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Mechanisms and regulation of meiotic recombination"

减数分裂重组机制及调控"

基本信息

批准号：
10313233
负责人：
Carolyn Anne Turcotte
金额：
$ 3.71万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10313233
关键词：
Age Aging Aneuploidy Biological Assay Chromosome Segregation Chromosomes Cleaved cell Computer Models Congenital chromosomal disease Cruciform DNA DNA DNA Double Strand Break Data Defect Down Syndrome Drosophila genus Drosophila melanogaster Elements Ensure Failure Frequencies Genes Genetic Genetic Nondisjunction Genetic Recombination Genome Genomics Germ Cells Haploidy Heteroduplex Analysis Heteroduplex DNA Homologous Gene Human Incidence Infertility Light Link Location Malignant Neoplasms Maps Maternal Age Meiosis Meiotic Recombination Methodology Modeling Mutation Oocytes Organism Output Ovulation Pathway interactions Pattern Phenotype Process Proteins Recombinants Regulation Risk Sister Chromatid Site Spontaneous abortion Structure Techniques Testing age related base cohesion ds-DNA experimental study genome sequencing genome-wide homologous recombination in silico in vivo insight mathematical model models and simulation mutant predictive modeling prevent repaired segregation simulation tool whole genome

项目摘要

Project Summary/Abstract Meiosis is a tightly regulated process that ensures formation of haploid gametes. Failure to segregate homologous chromosomes during meiosis results in aneuploidy, leading to chromosomal disorders such as Down syndrome and miscarriage. Incidences of homolog nondisjunction increase with oocyte age. A hypothesized cause of age-related nondisjunction is that aging oocytes are unable to maintain chiasmata, physical linkages between homologs, until they are ovulated. Chiasmata are formed via crossovers, genetic exchanges between homologs that are formed by repairing double-strand DNA breaks via homologous recombination. To ensure proper homolog segregation, the number and spatial patterning of crossovers is tightly regulated in a phenomenon known as “crossover patterning.” Understanding regulation of crossover formation and patterning, and therefore homologous recombination mechanism, is integral to combatting age-related infertility. Pathway choices within homologous recombination are traceable in products via heteroduplex DNA (hDNA), DNA in which the strands come from different parental chromosomes. The classic meiotic HR model indicates that a crossover is formed via a double Holliday junction (dHJ), a structure in which two DNA molecules are linked via criss-crossing of their strands at two adjacent sites. In this classic model, ligated dHJs give rise to all crossovers by being cleaved in one of two patterns, generating two possible hDNA signatures. The model predicts that both patterns are equally likely, yet only one of the hDNA signatures has been observed. This hDNA signature bias demands revision of the meiotic recombination model. Our lab has mapped hDNA at recombinants of a test locus in Drosophila melanogaster, but redefining the meiotic recombination model requires much more extensive analysis of hDNA than is possible with this methodology. To overcome this obstacle, I will pioneer “hetSeq”, a whole-genome sequencing technique to detect hDNA from meiotic products, to continue redefining this model. A further gap in our understanding of crossover regulation is that although crossover patterning has been observed since the early 1900s, its relationship to homologous recombination mechanism remains unclear. Many meiotic proteins have a known function in homologous recombination, and their depletion leads to crossover patterning defects. I am developing a mathematical model of recombination to test hypotheses about these proteins. To do this, I will alter aspects of crossover patterning within the model and compare the output to previously obtained experimental data from mutants lacking these proteins. I am additionally using this model to develop a simulation of recombination using whole- genome sequencing data. The proposed experiments will strengthen understanding of crossover regulation to provide guidance in combatting age-related infertility and aneuploidy.

项目总结/文摘