人类线粒体基因组自然选择压力减弱与肥胖的相关性研究

According to the thrifty gene theory, human genomes have been adaptive to famines, but their phenotypes become obesity when food is abundant. This is a mainstream opinion on the etiology of complex metabolism-related diseases. Obesity is a type of metabolic disease with globally high prevalence, evaluated by body mass index (BMI). Mitochondrial genomes were considered probable thrifty gene candidates causing obesity. In our previous study on Uyghur population, a two-fold high N/S (non-synonymous mutation/synonymous mutation) in whole mtDNA genomes was observed in the low-BMI group compared to that in the high-BMI samples. The statistically significant results indicated that there were relaxed selective constraints on low-BMI individuals. Thus, we hypothesize that deleterious mutations accumulated in mtDNA resulted in the malfunction of mitochondria which were original thrifty phenotypes, and finally helped to avoid obesity. To verify this hypothesis, the aims of this project proposed here are to analyze the relationship between the variation of N/S on mtDNA and BMI in a normal Han Chinese population (samples from Taizhou Longitudinal Study), and further analyze the variation of N/S and other metabolism-related physiological traits. The accomplishment of this work would help to reveal the effect of relaxation of selective constraints on human diseases, renew the theory how thrifty genes were maintained in modern humans and lay foundations for further evolutionary research on the etiology of obesity.

节俭基因假说认为人类基因组原本适应饥饿条件，而在食物充足时的表型为肥胖，是人类复杂代谢疾病产生的主流假说。肥胖是一种全球高发的代谢性疾病，以身体质量指数（BMI）衡量。而线粒体基因组是一个可能导致肥胖的候选节俭基因。我们的前期研究发现，维吾尔族群体低BMI组中的线粒体基因组新发突变N/S(非同义突变/同义突变）是高BMI组的2倍多，统计上差异显著，提示低BMI组人群所携线粒体基因组经历的自然选择压力的减弱。因此推测，有害非同义突变的累积损害了节俭基因型线粒体的代谢功能，从而防止了肥胖的发生。为进一步检验这个假设，本项目拟在一个汉族人群（泰州健康队列）中研究线粒体基因组新发突变N/S的变化与BMI的关系，并进一步研究该值的变化与肥胖相关代谢性状的关系。本项目的完成，将揭示自然选择的减弱在人类疾病发生中作用，对节俭基因在现代人群中的维持提供理论上的补充，为从进化生物学角度研究肥胖成因奠定基础。

节俭基因假说认为人类基因组原本适应饥饿条件，而在食物充足时的表型为肥胖，是人类复杂代谢疾病产生的主流假说。肥胖是一种全球高发的代谢性疾病，以身体质量指数（BMI）衡量。而线粒体基因组是一个可能导致肥胖的候选节俭基因。我们的前期研究发现，维吾尔族群体低BMI组中的线粒体基因组新发突变N/S(非同义突变/同义突变）是高BMI组的2倍多，统计上差异显著，提示低BMI组人群所携线粒体基因组经历的自然选择压力的减弱。而本项目拟在一个汉族人群（泰州健康队列）中研究线粒体基因组新发突变N/S的变化与BMI的关系，从而进一步验证前期工作的结论。本项目最终完成了701个江苏泰州健康队列汉族样本的线粒体DNA测序。我们进而检测了泰州汉族的近期特有突变，发现样本随着BMI的升高，其携带突变N/S显著下降，与我们前期工作中在维族群体中所观测到的结果相一致。综合两个群体的结果推测，有害非同义突变的累积损害了节俭基因型线粒体的代谢功能，从而防止了肥胖的发生。另外，项目所测的线粒体DNA数据还应用于中国南方支系的群体扩张研究，以及作为参照群体应用于青藏高原族群的高原适应研究。