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Search for new genes involved in male infertility through novel approaches

通过新方法寻找与男性不育相关的新基因

基本信息

批准号：
10577839
负责人：
Thomas Garcia
金额：
$ 55万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-22 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10577839
关键词：
Affect Alleles Animal Model Area Bioinformatics Biological Process Biological Specimen Banks Biology Blood CRISPR/Cas technology Candidate Disease Gene Cells Child Chromosomes Classification Clinic Clinical Management Code Complex Contraceptive Agents Contraceptive methods Copy Number Polymorphism Couples Development Diagnosis Diagnostic Etiology Evaluation FDA approved Family Fertility Functional disorder Future Genes Genetic Genetic Counseling Genome Genomic Segment Goals Haploid Cells Haploidy Haplotypes Heterozygote Hormonal Human Impairment Individual Infertility Intervention Investigation Knowledge Laboratories Link Male Contraceptive Agents Male Infertility Mediating Meiosis Methods Modeling Molecular Molecular Abnormality Molecular Diagnostic Testing Mus Mutant Strains Mice Mutation Pathway interactions Patients Pharmaceutical Preparations Phenotype Population Research Resolution Role Sampling Spermiogenesis Therapeutic Third Generation Sequencing Time Translating United States National Institutes of Health Untranslated RNA Validation Variant Vertebrates Whole Blood Woman Work analysis pipeline candidate identification clinical infrastructure cohort contraceptive target empowerment gene product gene synthesis gene therapy genetic testing genetic variant genome sequencing improved large datasets loss of function male male fertility men mouse model next generation novel novel strategies reproductive small molecule inhibitor sperm cell standard of care subfertility technology validation transmission process whole genome

项目摘要

SUMMARY To date, the etiology of idiopathic male infertility is not fully understood, and hormonal male contraceptives have not been effective. Through novel approaches to sequencing and sequencing analysis of male infertile patients and controls, this proposal seeks to identify new coding and non-coding genes and genomic regions required for male fertility and to validate the functional requirement of newly identified genes through mouse models. Past limited sequencing-based approaches have so far only been able to provide diagnostic variants to 1.5% of infertile men who present to the clinic, a yield that will improve with identification of more genes underlying infertility in men. One limitation to past progress has been the inability of conventional short-read sequencing to resolve haplotype-specific information: whether two or more mutations in each gene are on the same or separate alleles. Since gene loss-of-function typically requires damage to both alleles, it is of paramount importance to be able to resolve this information. Through long-read sequencing (a newly established and validated technology) we will identify novel damaging mutations at haplotype-specific resolution, correlating multiple novel damaging mutations with potential loss-of-function in our newly sequenced patients. Additionally, since sperm are haploid and previous studies have demonstrated a requirement for newly synthesized genes after meiosis, we will identify mutations lethal to sperm development through sequencing of both whole blood and sperm. Mutations present in blood (representing both maternal and paternal genomes) that are absent in sperm [with haploid genomes representing 8 million (2^23) chromosome combinations] demonstrate a requirement for those genes in the later stages of sperm development. Thus, through our proposed work we will identify for the first-time genes required for male fertility in men who may in fact be fertile. Lastly, we will apply CRISPR/Cas9 in mice to validate the functional requirement of candidate genes that we identify through our sequencing studies. Novel male infertility associated genes that are found to be expressed in sperm or epididymal cells, are evolutionarily conserved in vertebrates, including mice and humans, and rank among the highest in our patients will be prioritized for validation. We will assess the fertility phenotype of mutant mice and further explore molecular pathophysiology, which for some genes may determine candidacy as a contraceptive target.

总结