人群经历长期分化和适应世居地环境，基因组中有害突变一般维持在一个较低水平。而彼此隔离分化的人群在近期大规模基因交流产生的混合人群，遗传负荷(genetic load)可能发生显著波动，这对人群的微观进化和疾病风险研究有重要影响。本项目选择我国典型的混合人群——新疆维吾尔族，采用新一代测序技术考察全基因组遗传变异，在群体和个体水平定量估计维吾尔族的遗传负荷；并与欧洲和东亚人群进行比较分析，确定维吾尔族中遗传负荷显著增加和降低的基因或基因组区域；进一步探讨基因交流对人群遗传负荷的作用机制，同时评估高遗传负荷基因变异在维族高发疾病如II-型糖尿病中的可能贡献；力图把维吾尔族进化遗传研究和医学遗传研究纳入到统一框架。本项目不仅从长期尺度上探讨维吾尔族遗传负荷形成和演化的机制，而且在近期尺度上揭示维吾尔族遗传负荷与其罹患高发性疾病的内在联系，因此在进化和生物医学研究中都具有重要科学价值和现实意义。

Harmful, or deleterious mutations decrease the fitness of the carriers in the population but are maintained on a low level due to natural selection, especially in those populations experienced a long time isolation and have adapted to the environment where they have been residing. However, deleterious mutations could significantly increase in a recent admixed population resulted from inter-marriages between previously mutually isolated populations when they come into contact through colonization and migration. Consequently, genetic load of the admixed population is expected to fluctuate significantly, most likely increase, which has great impact on both evolutionary and medical studies. In this proposed project, we focus on the genetic load analysis of the Uyghur population in Xinjiang, a typical admixed population with both East Eurasian and West Eurasian ancestries, as we have previously revealed. Next-generation sequencing technology will be used for generating whole-genome data in 50 individuals and genetic variation will be analyzed to estimate and evaluate the genetic load of the Uyghurs. Genes or genomic regions with genetic load significantly increased or decreased in the Uyghurs can be identified with comparisons to the data of the European and East Asian populations which are public available such as the 1000 Genomes Project. The mechanism of the genetic load fluctuation driven by gene flow between populations will be explored and the contribution of genes with high genetic load to high incidence diseases such as type II diabetes will be further estimated and evaluated. The ambition of this project is to establish a integrative paradigm for both the evolutionary genetics and medical genetics, so that not only the long-term microevolution of genetic load in an admixed population such as the Uyghur, but also the short-term risk impact of genomic variations in the Uyghur can be elucidated.