基诺族人群血糖调控适应环境与进化的多基因作用机制

As the fifty-sixth minority of China, the Jino minority nationality lives in Keno Town, Jinghong City, Sibsongbanna. It’s a special ethnic group which graded from primitive society to modern society directly. Our research group conducted an epidemiological survey of diabetes mellitus in Jino adults in 2012, and we found that Jino population showed significantly higher fasting glucose levels in comparison with Han Chinese. This finding may reflect that Jino people have higher capacity for storage and usage of nutrients, which might be closely related to their harsher living environment from generation to generation and later onset of agriculture. We further conducted genome-wide SNP genotying in 50 Jino samples, and found that genes involved in response to nutrients showed evidence of positive selection in Jinos, using FST-based test and statistic tests for detecting positive selection. On the basis of these important findings, we will analyze the association between these genes and glucose metabolism-related traits in a large Jino population (n=5987) in this project, aiming at discovering genes regulating glucose metabolism in Jinos. Then we will identify critical functional variants that underlie glucose regulation through target region enrichment deep re-sequencing. Finally, we will also elucidate the underlying mechanism by functional studies. This study is important for the interpretation of genetic mechanisms of metabolic adaptations in Jinos and will promote the understanding for adaptive evolution.

基诺族是我国第56个少数民族，聚居于西双版纳景洪市基诺乡，是一个由原始社会直接进入现代社会的特殊民族。课题组前期开展了基诺族糖尿病流行病学调查，发现基诺族血糖谱的特点与汉族人群存在显著差别，空腹血糖水平显著高于汉族人，该发现表明基诺族人群营养储存能力和利用效率更高，与其世代生存环境恶劣、农业起源晚密切相关。课题组进一步对50例基诺族样本进行了全基因组SNP检测，并通过遗传结构分析、正选择检验显示，基诺族受正选择的基因显著富集到营养素代谢相关通路上。本课题组拟以此重要发现为基础，通过研究正选择基因在5987例基诺族样本中与糖代谢相关复杂性状的关系，寻找基诺族血糖调控的重要基因，通过目标区域捕获测序，发现影响血糖调控的关键功能性变异，并通过分子和细胞生物学方法，解析功能性变异调控血糖的分子机制。本研究对认识人类进化过程中适应环境的机制具有重要理论意义。

基诺族是我国的第56个少数民族，直接由原始社会过渡到现代社会。本项目聚焦基诺族人群特点，开展大型流行病学调查研究，结果显示，基诺人群糖尿病前期患者中单独空腹血糖受损（FPG≥6.1mmol/L 并且<7.0 mmol/L）的占54.3%，在新诊断糖尿病患者中，单纯空腹血糖≥7.0mmol/L占50.1%，也就是说基诺族人群具有特殊的血糖谱，即以空腹血糖水平显著升高为主要特点。故我们推测节俭基因可能对于基诺族异常高的空腹血糖水平起了作用。本项目选取基诺个体共计212例，高血糖个体105例(≥ 7.46 mmol/L, 10.87 ± 3.77 mmol/L)，低血糖个体107例（仍处于正常范围，3.0~4.60 mmol/L, 4.28 ± 0.33 mmol/L），针对线粒体DNA进行全基因组测序，结果并没有找到一个常见的线粒体DNA突变能够导致高血糖的表型变化。随后，我们构建了一棵高分辨率线粒体DNA系统发生树，发现高血糖个体的比例随着个体分化时间越早则变得越高（P=0.038, R2=0.7009）。另外，我们对基诺族群作了奠基者分析，发现旧石器时代支系的高血糖个体比例（60.24%）要显著高于新石器时代支系的比例（38.27%，P=5.29×10-3）。结果指示在农业起源之前定居的基诺支系含有较高的空腹血糖水平，非常可能是当时长期的食物短缺的选择压力所导致的，而线粒体DNA非常可能作为一个节俭基因对基诺族的高空腹血糖水平起到作用。最后，项目对基诺人群的血液学检测进行分析，显示所有地中海贫血基因型携带者比非携带者小细胞低色素更严重。该地区成人地贫患病率约为12.6%，最常见的α地中海贫血基因突变类型为—SEA，β地中海贫血基因突变类型为HbE。相关论文发表于《BMJ-Open》杂志（2015 Dec 29;5(12):e010047）。