Dissertation Research: The Genetics of Malarial Selection in Sub-Saharan Africa

人类基因组近乎完整的序列极大地增强了我们对人类遗传学的理解。 然而，这个单一的参考序列无法捕捉人类遗传变异的程度和性质。 现在的努力正在转向描述跨人群和基因组区域的变异模式，特别是与人类遗传疾病相关的变异模式。 疾病关联研究被证明有助于识别有患某些疾病风险的个体；然而，许多人类基因组变异与疾病无关。 变异模式可以通过自然选择（例如疾病相关基因的变异）和历史过程（例如迁移和遗传漂变）来形成。 自然选择影响与特定基因或一组基因相关的变异。 此外，与给定疾病相关的区域仅占整个基因组的相对较小部分。 另一方面，历史过程影响整个基因组。 虽然人类进化史的更清晰图景正在浮现，但尚不清楚历史进程在多大程度上塑造了疾病基因的变异模式。 这项研究将评估历史过程在形成赋予对传染病疟疾抵抗力的基因变异方面的作用。每年疟疾影响约 5 亿人并导致约 200 万人死亡，其中绝大多数死亡发生在非洲。 已知 β-珠蛋白和 G6PD 基因的替代形式（等位基因）可赋予对疟疾的抵抗力，并且这些等位基因在居住在疟疾环境中的人群中出现频率较高。 有趣的是，赋予疟疾抵抗力的相同等位基因也可能导致遗传性疾病（即镰状细胞性贫血、G6PD 缺乏症）。 问题是自然选择和历史过程在塑造这些基因内部和周围的变异模式方面的相对作用是什么？ 为了解决这个问题，研究人员将作为选择剂，对四个对疟疾具有不同易感性的非洲人群中这两个基因的 DNA 序列变异模式进行双向控制比较。 四个人口中的两个（洛人和多贡人）居住在受疟疾严重影响的撒哈拉以南非洲地区，另外两个人口（桑人和东南班图斯人）生活在疟疾地区之外。 此外，为了剖析历史过程在形成这些人群变异中的作用，还将确定其他两个不受疟疾影响的基因区域的 DNA 序列。 其中一个区域位于 16 号染色体 (16p13.3) 的顶端，另一个区域位于 X 染色体上杜氏肌营养不良症基因 (Dmd 内含子 44) 的内含子内。 这种实验设计应该提供一个合理的假设检验框架，用于区分作用于单个基因的力量和影响整个基因组的力量。 此外，与亚特兰大疾病控制中心和肯尼亚内罗毕肯尼亚医学研究所的研究人员的合作，以及亚利桑那大学和皮马社区学院学生的参与，将增强这项研究的智力和培训环境。

The nearly complete sequence of the human genome has greatly enhanced our understanding of human genetics. This single reference sequence, however, is not able to capture the extent and nature of human genetic variation. Efforts are now are shifting to describing patterns of variation across populations and regions of the genome particularly as it relates to human genetic diseases. Disease association studies are proving useful in identifying individuals at risk for certain diseases; however, much of human genomic variation is not related to disease. Patterns of variation can be shaped by natural selection (e.g. on variants in disease-related genes) and historical processes (e.g., migration and genetic drift). Natural selection affects variation associated with a specific gene or set of genes. Additionally, regions associated with a given disease comprise a relatively small portion of the entire genome. Historical processes, on the other hand, affect the entire genome. While a clearer picture of human evolutionary history is emerging, it is not known to what extent historical processes have shaped patterns of variation at disease genes. This study will assess the role of historical processes in shaping variation at genes conferring resistance to the infectious disease, malaria.Each year malaria affects ~500 million people and kills ~2 million with the vast majority of these deaths occurring in Africa. Alternate forms (alleles) of the beta-globin and G6PD genes are known to confer resistance to malaria and these alleles are found at high frequencies in populations residing in malarial environments. Interestingly the same alleles that confer resistance to malaria can also cause inherited diseases (i.e., sickle cell anemia, G6PD deficiency). The question is what is the relative role of natural selection and historical processes in shaping patterns of variation in and around these genes? To address this the reseachers will perform a two-way controlled comparison of patterns of DNA sequence variation in these two genes in four African populations with different susceptibility to malaria as a selective agent. Two of the four populations (the Luo and Dogon) occupy regions of sub-Saharan Africa that are strongly impacted by malaria, and two populations (the San and Southeastern Bantus) live outside malaria areas. Additionally, to dissect the role of historical processes in shaping variation in these populations, DNA sequences of two other gene regions that are not affected by malaria will be determined. One of these regions is on the tip of chromosome 16 (16p13.3) and the other is within an intron of Duchenne Muscular Dystrophy gene (Dmd intron 44) on the X chromosome. This experimental design should provide a sound hypothesis-testing framework for distinguishing those forces that act a single gene from those that affect the whole genome. Furthermore, collaborations with researchers at the Center for Disease Control in Atlanta and at the Kenya Medical Research Institute in Nairobi, Kenya, as well as the involvement of students from the University of Arizona and Pima Community College, will enhance the intellectual and training environment of this research.