The Evolution of Adipocytes During Human Origins: An Integrative Genomic, Cellular, and Molecular Approach

Abstract

Until recently, understanding of the evolutionary and molecular basis of many uniquely human traits has largely been hampered by the limited ability to perform experiments on, and access to samples from non-human primates. Induced pluripotent stem cell (iPSC) lines have provided virtually unlimited samples and allow, for the first time, precise experimental control in order to understand the relative roles of genetic, epigenetic and environmental effects. Selective forces have shaped our species throughout our evolutionary history, and by understanding how these forces work, we can gain valuable insight into how we are influenced by our environment. More specifically, by understanding how the traits that make us uniquely human evolved, we can begin to learn about the benefits, tradeoffs, and environmental interactions of each trait in the context of our survival and health. Traits that today are maladaptive may have been beneficial to us in the past when we were living in different environmental conditions.This dissertation focuses on adipocytes, the key component cell of fat, whose function was crucial during human evolutionary origins, as metabolic traits and diet were of particular importance. We have utilized of iPSCs from humans and chimpanzees to examine genome-wide gene expression and regulatory-element activity as well as perform experimental manipulation. Comparisons of human and chimpanzee adipocytes has allowed for the identification of species-specific differences in gene expression and open chromatin regions. We find enrichment in several interesting categories including ‘energy homeostasis, ‘diacylglycerol metabolism’ and ‘carnitine biosynthetic process’. We identify several genes related to the processing of dietary fatty acids that are expressed at a higher level in human adipocytes (FADS1/2 and ACSL5/6). Furthermore, we show that human lipid droplets are larger than chimpanzee droplets in white adipocytes but not brown adipocytes. Together this suggests concerted differences in how humans process and store dietary fatty acids.