Elucidating the roles of naturally occurring silent mutations in Polycystic Ovary Syndrome (PCOS)

Abstract Polycystic ovary syndrome (PCOS) is a complex genetic disorder, which often causes infertility in women. Most of the PCOS-related genes are also linked with metabolic diseases, inflammatory responses, or certain types of cancer. GWAS studies connect single nucleotide polymorphisms (SNPs) with these diseases, emphasizing their critical role in understanding the impacts of SNPs that exchange nucleotides. However, their response to changes in protein conformation and corresponding functional characteristics remains ambiguous. The present study provides evidence that elucidates for the role of specific SNPs known as silent mutations by studying impacts on INSR (insulin receptor), FST (follistatin), and AR (androgen receptor) genes, all strongly associated with PCOS pathogenesis. Although silent mutations do not change the amino acid type, their effects on protein expression may cause disease progression. To assess the potential impacts of silent mutations, we first calculated the anti-codon availabilities through RFMapp. To avoid the controversial issues regarding anti-codon stability for certain SNPs, MFE (minimum free energy) was calculated as a measure of the thermodynamic stability of newly formed mRNA structures to provide more information. For rs2059806 and rs1799817 located in the INSR gene, we reported depletion in anti-codon availabilities of newly existed codons. For rs6152 and rs2059806 cases, we calculated both increase and decrease in mRNA stabilities, which were noted as instabilities of the tRNA-mRNA complex. With the results obtained, we referred to the case of codon optimality for providing a plausible explanation between the existence of these SNPs and PCOS. Herein, the effects of silent mutations on complex PCOS diseases have been demonstrated.