Doctoral Dissertation Improvement: Patterns of Genetic Diversity and Signatures of Natural Selection at the Intercellular Adhesion Molecule-1 (ICAM-1) and CD36 Loci

博士论文改进：细胞间粘附分子 1 (ICAM-1) 和 CD36 位点的遗传多样性模式和自然选择特征

• 批准号: 0925802
• 负责人: Sarah Tishkoff
• 金额: --
• 依托单位: University of Pennsylvania
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0925802&HistoricalAwards=false
• 关键词: Doctoral; Dissertation; Improvement; Patterns; Genetic

Understanding the scope of human genetic variation and how evolutionary forces like natural selection, genetic drift, and mutation have shaped the human genome is key to describing the genetic history that underlies all human populations. Identifying patterns of nucleotide variation that have resulted from natural selection may also help identify genetic variants that influence disease susceptibility and will further clarify the context of modern human evolution. Malaria, resulting from infection by Plasmodium falciparum, causes millions of deaths each year, and is one of the strongest selective forces in recent human evolution. Because genetic variants at malaria resistance candidate genes may be targets of natural selection, nucleotide diversity at these loci can be examined to identify variants that affect susceptibility to malarial disease. African populations are particularly informative for studying patterns of genetic variation at malaria susceptibility candidate genes because they contain a high level of genetic diversity and are likely to have previously unknown genetic variants. In addition, due to high malarial endemicity in certain regions of Africa, it is likely that evidence of local adaptation to malaria will be detected within diverse African populations. The aim of this project is to examine patterns of nucleotide variation, using DNA re-sequencing technology, at two malaria resistance candidate genes, intercellular adhesion molecule-1 (ICAM-1) and CD36, in a diverse group of African and non-African human populations (39 total populations). This project will: 1) identify and characterize patterns of nucleotide diversity at two loci that have been suggested to influence susceptibility to malarial disease, 2) conduct statistical analyses to identify signatures of natural selection and examine the effects of demography, and 3) test for correlations between genetic diversity and climate, subsistence strategy, ethnicity, and the prevalence of P. falciparum infection. These data will add to our limited knowledge of genetic diversity and the demographic history of African populations. These data will also add to our knowledge of how demography and natural selection have shaped patterns of variation within the human genome. Ultimately, this research will provide a clearer picture of human genetic adaptation and the co-evolution of human and P. falciparum genomes, and will contribute to the training of a doctoral student from an underrepresented group in anthropological genetics.

了解人类遗传变异的范围以及自然选择、遗传漂变和突变等进化力量如何塑造人类基因组，是描述所有人类种群遗传历史的关键。 识别自然选择导致的核苷酸变异模式也可能有助于识别影响疾病易感性的遗传变异，并将进一步澄清现代人类进化的背景。由恶性疟原虫感染引起的疟疾每年导致数百万人死亡，并且是最近人类进化中最强的选择性力量之一。 由于疟疾抗性候选基因的遗传变异可能是自然选择的目标，因此可以检查这些基因座的核苷酸多样性以鉴定影响疟疾疾病易感性的变异。 非洲人群对于研究疟疾易感性候选基因的遗传变异模式特别有用，因为他们含有高水平的遗传多样性，并且可能具有以前未知的遗传变异。 此外，由于非洲某些地区的疟疾流行率很高，很可能会在不同的非洲人口中发现当地适应疟疾的证据。 该项目的目的是利用DNA重测序技术，在非洲和非非洲人口的不同群体（总共39个人口）中，检查两个疟疾抗性候选基因细胞间粘附分子-1（ICAM-1）和CD 36的核苷酸变异模式。 该项目将：1）确定和表征两个位点的核苷酸多样性模式，这两个位点被认为会影响对疟疾疾病的易感性，2）进行统计分析，以确定自然选择的特征，并检查人口统计学的影响，3）测试遗传多样性与气候，生存策略，种族和恶性疟原虫感染流行率之间的相关性。这些数据将增加我们对非洲人口遗传多样性和人口统计历史的有限了解。 这些数据还将增加我们对人口统计学和自然选择如何塑造人类基因组内变异模式的认识。 最终，这项研究将为人类遗传适应以及人类和恶性疟原虫基因组的共同进化提供更清晰的画面，并将有助于培养来自人类遗传学代表性不足的博士生。