O-064 Genome-wide analysis of meiotic recombination reveals a subset of oocytes with reduced frequency of recombination and increased risk of aneuploidy.
Authors: Gunes Z , Wells D 
Published: June 2023

Abstract

Study question
Are there differences in recombination rates between male and female embryos, and is the frequency of recombination associated with the risk of aneuploidy?

Summary answer
There is more recombination in female meiosis than in males. Aneuploidy is associated with fewer recombination events. Genome-wide reduction in recombination predisposes oocytes to aneuploidy.

What is known already
Aneuploidy is believed to be the primary explanation for embryo implantation failure and miscarriage and is, therefore, of great relevance to IVF. Despite the high frequency and clinical importance of aneuploidy, the mechanisms causing a gamete to become chromosomally abnormal are only partially understood. One factor known to influence the risk of aneuploidy is meiotic recombination. An absence of recombination or atypical positioning of chiasmata predisposes to chromosomal malsegregation. Most data on the subject of meiotic recombination and aneuploidy comes from miscarriages and aneuploid births, but this provides an incomplete view since most aneuploidies are lethal at earlier developmental stages.

Study design, size, duration
∼300,000 polymorphisms scattered across the genome were genotyped in DNA from 125 couples and 543 blastocysts that they produced. The inheritance of individual alleles was tracked from parents to embryos, allowing the parental origin of each chromosome to be determined. This strategy also permitted the detection of abnormal numbers of chromosomes, allowed deduction of which meiotic division aneuploidy had arisen in, and revealed the sites of meiotic recombination on each chromosome in the embryos analysed.

Participants/materials, setting, methods
Embryo analysis involved trophectoderm biopsy, followed by multiple displacement amplification. Parental DNA and amplified embryo samples were then tested using a microarray. 22,133 individual recombination events on 14,561 chromatids were evaluated. The relationship between aneuploidy and recombination frequency was considered. The average distance between recombination events was calculated by dividing the size of each autosome (in Mega bases – Mb) by the number of detected recombination events. An unpaired t-test was conducted for statistical analysis.

Main results and the role of chance
A quarter of all embryos were found to carry one or more chromosome abnormalities (altogether, 221 chromosome abnormalities were detected). Of these, 82% had a maternal (oocyte) origin, while 18% were paternal. Chromosomes 16 and 22 were the most frequently affected by aneuploidy, together accounting for 33% of all maternal chromosome abnormalities. Analysis of recombination events in maternally and paternally inherited chromosomes confirmed that female meiosis is associated with a significantly higher frequency of recombination (41.4 ±7.7 recombination events compared with 24.4±4 in chromosomes of paternal origin). Chromosomes 21 and 22 showed the lowest number of recombination events, consistent with their small size (average of 0.6 and 0.7 recombination sites per chromosome, respectively). As expected, a complete failure of recombination occurred more frequently for chromosomes with lower numbers of recombination events. Interestingly, embryos with aneuploidies of maternal origin showed evidence that the oocytes that produced them had lower recombination rates in general (not restricted to the affected chromosomes) than those producing euploid embryos (P = 0.01). Across the genome, average distances between recombination events were ∼10% lower for euploid embryos compared with aneuploid embryos (72.4 +/-14 Mb versus 81+-18 Mb) (P = 0.0004).

Limitations, reasons for caution
It is possible that the pattern and frequency of recombination sites that exist in sperm and oocytes might show some differences from the blastocysts tested during this study, considering that more than half of all oocytes either fail to fertilise or produce embryos that arrest before the blastocyst stage.

Wider implications of the findings
As expected, a higher aneuploidy rate and more recombination events were seen in female meiosis compared with male meiosis. Interestingly, aneuploidy was associated with lower levels of recombination across the whole genome, not only for the affected chromosomes, suggesting that unusually low recombination activity predisposes some oocytes to chromosome malsegregation.

Trial registration number
not applicable