Molecular Genetic Studies of Fertility in the Hutterites

描述（由申请人提供）：在过去的25年里，我们研究了>500对哈特夫妇的生殖表型。虽然我们以前的重点是HLA区域基因，我们的研究也表明，非HLA基因影响生育力也分离的人口。因此，在这个更新的申请中，我们将继续研究哈特人生育力的遗传学，但现在使用全基因组方法来识别新基因。我们建议识别和表征有助于女性和男性生育力的基因，以婚姻中每年出生的数量来衡量，这些基因在哈特人中具有高度遗传性（女性遗传率为66%，男性遗传率为42%）。使用约1，500个标记进行的初步全基因组筛选已经发现了5个符合全基因组意义标准的新基因（女性1个，男性4个）。在本申请中，我们提出进一步表征参与妊娠结果的前瞻性研究（目前在其第20年）的哈特夫妇和远系繁殖群体（包括患有复发性妊娠丢失和不孕症的女性;以及患有非梗阻性无精子症的男性）中的这些潜在生育基因中的4个。此外，我们建议进行全基因组关联研究的女性和男性的生育能力在哈特派使用50万个SNP来识别额外的生育基因，然后表征这些基因以及在哈特派和远交人群。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，我们建议将我们的映射方法扩展到包括非常染色体上的基因（X，Y，线粒体），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力和可能的不孕症的新基因和途径，并可能导致改善不孕症或复发性流产的治疗方法，或改善避孕方法。

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.