Genetic instabilities (expansion and deletions of simple repeating sequences) are important in the life cycles of both prokaryotic and eukaryotic cells. This fundamental mechanism of mutagenesis has been found in mycoplasma, bacteria, yeast, mammalian cells, and in humans. In lower organisms, these genetic polymorphisms are the basis for phase variations which control the expression of genes. In humans, the expansions and deletions of simple repeating sequences are closely tied to the etiologies of cancers as well as hereditary neurological diseases. Prior work has revealed that expansions are mediated by DNA replication and repair by the slippage of the complementary strands of the repeats to form hairpin loop structures with differing relative stabilities. The principal investigator has recently demonstrated that recombination is a powerful mechanism for generating large expansions. To the extent that this work can be extrapolated to human diseases, recombination may be an important mechanism for the large expansions found in fragile X syndrome, myotonic dystrophy, and SCA8. The first Specific Aim is to elucidate the mechanisms of genetic recombination which mediate the triplet repeat sequence (TRS) expansions.
Specific Aim 2 will evaluate the role of recombinational repair of double strand breaks in genetic instabilities. The third Specific Aim is to establish a genetic assay for determining the recombination frequency.
Specific Aim 4 will investigate tandem duplication-based instabilities in vivo in recA- cells. In summary, the principal investigator will investigate the molecular mechanisms (replication, recombination, repair) that cause genetic instabilities in simple repeat sequences.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES011347-02
Application #
6518257
Study Section
Biochemistry Study Section (BIO)
Program Officer
Reinlib, Leslie J
Project Start
2001-06-01
Project End
2006-05-31
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
2
Fiscal Year
2002
Total Cost
$277,332
Indirect Cost
Name
Texas A&M University
Department
Genetics
Type
Schools of Medicine
DUNS #
City
College Station
State
TX
Country
United States
Zip Code
77845
Lin, Yunfu; Dent, Sharon Y R; Wilson, John H et al. (2010) R loops stimulate genetic instability of CTG.CAG repeats. Proc Natl Acad Sci U S A 107:692-7
Chuzhanova, Nadia; Chen, Jian-Min; Bacolla, Albino et al. (2009) Gene conversion causing human inherited disease: evidence for involvement of non-B-DNA-forming sequences and recombination-promoting motifs in DNA breakage and repair. Hum Mutat 30:1189-98
Wells, Robert D (2009) Mutation spectra in fragile X syndrome induced by deletions of CGG*CCG repeats. J Biol Chem 284:7407-11
Wells, Robert D (2009) Discovery of the role of non-B DNA structures in mutagenesis and human genomic disorders. J Biol Chem 284:8997-9009
Bacolla, Albino; Larson, Jacquelynn E; Collins, Jack R et al. (2008) Abundance and length of simple repeats in vertebrate genomes are determined by their structural properties. Genome Res 18:1545-53
Soragni, E; Herman, D; Dent, S Y R et al. (2008) Long intronic GAA*TTC repeats induce epigenetic changes and reporter gene silencing in a molecular model of Friedreich ataxia. Nucleic Acids Res 36:6056-65
Wells, Robert D (2008) DNA triplexes and Friedreich ataxia. FASEB J 22:1625-34
Kosmider, Beata; Wells, Robert D (2007) Fragile X repeats are potent inducers of complex, multiple site rearrangements in flanking sequences in Escherichia coli. DNA Repair (Amst) 6:1850-63
Wells, Robert D (2007) Non-B DNA conformations, mutagenesis and disease. Trends Biochem Sci 32:271-8
Kosmider, Beata; Wells, Robert D (2006) Double-strand breaks in the myotonic dystrophy type 1 and the fragile X syndrome triplet repeat sequences induce different types of mutations in DNA flanking sequences in Escherichia coli. Nucleic Acids Res 34:5369-82

Showing the most recent 10 out of 32 publications