The objectives of the proposed investigation are two-fold: 1) to identify major histocompatibility complex (MHC) genes or regions that influence reproductive outcome in the Hutterites; and 2) to elucidate the selective mechanisms that affect the patterning of HLA haplotypes in this population. We propose to continue our population-based and prospective studies in the S-leut Hutterites of South Dakota. This population is most notable for its high fertility rates (median completed family sizes = 8), small number of founding ancestors (mean inbreeding coefficient = 0.031), and communal lifestyle. Accurate vital statistic records and genealogical information back to the 1700's are available for the more than 35,000 living Hutterites. Previously we reported significantly longer intervals to a recognized pregnancy in couples sharing HLA-DR as compared with couples not sharing HLA-DR, and increased fetal loss rates among couples sharing HLA-B as compared with couples not sharing HLA-B (Ober et al., Am J Hum Genet 50:6-14,1992). In addition, we demonstrated a statistically significant deficit of couples sharing a 5-locus HLA haplotype, that cannot be explained by population-specific marriage patterns, suggesting that mate choice is influenced by MHC genes. In the current application we propose to further these investigations by examining the effects of specific MHC regions (class I, class II, class III) on fecundity, fetal loss rates, and mate choice. To accomplish this goal we will assign alleles at additional MHC loci (eg., HLA-G, HLA-DQA1, HLA-DQB1, HLA-DPB1, C4A, C4B) to each of the known haplotypes in the population and examine the effects of each locus and each region. In addition, we will study non- MHC linked microsatellite markers to determine directly the effects of population structure and marriage patterns on """"""""random"""""""" mate selection. To determine if there is a preferential loss of homozygous or compatible fetuses and to determine whether there is selection for certain haplotypes, we will examine segregation ratios in the offspring of families that share alleles, regions, or haplotypes or in families with certain haplotypes. Lastly, we will evaluate the effects of prenatal selection (i.e., peri-implantational losses in couples sharing HLA-DR and recognized fetal losses in couples sharing HLA-B) and preconception selection (i.e., MHC-mediated mate choice) on MHC haplotype frequencies and homozygosity levels in the Hutterites using computer simulation models. Thus, this population offers the unique opportunity to study a variety of MHC-mediated mechanisms that occur at different stages of the reproductive cycle and to elucidate the effects of MHC genes on fertility.
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