Reconciling observations from human genetics and phylogenetics: an integrated approach to the study of mutation
Active Project Grant Awarded Last action
- Award ID
- F32GM163397
- Recipient
-
The Trustees Of Columbia University In The City Of New York UEI F4N1QNPB95M4
- Awarding agency
-
National Institute of General Medical Sciences
National Institutes of Health, Department of Health and Human Services
- Obligated
- $79,348
Award facts
- Assistance listing
- 93.859 Biomedical Research and Research Training
- Completion date 0% complete
- Place of performance
- New York, NY 10027, USA
Award details come from USAspending.gov.
Description
- Abstract
- Germline mutations cause developmental disorders and cancers, yet their origins are poorly understood. Even for the most commonly-occurring mutation type in humans, CPG transitions (i.e., C to T mutations at CG dinucleotides), different lines of evidence provide conflicting results about their dependence on cell division. Within an individual, rapidly-dividing cell types carry more CPG transitions than do slowly-dividing ones, which suggests that CPG transitions accrue with DNA replication cycles. However, primate species with vastly different rates of cell division appear to accumulate C>T substitutions at CPG sites at similar rates, indicating that CPG transitions do not track cell divisions. Possible explanations are: (I) CPG transitions do arise with cell division, but population processes that lead mutations to become substitutions obscure this relationship (e.g., biased gene conversion). (II) sources of CPG transitions differ between germline and soma. (III) existing phylogenetic analyses, based on a limited number of species, are unreliable. I propose to distinguish among these possibilities, by integrating phylogenetic analyses, somatic and germline mutation data, and modeling. In aim 1, I plan to revisit how substitution rates vary among primates by taking advantage of substantial improvements in genomic resources. The goal is to understand whether CPG transitions (or any other substitution type) accumulate independently of cell division and how that behavior depends on genomic features. This analysis will help establish whether CPG transitions can be used to reliably date evolutionary events or as a cell division counter. In aim 2, I will examine whether variation in substitution rates arises from changes in the mutation or the fixation process. To that end, I will rely on rare polymorphisms and DE novo mutations in testis samples to estimate germline mutation rates for primate species. I will also analyze somatic mutation rates to test if differences across species recapitulate those that I identify in the germline. In aim 3, I will model the biochemical, cellular, and developmental factors that generate mutations and the evolutionary processes that give rise to substitutions. Using this integrated model, I will map out the parameter space that reproduces my findings from aims 1 and 2 and others in human genetics. This research will advance our understanding of mechanisms that give rise to mutations and underlie genetic risk of disease and cancer. The proposed project builds on my background in modeling, but provides an opportunity to learn about the analysis of different types of genetic variation data and receive biological training in the study of mutation. My choice of sponsor, DR. Przeworski, is a leading researcher on germline mutagenesis and has an excellent mentorship record; furthermore, the irving institute for cancer dynamics (IICD), of which I am now a member, provides a rich scientific environment for studying somatic mutagenesis. Her lab and IICD provide the requisite resources to complete the proposed project and also offers ample opportunity to strengthen my teaching, communication, and experimental design skills.
Quick answers
Who received award F32GM163397?
F32GM163397 was awarded to The Trustees Of Columbia University In The City Of New York by National Institute of General Medical Sciences (National Institutes of Health) on January 29, 2027.
How much is award F32GM163397 worth?
$79,348 has been obligated on F32GM163397.
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