Meiosis is a complex, highly conserved process that ensures that the parental genomes are properly distributed to the gametes to prevent aneuploidy in the offspring. Model organisms such as yeast, flies, and worms have contributed the bulk of what is understood about meiosis: how the chromosomes replicate, condense, and how the protein zipper called the Synaptonemal Complex assembles between the homologous parental chromosomes. The machinery that generates the double-stranded DNA breaks required for recombination, and the processes that guide DNA repair to yield cross-overs between the homologs have also been highly studied. In contrast, little is understood about how the homologous chromosome sets recognize each other, exclude heterologous interactions, and pair and align with each other in any organism. Without proper homolog recognition and alignment, all other meiotic processes are usually rendered moot, since recombination-mediated attachments must only occur between homologs for proper distribution of the genome into the gametes. Most eukaryotic genomes are highly repetitive, thus homology recognition may not include, and may actively prevent, recognition by DNA sequence alone. DNA sequences may play some role, but other features of meiotic chromosomes must contribute to homolog identity. One feature unique to each chromosome is their linear arrangement of genes. The gene pattern for each chromosome is further refined by which genes are active during meiosis. Recent results from a variety of species indicate histone modifications play important and conserved roles in meiotic events. Furthermore, there is evidence that readers of histone modifications are also important for meiotic processes, including homolog pairing and alignment. We propose that the histone modifications produced by active gene expression create a stable ?epigenetic bar code? that is unique to each chromosome. This bar code is then recognized by ?epigenetic readers? that provide a Velcro-like interface in which the most stable linear alignments between all chromosomes in a set are those between homologs. The dynein-dependent forces that are known to pull on the aligned chromosomes during meiotic pairing provide the force required to select for maximal alignment of the bar-code, and hence interpret homology. The C. elegans germline represents an ideal system to test the predictions of the epigenetic bar-code model, since the writers and readers of the histone modifications in germ cells are largely known. Importantly, mutations in the enzymes involved are known to have only minor effects on germ cell transcription, which allows for testing of the hypothesis with minimal interference from indirect effects. We are thus poised to investigate the role of chromatin architecture produced by transcription dependent patterns of histone modifications in meiotic chromosome homolog recognition and pairing, which will provide the first mechanistic insights into this poorly understood but highly essential process.
The proposed research focuses on mechanisms that affect the proper segregation of the genome during meiosis and hence the correct transmission of each parent's DNA to the offspring. Defective meiosis results in children that inherit an improper number of genes or chromosomes from their parents, leading to abnormal development and/or death. These studies are therefore highly relevant to NIH's mission to develop fundamental understanding, and ultimately reduce the burdens of, human developmental defects and disability.
