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

疟疾是人类患病和死亡的一个主要原因。每年有近5亿人患疟疾，200多万人死于这种热带寄生虫病。历史上生活在疟疾高感染率地区的一些人群携带对该疾病的遗传抗性因素。这些遗传抗性因子包括编码葡萄糖-6-磷酸脱氢酶（G6PD）基因的一些变异（等位基因）。因此，在疟疾流行地区的一些人群中，G6pd受到正自然选择的影响。在人类分子水平上认识到的积极自然选择的例子很少，选择对基因组的影响尚未得到很好的理解。为了了解选择对DNA核苷酸变异性的影响，并在分子水平上确定积极自然选择的特征，本研究将描述人类G6PD基因编码内部和周围的核苷酸变异性模式。具体来说，本研究将描述G6pd内的核苷酸变异模式，以及来自非洲和伊拉克的两个不同人群中G6pd周围超过2 Mb的其他10个邻近基因，这些基因具有独立出现的G6pd多态性，从而赋予疟疾抗性。研究将随机抽取50名肯尼亚罗人和50名伊拉克犹太人的样本，以(i)表征G6pd的选择特征，（ii）表征与G6pd相关的位点变异，（iii）根据核苷酸变异模式估计所选等位基因的年龄。（iv）比较非洲和伊拉克的G6pd系统，以区分形成所观察到的核苷酸模式的决定性因素（如自然选择）和随机因素（如遗传漂变）。本研究在G6pd发现的由疟疾选择引起的核苷酸变异模式，将揭示恶性疟原虫（主要的人类疟疾寄生虫）与人类之间关联的进化史，这一主题仍未得到明确理解。此外，在人类分子水平上识别一般积极自然选择特征的能力将有助于可能识别受各种传染病和生态因素选择影响的其他人类基因。

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.