The 84th Annual Meeting of the American Association of Physical Anthropologists (2015)


Genetic modifiers of IVD expression and leucine oxidation on a positively selected haplotype in East Asians

ELIZABETH A. BROWN1, TERENCE CAPELLINI1, MARYELLEN RUVOLO1 and PARDIS C. SABETI2.

1Department of Human Evolutionary Biology, Harvard University, 2Department of Organismic and Evolutionary Biology, Harvard University

March 26, 2015 3:00, Lindbergh Add to calendar

Human phenotypic variation along with genome-wide analyses of selection both indicate that infectious disease, climate, and diet have exerted strong selective pressure on diverse human populations within the past 50,000 years. However, few examples exist of selection on genetic loci firmly linked to metabolic phenotypes and selective factors. Here we use overlap between positively selected genetic loci and loci that associate with gene expression and phenotype to find functional candidates for selection. This method captures genetic loci that impact phenotype through modulating gene expression. Then, we use in vitro experiments and haplotype analysis to study the metabolic significance of loci under selection. Specifically, we probe genetic variants associated with expression of isovaleryl-CoA dehydrogenase (IVD), a gene responsible for leucine catabolism, in a region under positive selection in East Asians. Leucine is an essential amino acid in the human diet, found at high concentrations in eggs and cheeses, as well as soy beans, originally domesticated in East Asia. These genetic variants also associate with leucine metabolite levels in the blood. We use luciferase reporter gene assays in relevant human cell lines to show that derived alleles, at 80% frequency in East Asians, drive a 2.5-fold increase in expression over ancestral alleles. We further explore how differences in IVD mRNA expression in vitro translate into IVD protein expression and activity, through quantifying its metabolite, 3-Methylcrotonyl-Coenzyme A. Our results are consistent with selection on a haplotype that increases efficiency of leucine oxidation in Asians.

This project was funded by the National Institute of Health and Harvard University.