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

人类基因组的几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不能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基因组在人群和区域之间的变异模式，特别是当它与人类遗传疾病有关时。 疾病相关性研究被证明在识别某些疾病的风险个体方面是有用的;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）。 自然选择影响与特定基因或基因组相关的变异。 此外，与给定疾病相关的区域包含整个基因组的相对小的部分。 另一方面，历史进程会影响整个基因组。 虽然人类进化史的清晰图景正在浮现，但历史进程在多大程度上塑造了疾病基因的变异模式尚不清楚。 这项研究将评估历史进程在形成对传染病疟疾具有抵抗力的基因变异方面的作用。每年疟疾影响约5亿人，造成约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G6 PD基因的替代形式（等位基因）赋予对疟疾的抗性，并且这些等位基因在居住在疟疾环境中的人群中以高频率被发现。 有趣的是，赋予疟疾抗性的相同等位基因也可以引起遗传性疾病（即，镰状细胞性贫血、G6 PD缺乏）。 问题是，自然选择和历史进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，研究人员将对这两个基因的DNA序列变异模式进行双向控制比较，这些基因来自四个对疟疾具有不同易感性的非洲人群，作为选择剂。 四个种群中的两个（卢奥人和多贡人）居住在撒哈拉以南非洲受疟疾严重影响的地区，两个种群（桑人和东南班图人）生活在疟疾地区以外。 此外，为了剖析历史进程在这些人群中形成变异的作用，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号染色体的顶端（16p13.3），另一个区域位于X染色体上Duchenne肌营养不良基因的内含子（Dmd内含子44）内。 这个实验设计应该提供一个合理的假设检验框架，以区分那些影响单个基因的力量和那些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合作，以及亚利桑那大学和皮马社区学院学生的参与，将加强这项研究的知识和培训环境。

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.