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，影响到约41%的世界人口。每年因疟疾死亡的100万人中，90%以上在撒哈拉以南非洲。尽管已经确定了许多候选基因在抵抗疟疾感染中发挥作用，但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，对这些基因的核苷酸变异的研究很少没有确定偏差。了解非洲人口的遗传变异模式和单倍型结构，以及这些模式如何受到人口历史和自然选择的影响，对于确定在非洲近代史人群中对疾病易感性起作用的遗传变异具有重要意义。本研究的目的是：(1)在13个不同种族的非洲人群中，通过对12个可能在疟疾感染抗性中起作用的位点和20个非编码控制区进行重测序，确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)对来自非洲的1100个个体和欧洲人与亚洲人的比较样本中候选位点上的小等位基因频率（MAF）为0 ~ 10%的单核苷酸多态性（snp）进行基因型分析；(3)重建疟疾耐药候选基因的进化史，通过筛选自然选择特征，鉴定含有潜在功能显著变异的基因区域和单倍型。这个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，我们将确定对未来非洲人后裔疾病易感性关联研究有用的标记。最后，我们将更好地了解人类疟疾感染的进化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.