Gene and Protein Annotation in Highly-Identical Segmental Duplications

项目概要/摘要： 高度相同的片段重复（SD）基因在人类进化和疾病中起着关键作用。SDS 它们本身介导致病性复制、缺失和其他重排，其影响范围从 从自闭症到先天性综合症其中所含的基因 SDs一旦被复制，就成为适应性修补的肥沃土壤，并可能提供创新， 人类特定特征的进化。 然而，这些基因的重复性质总是给他们的研究带来额外的挑战。他们是 在基因组中最难测序和组装的区域发现， 由于难以正确分配和组装， 转录物的测序片段;与此相关，对于许多重复的基因，不知道它们是否是 功能性的-即，如果它们编码一个翻译的和功能性的蛋白质。 该项目旨在在转录和翻译水平上注释片段重复的基因， 提出了应对这些挑战的战略。我们将利用单倍体基因组来更好地区分 我们将联合收割机结合单分子长读段测序 采用定制cDNA富集策略的技术，以准确确定SD基因的转录，以及 我们将利用质谱技术的新发展， 并确定哪些基因被翻译。 本研究的目的是在基因组的片段重复区域中鉴定功能性蛋白质编码基因。 人类基因组本研究所发展之可推广方法可应用于重复空间 在其他基因组中也是如此。这些基因将成为未来人类进化研究的候选基因， 疾病如果成功的话，这项研究将为人类历史上最古老、最具挑战性的 人类基因组研究中的问题。

Project Summary/Abstract: Genes in highly identical segmental duplications (SDs) play critical roles in human evolution and disease. SDs themselves mediate pathogenic duplications, deletions, and other rearrangements whose effects range from neurodevelopmental conditions like autism to syndromic congenital diseases. The genes contained within SDs, once duplicated, are fertile ground for adaptive tinkering, and may provide innovations that underlie the evolution of human-specific traits. However, the duplicate nature of these genes has always presented extra challenges to their study. They are found in regions of the genome that are some of the most difficult to sequence and assemble; they suffer from incomplete and inaccurate annotation due to the difficulty of correctly assigning and assembling sequenced fragments of transcripts; and related to this, for many duplicated genes it is not known if they are functional—i.e., if they encode a translated and functioning protein. This project seeks to annotate segmentally duplicated genes at the level of transcription and translation and proposes a strategy to address these challenges. We will leverage a haploid genome to better discriminate between highly identical copies of genome sequence, we will combine single-molecule long-read sequencing technology with a custom cDNA enrichment strategy to accurately determine transcription of SD genes, and we will take advantage of new developments in mass spectrometry technology to identify paralog-specific peptides and determine which of these genes are translated. The goal of this study is identify functional, protein-coding genes among segmentally duplicated regions of the human genome. The generalizable approach developed in this study can be applied to duplicated space in other genomes as well. These genes will serve as candidates for future studies of human evolution and disease. If successful, this study will shed enormous light onto one of the oldest and most challenging problems in the study of the human genome.