Genetics and evolution of lethal alleles in Drosophila

地球上所有物种都会出现不良突变。有些突变对携带者非常不利，以至于当一个人从父母双方继承一个拷贝时，他们无法存活到成年。人们会认为，这种致命的突变很少被观察到，因为自然选择应该迅速将它们从自然种群中消除。然而，近世纪来，对不同物种的研究发现，这种致命的变异令人惊讶地普遍存在。至少有两种假设可以解释这种致命变异的持续性：1）致命突变以足够高的速度出现，以至于它们在自然选择可以将它们全部消除之前被补充，以及2）致命突变的子集可以通过自然选择被积极地维持，例如，如果它们对仅携带一个拷贝的携带者稍微有利。该项目将使用经典遗传学和基因组测序的组合来识别携带这些致命突变的基因，并推断导致突变在自然种群中以如此高的丰度持续存在的进化力量。这项研究对于理解这种突变对健康的负担以及理解自然群体中变异的持续性至关重要。该项目还将为高中生、大学生和研究生的教育和培训做出重大贡献。该项目以当前的科幻小说为背景，教授进化生物学的基本原理。将使用模型系统黑腹果蝇（Drosophila melanogaster），从50年前广泛研究的自然种群中分离出数百个这样的突变。所有分离的致命突变将使用染色体缺陷进行定位，并且一个子集将被定位到单个基因。这种定位将确定致死效应是否如通常假设的那样由单位点、功能丧失突变引起。持续的研究将特别关注自然种群中最普遍的致命突变，因为它们是自然选择积极维持的最佳候选者。研究人员将使用现代群体遗传学方法来推断作用于这些丰富的致命等位基因的进化力量。流行的教条是，几乎所有的致命突变都是通过突变和选择的平衡而持续存在的，这项研究将严格评估这个长期存在的问题。这项工作由分子细胞生物学部的遗传机制小组和环境生物学部的进化过程小组共同资助。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Bad mutations arise in all species on Earth. Some mutations are so bad for the bearer that, when an individual inherits a copy from both parents, they cannot survive to adulthood. One would presume that such lethal mutations would rarely be observed, since natural selection should eliminate them rapidly from natural populations. However, for nearly a century studies in various species have found that such lethal variation is surprisingly common. At least two hypotheses can explain the persistence of such lethal variation: 1) lethal mutations arise at a high enough rate that they are replenished before natural selection can eliminate them all, and 2) a subset of lethal mutations may be actively maintained through natural selection, for example if they are slightly advantageous to bearers who carry only one copy. This project will use a mix of classical genetics and genome sequencing to identify the genes bearing these lethal mutations and to infer the evolutionary forces that cause the mutations to persist at such high abundance in natural populations. This research is vital to understanding the burden of such mutations on health as well as to understanding the persistence of variation in natural populations. This project will also contribute substantially to the education and training high school, college and graduate students. The project uses current science fiction as a backdrop for teaching fundamental principles in evolutionary biology.Hundreds of such mutations will be isolated using the model system Drosophila melanogaster from a natural population studied extensively 50 years ago. All of the lethal mutations isolated will be mapped using chromosomal deficiencies, and a subset will be mapped to single genes. This mapping will determine if the lethal effects result from single-locus, loss-of-function mutations, as often assumed. The continued research will focus especially on lethal mutations that are most prevalent in the natural population, since they are the best candidates for ones to have been actively been maintained by natural selection. The researchers will use modern population genetic approaches to infer the evolutionary forces that have acted on these abundant lethal alleles. The prevailing dogma has been that virtually all lethal mutations simply persist through a balance of mutation and selection, and this research will rigorously assess this long-standing question. This work is jointly funded by the Genetic Mechanisms Cluster in the Division of Molecular & Cellular Biology and the Evolutionary Processes Cluster in the Division of Environmental Biology.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.