论文 | 金力/郑鸿翔团队揭示现代人近期扩张过程中负向选择作用的弱化

MtDNA genomes reveal relaxed purifying selection during human population expansion after the Last Glacial Maximum

发表期刊 |Molecular Biology and Evolution（《分子生物学与进化》）

2024年8月20日

在进化中，负向 自然 选择作用可清除包括非同义突变在内的有害突变，其强度与人类基因组中的突变负荷密切相关。 突变负荷对人类疾病的发生起着重要作用，故阐明负向自然选择效应是人类进化遗传学中的一个重要科学问题。 现代人类在过去的几千年中经历了爆炸式的人口增长，而人群的主扩张阶段可能开始于旧石器时期晚期。 末次冰盛期的终结（距今约22,000-20,000年前）以及农业的产生和发展（距今约11,000-4,000年前）一方面可促使人群扩张； 另一方面也使现代人的生存环境发生重大改善，推测可使负向选择效应减弱，但后者尚缺乏遗传学证据。

2024年8月20日，复旦大学校长、复旦发展研究院院长金力院士和生命科学学院郑鸿翔副研究员团队在国际顶尖进化生物学期刊《分子生物学与进化》（Molecular Biology and Evolution）发表题为“MtDNA genomes reveal relaxed purifying selection during human population expansion after the Last Glacial Maximum”的研究论文。该研究整合了超过三万个全球人群线粒体基因组数据，通过系统进化分析和群体模拟等方法，发现在末次冰盛期后的现代人群主扩张过程中，扩张的线粒体支系所累积的非同义突变的比例较高，证实了负向自然选择的弱化，且极可能与环境选择压力的放松有关。

该研究结合了分子进化和群体遗传学研究方法，整合了海量的线粒体基因组数据，绘制了东亚人群具极限精度的线粒体DNA进化树（图1），该进化树可为线粒体DNA在中国人群的分子人类学、医学以及法医学相关领域中的应用奠定重要基础。该项工作也着重研究有害突变在现代人群中的遗传规律，为进一步研究突变负荷在生物医学领域中的价值提供依据。

高精度东亚线粒体DNA进化树示意图

该项工作得到了国家自然科学基金和上海市市级科技重大专项等项目的资助。郑鸿翔副研究员为所发表论文的第一作者，并与金力院士共为论文的通讯作者。中央民族大学的严实副教授，复旦大学现代语言学研究院、复旦大学智能复杂体系实验室的张梦翰研究员，复旦大学粤港澳大湾区精准医学研究院的顾正龙教授，复旦大学生命科学学院的王久存教授亦对该项研究做出了重要贡献。

作 者

Hong-Xiang Zheng

State Key Laboratory of Genetic Engineering, School of Life Sciences, Human Phenome Institute and Center for Evolutionary Biology, Fudan University

Shi Yan

Ministry of Education Key Laboratory of Contemporary Anthropology, Department of Anthropology and Human Genetics, School of Life Sciences, Fudan University

School of Ethnology and Sociology, Minzu University of China

Menghan Zhang

Institute of Modern Languages and Linguistics, Fudan University

Zhenglong Gu

State Key Laboratory of Genetic Engineering, School of Life Sciences, Human Phenome Institute and Center for Evolutionary Biology, Fudan University

Jiucun Wang

State Key Laboratory of Genetic Engineering, School of Life Sciences, Human Phenome Institute and Center for Evolutionary Biology, Fudan University

Li Jin

State Key Laboratory of Genetic Engineering, School of Life Sciences, Human Phenome Institute and Center for Evolutionary Biology, Fudan University

Research Unit of Dissecting Population Genetics and Developing New Technologies for Treatment and Prevention of Skin Phenotypes and Dermatological Diseases (2019RU058), Chinese Academy of Medical Sciences

摘 要

Modern humans have experienced explosive population growth in the past thousand years. We hypothesized that recent human populations have inhabited environments with relaxation of selective constraints, possibly due to the more abundant food supply after the Last Glacial Maximum. The ratio of nonsynonymous to synonymous mutations (N/S ratio) is a useful and common statistic for measuring selective constraints. In this study, we reconstructed a high-resolution phylogenetic tree using a total of 26,419 East Eurasian mitochondrial DNA genomes, which were further classified into expansion and nonexpansion groups on the basis of the frequencies of their founder lineages. We observed a much higher N/S ratio in the expansion group, especially for nonsynonymous mutations with moderately deleterious effects, indicating a weaker effect of purifying selection in the expanded clades. However, this observation on N/S ratio was unlikely in computer simulations where all individuals were under the same selective constraints. Thus, we argue that the expanded populations were subjected to weaker selective constraints than the nonexpanded populations were. The mildly deleterious mutations were retained during population expansion, which could have a profound impact on present-day disease patterns.

关键词

mitochondrial DNA, relaxation of selective constraints, deleterious mutations, purifying selection

或访问以下链接：

https://academic.oup.com/mbe/article/41/9/msae175/7736830

来源 | 复旦大学生命科学学院

排版 | 胡珂玚