An examination of the relationship between hotspots and recombination associated with chromosome 21 nondisjunction.

Tiffany Renee Oliver,Stuart W Tinker,Lora J H Bean,Candace D Middlebrooks,Stephanie L Sherman,Vivian Cheung,Eleanor Feingold,Emily Graves Allen,Ferdouse Begum,Reshmi Chowdhury

doi:10.1371/journal.pone.0099560

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.

Highlights

Trisomy 21, leading to Down Syndrome (DS), is the most common autosomal trisomy among live-born infants, occurring in approximately 1 in 700 live-births, and is caused mainly by the failure of chromosome 21 to properly segregate during oogenesis [1]
There was one exception to this pattern: among the Meiosis II (MII) errors with a single recombinant, both location and GC content were significant predictors of the amount of recombination. This suggests that among MII single recombinant events, where the increased risk is associated with a pericentromeric recombinant, there may be a preference for recombination to occur in regions with elevated GC content and close to the centromere
For proximal recombinant events (Table 3), GC and CpG content as well as bin location were found to be positively correlated with recombination among meiosis I (MI) and MII errors; no association for these features was found among normal meiotic control recombinant events of this type (Table 3)

Summary

Introduction

Trisomy 21, leading to Down Syndrome (DS), is the most common autosomal trisomy among live-born infants, occurring in approximately 1 in 700 live-births, and is caused mainly by the failure of chromosome 21 to properly segregate during oogenesis [1]. Allelic differences in the zinc finger binding domain of PRDM9 explain approximately 80% of the heritable variation in ‘‘hotspot usage’’ ’’ (i.e. the frequency in which recombination occurs within linkage disequilibrium (LD) or ‘‘historically’’-defined hotspots) [8,11,12]. The observation that both cis and trans-acting factors are associated with the placement of recombination led us to question whether the altered patterns of recombination associated with nondisjunction of chromosome 21 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. This paper presents the first analyses of the relationship between recombination rate and the quantity of genomic features or LD-defined hotspots along chromosome 21 in oocytes with a normal meiotic outcome, a MI nondisjunction error or a MII nondisjunction error

Methods

Results

Conclusion