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导致Myhre综合征的SMAD4突变在男性生殖系中处于积极选择状态

Katherine A Wood¹, R Spencer Tong¹, Marialetizia Motta²

¹MRC Weatherall Institute of Molecular Medicine, Oxford OX39DS, UK; Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford OX39DS, UK; NIHR Oxford Biomedical Research Centre, Oxford OX39DU, UK.

American journal of human genetics

|August 8, 2024

概括

自私的新生突变 (DNM) 在老化丸中被积极选择. 这项研究表明,导致Myhre综合征的SMAD4突变表现出自私的特性,扩大了人类丸中已知的受选择基因.

科学领域:

遗传学遗传学是一个
生殖生物学生殖生物学
发展生物学发展生物学

背景情况:

新突变 (DNM) 通常被认为是随机事件.
之前的研究已经确定了"自私的"DNM,在衰老的男性丸中丰富,与RTK-RAS-MAPK通路相关.
这些自私的突变具有共同的特征:父亲的起源,父亲的年龄增加,以及明显高的生殖系突变率.

研究的目的:

调查SMAD4中引起Myhre综合征 (MYHRS) 的新突变 (DNMs) 是否表现出自私的特性.
为了确定SMAD4突变是否在老化的人类丸中受到积极选择.
探索在精子中丰富的SMAD4变体的功能后果.

主要方法:

对16个信息三元组进行分析,以确定引起MYHRS的DNMs的来源.
流行病学分析以评估MYHRS病例中父亲年龄的影响.
开发一种超灵敏的测试方法来量化精子中的SMAD4变异.
试验室试验验证用于验证所选DNM的功能行为.

主要成果:

所有分析的引起MYHRS的DNAM都源自父亲的等位基因.
在MYHRS试验对象的父亲中观察到显著的父亲年龄效应 (超过6.3年).
病原性SMAD4变体在500号码区在精子中升高,并且与供体年龄呈正相关性.
在体外测试证实了精子丰富的SMAD4变体的功能影响.

结论:

导致Myhre综合征的SMAD4 DNM表现出自私的精子选择,类似于RTK-RAS-MAPK通路基因.
这一发现扩大了对老化人类丸中超越RTK-RAS-MAPK通路的积极选择的理解.
这表明其他基因和途径也可能在男性生殖细胞中受到积极选择.

关键词:

通过TGF-β/BMP/活性因通路.这是一种de novo突变.父亲年龄的影响.罕见疾病是一种罕见的疾病.自私的选择,自私的选择.精子干细胞是精子干细胞.

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