Causes and consequences of genetic variation in fitness

进化生物学正在经历根本性的变革，因为它的拥抱越来越深入到有机体、细胞和基因组的工作中。越来越多地，基因组似乎不仅仅是一张井然有序的蓝图，而是由相互作用的基因组成的嘈杂的“议会”。我的研究团队使用原创和强大的技术研究了普通果蝇--果蝇--的遗传变异的起源和本质。我们的研究表明，与生存和终身生殖成功相关的基因变异水平令人惊讶地高，因为这些都是达尔文式适应能力的组成部分。这项拟议的研究使用特殊的克隆方法来量化三个不同的变异来源：自发突变、基因-基因相互作用和性拮抗基因。首先，我们将暂停整个基因组的自然选择，允许突变在许多世代中不受限制地积累。初步结果显示，突变很快就会显现出来，同样的突变对男性的影响要比女性严重得多。实验将测量苍蝇整个生命周期内健康状况的遗传变异。我们将在我们的系列中描述生长、繁殖、衰老和死亡的特征，并调查有争议的现象--衰老中的高原现象，即衰老似乎在生命后期停止。下一步，我们将分解克隆的基因组并组装新的混合物，以研究基因相互作用的效果或协同作用的程度。最后，在所有实验中，我们将测量两性之间遗传效应的一致性，并分析性对抗基因。我们的研究表明，SA基因会降低女性和男性的平均健康水平。这项研究是模块化的和可扩展的，促进了各级专家人员的培训。它探索进化遗传学中的基本问题，并最终提供对各种问题的洞察，如遗传病、不孕不育和衰老。通过展示瓶装果蝇的适合性是如何决定的，我们希望阐明其他基因组的工作原理，特别是我们自己的基因组，并塑造对生物学中一个核心问题的理解：为什么会有如此多与适合性相关的变异？

Evolutionary Biology is undergoing radical transformation as its embrace extends ever further into the workings of the organism, the cell, and the genome. More and more, the genome appears to be not simply a well-ordered blueprint but a noisy 'parliament' of interacting genes. My research team studies the origins and nature of genetic variation using original and powerful techniques in the ordinary fruit fly, Drosophila. Our research has shown that levels of genetic variation related to survival and lifetime reproductive success are surprisingly high, given that these are the very components of Darwinian fitness. The proposed research uses special cloning methods to quantify three distinct sources of variation: spontaneous mutation, gene-gene interactions, and sexually antagonistic genes. First, we will suspend natural selection across the entire genome, allowing mutations to accumulate unchecked over many generations. Preliminary results show that mutations manifest themselves quickly, and the same mutations have a much more severe impact on males than females. Experiments will measure genetic variation in fitness over the full lifespan of the fly. We will characterize growth, reproduction, ageing and death in our lines, and investigate the controversial phenomenon of 'plateaus in senescence', in which ageing appears to stop late in life. Next, we will break apart the cloned genomes and assemble new mixtures to study the degree to which genes add together in effect or interact synergistically. Finally, in all experiments, we will measure the consistency of genetic effects in the two sexes and analyze for sexually antagonistic genes. Our research has implicated SA genes in reducing the average fitness of both females and males. This research is modular and scalable, facilitating the training of expert personnel at every level. It explores fundamental questions in evolutionary genetics, and ultimately provides insight into problems as diverse as genetic diseases, infertility, and senescence. By showing how fitness is governed in bottled flies, we hope to illuminate the workings of other genomes, notably our own, and shape understanding of a central question in Biology: why so much fitness-related variation?