Y连锁遗传性耳聋是申请人于2004年在国际上首次发现的一种新型遗传性耳聋方式，定位和命名了Y染色体上的第一个耳聋DFNY1基因。2013年，申请人与英国小组合作，发现Y连锁遗传性耳聋家系中所有男性患者Y染色体上由于复制叉停滞与模板转换（FoSTeS）而产生了160kb基因组的复杂重组，并与耳聋表型共分离，文章发表在美国人类遗传学杂志上，并被称为国际遗传学领域唯一被证实的Y连锁遗传孟德尔疾病。那么，这种基因组复杂重组的断点在何处？复制重组的第三个基因拷贝如何影响听觉功能？如何导致耳聋发生的？本项目应用Tail PCR、Split reads技术分析FoSTeS突变断点，明确Y染色体短臂复杂扩增的精细结构；利用CRISPR/Cas9技术构建候选基因小鼠模型，从听力学、内耳形态、离子通道等系统观察候选基因在内耳中的作用，阐明DFNY1分子病理机制。这将对耳聋遗传学及基因组变异研究产生重大新突破。

Y-linked hearing loss is the only one Mendelian trait linked to the human Y chromosome so far. It is based on the extensive investigation of a large hearing loss pedigree which had a family history of more than 1000 years and was ascertained by the applicant in 2000. In 2004, the applicant reported the Y-linked inheritance pattern of hereditary hearing loss in this Chinese family for the first time and denominated it as DFNY1 locus. In Feb. 2013, the applicant co-operating with the British scientist found that the Y chromosomes of all the male patients in DFNY1 family carried the same duplicated region arising from a complex rearrangement and including three sections of Y chromosome and 160kb sequence from chromosome 1. The 160kb sequence carried five RefSeq genes and was completely cosegregated with the phenotype of the family. All the breakpoint sequences revealed microhomology, a pattern indicative of fork stalling and template switching (FoSTeS). Our previous study is the first report of an interchromosomal rearrangement resulting from FoSTeS. So, this project is focusing on the following questions: How to identify the exact breakpoints of the complex rearrangement in DFNY1? How the copy number variation caused by FoSTeS in DFNY1 affect the hearing function? How about the pathophysiological change in the related animal model? In this project, the TAIL-PCR, qPCR, CRISPR/Cas9 making transgenic mouse models, and auditory electrophysiological and pathological methods will be used to discover the detailed structure of the complex duplication segment, to identify the causative gene for DFNY1 family, and to explain the molecular mechanisms of Y-linked hereditary hearing loss. This project will disclose the novel genetic and genomic mechanism of hereditary hearing loss caused by FoSTeS-mediated complex duplication. This study will help to improve the classic genetic theory and have theoretical innovation.