The autoimmune disease type 1 diabetes (T1D), also known as juvenile diabetes, is diagnosed in approximately 70,000 children worldwide per year. Genetics is increasingly being recognized as playing a significant role in susceptibility to the disorder, but outside a handful of genes, a clear understanding of the genetic architecture that underlies T1D has remained elusive. In a study published online today in Genome Research (http://www.genome.org), scientists have identified a novel gene associated with diabetes in mice that is revealing new clues about genomic mechanisms that could underlie T1D susceptibility.

Genome-wide association studies (GWAS), genetic scans that look for variants that occur more frequently in people with a certain trait or disease, have recently uncovered more than 40 regions of the genome associated with T1D susceptibility. However, because of the diversity of the human population, isolating the genetic variants that actually cause the disease has been a challenge for researchers.

To avoid the complication of genetic diversity, a team of researchers in Australia have used selective breeding of a non-obese diabetic (NOD) mouse strain to narrow down one of 25 genomic regions associated with increased risk for diabetes to a single gene of unknown function, called AK005651. “We actually got a bit lucky in identifying a mouse gene that hadn’t been studied before,” said Thomas Brodnicki of St. Vincent’s Institute of Medical Research, senior author of the study.

Brodnicki described how selective mouse mating in inbred strains shuffles small pieces of DNA between mice, analogous to shuffling a deck of cards, that will reveal which piece of DNA encodes a disease-related gene. “In our case, a unique chromosome feature, called a recombination hotspot, stacked the DNA deck in favor of finding this gene,” Brodnicki noted.

Genetic recombination is the process during cell division in which DNA regions are broken and rejoined, a mechanism beneficial in creating genetic diversity. However, there is also a risk that recombination will generate deleterious alleles. “This particular hotspot actually changed the identified gene’s DNA makeup so that it altered diabetes onset in certain mice,” Brodnicki said, explaining how the DNA sequence variations in AK005651 were associated with decreased expression of the gene in the thymus and spleen of diabetic mice.

Brodnicki added that it is not yet clear if the mouse diabetes gene has an equivalent in humans, and exactly how the gene confers T1D susceptibility remains unknown. “Our work does demonstrate that recombination hotspots, which have been relatively neglected in recent genetic studies, should be investigated further for their ability to produce DNA changes in genes that can affect one’s risk for developing common polygenic diseases, such as type 1 diabetes.”

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Scientists from the St. Vincent’s Institute of Medical Research (Fitzroy, Australia), The University of Melbourne (Parkville, Australia), The Walter & Eliza Hall Institute of Medical Research (Parkville, Australia), The Western Australian Institute of Medical Research (Perth, Australia) contributed to this study.

This work was supported by the Juvenile Diabetes Research Foundation, the Cooperative Research Centre for Discovery of Genes for Common Human Diseases, the National Health and Medical Research Council (Australia), and the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (USA).

Media contacts: The authors are available for more information by contacting Anne Johnston, Press Officer for St. Vincent’s Institute of Medical Research (+61 3 9288 2484; .(JavaScript must be enabled to view this email address)).

Interested reporters may obtain copies of the manuscript from Peggy Calicchia, Editorial Secretary, Genome Research (.(JavaScript must be enabled to view this email address); +1-516-422-4012).

About the article: The manuscript will be published online ahead of print on November 4, 2010. Its full citation is as follows: Tan IKL, Mackin L, Wang N, Papenfuss AT, Elso CM, Ashton MP, Quirk F, Phipson B, Bahlo M, Speed TP, Smyth GK, Morahan G, Brodnicki TC. A recombination hotspot leads to sequence variability within a novel gene (AK005651) and contributes to type 1 diabetes susceptibility. Genome Res doi:10.1101/gr.101881.109.

About Genome Research:

Launched in 1995, Genome Research (http://www.genome.org) is an international, continuously published, peer-reviewed journal that focuses on research that provides novel insights into the genome biology of all organisms, including advances in genomic medicine. Among the topics considered by the journal are genome structure and function, comparative genomics, molecular evolution, genome-scale quantitative and population genetics, proteomics, epigenomics, and systems biology. The journal also features exciting gene discoveries and reports of cutting-edge computational biology and high-throughput methodologies.

About Cold Spring Harbor Laboratory Press:

Cold Spring Harbor Laboratory is a private, nonprofit institution in New York that conducts research in cancer and other life sciences and has a variety of educational programs. Its Press, originating in 1933, is the largest of the Laboratory’s five education divisions and is a publisher of books, journals, and electronic media for scientists, students, and the general public.

Genome Research issues press releases to highlight significant research studies that are published in the journal.

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Contact: Peggy Calicchia
.(JavaScript must be enabled to view this email address)
516-422-4012
Cold Spring Harbor Laboratory