Causes and consequences of genetic variation in fitness

进化生物学正经历着彻底的转变，因为它的研究范围已进一步扩展到生物体、细胞和基因组的运作中。越来越多的人发现，基因组似乎不仅仅是一张有序的蓝图，而是一个由相互作用的基因组成的嘈杂的“议会”。我的研究小组使用原始和强大的技术在普通果蝇果蝇中研究遗传变异的起源和本质。我们的研究表明，与生存和终生生殖成功相关的遗传变异水平惊人地高，因为这些正是达尔文适应度的组成部分。提出的研究使用特殊的克隆方法来量化三种不同的变异来源：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，允许突变在许多代中不受限制地积累。初步结果表明，突变表现得很快，同样的突变对雄性的影响要比雌性严重得多。实验将在果蝇的整个生命周期中测量适合度的遗传变异。我们将在我们的系列中描述生长、繁殖、衰老和死亡的特征，并研究有争议的“衰老停滞期”现象，即衰老似乎在生命的后期停止。接下来，我们将分解克隆的基因组并组装新的混合物，以研究基因加在一起的效果或协同作用的程度。最后，在所有的实验中，我们将测量遗传效应在两性中的一致性，并分析性别对抗基因。我们的研究表明SA基因降低了雌性和雄性的平均适合度。这项研究是模块化和可扩展的，促进了各级专家人员的培训。它探索了进化遗传学的基本问题，并最终提供了对遗传疾病、不孕症和衰老等各种问题的见解。通过展示瓶装苍蝇的适应性是如何控制的，我们希望阐明其他基因组的工作原理，尤其是我们自己的基因组，并形成对生物学核心问题的理解：为什么有这么多与适应性相关的变异？

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?