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The Genetic Contribution to Mammalian Meiosis Why Gametogenesis? • Worldwide, 15% of couples are infertile. • Data suggest that 60% of idiopathic infertility (in males) has a recessive autosomal etiology. • Of the nearly 30,000 genes in the mammalian genome, only 300 have been identified so far to affect gametogenesis. • Of the genes known to function during gametogenesis, there are tumor-suppressor genes, oncogenes, DNA repair enzymes, and genes involved in the maintenance of genomic integrity. • The biology of reproduction plays a central role in species proliferation and, during sexual reproduction, in the generation and maintenance of genetic diversity. The progression of meiosis I and the interplay of DNA repair and positive regulatory signals mei4/mei4 animals are sterile and display sexually dimorphic development ENU G0 (C57BL/6J) male X C3HeB/FeJ (female) G1(male) X C3HeB/FeJ (female) X G2 (females) G3 mei4/mei4 animals fail to congress to the metaphase plate and have aberrant spindle morphology in meiosis I mei4/mei4 animals are unable to form and/or maintain bivalent structure mei4/mei4 animals fail to maintain chiasmata in diplonema DSB repair and recombination are interrupted in mei4/mei4 mutants mei4 maps to a 0.7cM (2.5 MB) region on central chromosome 14 mei4 is a deletion allele of HEI10 (HEI10mei4), a gene that is primarily expressed in the testis and embryo control mHEI10 is a RING finger E3 ubiquitin ligase with cyclin B/cdk specificity Mechanism of the meiotic defect caused by the HEI10mei4 allele HEI10mei4 provides a link between the cell cycle and meiotic DNA repair Future Research •Determine genetic structure, i.e. the promoter, intron/exon boundries, and 3’/5’ sequences. •Assay function during gametogenesis - interacting partners, transcription profile, immunofluorescence, translational control, DNA damage role, and comparative biology. •Develop a collection of gametogenic genes with the aim of determining over-reaching themes in gene control during early gametogenesis. Acknowledgements Middlebury College Jackson Laboratory Ward Laboratory Dr. Vickie Backus Lisa Niswander Laura Helft Will Motley Kyle von Hasseln Eppig Laboratory Dr. John Eppig Marilyn O’Brien Biology Department Middlebury Imaging Facility Scientific Services Tim Allen Middlebury Research Animal Facility Sarah Froebel Vicki Major Joanne Huyler, DVM Cornell University Schimenti Laboratory Dr. John Schimenti Dr. Laura Reinholdt Dr. Gareth Howell Rob Munroe Becky Bergstrom Dr. Dave Bergstrom Funding for this Work Vermont Genetics Network (JW) Middlebury Biology Department (WM) NIH (JW) Bicentennial Fund Fellowship (LN) Janet C. Curry ‘49 Fellowship (LH)