The objective of the proposed investigation is to identify human major histocompatibility complex (MHC) and non-MHC genes or regions that influence reproductive outcome. we propose to continue our population-based studies in the Hutterites and, in addition, conduct a prospective cohort study of pregnancy outcome among young Hutterite couples who have not yet completed their families. The Hutterites are an anabaptist sect that lives communally and proscribes contraception. Our data continue to show longer intervals from marriage to each birth among couples sharing HLA-A, -B, or -DR antigens (Ober et. al., Fert. Steril. 44:227-232, 1985). Results of a prospective pilot study of pregnancy outcome in the Hutterites initiated in year -02 of our grant period, suggest that longer birth intervals among couples sharing antigens may result from the effects of genes in more than one MHC region (i.e., HLA- A linked and HLA-Dr linked) and that these genes may exert different effects fat different stages of gestation. Our pilot data indicate that Hutterite couples sharing HLA-Dr antigens have longer intervals to a recognized pregnancy (p<.05). Whether these differences are due to peri-implantation losses or factors that interfere with conception is unknown. On the other hand, Hutterite couples sharing HLA-A antigens experience increased recognized (>6 weeks gestation) fetal loss rates (p<.05). In addition, signification effects of Gm (immunoglobulin allotypes) mating types on Hutterite family sizes were also observed (Ober et. al., Am. J. Hum. Gen. 39:A242, 1986). In our renewal grant, we propose to better define MHC genes or regions that influence Hutterite fertility and examine their interactions with non-MHC genes (such as immunoglobulin and transferrin). In addition, we propose to elucidate the effects (reduced pregnancy rates v. increased fetal loss rates) and mechanisms (immunologic v. genetic) of these genes. Further refinement of MHC sharing will be possible using restriction fragment length polymorphim (RFLP) analysis with probes for MHC genes. RFLP studies for immunoglobulin and transferrin genes will increase the number of informative couples for analyses of fertility effects of these genes. RFLP analysis has proven to be a valuable technique for identifying MHC disease susceptibility genes. To our knowledge, this approach has not been applied to studies of genes that affect fertility, but offers a powerful tool by which such genes can be identified.

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Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Human Embryology and Development Subcommittee 1 (HED)
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University of Chicago
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Sengupta, Subhajit; Gulukota, Kamalakar; Zhu, Yitan et al. (2016) Ultra-fast local-haplotype variant calling using paired-end DNA-sequencing data reveals somatic mosaicism in tumor and normal blood samples. Nucleic Acids Res 44:e25
Burrows, Courtney K; Kosova, Gülüm; Herman, Catherine et al. (2016) Expression Quantitative Trait Locus Mapping Studies in Mid-secretory Phase Endometrial Cells Identifies HLA-F and TAP2 as Fecundability-Associated Genes. PLoS Genet 12:e1005858
Livne, Oren E; Han, Lide; Alkorta-Aranburu, Gorka et al. (2015) PRIMAL: Fast and accurate pedigree-based imputation from sequence data in a founder population. PLoS Comput Biol 11:e1004139
Gao, Ziyue; Waggoner, Darrel; Stephens, Matthew et al. (2015) An estimate of the average number of recessive lethal mutations carried by humans. Genetics 199:1243-54
Kosova, Gülüm; Stephenson, Mary D; Lynch, Vincent J et al. (2015) Evolutionary forward genomics reveals novel insights into the genes and pathways dysregulated in recurrent early pregnancy loss. Hum Reprod 30:519-29
Campbell, Catarina D; Mohajeri, Kiana; Malig, Maika et al. (2014) Whole-genome sequencing of individuals from a founder population identifies candidate genes for asthma. PLoS One 9:e104396
Kosova, Gülüm; Hotaling, James M; Ohlander, Samuel et al. (2014) Variants in DPF3 and DSCAML1 are associated with sperm morphology. J Assist Reprod Genet 31:131-7
Anderson, Rebecca L; Murray, Kathleen; Chong, Jessica X et al. (2014) Disclosure of genetic research results to members of a founder population. J Genet Couns 23:984-91
Bögershausen, Nina; Shahrzad, Nassim; Chong, Jessica X et al. (2013) Recessive TRAPPC11 mutations cause a disease spectrum of limb girdle muscular dystrophy and myopathy with movement disorder and intellectual disability. Am J Hum Genet 93:181-90
Gerull, Brenda; Kirchner, Florian; Chong, Jessica X et al. (2013) Homozygous founder mutation in desmocollin-2 (DSC2) causes arrhythmogenic cardiomyopathy in the Hutterite population. Circ Cardiovasc Genet 6:327-36

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