Tower John
Molecular and Computational Biology Program, Department of Biological Sciences, University of Southern California, University Park, Los Angeles, 90089-2910, USA.
Mech Ageing Dev. 2006 Sep;127(9):705-18. doi: 10.1016/j.mad.2006.05.001. Epub 2006 Jun 9.
Genetic analysis of Drosophila, mice and humans indicates that gene alleles, mutations and transgenes that affect life span tend to do so differently depending on the sex of the organism. The likely reason for this is that the sexes are different genotypes (e.g., X/X vs. X/Y) and face quite different environments: e.g., to reproduce, males have to mate with females while females have to mate with males. Genes are subject to different genetic interactions and different gene-by-environment effects in male vs. female. The consequence is that through evolution certain genes are differently selected and optimized for each sex. Both the mitochondrial genome and the X chromosome are asymmetrically inherited in Drosophila and mammals; through evolution these genes spend relatively more time under selection in females and are therefore expected to be better optimized for function in the female than in the male. Consistent with this the Drosophila X chromosome has been found to be a hotspot for sexually antagonistic fitness variation. Old Drosophila and old mammals exhibit apoptosis-an observation consistent with the idea that the mitochondria are less functional during aging due to maternal-only inheritance. One feature of aging that is common to Drosophila and mammals is that females tend to live longer than males, and this may be due in part to sub-optimal mitochondrial function in males. The data support the conclusion that a significant part of the aging phenotype is due to antagonistic pleiotropy of gene function between the sexes. Liberal application of Occam's razor yields a molecular model for the co-regulation of sex, apoptosis and life span based on the on/off status of a single gene: Sxl in Drosophila melanogaster and Xist in humans. Aging may simply represent an ancient and conserved mechanism by which genes re-assort.
对果蝇、小鼠和人类的基因分析表明，影响寿命的基因等位基因、突变和转基因往往因生物体的性别不同而产生不同的影响。其可能的原因是，两性具有不同的基因型（例如，XX对XY），并且面临截然不同的环境：例如，为了繁殖，雄性必须与雌性交配，而雌性必须与雄性交配。在雄性和雌性中，基因受到不同的遗传相互作用以及不同的基因-环境效应的影响。结果是，经过进化，某些基因针对每种性别进行了不同的选择和优化。线粒体基因组和X染色体在果蝇和哺乳动物中都是不对称遗传的；经过进化，这些基因在雌性中受到选择的时间相对更长，因此预计它们在雌性中的功能比在雄性中得到了更好的优化。与此一致的是，已发现果蝇的X染色体是性拮抗适应性变异的热点。老年果蝇和老年哺乳动物会出现细胞凋亡——这一观察结果与以下观点一致，即由于仅通过母系遗传，线粒体在衰老过程中的功能会减弱。果蝇和哺乳动物衰老的一个共同特征是，雌性往往比雄性寿命更长，这可能部分归因于雄性线粒体功能欠佳。这些数据支持了这样一个结论，即衰老表型的很大一部分是由于两性之间基因功能的拮抗多效性所致。运用奥卡姆剃刀原理可以得出一个基于单个基因的开/关状态对性别、细胞凋亡和寿命进行共同调节的分子模型：果蝇中的性致死基因（Sxl）和人类中的X染色体失活特异转录本（Xist）。衰老可能仅仅代表了一种古老且保守的基因重新组合机制。
