Doctoral Dissertation Research: Characterization and Functional Validation of the Genetic Architecture of Skin Pigmentation

University Of California-Davis, Davis CA

Investigators

Abstract

Research on the evolution of human skin pigmentation includes the characterization of this characteristic's underlying genetic variation. Recent studies have shown that the number of genes associated with skin pigmentation differs across populations and that much of this genetic variation is still unidentified due to underrepresentation of some populations in human genetic research. This doctoral dissertation project lays the groundwork necessary to model human skin pigmentation evolution by characterizing and functionally validating the genetic architecture of skin pigmentation in a population that has been underrepresented in such research. Data generated from this project can inform several pigmentation research objectives, including understanding the role of natural selection in shaping this human trait. The project can also be used as a model for research on other complex genetic traits and may inform other fields including bioarchaeology and forensic anthropology. Additionally, this project contributes to the skill development of undergraduate and graduate students through wet lab, computational, and fieldwork training. The research team conducts fieldwork to collect paired genetic and pigmentation data from individuals in a population with high levels of ancestral alleles and higher levels of genetic diversity than other extant human populations. The research presents an opportunity to research pigmentation variation that may have been present in ancestral human populations, and therefore potentially broadens our understanding of pigmentation genetics globally. Newly collected samples will be genotyped and then evaluated using a genome-wide association (GWA) approach. Data from four different descent populations will be meta-analyzed to increase power to detect low-effect size loci. Regions identified in the GWA study are not necessarily causal pigmentation loci, rendering functional validation necessary. Top candidate genes are therefore identified and functionally evaluated for causality with CRISPR (clustered regularly interspaced short palindromic repeats) gene editing in zebrafish, an effective model organism to study human skin pigmentation. Using a rapid automated phenotyping platform to image larvae, pigmentation is analyzed comparing CRISPR- mosaic “knockout” fish with “mock” injected sibling controls. This strategy can functionally verify whether novel associated genes from the GWAS are causal pigmentation genes. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.