Age-Dependent Alterations in Meiotic Recombination Cause Chromosome Segregation Errors in Spermatocytes

• Published in: Cell 2017-10, Vol.171 (3), p.601-614.e13
• Main Authors: Zelazowski, Maciej J., Sandoval, Maria, Paniker, Lakshmi, Hamilton, Holly M., Han, Jiaying, Gribbell, Mikalah A., Kang, Rhea, Cole, Francesca
• Format: Article
• Language: English
• Subjects: Aging; aneuploidy; Animals; Chromosome Aberrations; Chromosome Segregation; crossing over; DNA Repair; gene conversion; germ cells; homologous recombination; Humans; Male; Meiosis; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; noncrossovers; Recombination, Genetic; spermatocytes; Spermatocytes - cytology; Spermatocytes - metabolism
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2017.08.042

Faithful chromosome segregation in meiosis requires crossover (CO) recombination, which is regulated to ensure at least one CO per homolog pair. We investigate the failure to ensure COs in juvenile male mice. By monitoring recombination genome-wide using cytological assays and at hotspots using molecular assays, we show that juvenile mouse spermatocytes have fewer COs relative to adults. Analysis of recombination in the absence of MLH3 provides evidence for greater utilization in juveniles of pathways involving structure-selective nucleases and alternative complexes, which can act upon precursors to generate noncrossovers (NCOs) at the expense of COs. We propose that some designated CO sites fail to mature efficiently in juveniles owing to inappropriate activity of these alternative repair pathways, leading to chromosome mis-segregation. We also find lower MutLγ focus density in juvenile human spermatocytes, suggesting that weaker CO maturation efficiency may explain why younger men have a higher risk of fathering children with Down syndrome. [Display omitted] •Juvenile mouse spermatocytes have fewer crossovers and more achiasmate chromosomes•Greater use of alternative DNA repair pathways in juvenile mouse spermatocytes•Lower MutLγ focus density in juvenile human spermatocytes•Juvenile spermatocytes likely suffer from crossover maturation inefficiency A lower incidence of efficient meiotic crossover recombination in young males is attributed to the preferred utilization of pathways involving structure-selective nucleases and alternative complexes that generate noncrossovers at the expense of crossovers.