Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Obstetrics,Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
Genet Med. 2019 Oct;21(10):2275-2284. doi: 10.1038/s41436-019-0505-2. Epub 2019 Apr 5.
Sex-biased expression of genes on the X chromosome is accomplished by a complex mechanism of dosage regulation that leads to anatomical and physiological differences between males and females. Copy-number variations (CNVs) may impact the human genome by either affecting gene dosage or disturbing a chromosome structural and/or functional integrity.
We performed a high-resolution CNV profiling to investigate the X chromosome integrity in cohorts of 269 fertile females and 111 women affected with primary ovarian insufficiency (POI) and assessed CNVs impact into functional and nonfunctional genomic elements.
In POI patients, we observed a 2.5-fold enrichment for rare CNVs comprising ovary-expressed genes, and genes implicated in autoimmune response and apoptotic signaling. Moreover, there was a higher prevalence of deletions encompassing genes that escape X inactivation, noncoding RNAs, and intergenic DNA sequences among POI females, highlighting structural differences between X chromosomes of fertile and POI females. Furthermore, we discovered a ~4% carrier incidence for X-linked disorders among fertile women.
We constructed a high-resolution map of female-specific CNVs that provides critical insights into the spectrum of human genetic variation, sex-specific disease risk factors, and reproductive potential. We discovered novel CNVs associated with ovarian dysfunction and support polygenic models for POI.
X 染色体上基因的性别偏性表达是通过一种复杂的剂量调节机制来实现的，这种机制导致了男性和女性之间的解剖学和生理学差异。拷贝数变异（CNVs）可能通过影响基因剂量或干扰染色体结构和/或功能完整性来影响人类基因组。
我们进行了高分辨率的 CNV 谱分析，以研究 269 名生育力正常的女性和 111 名原发性卵巢功能不全（POI）女性队列的 X 染色体完整性，并评估 CNVs 对功能和非功能基因组元件的影响。
在 POI 患者中，我们观察到包含卵巢表达基因、自身免疫反应和细胞凋亡信号相关基因的罕见 CNVs 富集了 2.5 倍。此外，POI 女性的 X 染色体中包含逃避 X 失活的基因、非编码 RNA 和基因间 DNA 序列的缺失更为常见，这突出了生育和 POI 女性的 X 染色体之间的结构差异。此外，我们发现生育女性中 X 连锁疾病的携带者发生率约为 4%。
我们构建了女性特异性 CNVs 的高分辨率图谱，为人类遗传变异、性别特异性疾病风险因素和生殖潜能提供了重要的见解。我们发现了与卵巢功能障碍相关的新的 CNVs，并支持 POI 的多基因模型。
