Using reference-assisted chromosome assemblies to study chromosome structures and evolution in vertebrates

使用参考辅助染色体组装来研究脊椎动物的染色体结构和进化

• 批准号: BB/J010170/2
• 负责人: Denis Larkin
• 金额: $ 22.12万
• 依托单位: Royal Veterinary College
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FJ010170%2F2
• 关键词: Using; reference; assisted; chromosome; assemblies

Genomes contain genes that encode proteins that build organisms. In the course of evolution genomes change and these changes affect genes by changing the time when proteins are formed or even leading to formation of new genes or death of old genes. These events together form one of the sources of variations used by the natural selection to form new species or for species adaptation to the environment. Complete sequencing of a genome refers to the identification of the sequence of nucleotides along chromosomes. To understand what mechanisms drive changes in chromosome structures in different species and how this affects formation of new species or an adaptation of existing species to changing environment we will reconstruct complete chromosome structures of newly sequenced species using an novel algorithm called "reference-assisted chromosome assembly" or RACA. This algorithm compares sequenced parts of one organism' genome to existing complete chromosome assembly of another and reconstructs chromosomes of their putative common ancestor. Then it uses parts of the newly sequenced genome and searches for the differences between the ancestral organization of chromosomes and the organization proposed by parts of chromosomes that are generated for the organism. At the final step it organizes parts or ancestral chromosomes according to the order proposed by sequence scaffolds. In the research proposed in this proposal we will develop several algorithms to verify these reconstructions by looking at the specific features of chromosomes like "telomeres" - chromosome ends and "centromeres" - important for cell division. These structures contain specific sequence features that could be reconstructed from the sequence data produced during sequencing projects. By detecting positions of these features in the reconstructed chromosomes we will be able to check how close the structure of reconstructed chromosomes is to real chromosomes in the species of interest. If there are issues, we will adapt the RACA algorithm to improve the assembly. In the next step we will use RACA-generated chromosomes to investigate mechanisms driving chromosomal changes at the DNA level. We will check if the distribution of chromosome parts that are not rearranged in all genomes included in our analysis can be explained by the random breakage of chromosomes in evolution, or if there is a selection against chromosomal rearrangements in some parts of a vertebrate genome. If we analyze a large set of species we might be able to find "built blocks" of mammalian, amniote, or vertebrate genomes that cannot be rearranged without a lethal effect for the organism. Evolutionary breakpoint regions are regions of chromosomes where chromosomes were broken and then rejoined in a different combinations or orientation in evolution. We will use multiple RACA genomes to investigate what features of the genomes are driving these events. An important question to answer is "which genes would more likely be affected by these evolutionary events?" Previously we demonstrated that the evolutionary breakpoint regions are enriched for the genes that are associated with the lineage-specific features. In this project we will perform bioinformatics analysis of these intervals in an attempt to classify lineage-specific changes that happened in ancestral genomes of some lineages leading to the formation of their specific traits chosen by natural selection, e.g., formation of the rumen in ruminant species. Our hypothesis is that the changes in ancestral genomes of the livestock species will be connected to those features of the species that made them attractive source of proteins for humans. Therefore, detection of these ancestral changes is an important step for improving genetics of these species as it will identify best gene and other targets for future artificial selection and breed improvement.

基因组包含编码构建有机体的蛋白质的基因。在进化过程中，基因组发生变化，这些变化通过改变蛋白质形成的时间来影响基因，甚至导致新基因的形成或旧基因的死亡。这些事件共同构成了自然选择用来形成新物种或物种适应环境的变异来源之一。基因组的完整测序是指识别染色体上的核苷酸序列。为了了解是什么机制导致不同物种的染色体结构发生变化，以及这如何影响新物种的形成或现有物种对不断变化的环境的适应，我们将使用一种名为“参考辅助染色体组装”(RACA)的新算法来重建新测序物种的完整染色体结构。该算法将一个生物体基因组的测序部分与另一个生物体现有的完整染色体组合进行比较，并重建它们假定的共同祖先的染色体。然后，它使用新测序的基因组的一部分，并搜索染色体的祖先组织和为有机体产生的部分染色体所提出的组织之间的差异。在最后一步，它按照序列支架提出的顺序组织部分或祖先染色体。在这项提议中提出的研究中，我们将开发几种算法来验证这些重建，方法是观察染色体的特定特征，如“端粒”--染色体末端和“着丝粒”--对细胞分裂很重要。这些结构包含特定的序列特征，可以从测序过程中产生的序列数据中重建这些特征。通过检测这些特征在重构染色体中的位置，我们将能够检查重构染色体的结构与感兴趣物种的真实染色体的距离有多近。如果有问题，我们将调整RACA算法来改进汇编。在下一步，我们将使用RACA产生的染色体在DNA水平上研究驱动染色体变化的机制。我们将检查在我们的分析中包括的所有基因组中没有重排的染色体部分的分布是否可以用进化过程中染色体的随机断裂来解释，或者在脊椎动物基因组的某些部分中是否存在针对染色体重排的选择。如果我们分析一大组物种，我们也许能够找到哺乳动物、羊膜动物或脊椎动物基因组的“积木”，如果不对生物体造成致命影响，这些基因组就不可能重新排列。进化断点区域是染色体的区域，在该区域中，染色体被破坏，然后在进化中以不同的组合或方向重新结合。我们将使用多个RACA基因组来研究这些基因组的哪些特征在驱动这些事件。一个需要回答的重要问题是“哪些基因更有可能受到这些进化事件的影响？”在此之前，我们证明了进化断点区域对于与谱系特定特征相关的基因是丰富的。在这个项目中，我们将对这些间隔进行生物信息学分析，试图对一些谱系的祖先基因组中发生的特定谱系的变化进行分类，这些变化导致了自然选择所选择的特定特征的形成，例如，反刍动物物种瘤胃的形成。我们的假设是，家畜物种祖先基因组的变化将与该物种的那些特征有关，这些特征使它们成为对人类具有吸引力的蛋白质来源。因此，检测这些祖先的变化是改善这些物种遗传学的重要一步，因为它将为未来的人工选择和品种改良识别最佳基因和其他目标。

项目成果

Population structure and history of the Welsh sheep breeds determined by whole genome genotyping.

• DOI: 10.1186/s12863-015-0216-x
• 发表时间: 2015-06-20
• 期刊: BMC genetics
• 影响因子: 2.9
• 作者: Beynon SE;Slavov GT;Farré M;Sunduimijid B;Waddams K;Davies B;Haresign W;Kijas J;MacLeod IM;Newbold CJ;Davies L;Larkin DM
• 通讯作者: Larkin DM

Evolution of gene regulation in ruminants differs between evolutionary breakpoint regions and homologous synteny blocks

• DOI: 10.1101/gr.239863.118
• 发表时间: 2019-04-01
• 期刊: GENOME RESEARCH
• 影响因子: 7
• 作者: Farre, Marta;Kim, Jaebum;Larkin, Denis M.
• 通讯作者: Larkin, Denis M.

Novel Insights into Chromosome Evolution in Birds, Archosaurs, and Reptiles.

• DOI: 10.1093/gbe/evw166
• 发表时间: 2016-08-25
• 期刊: Genome biology and evolution
• 影响因子: 3.3
• 作者: Farré M;Narayan J;Slavov GT;Damas J;Auvil L;Li C;Jarvis ED;Burt DW;Griffin DK;Larkin DM
• 通讯作者: Larkin DM

The genetics of cattle

牛的遗传学

• DOI: 10.1079/9781780642215.0103
• 发表时间: 2015
• 作者: Larkin D

Upgrading short-read animal genome assemblies to chromosome level using comparative genomics and a universal probe set.

• DOI: 10.1101/gr.213660.116
• 发表时间: 2017-05
• 期刊: Genome research
• 影响因子: 7
• 作者: Damas J;O'Connor R;Farré M;Lenis VPE;Martell HJ;Mandawala A;Fowler K;Joseph S;Swain MT;Griffin DK;Larkin DM
• 通讯作者: Larkin DM