging mechanisms from the deep evolutionary origins of longevity differences among species, through population-level responses to environmental pressures, to the cellular processes of mutation accumulation within individual organisms.