Gene duplication in the evolution of novel phenotypes and human disease

描述（由申请人提供）：基因复制是遗传新颖性的关键来源，在最好的情况下会导致获得有利的表型，在最坏的情况下会导致疾病。功能复制基因可以通过三个不同的过程在基因组中维持：1)在一个拷贝中获得新功能（新功能化），2)在拷贝之间划分祖先功能（亚功能化），或3)在所有拷贝中保存祖先功能（保护）。尽管基因复制在进化和疾病中都很重要，但人们对这些过程的相对频率或机制知之甚少。为了解决这些问题，本研究将利用互补的高通量实验和计算方法来研究三个密切相关的果蝇物种中重复基因的相关序列和表达进化。特别地，这个项目被细分为三个具体目标。首先，它将通过对三个密切相关的果蝇物种的比较基因组分析来识别最近的基因重复。其次，它将使用基因表达作为功能的代理来解开果蝇年轻重复基因维持中的新功能化，亚功能化和保护过程。第三，从种内多态性数据，它将推断出驱动这些过程的进化力量。由于果蝇作为一种模式生物在遗传研究中发挥着核心作用，因此本研究的发现可能适用于广泛的生物，增强我们对新表型进化和复制相关人类疾病遗传基础的理解。

DESCRIPTION (provided by applicant): Gene duplication is a key source of genetic novelty, which in the best case leads to the acquisition of advantageous phenotypes, and in the worst results in disease. Functional duplicate genes can be maintained in the genome via three distinct processes: 1) the acquisition of a novel function in one copy (neofunctionalization), 2) the division of ancestral functions among copies (subfunctionalization), or 3) the preservation of ancestral functions in all copies (conservation). Despite the importance of gene duplications in both evolution and disease, little is known about the relative frequencies or mechanisms of each of these processes. To address these questions, this proposal will utilize complementary high-throughput experimental and computational approaches to investigate the correlated sequence and expression evolution of duplicate genes in three closely-related species of Drosophila. In particular, this project is subdivided into three specific aims. First, it will identify recent gen duplications via comparative genome analysis of three closely-related species of Drosophila. Second, it will use gene expression as a proxy for function to disentangle the processes of neofunctionalization, subfunctionalization, and conservation in the maintenance of young duplicate genes in Drosophila. Third, from intra-species polymorphism data, it will infer the evolutionary forces driving each of these processes. Due to the central role Drosophila has played as a model organism in genetic research, findings from this study will likely be applicable to a wide range of organisms, enhancing our understanding of both the evolution of novel phenotypes and the genetic basis of duplication-associated human diseases. PUBLIC HEALTH RELEVANCE: Gene duplication, which produces two copies of a gene in an individual's genome, can lead to the acquisition of novel character traits or phenotypes. If the resulting phenotype is beneficial, it can lead to the evolutionary diversification of species; otherwise, it can cause one of hundreds of diseases, including Alzheimer's, heart disease, and cancer. Thus, knowledge about how gene duplication results in new phenotypes is crucial to our understanding of both evolution and human disease.