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：
9974532
负责人：
Francesca Cole
金额：
$ 39.43万
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/9974532
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.

项目摘要/摘要减数分裂过程中染色体分离的错误是不孕，流产和出生的主要原因缺陷。忠实的隔离要求同源物被重组产品交叉束缚交换同源武器。 DNA双链断裂是在减数分裂过程中引起的重组。只有一小部分断裂变成了跨界，其余修理非交叉，是有助于配对但无法连接同源物的贴片状维修。因此，跨界的失调而不是非交叉的，可能导致异常的染色体分离。一个染色体和生殖生物学中的基本问题是细胞如何确保每个细胞之间的交叉同源物。为了设计疗法以防止减数分裂中的染色体错误分离，对需要减数分裂重组的分子基础。我们开发了可以区分小鼠精子细胞中高分辨率的主要重组途径。使用这项技术，我们发现在少年小鼠精子细胞中，涉及的替代途径结构选择性的内切酶和溶解交叉前体的复合物会产生非交叉代替跨界，导致交叉成熟效率低下。结果，在较低的密度导致染色体错误分离。我们发现年轻人类的跨界密度类似精子细胞暗示了为什么年轻父亲更有可能生孩子的根本原因综合征。该提议将调查1）重组途径在减数分裂预言期间作用时精子细胞和卵母细胞，2）是否有时间调节的表达，定位或活动执行重组途径的酶的变化，以及3）少年人类是什么方式精子细胞如人类卵母细胞。综上所述，拟议研究的成功执行将对精子细胞的年龄变化为何改变减数分裂重组的全面理解染色体如何脱粒于隔离。