Objective Fat deposition is modulated by environmental factors and genetic predisposition. Genome-wide association studies identified PNPLA3 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. Design 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 PNPLA3 p.I148M. To quantify changes through time, logistic and, by grouping individuals according to geography and age, linear regression analyses were performed. Results We find that archaic human individuals (Neanderthal, Denisovan) exclusively carried a fixed PNPLA3 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. Conclusion Archaic human individuals exclusively carried a fixed PNPLA3 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 PNPLA3 p.I148M. All data relevant to the study are included in the article or uploaded as supplementary information. All data and code for analysis are provided in a github repository: [https://github.com/stschiff/PNPLA3\_AADR\_analysis][1]. Raw data is from the Allen Ancient DNA Resource version 50. A reference list of all 172 publications that report primary data is available as online supplemental text file 1. [1]: https://github.com/stschiff/PNPLA3_AADR_analysis

中文翻译：

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PNPLA3 脂肪肝等位基因在尼安德特人中被固定，并在人类中中性分离

目的 脂肪沉积受环境因素和遗传倾向的调节。全基因组关联研究发现 PNPLA3 p.I148M (rs738409) 是一种常见变异，会增加肝脏脂肪变性的风险。迄今为止，尚未研究这种变异何时以及如何在人类中进化。设计 在这里，我们分析古代 DNA，以追踪该等位基因在整个人类历史中的历史。总共有 6444 个已发表的古代（现代人类、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 PNPLA3 p.I148M 的基因型调用后用于分析。为了量化随时间、逻辑的变化，并根据地理位置和年龄对个体进行分组，进行了线性回归分析。结果我们发现古代人类个体（尼安德特人、丹尼索瓦人）只携带固定的 PNPLA3 风险等位基因，而现代人群中的等位基因频率范围从非洲的非常低到中美洲的 >50%。在过去的 15 000 年里，祖先和衍生等位基因的分布与当今的分布大致相符。逻辑回归分析在过去一万年中没有产生自然选择的信号。结论 古代人类个体只携带与脂肪肝相关的固定 PNPLA3 等位基因，而现代人群中的等位基因频率甚至在最古老的样本中也是可变的。我们的观察可能强调了寒冷气候下脂肪储存的优势，特别是对于冰河时代条件下的尼安德特人来说。现代人类历史中自然选择信号的缺失并不支持 PNPLA3 p.I148M 的节俭基因假说。与研究相关的所有数据都包含在文章中或作为补充信息上传。用于分析的所有数据和代码均在 github 存储库中提供：[https://github.com/stschiff/PNPLA3\_AADR\_analysis][1]。原始数据来自 Allencient DNA 资源第 50 版。报告主要数据的所有 172 种出版物的参考列表可作为在线补充文本文件 1 获得。[1]：https://github.com/stschiff/PNPLA3_AADR_analysis