Variation in the Zinc Finger of PRDM9 is Associated with the Absence of Recombination along Nondisjoined Chromosomes 21 of Maternal Origin

Abstract

Variation in the zinc finger-binding domain (ZFBD) of the protein PR Domain-Containing Protein 9 (PRDM9) is associated with altered placement of recombination in the human genome. As both the absence and altered placement of recombination are observed among chromosomes 21 that nondisjoin, we genotyped the PRDM9 ZFBD among mothers of children with Trisomy 21 in efforts to determine if variation within this region is associated with the recombination-related risk for chromosome 21 nondisjunction (NDJ). In our approach, PCR was used to amplify the ZFBD of PRDM9 and products were then subjected to bi-directional Sanger sequencing. DNA sequencing reads were aligned and compared to the sequence of the PRDM9 alleles previously identified. Chi-Square analysis was used to compare allele frequencies between cases (N=235, mothers of children with maternally-derived Trisomy 21) and controls (N=48, fathers of children with maternally-derived Trisomy 21). Results of our analysis showed that the frequency of PRDM9 ZF minor alleles is significantly increased among women displaying NDJ of chromosome 21 and no recombination on 21q (p=0.02). Even more, when compared to those for the PRDM9 major A-allele, these minor alleles displayed fewer predicted binding sites on 21q. These findings suggest that allelic variation in the ZF of PRDM9 may play a role in the risk for chromosome 21 NDJ by leading to reduced recombination on 21q.

PRDM9, a driver of the genetic map

“…In humans, PRDM9 is the first hit in genome-wide association studies on recombination distribution, but there is no established evidence for a link to fertility. However, an association has been detected between human Prdm9 zinc finger polymorphism and reduced recombination on Chromosome 21 observed in cases of Chromosome 21 nondisjunction [ 118 ]. One may speculate that different PRDM9 zinc finger arrays could have distinct numbers of binding sites on a given chromosome, which could impact the rate of recombination.…”

Gene Polymorphisms That Predispose Women for Down Syndrome Child Birth

“…In respect to recombination Gene Polymorphisms That Predispose Women for Down Syndrome Child Birth DOI: http://dx.doi.org /10.5772/intechopen.89512 regulators, only gene that has been investigated in maternal genome is PRDM9. This study [9] is only known analyses on that gene and is needed to be replicated in other populations. Another gene is APOE that exhibited association with DS birth when APOE4 allele is present.…”

“…Carriers of PRDM9 minor alleles display reduced recombination at meiotic hotspots [8]. All these preceding observation led to the study [9] to inquire whether PRDM9 variants exhibit association with the recombination variation that underlies the NDJ events.…”

“…In this study [9] by US researcher group included 235 mothers having DS child and 85 controls having euploid baby. For characterizing the recombination profile along the 21q, the authors used genotyping with 1536 SNP loci on 21q by the Illumina Golden Gate Assay.…”

Genetic diagnosis of subfertility: the impact of meiosis and maternal effects

“…Paucity of chiasmata is most likely to lead to aneuploidy in the smallest chromosomes, for example, chromosome 21, there is evidence that the genome-wide frequency of crossover may have some genetic basis. In families where one offspring has Trisomy 21, genome-wide analysis indicates that the frequency of crossovers is reduced in the individual affected by Trisomy 21 and in siblings26; and this crossover frequency may be partly accounted for by variation in the recombination factor PRDM9 27…”