Institute of Genetics and Developmental Biology, Key State Laboratory of Molecular Development, Chinese Academy of Sciences, Beijing, China.
Dis Model Mech. 2013 Jan;6(1):236-51. doi: 10.1242/dmm.010009. Epub 2012 Aug 3.
The thrifty-gene hypothesis (TGH) posits that the modern genetic predisposition to obesity stems from a historical past where famine selected for genes that promote efficient fat deposition. It has been previously argued that such a scenario is unfeasible because under such strong selection any gene favouring fat deposition would rapidly move to fixation. Hence, we should all be predisposed to obesity: which we are not. The genetic architecture of obesity that has been revealed by genome-wide association studies (GWAS), however, calls into question such an argument. Obesity is caused by mutations in many hundreds (maybe thousands) of genes, each with a very minor, independent and additive impact. Selection on such genes would probably be very weak because the individual advantages they would confer would be very small. Hence, the genetic architecture of the epidemic may indeed be compatible with, and hence support, the TGH. To evaluate whether this is correct, it is necessary to know the likely effects of the identified GWAS alleles on survival during starvation. This would allow definition of their advantage in famine conditions, and hence the likely selection pressure for such alleles to have spread over the time course of human evolution. We constructed a mathematical model of weight loss under total starvation using the established principles of energy balance. Using the model, we found that fatter individuals would indeed survive longer and, at a given body weight, females would survive longer than males, when totally starved. An allele causing deposition of an extra 80 g of fat would result in an extension of life under total starvation by about 1.1-1.6% in an individual with 10 kg of fat and by 0.25-0.27% in an individual carrying 32 kg of fat. A mutation causing a per allele effect of 0.25% would become completely fixed in a population with an effective size of 5 million individuals in 6000 selection events. Because there have probably been about 24,000 famine events since the evolution of hominins 4 million years ago, there has been ample time even for genes with only very minor impacts on adiposity to move to fixation. The observed polymorphic variation in the genes causing the predisposition to obesity is incompatible with the TGH, unless all these single nucleotide polymorphisms (SNPs) arose in the last 900,000 years, a requirement we know is incorrect. The TGH is further weakened by the observation of no link between the effect size of these SNPs and their prevalence, which would be anticipated under the TGH model of selection if all the SNPs had arisen in the last 900,000 years.
节俭基因假说（TGH）认为，现代肥胖的遗传倾向源于过去的饥荒时期，当时选择了促进脂肪有效沉积的基因。之前有人认为，这种情况是不可行的，因为在这种强烈的选择下，任何有利于脂肪沉积的基因都会迅速达到固定状态。因此，我们应该都容易肥胖：但事实并非如此。然而，全基因组关联研究（GWAS）揭示的肥胖遗传结构对这种观点提出了质疑。肥胖是由数百个（也许数千个）基因突变引起的，每个基因的影响都非常微小、独立且累加。对这些基因的选择可能非常弱，因为它们赋予的个体优势非常小。因此，肥胖的遗传结构确实可能与 TGH 相符，并支持 TGH。要评估这是否正确，就有必要了解已识别的 GWAS 等位基因对饥饿期间生存的可能影响。这将定义它们在饥荒条件下的优势，从而确定在人类进化的过程中，这些等位基因可能传播的选择压力。我们使用已建立的能量平衡原则，构建了一个在完全饥饿下体重减轻的数学模型。使用该模型，我们发现，在完全饥饿的情况下，肥胖的个体确实会存活更长时间，而且在给定的体重下，女性比男性存活的时间更长。一个导致额外沉积 80 克脂肪的等位基因，会使一个体脂 10 公斤的个体在完全饥饿状态下的寿命延长约 1.1%-1.6%，使一个体脂 32 公斤的个体的寿命延长约 0.25%-0.27%。一个导致每个等位基因效应为 0.25%的突变，在一个有效大小为 500 万个体的种群中，经过 6000 次选择事件，就会完全固定。因为自从 400 万年前人类进化以来，可能已经发生了大约 24000 次饥荒事件，即使是对肥胖只有微小影响的基因，也有足够的时间达到固定状态。在导致肥胖倾向的基因中观察到的多态性变化与 TGH 不符，除非所有这些单核苷酸多态性（SNP）都是在过去 90 万年中产生的，我们知道这一要求是不正确的。如果所有的 SNP 都是在过去 90 万年中产生的，那么我们从 TGH 模型的选择中可以预期，这些 SNP 的效应大小与它们的流行率之间没有联系，这进一步削弱了 TGH。
