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Researchers Find Retrotransposon That Affects Type 2 Diabetes Risk in Mice

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In the search for genes involved in developing type 2 diabetes, German researchers found that one candidate gene's expression and effect on diabetes risk is modulated by a transposon.

The German Institute of Human Nutrition's Hans-Georg Joost and colleagues began with a previously identified QTL, Nidd1 and Nidd/SJL, that contributes to obesity-associated diabetes in the mouse strain New Zealand Obese. Through breeding experiments, they narrowed their search to a chromosomal region that contains 10 genes. They then studied each of those genes for any abnormalities. "We isolated chromosomal segments in one strain on a different genetic background, and then we looked for divergent genetic activity," Joost says. "That's a classical strategy."

From that they found that one gene, the zinc finger transcription factor Zfp69, was expressed in one strain — the lean mice — and silenced in the others. The silencing, they discovered, and reported in PLoS Genetics, was due to a retrotransposon. "It is the most obvious candidate [gene] in this region," Joost says of Zfp69. The human version of the gene, Nf642, is more highly expressed in adipose tissue of type 2 diabetes patients. Joost also adds that there is no evidence of a retrotransposon in the human version of the gene.

Though likely not in the human version of this diabetes candidate gene, retrotransposons may be more common in genetic regulation than previously thought. Joost and his team searched through the genome of another mouse model, Black 6, for the same retrotransposon. From a BLAT search, they found 202 instances where the retrotransposon was incorporated into the Black 6 genome. They then checked the expressed sequence tags of the incorporated regions and found that eight of those regions were genes whose expression was affected by the retrotransposon. "In our opinion, there's a huge influence of the function of the genome by these retrotransposons," Joost says. "Actually, it's a bit scary because you don't want to have this in a tumor suppressor gene."
Joost and his colleagues are now examining more of the QTLs to determine which of them contribute to diabetes and obesity and which are sufficient to cause or suppress diabetes. From these studies, he and his group hope to uncover novel targets for therapy.

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