Failure to recombine is a common feature of human oogenesis

Abstract

Failure of homologous chromosomes to recombine is arguably the most important cause of human meiotic nondisjunction, having been linked to numerous autosomal and sex chromosome trisomies of maternal origin. However, almost all information on these "exchangeless" homologs has come from genetic mapping studies of trisomic conceptuses, so the incidence of this defect and its impact on gametogenesis are not clear. If oocytes containing exchangeless homologs are selected against during meiosis, the incidence may be much higher in developing germ cells than in zygotes. To address this, we initiated studies of exchangeless chromosomes in fetal ovarian samples from elective terminations of pregnancy. In total, we examined more than 7,000 oocytes from 160 tissue samples, scoring for the number of foci per cell of the crossover-associated protein MLH1. We identified a surprisingly high level of recombination failure, with more than 7% of oocytes containing at least one chromosome pair that lacked an MLH1 focus. Detailed analyses indicate striking chromosome-specific differences, with a preponderance of MLH1-less homologs involving chromosomes 21 or 22. Further, the effect was linked to the overall level of recombination in the cell, with the presence of one or two exchangeless chromosomes in a cell associated with a 10%-20% reduction in the total number of crossovers. This suggests individuals with lower rates of meiotic recombination are at an increased risk of producing aneuploid offspring.

Keywords: aneuploidy; exchangeless homologs; meiosis; oogenesis; recombination.

Figure 1

Exchangeless homologs (A–D) Representative images of pachytene oocytes with (A) no exchangeless homologs, (B) an exchangeless D group homolog, (C) an exchangeless E group homolog, and (D) two exchangeless homologs. For these images, the synaptonemal complex protein SYCP3 is in red, centromere-associated CREST is in blue, and the crossover-associated protein MLH1 is in green. (E) Summary of results on the total number of cells with 0, 1, 2, or 3 exchangeless homologs. (F) Distribution of exchangeless homologs by chromosome group.

Figure 2

Meiotic recombination and exchangeless chromosomes Mean MLH1 foci (±SD) per cell (A) for cells with 0, 1, 2, or 3 exchangeless chromosomes and (B) by chromosome group for cells containing a single E0 chromosome.

Figure 3

Individual variation in E0 chromosomes Proportion of cells with E0 chromosomes among 160 fetal ovarian samples (A) and mean MLH1 foci (±SD) per cell for subjects with differing levels of E0-containing cells (B); samples were divided into five groups of approximately equal size.

Figure 4

MLH1 values per cell for each of the 160 samples Filled-in circles denote cells with 1 or more E0 chromosomes; unfilled circles denote cells without E0 chromosomes. Samples are arranged from left to right by increasing mean MLH1 values.

Figure 5

Gestational and maternal age and meiotic recombination (A and B) Relationship between gestational age of the fetus and (A) mean MLH1 foci per subject and (B) proportion of cells per subject containing E0s. (C and D) Relationship between maternal age and (C) mean MLH1 foci per subject and (D) proportion of E0-containing cells per subject. Graph axes could be simplified (% E0s per case; mean MLH1 foci per case)