Molecular Genetic Studies of Fertility in the Hutterites

哈特人生育力的分子遗传学研究

• 批准号: 7635915
• 负责人: Carole Ober
• 金额: $ 27.08万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-10-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7635915
• 关键词: Alleles; Architecture; Birth; Chromosome Mapping; Chromosomes; Complex; Contraceptive methods; Couples; Data; European; Family; Female; Fertility; Fertility Study; Fibroblast Growth Factor Receptor 2; Gene Cluster; Genes; Genetic; Genotype; Goals; Grant; HLA G antigen; Habitual Abortion; Haplotypes; Heritability; ITGAM gene; In Vitro; Individual Differences; Infertility; Interferons; Lead; Link; Male Infertility; Maps; Marriage; Measures; Methods; Mitochondria; Modeling; Molecular Genetics; Pathway interactions; Phenotype; Population; Pregnancy Outcome; Pregnancy loss; Process; Prospective Studies; Recurrence; Religion and Spirituality; Reproduction; Research Infrastructure; Research Personnel; Sex Chromosomes; Short Tandem Repeat Polymorphism; Single Nucleotide Polymorphism; Single Nucleotide Polymorphism Map; Testing; Variant; Woman; X Chromosome; Y Chromosome; analytical tool; computing resources; genetic pedigree; genome wide association study; genome-wide; genome-wide linkage; human leukocyte antigen gene; hutterite; improved; male; meetings; men; novel; protocadherin 10; reproductive; trait

DESCRIPTION (provided by applicant): Over the past -25 years, we have studied reproductive phenotypes in >500 Hutterite couples. Although our previous focus was on HLA region genes, our studies also suggested that non-HLA genes influencing fertility were also segregating in the population. Thus, in this renewal application, we will continue to study the genetics of fertility in the Hutterites, but now use genome-wide approaches to identify novel genes. We propose to identify and characterize genes that contribute to female and male fertility, measured by the number of births per years of marriage, which are highly heritable traits in the Hutterites (66% heritability in females and 42% heritability in males). An initial genome-wide screen with ~1,500 markers already identified 5 novel genes (1 in females, 4 in males) that met criteria for genome-wide significance. In this application we propose to further characterize 4 of these potential fertility genes in Hutterite couples participating in a prospective study of pregnancy outcome (currently in it's 20th year) and in outbred populations (including women with recurrent pregnancy loss and infertility; and males with nonobstructive azoospermia). In addition, we propose to conduct genome-wide association studies of female and male fertility in the Hutterites using 500,000 SNPs to identify additional fertility genes, and then characterize those genes as well in the Hutterites and in outbred populations. These studies will largely utilize infrastructure (genotypes, phenotypes, computational resources) already available to us. Lastly, we propose to extend our mapping methods to include genes on non-autosomal chromosomes (X, Y, mitochondrial) and study the impact of genes on those chromosomes on fertility in women (X, mitochondrial) and in men (X, Y, mitochondrial). These studies have the potential to identify novel genes and pathways that influence fertility, and possibly infertility, and could lead to improved treatments for infertility or recurrent miscarriage, or to improved methods of contraception.

描述（由申请人提供）：在过去的-25年里，我们研究了bb500huterite夫妇的生殖表型。虽然我们之前的研究重点是HLA区域基因，但我们的研究也表明，影响生育能力的非HLA基因也在人群中分离。因此，在这个更新的应用中，我们将继续研究huterites的生育遗传学，但现在使用全基因组方法来鉴定新基因。我们建议通过每年结婚生育的数量来确定和表征对女性和男性生育能力有贡献的基因，这是hutterite人高度遗传的特征（女性遗传率66%，男性遗传率42%）。最初的全基因组筛选大约有1500个标记，已经确定了5个符合全基因组显著性标准的新基因（1个在女性中，4个在男性中）。在这项应用中，我们建议在参与妊娠结局前瞻性研究（目前已进入第20年）的Hutterite夫妇和远交人群（包括复发性妊娠丢失和不育的女性，以及患有非阻塞性无精子症的男性）中进一步表征这些潜在生育基因中的4个。此外，我们建议在Hutterites人中使用500,000个snp进行女性和男性生育能力的全基因组关联研究，以确定额外的生育基因，然后在Hutterites和近交群体中对这些基因进行表征。这些研究将在很大程度上利用我们现有的基础设施（基因型、表型、计算资源）。最后，我们建议将我们的定位方法扩展到包括非常染色体染色体（X， Y，线粒体）上的基因，并研究这些染色体上的基因对女性（X，线粒体）和男性（X， Y，线粒体）生育能力的影响。这些研究有可能确定影响生育能力和可能影响不孕症的新基因和途径，并可能导致改进对不孕症或复发性流产的治疗，或改进避孕方法。