An Examination of the Relationship between Hotspots and Recombination Associated with Chromosome 21 Nondisjunction

Abstract

Trisomy 21, resulting in Down Syndrome (DS), is the most common autosomal trisomy among live-born infants and is caused mainly by nondisjunction of chromosome 21 within oocytes. Risk factors for nondisjunction depend on the parental origin and type of meiotic error. For errors in the oocyte, increased maternal age and altered patterns of recombination are highly associated with nondisjunction. Studies of normal meiotic events in humans have shown that recombination clusters in regions referred to as hotspots. In addition, GC content, CpG fraction, Poly(A)/Poly(T) fraction and gene density have been found to be significant predictors of the placement of sex-averaged recombination in the human genome. These observations led us to ask whether the altered patterns of recombination associated with maternal nondisjunction of chromosome 21 could be explained by differences in the relationship between recombination placement and recombination-related genomic features (i.e., GC content, CpG fraction, Poly(A)/Poly(T) fraction or gene density) on 21q or differential hot-spot usage along the nondisjoined chromosome 21. We found several significant associations between our genomic features of interest and recombination, interestingly, these results were not consistent among recombination types (single and double proximal or distal events). We also found statistically significant relationships between the frequency of hotspots and the distribution of recombination along nondisjoined chromosomes. Collectively, these findings suggest that factors that affect the accessibility of a specific chromosome region to recombination may be altered in at least a proportion of oocytes with MI and MII errors.

Genetic Etiology of Chromosome 21 Nondisjunction and Down syndrome Birth: Aberrant Recombination and Beyond

“…Very recently, Oliver et al [30] has analyzed the molecular features and distribution of recombination hotspots along the length of nondisjoined Ch21 to get more insight on the relationship between recombination and Ch21 NDJ. Studies of normal meiotic events in humans show that the placement of recombination is not a random event.…”

“…In addition, sequence variation in the zinc-finger domain of the gene Proline Rich Domain Containing 9 (PRDM9) has a major impact on the location of recombination in humans [32]. The observation that both cis and trans-acting factors are associated with the placement of recombination led authors to enquire whether the altered patterns of recombination associated with NDJ of Ch21 could be explained by differences in the relationship between recombination and genomic features (i.e., GC content, CpG fraction, Poly(A)/Poly(T) fraction or gene density) on 21q or differential hot-spot usage [30].…”

“…Oliver et al [30] used Illumina Golden gate platform for trisomy genotyping which included ~509000 SNP markers and found that for single recombinant events only the location of recombination hotspot has been proved to a significant predictor for MI NDJ and for MII NDJ both centromeric location and GC content have been proved to predictor of the error. Among the nondisjoined chromosomes with two exchange, authors found MI and MII proximal recombinant events occur in GC rich regions more often than statistically expected if there was no relationship between the amount of recombination and GC (or CpG) content.…”

Folic Acid Deficiency Does Not Adversely Affect Oocyte Meiosis in Mice

“…Nondisjunction of chromosome 21 in particular is known as Down syndrome, which easily causes infertility, abortion and chromosomal abnormalities (1)(2)(3). Folic acid (FA) is a water-soluble vitamin, which is an essential nutrient for normal cell growth, fetal development (4), methylation (5) and DNA stability (6).…”

“…Wang et al (9) reported that when human lymphocytes were incubated in a low-FA medium, there was an increase in aneuploidy of chromosome 21. Meanwhile Takamura et al (2) and Oliver et al (3) reported that mothers of Down syndrome children have lower serum and plasma FA levels than mothers of non-Down syndrome children. James et al (10) reported that there were increased levels and frequencies of homocysteine in plasma and methylenetetrahydrofolate reductase (MTHFR) 677CT and 677TT genotypes in mothers of Down syndrome children, respectively.…”