人类基因组体重调控相关基因位点的选择信号：对“节俭基因”假说的验证

The thrifty gene hypothesis proposes that obesity is a consequence of selection in our evolutionary history which favored the spread of genes that promote fat storage. It is suggested that these thrifty genes were positively selected because people storing greater amounts of body fat were more likely to survive during periods of famine. It has been proposed that a direct test of this hypothesis would be to examine the human genome for signs of strong selection in the neighborhood of genes that have been associated with obesity. To date about 38 SNPs have been associated with body mass index (BMI) in genome wide association studies (GWAS).. Unfortunately BMI is a very imprecise measure of body fatness and SNPs leading to changes in BMI do not necessarily need to impact on stored body fat levels. For example, genes influencing lean tissue mass will also have effects on BMI. The de novo data set will include measurements of body fatness using more precise and accurate measurements than BMI (based on deuterium dilution and the bioimpedance methods) in a population of 300 urban living Han Chinese. In addition we will measure the SNP profiles of these individuals using the affymetrix axiom phase I and II arrays which contain 1.2 million SNPs covering 90% of the genome. We will use these data to confirm which SNPs link to adiposity and then explore the haplotype configuration around the target SNPs aiming to identify regions of homozygosity reflective of strong selective sweeps using the 1000 genomes and hapmap databases, as well as the data provided by the axom arrays. This is a ‘gene to sweep’ approach. The second strategy will be to take the reverse path. Looking for regions of homozygosity in the genome that might reflect selection events and then taking target SNPS in this region and looking for linkage to obesity measured using the more sophisticated measurements than BMI – the ‘sweep to gene’ approach. This work will provide a direct test of the thrifty gene hypothesis in relation to the causes of obesity.

节俭基因理论认为，人类进化史选择倾向于那些促进脂肪储存的基因的扩散，从而导致肥胖。储存脂肪越多，越能活过荒年，因此节俭基因被正向选择下来。支持这一假说的直接证据就是人类基因组上肥胖相关基因附近是否存在强的选择信号。GWAS分析找到了38个与BMI相关的SNP，但BMI并不能准确衡量肥胖，导致BMI变化的SNP并不一定影响肥胖水平。本研究中，我们将以300例中国汉族城市居民人群为对象，采用比BMI更精确的指标来评价每个个体的肥胖度，并检测其SNP表达谱，用于确认哪些SNP与肥胖相关，然后检测这些SNP附近的单倍体构型，以期发现能反映选择漂变的纯和子区域，这是gene to sweep策略；另一种反向策略是，先找到基因组上可能反映选择事件的纯合子区域，然后选取该区域的目标SNP，寻找这些SNP与肥胖度之间的相关性，即sweep to gene策略。本项目对导致肥胖发生的节俭基因假说是最直接验证

肥胖是一种可遗传的复杂表型。家系和双生子试验证明，肥胖个体间的差异的65%来源于遗传因素。关于肥胖进化理论的一种流行的解释是“节俭基因”假说，根据该假说，在进化过程中，肥胖的个体能在食物短缺时存活下来，因此肥胖表型被优先选择。该假说的一个分支认为，节俭基因在人类进化的早期是普遍存在的，另一种认为，直到15000年前，即农耕文明开始的时候进化才优先选择肥胖表型。本项目的目的是通过对公共数据库的数据进行检索和分析，以验证之前被认为与体重指数（BMI）相关的SNP上潜在的正选择信号。我们采用了一系列指标来计算正选择，找到了9个基因上存在正选择信号，这对于最近发生的正选择来说值并不高，即便如此，在这9个当中，有7个基因选择信号是倾向于瘦而不是肥胖表型的。这一结果有力的驳斥了“节俭基因”假说。本项目的另一个目标是通过分析身材吸引力和肥胖的关系来从另一个侧面验证“节俭基因”假说，论点是如果肥胖使我们能度过食物短缺时期，那么肥胖就应该是一种适应性信号，也就应该是一种第二性征。我们根据这种预测的适应性和肥胖的关系建立了一个数学模型来验证身材吸引力和肥胖之间关系是否是这种模式的映照。通过对来自10个不同人群的调查结果发现并不支持这一理论。此外，我们进行了其他两项研究来探索能量摄入、代谢和肥胖之间的关系。首先，我们首次检测了大熊猫的代谢率证明了其代谢率极低，并将其极低的代谢率归因于duox2基因上一个突变。其次，我们检测了两个不同中国人群的身体活动性水平。