Doctoral Dissertation Research: Nucleotide Variabilityand Signatures of Natural Selection at the Human Vasopressin Type 2 and Oxytocin Receptor Loci

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Factors that affect an organism's survival and reproduction may be targets of natural selection, a major force influencing human evolution. A gene that has been subjected to selection may leave a "footprint" in the genome that can provide clues about the genetic basis of adaptation. Two genes (the oxytocin receptor [OTR] and vasopressin type II receptor [AVPR2]) that are vital to mammalian reproduction, homeostasis, and behavior will be sequenced in order to characterize nucleotide diversity among ethnically diverse humans. OTR plays critical roles in birth, lactation, and social and sexual behavior while AVPR2 is important for regulation of body water and electrolytes. These genes may have been targets of selection in primates, including humans. This will be the first study to survey both genes in a large sample (approximately 315 individuals) of healthy individuals from 21 geographically and ethnically diverse populations, including 11 distinct African populations. OTR and AVPR2 will also be sequenced in a number of nonhuman primate (NHP) species. The researchers will apply a variety of analytical tools to the data in order to: (1) characterize levels and patterns genetic diversity (2) detect signatures of selection and (3) clarify the evolutionary history of OTR and AVPR2. They will also test for correlations among genetic diversity and geography, climate, subsistence (e.g. hunting/gathering, agriculture) and ethnicity to look for evidence of local adaptation. Since this type of data can be influenced by factors such as historical population size, computer modeling will be used to distinguish the effects of selection and demography. This study will increase understanding of the genetic basis of human adaptations during the course of human evolution. Combined with findings from other studies, these data will help to distinguish the role of human demographic history, recombination, and natural selection on shaping patterns of variation in the human genome. This analysis of non-coding variation will improve knowledge about the demographic history of African populations and help to reconstruct modern human origins. By comparing AVPR2 and OTR in humans and NHP, we will gain knowledge about protein evolution in primates and genetic differences and similarities between humans and NHP. Due to the size and diversity of the sample, the SNPs identified should include both rare and common variants, some of which may be useful for the study of genetic susceptibility to disease. This project will directly support the training of a U.S. graduate student in molecular biology and population genetics and includes a number of African populations, which are underrepresented in many types of human genetics research. The data, including SNPs, will be made available publicly in online databases.