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

Maciej Jakub Zelazowski, Maria Sandoval, Lakshmi Paniker, Holly Hamilton, Jiaying Han, Mikalah A. Gribbell, Rhea Kang, Francesca Cole

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

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. 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.

Original languageEnglish (US)
Pages (from-to)601-614.e13
JournalCell
Volume171
Issue number3
DOIs
StatePublished - Oct 19 2017

Keywords

  • DNA repair
  • aneuploidy
  • chromosome segregation
  • crossing over
  • gene conversion
  • germ cells
  • homologous recombination
  • meiosis
  • noncrossovers
  • spermatocytes

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

MD Anderson CCSG core facilities

  • Flow Cytometry and Cellular Imaging Facility
  • Research Animal Support Facility

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