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How age-dependent alterations in meiotic recombination cause chromosome mis-segregation in sperm

减数分裂重组的年龄依赖性改变如何导致精子中染色体错误分离

基本信息

批准号：
10440306
负责人：
Francesca Cole
金额：
$ 38.64万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10440306
关键词：
Address Adolescent Adult Age Aneuploidy Architecture Back Biological Assay Cells Characteristics Child Chromatids Chromosome Segregation Chromosome abnormality Chromosomes Complex Congenital Abnormality Cytology DNA Double Strand Break Data Down Syndrome Ensure Enzymes Fathers Frequencies Genetic Genetic Recombination Genome Stability Genomic Instability Germ Cells Goals Health Homologous Gene Human Individual Infertility Lead MLH1 gene Mammals Meiosis Meiotic Recombination Methods Molecular Mus Mutant Strains Mice Oocytes Pathway interactions Plant Roots Process Prophase Regulation Reproductive Biology Research Resolution Resolvase Site Spermatocytes Spermatogenesis Spontaneous abortion Structure System Technology Therapeutic Intervention Yeasts age related arm base chromosome missegregation density design endonuclease enzyme activity experimental study genome-wide improved insight mathematical model novel novel strategies prevent repaired segregation sexual dimorphism sperm cell therapy design young man

项目摘要

PROJECT SUMMARY/ABSTRACT Errors of chromosome segregation during meiosis are a leading cause of infertility, miscarriage, and birth defects. Faithful segregation requires homologs to become tethered by crossovers, a recombination product that exchanges homolog arms. DNA double-strand breaks are induced during meiosis to provoke recombination. Only a small subset of breaks become crossovers with the remaining repaired as noncrossovers, which are patch-like repairs that facilitate pairing, but cannot connect homologs. Thus, dysregulation of crossovers in favor of noncrossovers can lead to aberrant chromosome segregation. A fundamental question in chromosome and reproductive biology is how cells ensure crossovers between each homolog. In order to design therapies to prevent chromosome mis-segregation in meiosis, an understanding of the molecular underpinnings of meiotic recombination is required. We have developed assays that can distinguish contributions from the major recombination pathways at high resolution in mouse spermatocytes. Using this technology, we found that in juvenile mouse spermatocytes, alternative pathways involving structure-selective endonucleases and complexes that dissolve crossover precursors generate noncrossovers in lieu of crossovers, causing crossover maturation inefficiency. As a result, crossovers are found at lower density leading to chromosome mis-segregation. We found similarly lower crossover density in young human spermatocytes suggesting a root cause for why younger fathers are more likely to have children with Down syndrome. This proposal will investigate 1) when recombination pathways act during meiotic prophase in spermatocytes and oocytes, 2) whether there are temporally regulated expression, localization, or activity changes of enzymes that execute recombination pathways, and 3) in what way are juvenile human spermatocytes like human oocytes. Taken together, the successful execution of the proposed research will provide a comprehensive understanding of why meiotic recombination is altered with age in spermatocytes and how chromosomes mis-segregate as a consequence.

项目总结/文摘