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Dissertation Research: Nucleotide Variability at G6pd and the Signature of Malarial Selection in Humans

论文研究：G6pd 的核苷酸变异性和人类疟疾选择的特征

基本信息

批准号：
0206756
负责人：
Michael Nachman
金额：
$ 1.01万
依托单位：
University of Arizona
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2002
资助国家：
美国
起止时间：
2002-08-01 至 2004-07-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=0206756&HistoricalAwards=false
关键词：
Dissertation Research Nucleotide Variability G6pd

项目摘要

Malaria is a major cause of illness and mortality in humans. Every year nearly 500 million people suffer from malaria and upward of 2 million people die from this tropical parasitic disease. Some human populations that have historically lived in regions with high levels of malaria infections carry genetic resistance factors to the disease. Among these genetic resistance factors are some variants (alleles) of the gene coding for glucose-6-phosphate dehydrogenase (G6PD). Thus G6pd is subject to positive natural selection in some human populations in malarious areas. Few examples of positive natural selection are recognized at the molecular level in humans and the effect of selection on the genome is not yet well understood. To understand the effect of selection on DNA nucleotide variability and to identify a signature of positive natural selection at the molecular level, this research will describe patterns of nucleotide variability within and around the gene coding for G6PD in humans. Specifically, this research will describe patterns of nucleotide variability within G6pd, and at ten other neighboring genes spanning over 2 Mb around G6pd in two distinct human populations from Africa and Iraq that bear independently arisen polymorphisms at G6pd that confer resistance to malaria. A random sample of 50 individuals from the Luo of Kenya, and 50 Iraqi Jews will be used in the study to (i) characterize the signature of selection on G6pd, (ii) characterize variation at loci linked to G6pd, (iii) estimate the age of the selected alleles based on patterns of nucleotide variability, and (iv) compare G6pd systems in Africa and Iraq to distinguish between deterministic factors (e.g. natural selection) and stochastic factors (e.g. genetic drift) that are responsible for shaping the observed nucleotide patterns.Patterns of nucleotide variability found in this study at G6pd that are due to selection by malaria will shed light on the evolutionary history of the association between Plasmodium falciparum (the primary human malaria parasite) and humans, a topic that is still not clearly understood. Furthermore, the ability to recognize the signature of positive natural selection in general at the molecular level in humans will be useful to possibly identify additional human genes that are subject to selection by various infectious diseases and ecological factors.

疟疾是人类疾病和死亡的主要原因。每年有近5亿人罹患疟疾，超过200万人死于这种热带寄生虫病。历史上生活在疟疾感染水平高的地区的一些人类人口携带着对这种疾病的遗传抗性因素。在这些遗传抗性因素中，有一些编码葡萄糖-6-磷酸脱氢酶(G6PD)基因的变异(等位基因)。因此，在疟疾地区的一些人群中，G6PD受到积极的自然选择的影响。人类在分子水平上认识到的积极自然选择的例子很少，而且选择对基因组的影响还没有被很好地理解。为了了解选择对DNA核苷酸变异的影响，并在分子水平上识别正向自然选择的特征，本研究将描述人类G6PD编码基因内部和周围的核苷酸变异模式。具体地说，这项研究将描述在来自非洲和伊拉克的两个不同的人类群体中，G6PD以及G6PD周围其他10个跨越2Mb以上的邻近基因的核苷酸变异模式，这两个不同的人群在G6PD上独立出现了赋予疟疾抗性的多态。来自肯尼亚卢奥人和50名伊拉克犹太人的随机样本将被用于研究中，以(I)表征G6PD上选择的特征，(Ii)表征与G6PD相关的基因座的变异，(Iii)基于核苷酸变异性的模式估计所选等位基因的年龄，以及(Iv)比较非洲和伊拉克的G6PD系统，以区分负责形成所观察到的核苷酸模式的确定性因素(例如自然选择)和随机因素(例如遗传漂移)。这项研究中在G6PD发现的由于疟疾选择而导致的核苷酸可变性模式将揭示恶性疟原虫(人类主要疟疾寄生虫)与人类之间关系的进化史，这一主题仍未被清楚地理解。此外，在分子水平上识别人类总体上的积极自然选择的特征的能力将有助于识别更多的人类基因，这些基因可能受到各种传染病和生态因素的选择。