中国科学院昆明动物研究所机构知识库

随着测序技术的不断发展以及测序成本的不断降低，高通量测序技术的普及为研究生物复杂性状提供了强有力的支撑。多指（趾）(Polydactyly)是一种非常常见的先天性肢体出生缺陷(Birth defects)，表现为一个或多个指（趾）的全部或部分的重复发生，在我国新生儿出生缺陷中的发病率位列前三，在人群中的发生率高达1.6-10.7‰，除在人中发病率较高外，在鼠、鸡、猫、猪等物种中均时有发生，性状表型相似。作为研究人类疾病的一种常用实验材料，猪与人之间的基因同源性较高，在解剖学、生理学和疾病发生机理等方面与人具有很高的相似性，且猪的窝产仔数多，繁育周期较快，遗传配种方案灵活，是研究人类疾病非常理想的一种动物模型，在临床医学的各个学科领域具有广泛的研究应用。本研究以两个轴前多趾(Preaxial polydactyly，PPD)猪家系作为实验材料，通过高深度测序获得个体的全基因组序列，利用计算群体分化(FST)和单倍型连锁不平衡(XP-EHH)的方法在全基因组水平上筛选患病个体与正常个体间高分化的SNP和INDEL标签位点，探究这些位点所处的基因组区域以及相关候选基因与轴前多趾的关联性，并结合基于家系的关联分析(Family-Based association tests，FBAT)方法，探究轴前多趾的遗传方式及其遗传机制。通过上述分析，我们发现了一个新的候选基因ABCC4与该多趾性状显著关联，进一步对该基因的分析发现其功能与纤毛的形成密切相关，而纤毛作为细胞信号传导过程中重要的细胞结构，其功能上的缺失或紊乱将导致包括多趾在内的多种纤毛病发生。本研究为肢体发育临床相关研究提供了新的材料与数据，为家猪优质性状遗传选育提供了一定的参考，对进一步解析脊椎动物肢体发育过程和轴模式形成等方面具有一定意义。 

The continuous development of sequencing technology and the reduction in sequencing cost has made it possible for the study of complex biological characters and problems. Polydactyly is one of the most common congenital birth defects, characterized with additional digits in fingers or toes and several genes and complication diseases have been reported to be associated with this disorder. In China, the incidence of polydactyly in newborn ranged to top three of birth defects and as high as 1.6-10.7 ‰. In addition to a high incidence in human, polydactyly also occur in other animal species such as in mouse, chicken, cat and pig with the similar phenotype. Pig has high genetic homology and similarities with human in terms of anatomy, physiology, mechanism of disease development and as well as an ideal animal model for studying human diseases with the more litter size, rapid breeding cycle and flexibility with extensive research applications in various fields of clinical medicine.In this study, after obtaining a high-depth genomic sequence of two preaxial polydactyly (PPD) swine families, highly differentiated SNPs and INDELs were used for computing the population differentiation index (FST) and comparing the haplotype linkage disequilibrium with XP-EHH for screening between affected and normal individuals and exploring of PPD phenotype. And further explore the association of these highly differentiated genomic regions with PPD phenotype. Moreover, by combining the family-based association tests (FBAT), we aim to explore the inheritance pattern and genetic mechanism of polydactyly.According to these analysis, we found a new candidate gene ABCC4, which was significantly associated with this polydactyly trait. Further analysis of this gene revealed that its function is closely related to the formation of cilia, which is important cellular structure in cell signaling processes. Therefore, defect or disorder of its function will result in the occurrence of many ciliopathies including polydactyly.This study provides new resources and data for the clinical study of limb development and also a reference for the genetic breeding of high quality traits in domesticated pigs. Finally, it has important significance for further study of vertebrate limb development and axis pattern formation.