Uncovering the origin of hypermutability in adult brains
Active Project Grant Awarded Last action
- Award ID
- R01MH131623
- Recipient
-
Mayo Clinic UEI Y2K4F9RPRRG7 Part of Mayo Clinic
- Awarding agency
-
National Institute of Mental Health
National Institutes of Health, Department of Health and Human Services
- Obligated
- $5,159,192
Award facts
- Assistance listing
- 93.242 Mental Health Research Grants
- Completion date 59% complete
- Place of performance
- Rochester, MN 55905, USA
Award details come from USAspending.gov.
Description
- Abstract
- Genomic variants in an individual may be either inherited (i.e., transmitted through the germline) or generated by mutagenesis in post-zygotic cells. Widespread genomic mosaicism in somatic cells of phenotypically normal individuals is now well established. In certain cases, IT is known that mutations have causative role in diseases and contribute to neuropsychiatric disorders. But generally, little is known about to what extent natural mosaicism influences an individual's susceptibility to disease. In our recent study we discovered a phenomenon of hypermutability in adult brains. Hypermutability was not related to diagnosis but increased with age, reaching at least 3% population frequency (95% confidence interval) for brains over 40 years old. The phenomenon of hypermutability could have implications for a number of conditions. Since IT correlates with aging, IT could be important for age-related neurodegenerative diseases; or, as IT involves mutations in cancer-related genes, IT may be related to predisposition for brain cancer. Alternatively, hypermutability may reflect imbalances (expansion/contraction) between cell lineages in the developing brain. We have three hypotheses explaining hypermutability. The goal of the proposed study is to firmly establish the origin(s) of hypermutability. To conduct the study, we will first expand the set of hypermutable brains (aim 1). The ultimate judgement about the origins will be made from the regional distribution and frequency of mutations in the brains (aim 2), the cell type(s) carrying the mutations (aim 3), and proving (or disproving) that mutations in the hypermutable brains arose from a clonally expanded cell lineage (aim 4). Proving the hypothesized origins of hypermutability will be a fundamental contribution to understanding brain development and aging in humans and will lay the foundation for future studies of the underlying mechanisms.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $844,959 | |
| Amendment | $127,286 | |
| Amendment | $127,286 | |
| Amendment | $721,292 | |
| Amendment | $721,292 | |
| Amendment | $87,069 | |
| Amendment | $87,069 | |
| Amendment | $814,313 | |
| Amendment | $814,313 | |
| Original award | $814,313 |
Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| Yale Univ | $275,573 | |
| Lieber Institute Inc. | $296,264 | |
| Yale Univ | $41,336 | |
| Lieber Institute Inc. | $44,541 | |
| Yale Univ | $234,237 | |
| Lieber Institute Inc. | $252,403 | |
| Lieber Institute Inc. | $457,886 | |
| Yale Univ | $174,073 |
Quick answers
Who received award R01MH131623?
R01MH131623 was awarded to Mayo Clinic by National Institute of Mental Health (National Institutes of Health) on November 15, 2023.
How much is award R01MH131623 worth?
$5,159,192 has been obligated on R01MH131623.
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