Mutation Projects Home

Home page with links to sub-project, plus top-level stuff.

Quick links to active projects

• MutationAnalysis -- work with NIST collaborators to develop validated models
• CAMP -- Critical Assessment of Mutant Prediction (pilot project)
• MutationDamageAnalysis^? -- leverage biochemical methods to understand mutation
• MutationEvolutionModels^? -- evaluate role of mutation in sequence evolution

Overview of projects, plans and ideas

• MutationAnalysis -- work with NIST collaborators to develop
  • validated models of mutation
  • standard reference data sets
  • more sensitive methods for analysis
• MutationDamageAnalysis^? -- find damage methods and apply data
  • hydroxyl radical sensitivity
  • 8-oxo-G
  • methylation
• Applications for improved understanding of mutation
  • phylogenetics (tree of life)
    • mito sequences
    • rDNA sequences
    • protein sequences
  • functional inference, e.g., phylogenetic footprinting
  • prediction of emerging infectious diseases
  • predictive personalized medicine
  • cancer biomarkers
  • more sensitive toxicity assays
• MutationEvolutionModels^?
  • molecular sequences
    • codon usage
    • amino acid usage
    • amino acid replacement
    • isochores and other aspects of genome architecture
  • other omics data
    • network structure
    • expression divergence
  • "phenotypes"
    • methods to apply
      • evolutionary character analysis
      • MA analysis in multiple species
      • developmental models
      • phenotypic challenge (stress) as perturbation
    • systems to consider
      • rhabditid vulva as in Kiontke, et al
      • amphibian autopod as in Alberch and Gale
      • rodent cranium

Relevant funding

• Community of Science database search

Agencies, foundations, and programs

• NSF
  • Tree of Life
• DOE
  • Low-Dose Radiation. possible pitches:
    • need models of enogenous-damage-induced mutation to detect and understand effects of radiation
• NIH : investigator-initiated RO1 grant
• Templeton foundation

Relevant projects from other investigators

• Mike Lynch's 20-year project on The Rate and Molecular Spectrum of Spontaneous Mutations
• Nadia Singh (formerly of Dmitri Petrov's lab, I think I met her there) project on Role of mutation rate variation in patterns of molecular evolution in Drosophia
• another nematode MA project, this from Charles Baer Evolutionary Causes and Consequences of Variation in the Rate of Mutation
• Howard Liber (Mass General), MUTAGENESIS induced by ROS in cellular models, involves spectrum analysis in p53 gene
• Lawrence Sowers (Loma Linda) Base Pairing and Mutagenesis project, with experimental and computational work
• AS Bhagwat project on Transcription-induced mutations focuses on "effects of supercoiling, R-loop formation and other structural features on strand bias and clustering of mutations" (C-to-T mutations, specifically)

• http://crisp.cit.nih.gov/crisp/CRISP_LIB.getdoc?textkey=7321551&p_grant_num=1Z01HL001051-09&p_query=$(mutation+%26+model)&ticket=61281828&p_audit_session_id=308355116&p_audit_score=25&p_audit_numfound=55&p_keywords=mutation+model^?
• pubmed link to work related to above on modeling mutations in GroEL^? Zheng, et al., 2007

Some notes on using CRISP database at NIH

• most "mutation" projects focus on specific diseases associated with germline or somatic mutations
• some "mutation" projects focus on a mechanism or damage agent example project focused on NO-induced damage
• mutation + germline + model (or damage instead of model): very few relevant hits, mostly cancer-related
• the best way to find relevant hits is to search "mutation" and "spectrum"

Proposed project

1. develop and validate models of germline mutation
2. quantify contribution of mutation to non-randomness for targeted molecular features
3. apply results to improve comparative analysis (demonstrate efficacy)
4. develop a web resource for models of mutation

Background

1. role of models of germline mutation in biological analysis
2. spectrum model of germline mutation
   1. prior work illustrating specific patterns of non-randomness (indels, context)
   2. outstanding issues
   3. approach used here
3. contribution of mutation non-randomness to evolution (and other phenomena)

Preliminary results

1. hydroxyl stuff
2. YS human-chimp analysis in press?

Research design

Mutation Web Utilities