Variation at Malaria Resistance Genes in Africans

描述（由申请人提供）：疟疾是世界范围内的主要死亡原因，影响世界人口的约41%。每年死于疟疾的100万人中，90%以上在撒哈拉以南非洲。虽然已经确定了一些候选基因在抵抗疟疾感染中发挥作用，但很少有研究表明这些基因的核苷酸变异在地理上不同的种族群体中，特别是来自非洲的种族群体中没有确定偏见。了解非洲人群的遗传变异和单倍型结构模式，以及这些模式如何受到人口统计学历史和自然选择的影响，对于确定在最近非洲起源的人群中对疾病易感性发挥作用的遗传变异将是重要的。本研究的目的是：（1）通过对13个不同种族的非洲人群中可能在抗疟疾感染中发挥作用的12个基因座和20个非编码对照区进行重测序，鉴定核苷酸变异并表征遗传多样性、单倍型结构和连锁不平衡（LD），（2）对次要等位基因频率（MAF）>10%的单核苷酸多态性（SNP）进行基因分型在来自非洲的1100个个体的样本以及欧洲人和亚洲人的比较样本中的候选基因座处，为了描述疟疾抗性基因座单倍型变异的地理分布（3），重建疟疾抗性候选基因的进化历史，并通过筛选自然选择的特征来鉴定包含潜在功能显著变异的基因区域和单倍型。该项目将有助于我们了解非洲人易受疟疾感染的遗传基础。此外，我们将确定标记有用的未来的关联研究的疾病易感性在非洲裔人口。最后，我们将更好地了解人类疟疾感染的进化历史以及自然选择和人口统计学对遗传疾病的流行和分布的作用。

DESCRIPTION (provided by applicant): Malaria is a leading cause of death worldwide, affecting approximately 41 % of the world's population. Over 90% of the 1 million deaths per year due to malaria are in sub-Saharan Africa. Although a number of candidate genes have been identified that play a role in resistance to malarial infection, there are few studies of nucleotide variation at these genes without ascertainment bias across geographically diverse ethnic groups, particularly from Africa. Knowledge of patterns of genetic variation and haplotype structure in African populations, and how these patterns are influenced by demographic history and natural selection, will be important for identifying genetic variants that play a role in susceptibility to disease in people of recent African origin. The aims of this study are (1) To identify nucleotide variation and characterize genetic diversity, haplotype structure, and linkage disequilibrium (LD) by resequencing at 12 loci that may play a role in resistance to malarial infection, and at 20 non-coding control regions, in 13 ethnically diverse African populations, and in a comparative sample of Europeans and Asians (2) To genotype Single Nucleotide Polymorphisms (SNPs) with minor allele frequency (MAF) >10% at the candidate loci in a sample of 1100 individuals originating from Africa, and a comparative sample of Europeans and Asians, in order to characterize the geographic distribution of haplotype variability at malarial resistance loci (3) To reconstruct the evolutionary history of candidate genes for malarial resistance and to identify gene regions and haplotypes containing potentially functionally significant variants by screening for signatures of natural selection. This project will contribute to our knowledge of the genetic basis of susceptibility to malarial infection in Africans. Additionally, we will identify markers useful for future association studies of disease susceptibility in populations of African descent. Lastly, we will have a better understanding of the evolutionary history of malarial infection in humans and the role of natural selection and demography on the prevalence and distribution of genetic disease.