{"152691":{"#nid":"152691","#data":{"type":"news","title":"Study Identifies Genes Associated with Genomic Expansions that Cause Disease","body":[{"value":"\u003Cp\u003EA study of more than 6,000 genes in a common species of yeast has identified the pathways that govern the instability of GAA\/TTC repeats. In humans, the expansions of these repeats is known to inactivate a gene \u2013 FXN \u2013 which leads to Friedreich\u2019s ataxia, a neurodegenerative disease that is currently incurable. In yeast, long repeats also destabilize the genome, manifested by the breakage of chromosomes. \u0026nbsp;\u003C\/p\u003E\u003Cp\u003EWorking with collaborators at Tufts University, researchers at the Georgia Institute of Technology identified genetic deficiencies associated with the instability of the repeats in four different classes of genes that control replication, transcription initiation, checkpoint response and telomere maintenance. They were surprised to find that the GAA\/TTC repeats could promote gene expression in yeast, suggesting that the repeats may play both positive and negative roles in cells.\u003C\/p\u003E\u003Cp\u003EWhile the study examined the repeat metabolisms in the yeast Saccharomyces cerevisiae, the researchers believe their discoveries may have implications for human disease because many components of genetic machinery have been conserved in evolution. \u0026nbsp;\u003C\/p\u003E\u003Cp\u003EThe study was reported online Sept. 6 in the journal \u003Cem\u003EMolecular Cell\u003C\/em\u003E. The research was supported by the National Institutes of Health (NIH) and the National Science Foundation (NSF).\u003C\/p\u003E\u003Cp\u003EThe expansions occur in GAA\/TTC sequences located on the FXN gene that plays a vital role in cell metabolism. Patients with Friedreich\u2019s ataxia can have as many as 1,700 copies of the nucleotide sequence, compared to fewer than 65 copies in individuals without the genetic expansion. Although not yet observed in humans, in yeast the expanded repeats can cause chromosomal fragility, which \u2013 despite cellular repair mechanisms \u2013 can produce errors resulting in dramatic genomic rearrangements.\u003C\/p\u003E\u003Cp\u003E\u201cHow these expansions happen is a very mysterious process, and we do not know why some people get the disease and some people do not,\u201d said Kirill Lobachev, an associate professor in Georgia Tech\u2019s School of Biology. \u201cWe are trying to develop a simplistic way to determine what individuals may be predisposed to the disease and to find the genotypes where these expansions occur with great frequency.\u201d\u003C\/p\u003E\u003Cp\u003EAt the core of the study was detailed screening of the yeast\u2019s entire genome, some 6,000 genes in all. Conducted by graduate research assistant Yu Zhang, the exhaustive assay identified 33 genes associated with the repeats fragility and expansions.\u003C\/p\u003E\u003Cp\u003EThe connection between genomic expansion and genes that initiate transcription came as a surprise.\u003C\/p\u003E\u003Cp\u003E\u201cWe found that these repeats can recruit transcription initiation factors and induce transcription,\u201d said Lobachev. \u201cThe repeats seem to work as non-traditional promoters for an abnormal type of transcription. It turns out that this ability to drive transcription is a significant factor in their instability. That makes this a more complicated story for sure, however, it also opens new avenues to examine the repeats.\u201d\u003C\/p\u003E\u003Cp\u003EThe ability of the repeats to affect the activity of genes may indicate a broader effect on the genome, and if the effect is also seen in humans, could account for some of the subtle differences between individuals.\u003C\/p\u003E\u003Cp\u003E\u201cBy some estimates, there may be a thousand locations in our chromosomes where these repeats can expand,\u201d said Lobachev. \u201cProbably each person differs in the number of repeats in specific locations. This is important because of their ability to change gene expression.\u201d\u003C\/p\u003E\u003Cp\u003EAmong the next steps in the research is to determine how the expansions occur in cells that aren\u2019t dividing, such as neurons. The genetic mechanisms involved in cell replication offer clear opportunities for repeat expansions, but the mechanism for repeat amplification in non-dividing cells remains a mystery. The researchers believe the finding that GAA\/TTC repeats can promote transcription provides clues for understanding what is going on in terminally differentiated cells.\u003C\/p\u003E\u003Cp\u003EWhy repeats with the detrimental ability to expand have remained a part of the genomes also remains a question. Genetic processes that hinder an organism\u2019s competitiveness are normally eliminated during the process of evolution.\u003C\/p\u003E\u003Cp\u003E\u201cPerhaps these repeats play a positive role in the cell when they are small, but because of their ability to expand, they sometimes get out of control and become larger,\u201d Lobachev said.\u003C\/p\u003E\u003Cp\u003EThe findings reported in the yeast, which is commonly used in wine-making and brewing, may help chart a new course in human studies. Scientists often begin genetic research with simpler organisms such as yeast, and use the findings to provide direction for examining similar mechanisms in humans.\u003C\/p\u003E\u003Cp\u003E\u201cA lot of the processes that are going on in our cells and in yeast cells are the same,\u201d Lobachev noted. \u201cThese processes are highly conserved throughout evolution. The history of biology tells us that most probably what we find in yeast is going to turn out to be true in humans.\u201d\u003C\/p\u003E\u003Cp\u003ELobachev hopes the study will lead to new research, both in yeast genetics and humans.\u003C\/p\u003E\u003Cp\u003E\u201cWe have built a map for future analysis so that when people sequence the genome and find deficiencies in particular genes, that will be a clear prediction that individuals with those deficiencies will be predisposed to instability,\u201d Lobachev said. \u201cThere are now several directions for us and other labs to pursue to see what is really happening here.\u003C\/p\u003E\u003Cp\u003EIn addition to those already mentioned, the study\u2019s authors also included Alexander Shishkin, Dana Marcinkowski-Desmond and Sergei Mirkin from Tufts University, and Yuri Nishida, Natalie Saini and Kirill Volkov from Georgia Tech.\u003C\/p\u003E\u003Cp\u003E\u003Cem\u003EThis work was supported by award number R01GM0825950 from NIGMS\/NIH and MCB-0818122 from the NSF. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIGMS\/NIH or the NSF.\u003C\/em\u003E\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003ECITATION\u003C\/strong\u003E: Zhang et al., Genome-wide Screen Identifies Pathways that Govern GAA\/TTC Fragility and Expansions in Dividing and Nondividing Yeast Cells, Molecular Cell (2012): (dx.doi.org\/10.1016\/j.molcel.2012.08.002)\u003Cbr \/\u003E\u003Cbr \/\u003E\u003Cstrong\u003EResearch News \u0026amp; Publications Office\u003C\/strong\u003E\u003Cbr \/\u003E\u003Cstrong\u003EGeorgia Institute of Technology\u003C\/strong\u003E\u003Cbr \/\u003E\u003Cstrong\u003E75 Fifth Street, N.W., Suite 309\u003C\/strong\u003E\u003Cbr \/\u003E\u003Cstrong\u003EAtlanta, Georgia\u0026nbsp; 30308\u0026nbsp; USA\u003C\/strong\u003E\u003Cbr \/\u003E\u003Cbr \/\u003E\u003Cstrong\u003EMedia Relations Contact:\u003C\/strong\u003E John Toon (404-894-6986)(\u003Ca href=\u0022mailto:jtoon@gatech.edu\u0022\u003Ejtoon@gatech.edu\u003C\/a\u003E).\u003Cbr \/\u003E\u003Cstrong\u003EWriter:\u003C\/strong\u003E John Toon\u003C\/p\u003E","summary":null,"format":"limited_html"}],"field_subtitle":"","field_summary":[{"value":"\u003Cp\u003EA study of more than 6,000 genes in a common species of yeast has identified the pathways that govern the instability of GAA\/TTC repeats. In humans, the expansions of these repeats is known to inactivate a gene \u2013 FXN \u2013 which leads to Friedreich\u2019s ataxia, a neurodegenerative disease that is currently incurable. In yeast, long repeats also destabilize the genome, manifested by the breakage of chromosomes.\u0026nbsp;\u003C\/p\u003E","format":"limited_html"}],"field_summary_sentence":[{"value":"A study of more than 6,000 genes in a common species of yeast has identified the pathways that govern instability in GAA\/TTC repeats."}],"uid":"27303","created_gmt":"2012-09-09 20:22:16","changed_gmt":"2016-10-08 03:12:47","author":"John Toon","boilerplate_text":"","field_publication":"","field_article_url":"","dateline":{"date":"2012-09-09T00:00:00-04:00","iso_date":"2012-09-09T00:00:00-04:00","tz":"America\/New_York"},"extras":[],"hg_media":{"152681":{"id":"152681","type":"image","title":"Studying Trinucleotide Repeats","body":null,"created":"1449178848","gmt_created":"2015-12-03 21:40:48","changed":"1475894787","gmt_changed":"2016-10-08 02:46:27","alt":"Studying Trinucleotide Repeats","file":{"fid":"195222","name":"genetic-repeats53.jpg","image_path":"\/sites\/default\/files\/images\/genetic-repeats53_0.jpg","image_full_path":"http:\/\/www.tlwarc.hg.gatech.edu\/\/sites\/default\/files\/images\/genetic-repeats53_0.jpg","mime":"image\/jpeg","size":1192430,"path_740":"http:\/\/www.tlwarc.hg.gatech.edu\/sites\/default\/files\/styles\/740xx_scale\/public\/images\/genetic-repeats53_0.jpg?itok=KVz5RjO0"}}},"media_ids":["152681"],"groups":[{"id":"1188","name":"Research Horizons"}],"categories":[{"id":"146","name":"Life Sciences and Biology"}],"keywords":[{"id":"43031","name":"chromosome integrity"},{"id":"43021","name":"genomic expansion"},{"id":"43011","name":"trinucleotide repeats"}],"core_research_areas":[{"id":"39441","name":"Bioengineering and Bioscience"}],"news_room_topics":[],"event_categories":[],"invited_audience":[],"affiliations":[],"classification":[],"areas_of_expertise":[],"news_and_recent_appearances":[],"phone":[],"contact":[{"value":"\u003Cp\u003EJohn Toon\u003C\/p\u003E\u003Cp\u003EResearch News \u0026amp; Publications Office\u003C\/p\u003E\u003Cp\u003E(404) 894-6986\u003C\/p\u003E\u003Cp\u003E\u003Ca href=\u0022mailto:jtoon@gatech.edu\u0022\u003Ejtoon@gatech.edu\u003C\/a\u003E\u003C\/p\u003E","format":"limited_html"}],"email":["jtoon@gatech.edu"],"slides":[],"orientation":[],"userdata":""}}}