Genetic contribution to degenerative tendon and ligament rupture in Equus ferus caballus

项目总结/摘要 在理解基因对位点特异性自发性表达的贡献方面存在着根本性的空白。 肌腱/韧带断裂。跟腱、肩袖和前交叉韧带经常会发生病变。 这种情况代表慢性退化的肌腱/韧带的急性损伤。继续存在 这一知识缺口的存在是一个重要的问题，因为在填补这一缺口之前， 导致自发性肌腱/韧带断裂风险的遗传变异数量将在很大程度上保持不变， 无法理解长期目标是发现自发性肌腱/韧带断裂的遗传原因， 变体。我们的总体目标是通过全面的基因组解剖发现候选遗传变异 马退行性悬韧带韧带炎（DSLD），一个很好的大型动物模型，自发性 肌腱/韧带断裂。马的基因组结构通过以下方式增加SNP关联的能力： 品种内全基因组关联研究（GWAS），因为连锁不平衡相对于 人类基因组中心假设是DSLD具有重要的孟德尔遗传成分。 这一假设是根据申请人实验室提供的初步数据提出的。 提出这项研究的理由是，对支持DSLD的基因组结构的了解， 在马模型中发现候选遗传变异将使新的和创新的方法， 预防和治疗人类自发性肌腱/韧带断裂，也提供了一种新的治疗方法， 模型在强有力的初步数据的指导下，这一假设将通过追求两个具体目标进行检验：1）使用 RNA测序（RNA-Seq），以鉴定破裂DSLD组织中差异表达的基因; 2）发现 通过GWAS和随后基于区域的全基因组分析的DSLD断裂候选遗传变异 序列（WGS）数据。在第一个目标下，差异表达的基因将通过分析 疾病组织中的转录组，以评估生物网络的干扰。在第二个目标下， 基因组单核苷酸多态性（SNP）将用于发现GWAS。我们将测试我们的工作 假设DSLD是一种孟德尔疾病，可以通过遗传变异来解释， 受DSLD影响的品种。一个共同的变异更有可能与人类疾病密切相关。这项工作是 创新，因为它通过研究马模型而偏离了通常的GWAS方法。新的研究视野 是可以实现的。这项研究意义重大，因为它有望 发现一种新的自发性肌腱/韧带断裂候选基因变体和相关的生物学特性 途径。这项工作将有助于澄清在自发性高血压发病机制中受到干扰的共同途径。 肌腱/韧带断裂。马模型中发现的大效应变异将为 预防性或治疗性管理人类患者。

Project Summary/Abstract There is a fundamental gap in understanding the genetic contribution to site-specific spontaneous tendon/ligament rupture. The Achilles tendon, rotator cuff, and anterior cruciate ligament are often diseased. Such conditions represent acute damage of a chronically degenerated tendon/ligament. Continued existence of this knowledge gap represents an important problem because, until it is filled, understanding how the large number of genetic variants that contribute to risk of spontaneous tendon/ligament rupture will remain largely incomprehensible. The long-term goal is to discover spontaneous tendon/ligament rupture causal genetic variants. Our overall objective is to discover candidate genetic variants by comprehensive genomic dissection of equine degenerative suspensory ligament desmitis (DSLD), an excellent large animal model of spontaneous tendon/ligament rupture. The genomic architecture of horses acts to increase Power for SNP association by within-breed genome-wide association study (GWAS) as linkage disequilibrium is increased relative to the human genome. The central hypothesis is that DSLD has an important genetic component that is Mendelian. This hypothesis has been formulated on the basis of preliminary data produced in the applicant’s laboratory. The rationale for the proposed research is that knowledge of the genomic architecture underpinning DSLD and discovery of candidate genetic variants in the equine model will enable new and innovative approaches to prevention and treatment of human spontaneous tendon/ligament rupture and also provide a new treatment model. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Use RNA sequencing (RNA-Seq) to identify differentially expressed genes in ruptured DSLD tissue and 2) Discover DSLD rupture candidate genetic variants by GWAS and subsequent region-based analysis of whole genome sequence (WGS) data. Under the first aim, differentially expressed genes will be identified by analyzing the transcriptome in diseased tissue to assess disturbances to biological networks. Under the second aim, genomic single nucleotide polymorphisms (SNPs) will be used for discovery GWAS. We will test our working hypothesis that DSLD is a Mendelian disease that is explained by a genetic variant that is shared across DSLD-affected breeds. A shared variant is more likely to be strongly linked to human disease. The work is innovative as it departs from the usual GWAS approach by studying an equine model. New research horizons are expected to be attainable as a result. The proposed research is significant, because it is expected to discover a novel spontaneous tendon/ligament rupture candidate genetic variant and the associated biological pathways. This work will help clarify common pathways that are disturbed in the pathogenesis of spontaneous tendon/ligament rupture. Large effect variants identified in the equine model will provide new targets for preventative or therapeutic management of human patients.