Files
Abstract
Demographic dynamics and natural selection during human evolution shaped present-day patterns of genetic variation, contributing to varying disease prevalence across human populations. Natural selection of adaptive alleles in historically stable environments increased allele frequencies and forged gene-environment matches that maintained population fitness. However, modern rapid changes in lifestyle and environment have created gene-environment mismatches, which may partly explain current chronic disease epidemics. To enhance our understanding of these mismatches and facilitate the development of genome-informed personalized treatment plans, we aim to characterize the genetic variants for metabolic genes that play essential roles in human evolution and health. ACSL1 encodes long-chain fatty acyl-CoA synthetase 1, one of the rate-limiting enzymes in fatty acid metabolism that convert long-chain fatty acids to their corresponding fatty acyl-CoAs. In Chapter 2, we revealed that genetic variants around ACSL1 were adaptive to certain local environmental factors during human evolution and raised to high frequencies in some human populations. These genetic variants are associated with the risk of type 2 diabetes, the blood glucose level, the age at menopause, and the sizes of blood cells. The geographically varying frequencies of these variants may contribute to different trait levels or disease prevalence across human populations.
Another gene family involved in fatty acid metabolism, the fatty acid desaturases (FADS), has also undergone positive selection during human evolution. We reviewed the biological function of the FADS gene cluster, and summarized the genetic, epigenetic regulation and environmental factors that influence FADS expressions in Chapter 3. In chapter 4, we focused on characterizing the functional effects of two specific SNPs, rs174557 and rs968567, on the expression of FADS1 and FADS2. Using reporter assays and prime editing, we found that rs174557 and rs968567 may interact with each other to regulate FADS1 and FADS2 expression.
Overall, these findings provide valuable insights into the genetic regulation of fatty acid metabolic pathways, emphasizing the complexity of fatty acid metabolism and the significant influence of evolutionary dynamics on present-day health disparities. By characterizing these genetic variants, our study facilitates the development of precision medicine, aiming to mitigate the adverse effects of gene-environment mismatches through personalized treatment plans.