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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)