The etiology of Down syndrome: Maternal MCM9 polymorphisms increase risk of reduced recombination and nondisjunction of chromosome 21 during meiosis I within oocyte

Autoři: Upamanyu Pal aff001;  Pinku Halder aff001;  Anirban Ray aff002;  Sumantra Sarkar aff003;  Supratim Datta aff003;  Papiya Ghosh aff005;  Sujay Ghosh aff001
Působiště autorů: Cytogenetics and Genomics Research Unit, Department of Zoology, University of Calcutta, Taraknath Palit Siksha Prangan (Ballygunge Science College Campus), Kolkata, West Bengal, India aff001;  Department of Zoology, Bangabasi Morning College (affiliated to University of Calcutta), Kolkata, West Bengal, India aff002;  Department of Paediatric Medicine, Institute of Post Graduate Medical Education and Research (IPGMER), Bhowanipore, Kolkata, West Bengal, India aff003;  Department of Paediatric Medicine, Diamond Harbour Government Medical College & Hospital, Diamond Harbour, West Bengal, India aff004;  Department of Zoology, Bijoykrishna Girls’ College (Affiliated to University of Calcutta), Howrah, West Bengal, India aff005
Vyšlo v časopise: The etiology of Down syndrome: Maternal MCM9 polymorphisms increase risk of reduced recombination and nondisjunction of chromosome 21 during meiosis I within oocyte. PLoS Genet 17(3): e1009462. doi:10.1371/journal.pgen.1009462
Kategorie: Research Article


Altered patterns of recombination on 21q have long been associated with the nondisjunction chromosome 21 within 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.

Klíčová slova:

Age groups – Alleles – Homozygosity – Introns – Medical risk factors – Meiosis – Oocytes – Variant genotypes


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