Investigating evolutionary changes to the genetic architecture of the postcranial skeleton in humans and other mammals

Abstract

With a haploid size of over 3 billion base pairs, identifying the genomic regions involved in any given human trait is a daunting problem of finding a needle in a haystack. To add complexity, most traits are highly polygenic – that is, controlled by many genetic loci with small individual effects – so the problem is more akin to finding hundreds to thousands of tiny needles in that same haystack. A promising approach to making this problem more feasible is to partition the genome using biological information relevant to the trait, such as genome-wide association studies (GWAS) or chromatin accessibility data (e.g., ATAC-seq) in relevant tissues. In this dissertation, I use these approaches to identify genomic positions which have shaped the development of the postcranial skeleton in humans and other mammals. In Chapter 2, I combine human GWAS on eleven complex traits with genotypic and phenotypic data on hundreds of mammals to identify genomic positions that have evolved in parallel across Mammalia. I find that evolution in body size and red blood count across mammals has repeatedly utilized non-coding nucleotide changes underlying variation in those traits in humans. In Chapter 3, I investigate genomic evidence for the role of limb integration in autopod (hand and foot) evolution by characterizing regulatory elements and genes involved in the patterning and growth of the human autopod skeleton at the cartilage stage. I show that natural selection has acted more strongly on the foot than the hand and that while some regions of anatomical change in the autopod are consistent with a few loci of large effect, changes in the size of the posterior digits are consistent with an additive, polygenic model. In Chapter 4, I combine autopod regulatory regions with data on other skeletal elements across the postcranium to comprehensively test regulatory elements involved in the developing postcranial skeleton for differential enhancer activity between human and chimp using a massively parallel reporter assay (MPRA). In doing so, I simultaneously assess the efficacy of multiple methods for identifying genomic regions with human-specific regulatory properties based on comparative genomics. Altogether, this dissertation combines comparative and functional genomic approaches to identify genomic regions involved in the evolution and development of the human postcranial skeleton and highlights changes to regulatory elements that may play causative roles in trait biology.