Identification of Variants in Mitochondrial D-Loop and OriL Region and Analysis of Mitochondrial DNA Copy Number in Women with Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a multifactorial disorder characterized by irregular menstrual problems, hyperandrogenism, and presence of polycystic ovaries. Till date, molecular mechanism underlying PCOS remains elusive. Recently mitochondrial displacement loop (D-loop) variants have been identified to be novel players in the pathogenesis of PCOS. At present, rare variants, besides common variants, are also the focus of research as it is believed to make essential contribution to the risk of complex diseases. However, rare and low hetroplasmic variants in mitochondrial D-loop are still not investigated in PCOS women. Furthermore, variants in light-strand origin of DNA replication (OriL) of mitochondrial DNA (mtDNA) have not been explored in PCOS. Hence, in this study, we investigated rare to common mitochondrial D-loop and OriL region variants obtained using mtDNA next-generation sequencing in women with PCOS. Furthermore, we also assessed mtDNA copy number, a biomarker of mitochondrial dysfunction (MD) in women with PCOS, as the variants in mtDNA are known to be associated with low mtDNA copy number in PCOS women. A total of 67 D-loop variants including 6 novel variants were identified in 30 PCOS women. Among 67 variants, 29 variants were reported in PCOS women. A single variant, 5746A was found in OriL region in two PCOS women. Both transition and transversion variants were found but transition variants occur at very high frequency compared with transversions (82.35% vs. 17.64%, respectively). As transition variants in mtDNA are known to arise because of polymerase γ errors, occurrence of high transition rates indicates that most mutation arises because of defect in replication errors that causes mtDNA damage leading to MD. Furthermore, mtDNA copy number was found to be low in women with PCOS compared with healthy control women suggesting that MD may be the contributing factor in the pathogenesis of PCOS.