Wednesday, March 12, 2025
3/12/2025
This application proposes to develop fundamental genomic and bioinformatic resources that will better enable studies of the axolotl (Ambystoma mexicanum). The axolotl provides the best model for identifying mechanisms of regeneration that can translate to humans. This is because it can regenerate multiple damaged body parts, including whole limbs, spinal cord, and brain, and because it shares tetrapod biology with human. Understanding how axolotls regenerate complex tissues may reveal mechanisms to activate stem cells within human tissues to organize and reform damaged tissues. Beyond regeneration, the axolotl presents many untapped disease models that were identified and rigorously examined with traditional developmental approaches before the genetics/genomics era. With our recent development of the first chromosome-scale assembly of the axolotl genome, these and new models that will be created in coming years through genome editing, can be advanced for the first time to significantly impact biomedical research. However, to advance these models, improvements of the genome assembly are needed along with new datasets to enable genome-wide studies of the large axolotl genome. To accomplish these objectives, we propose three specific aims. In Aim 1, we will resolve inter- and intra-specific variation within the current assembly and resolve complex repetitive regions that have hampered the placement of ~6 Gb of the 32 Gb genome. Specifically, we will employ a powerful trio binning strategy that takes advantage of long read sequencing of DNA from axolotl x tiger salamander (A. tigrinum) hybrids. This approach leverages decades of experience in generating interspecific hybrids to resolve assembly gaps/errors and accurately place gene models within their non-coding regulatory environments. Additionally, we will analyze sequence data from 10 AGSC axolotls from branches of the pedigree that optimally sample laboratory genetic diversity. In Aim 2, we will perform Chip-Seq to identify changes in histone post-translational modifications during tail and limb regeneration. Characterization of epigenetic marks for embryo, larval, and adult models of regeneration will provide new resources for regeneration research and advance community efforts in performing genome wide studies. Aim 3 will address significant community needs, user-friendly access to large scale genomic datasets and improvement of genomic and bioinformatic capabilities of investigators in the axolotl community. Accomplishment of these aims will significantly advance axolotl as an animal model for biomedical research.
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