The major objectives of this proposal are to elucidate the genetic mechanisms that influence fertility and mate choice in a human population isolate. The small number of independent genomes and the relatively recent origins of founder populations make them well suited for genetic studies of complex traits, such as fertility and mate choice. These studies will be conducted in the Hutterites, an inbred, reproductive isolate of European origins that is notable for its high rate of fertility. In this population increased fetal loss rates among couples matching for the 16-locus, high resolution human leukocyte antigen (HLA) haplotype (P=0.002) and for serologically-defined HLA-B antigens (P = 0.019) have been noted, suggesting that an HLA-B-linked locus may be primarily associated with fetal loss. In addition, Hutterite mate choice is nonrandom with respect to the HLA haplotype, with fewer spouses than expected matching for the 16-locus, high resolution haplotype (P less than 0.001) and a deficiency of homozygotes for the haplotype in the population (P less than 0.030).
The specific aims of the proposed investigation are: 1) to identify the HLA-B-linked locus that is primarily associated with increased fetal loss rates in this population, by determining high resolution genotypes (i.e., DNA- based typing) for alleles at the HLA-A, HLA-B, and MICA loci; 2) to further evaluate the effects of Hutterite population structure on expectations of HLA haplotype matching between spouses and homozygosity levels in the population, by studying """"""""neutral"""""""" haplotypes composed of alleles at microsatellite loci in 20 non-MHC-linked regions of the genome; and 3) to study the HLA-linked polymorphisms and expression patterns of olfactory receptor genes on chromosome 6 and determine whether polymorphism at influence mate choice in the population. Identifying genes that influence fertility and mate choice in the Hutterites may reveal novel genes and pathways through which these traits are regulated in outbred couples and perhaps lead to novel therapies for miscarriage and infertility and a better understanding of individual recognition and chemosensory signaling in humans.
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