Genome wide association studies (GWAS) pinpoint the specific location in the human genome that is associated with a particular disease. Often, the regions of the genome identified in these studies are non- coding, i.e. do not change the sequence of the protein encoded by a gene. One possible mechanism by which a mutation can cause a disease without changing the protein sequence is by changing the structure of the messenger RNA (mRNA). Changes in the structure of the mRNA (in particular in the untranslated regions (UTRs)) can alter gene regulation. This is because significant components of the cell's regulatory machinery are encoded in the UTRs. This is the case for mutations in the untranslated region of the PTEN gene, which cause a rare genetic disorder called Cowden's Syndrome (which results in Hamartoma and Cancer) (Teresi et al., 2007). We hypothesize that those mutations in UTR mRNA that significantly alter its structure can modify the regulatory machinery of the gene and lead to the disease. We have developed both computational and experimental approaches to assess the structural changes caused by specific mutations in mRNA UTRs. We will scan all known disease-associated mutations in the Human Genetic Mutation database (HGMD) computationally to identify the subset that cause the largest changes in UTR mRNA structure. We will then confirm our findings using a high-throughput experimental approach we have developed that leverages multiplexed capillary electrophoresis technology (Mitra et al., 2008). This will allow us to identify and validate a subset of known disease-associated mutations where the structure of the mRNA is altered by mutation. These data will focus the research aimed at developing molecular treatments for the diseases associated with these mutations on the RNA. Our results will also begin to elucidate molecular mechanisms associated with Human disease in non-coding regions of the Human genome.
We aim to identify disease-associated mutations in the human genome that alter the structure of the messenger mRNA using computational and experimental approaches. By identifying the disease-associated mutations that alter regulatory RNAs, we will identify novel molecular targets for therapeutic development.

Public Health Relevance

We aim to identify disease-associated mutations in the human genome that alter the structure of the messenger mRNA using computational and experimental approaches. By identifying the disease-associated mutations that alter regulatory RNAs, we will identify novel molecular targets for therapeutic development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21MH087336-01
Application #
7759069
Study Section
Special Emphasis Panel (ZMH1-ERB-C (06))
Program Officer
Lehner, Thomas
Project Start
2009-08-12
Project End
2011-05-31
Budget Start
2009-08-12
Budget End
2010-05-31
Support Year
1
Fiscal Year
2009
Total Cost
$232,805
Indirect Cost
Name
Wadsworth Center
Department
Type
DUNS #
153695478
City
Menands
State
NY
Country
United States
Zip Code
12204
Gamache, Eric R; Doh, Jung H; Ritz, Justin et al. (2017) Structure-Function Model for Kissing Loop Interactions That Initiate Dimerization of Ty1 RNA. Viruses 9:
Chen, Chunxia; Mitra, Somdeb; Jonikas, Magdalena et al. (2013) Understanding the role of three-dimensional topology in determining the folding intermediates of group I introns. Biophys J 104:1326-37
Ritz, Justin; Martin, Joshua S; Laederach, Alain (2012) Evaluating our ability to predict the structural disruption of RNA by SNPs. BMC Genomics 13 Suppl 4:S6
Sansone, Susanna-Assunta; Rocca-Serra, Philippe; Field, Dawn et al. (2012) Toward interoperable bioscience data. Nat Genet 44:121-6
Martin, Joshua S; Halvorsen, Matthew; Davis-Neulander, Lauren et al. (2012) Structural effects of linkage disequilibrium on the transcriptome. RNA 18:77-87
Pelleymounter, Linda L; Moon, Irene; Johnson, Julie A et al. (2011) A novel application of pattern recognition for accurate SNP and indel discovery from high-throughput data: targeted resequencing of the glucocorticoid receptor co-chaperone FKBP5 in a Caucasian population. Mol Genet Metab 104:457-69
Rocca-Serra, Philippe; Bellaousov, Stanislav; Birmingham, Amanda et al. (2011) Sharing and archiving nucleic acid structure mapping data. RNA 17:1204-12
Sanders, Wes; Laederach, Alain (2011) Membrane RNAs in bacteria. Mol Microbiol 79:1-2
Poursina, Mohammad; Bhalerao, Kishor D; Flores, Samuel C et al. (2011) Strategies for articulated multibody-based adaptive coarse grain simulation of RNA. Methods Enzymol 487:73-98
Hamza, Taye H; Zabetian, Cyrus P; Tenesa, Albert et al. (2010) Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease. Nat Genet 42:781-5

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