Recombination hotspot stacks the DNA deck in finding a new diabetes susceptibility gene

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."

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).