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对哈特人夫妇的生殖表型。虽然我们之前关注的是人类白细胞抗原区域基因，但我们的研究也表明，影响生育能力的非人类白细胞抗原基因在人群中也是分离的。因此，在这次更新应用中，我们将继续研究哈特人生育的遗传学，但现在使用基因组范围的方法来识别新的基因。我们建议识别和描述影响女性和男性生育能力的基因，通过每结婚年生育的数量来衡量，这在哈特人中是高度可遗传的特征(女性遗传率为66%，男性遗传率为42%)。最初的全基因组筛查有大约1500个标记，已经确定了5个符合全基因组意义标准的新基因(1个在女性，4个在男性)。在这项应用中，我们建议在参与怀孕结果前瞻性研究的哈特人夫妇(目前已进入第20个年头)和近亲繁殖人群(包括反复妊娠丢失和不育的女性；以及患有非梗阻性无精子症的男性)中，进一步表征这些潜在的生育基因中的4个。此外，我们建议使用500,000个SNPs对哈特人的雌性和雄性可育性进行全基因组关联研究，以确定额外的可育性基因，然后在哈特人和近交系群体中也对这些基因进行特征描述。这些研究将在很大程度上利用我们已有的基础设施(基因类型、表型、计算资源)。最后，我们建议将我们的作图方法扩展到包括非常染色体(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和可能不育的新基因和途径，并可能导致改善对不孕不育或反复流产的治疗，或改进避孕方法。

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.