A high-resolution X chromosome copy-number variation map in fertile females and women with primary ovarian insufficiency

• Published in: Genetics in medicine Vol. 21; no. 10; pp. 2275 - 2284
• Main Authors: Yatsenko, Svetlana A., Wood-Trageser, Michelle, Chu, Tianjiao, Jiang, Huaiyang, Rajkovic, Aleksandar
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2019; Elsevier Limited
• Subjects: Adult; Biomedical and Life Sciences; Biomedicine; Chromosome Mapping - methods; Chromosomes; Chromosomes, Human, X - genetics; Comparative Genomic Hybridization; DNA Copy Number Variations - genetics; Female; Gene Dosage - genetics; Genome, Human; Genomics - methods; Human Genetics; Humans; Laboratory Medicine; Ovary - metabolism; Primary Ovarian Insufficiency - genetics; X-linked disease; high-resolution copy-number map; primary ovarian insufficiency; X chromosome; fertility
• ISSN: 1098-3600; 1530-0366
• DOI: 10.1038/s41436-019-0505-2

Purpose 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. Methods 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. Results 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. Conclusion 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.