The Etiology Of Down Syndrome: Maternal Mcm9 Polymorphisms Increase Risk Of Reduced Recombination And Nondisjunction Of Chromosome 21 During Meiosis I Within Oocyte

Altered patterns of recombination on 21q have long been associated withthe nondisjunction chromosome21within oocytes and the increased risk of having a child with Down syndrome. Unfortunately the genetic etiology of these altered patterns of recombination have yet to be elucidated. We for the first time genotyped the gene MCM9, a candidate gene for recombination regulation and DNA repair in mothers with or without children with Down syndrome. In our approach, we identified the location of recombination on the maternal chromosome 21 using short tandem repeat markers, then stratified our population by the origin of meiotic error and age at conception. We observed that twenty-five out of forty-one single nucleotide polymorphic sites within MCM9 exhibited an association with meiosis I error (N = 700), but not with meiosis II error (N = 125). This association was maternal age-independent. Several variants exhibited aprotective association with MI error, some were neutral. Maternal age stratified characterization of cases revealed that MCM9 risk variants were associated with an increased chance of reduced recombination on 21q within oocytes. The spatial distribution of single observed recombination events revealed no significant change in the location of recombination among women harbouring MCM9 risk, protective, or neutral variant. Additionally, we identified a total of six novel polymorphic variants and two novel alleles that were either risk imparting or protective against meiosis I nondisjunction. In silico analyses using five different programs suggest the risk variants either cause a change in protein function or may alter the splicing pattern of transcripts and disrupt the proportion of different isoforms of MCM9 products within oocytes. These observations bring us a significant step closer to understanding the molecular basis of recombination errors in chromosome 21 nondisjunction within oocytes that leads to birth of child with Down syndrome.Author summaryWe studied MCM9 variations in the genome of women with a Down syndrome child by stratifying the women based on MCM9 genotypes, meiotic error group, and their age of conception. Weidentified polymorphisms are associated with reduced recombination and nondisjunction of chromosome 21 at the meiosis I stage of oogenesis in a maternal age-independent manner. But these variants do not affecttheposition of chiasma formation. In Silico analyses revealed the presence of MCM9 variants that may cause alteration in protein function due to amino acid substitution. We also identified splice variants in MCM9. We hypothesize that the polymorphisms in MCM9 predispose women to experience reduced recombination on chromosome 21 in oocytes at meiosis I, which ultimately leads to the birth of a child with Down syndrome.