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

影响生物体生存和繁殖的因素可能是自然选择的目标，而自然选择是影响人类进化的主要力量。一个经过选择的基因可能会在基因组中留下“足迹”，为适应的遗传基础提供线索。两个对哺乳动物繁殖、动态平衡和行为至关重要的基因(催产素受体和加压素II型受体[AVPR2])将被测序，以表征不同种族人类之间的核苷酸多样性。OTR在出生、哺乳、社会和性行为中起着关键作用，而AVPR2在调节体内水分和电解质方面起着重要作用。这些基因可能是包括人类在内的灵长类动物的选择目标。这将是第一次对来自21个地理和种族不同的人群(包括11个不同的非洲人群)的健康个体的大样本(约315个个体)中的这两个基因进行调查。OTR和AVPR2也将在一些非人类灵长类动物(NHP)物种中进行测序。研究人员将对这些数据应用各种分析工具，以便：(1)表征遗传多样性的水平和模式；(2)检测选择的特征；(3)阐明OTR和AVPR2的进化史。他们还将测试遗传多样性与地理、气候、生存(如狩猎/采集、农业)和种族之间的相关性，以寻找当地适应的证据。由于这类数据可能会受到历史人口规模等因素的影响，因此将使用计算机建模来区分选择和人口统计的影响。这项研究将增加对人类进化过程中人类适应的遗传基础的理解。结合其他研究的发现，这些数据将有助于区分人类人口历史、重组和自然选择在塑造人类基因组变异模式方面的作用。这种对非编码变异的分析将增进对非洲人口历史的了解，并有助于重建现代人类起源。通过在人类和NHP中比较AVPR2和OTR，我们将获得关于灵长类动物蛋白质进化的知识，以及人类和NHP之间的遗传差异和相似之处。由于样本的大小和多样性，确定的SNPs应该包括罕见和常见的变异，其中一些可能有助于研究疾病的遗传易感性。该项目将直接支持一名美国研究生在分子生物学和人口遗传学方面的培训，并包括一些在许多类型的人类遗传学研究中代表性不足的非洲人口。包括SNPs在内的数据将在在线数据库中公开提供。

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.