Date of Award
Doctor of Philosophy (PhD)
Mosaicism is pervasive in humans and yet we understand little of its causes and functional consequences across the lifespan. To help solve these mysteries, we developed a suite of tools, called Lachesis, to analyze postzygotic mutations (PZMs). LachesisDetect is a novel and accurate method to detect PZMs with VAFs as low as 0.04% from bulk RNA-seq samples. LachesisMap is an innovative supervised method to reconstruct postzygotic mutation phylogenies from putative prenatal PZMs. We applied Lachesis to 17,382 samples derived from 948 donors across 54 diverse tissues and cell types from the NIH’s Genotype-Tissue Expression (GTEx) project to produce the most comprehensive atlas of PZM variation in normal tissues. PZMs were pervasive and their burden and spectra were highly variable across donors and tissues. Postzygotic technical and biological variables contributed substantially to variance in mutation burden; however, only a minority of the variance was attributable to donor-specific effects. By mapping putative prenatal mutations to a developmental tree, we observed that mutation burden, spectra, and functional impact vary throughout time and space with the majority of prenatal mutations occurring during embryogenesis. Strikingly, we identified a class of prenatal mutations predicted to be more deleterious than any other broad category of human genetic variation and to be under positive selection as strong as somatic mutations in cancers. Comparing postzygotic germline mutations in testis and ejaculated sperm and de novo mutations in live offspring revealed that germ cell mutation deleteriousness appears to decrease during the germ cell life cycle. Together, these results suggest that PZMs may experience differential selective pressures throughout the human lifecycle to result in a complex and dynamic myriad of genomes within an individual. Uncovering the impacts of these PZMs on human health and disease will be an exciting and valuable endeavor.
Chair and Committee
Donald F. Conrad Barak Cohen
Ira M. Hall, Robi D. Mitra, Zach S. Pincus, Tychele N. Turner,
Rockweiler, Nicole Briana, "The Origins & Functional Effects of Postzygotic Mutations Throughout the Human Lifespan" (2021). Arts & Sciences Electronic Theses and Dissertations. 2525.