Department of Medicine II, Division of Hepatology, University Hospital Wurzburg, Würzburg, Germany
Department of Medicine II, Division of Hepatology, University Hospital Wurzburg, Würzburg, Germany.
Gut. 2024 May 10;73(6):1008-1014. doi: 10.1136/gutjnl-2023-331594.
Fat deposition is modulated by environmental factors and genetic predisposition. Genome-wide association studies identified p.I148M (rs738409) as a common variant that increases risk of developing liver steatosis. When and how this variant evolved in humans has not been studied to date.
Here we analyse ancient DNA to track the history of this allele throughout human history. In total, 6444 published ancient (modern humans, Neanderthal, Denisovan) and 3943 published present day genomes were used for analysis after extracting genotype calls for p.I148M. To quantify changes through time, logistic and, by grouping individuals according to geography and age, linear regression analyses were performed.
We find that archaic human individuals (Neanderthal, Denisovan) exclusively carried a fixed risk allele, whereas allele frequencies in modern human populations range from very low in Africa to >50% in Mesoamerica. Over the last 15 000 years, distributions of ancestral and derived alleles roughly match the present day distribution. Logistic regression analyses did not yield signals of natural selection during the last 10 000 years.
Archaic human individuals exclusively carried a fixed allele associated with fatty liver, whereas allele frequencies in modern human populations are variable even in the oldest samples. Our observation might underscore the advantage of fat storage in cold climate and particularly for Neanderthal under ice age conditions. The absent signals of natural selection during modern human history does not support the thrifty gene hypothesis in case of p.I148M.
脂肪沉积受环境因素和遗传易感性的调节。全基因组关联研究发现 p.I148M(rs738409)是一个常见的变异，增加了发生肝脂肪变性的风险。迄今为止，尚未研究该变异在人类中何时以及如何进化。
在这里，我们分析古代 DNA，以追踪该等位基因在人类历史上的历史。总共分析了 6444 个已发表的古代（现代人、尼安德特人、丹尼索瓦人）和 3943 个已发表的现代基因组，在提取 p.I148M 的基因型后进行分析。为了定量随时间的变化，进行了逻辑回归和线性回归分析，将个体按地理和年龄分组。
我们发现，古人类（尼安德特人、丹尼索瓦人）仅携带固定的风险等位基因，而现代人种的等位基因频率从非洲的极低到中美洲的>50%不等。在过去的 15000 年中，祖先和衍生等位基因的分布大致与当今的分布相匹配。逻辑回归分析在过去的 10000 年中没有产生自然选择的信号。
古人类个体仅携带与脂肪肝相关的固定 等位基因，而现代人种的等位基因频率即使在最古老的样本中也存在差异。我们的观察结果可能强调了在寒冷气候下储存脂肪的优势，特别是在尼安德特人处于冰河时代条件下的优势。在现代人类历史上没有自然选择的信号并不支持 p.I148M 的节俭基因假说。
