Scientists Map Imprinted Genes

Scientists at Duke University have created the first map of imprinted genes throughout the human genome, and they say a modern-day Rosetta stone – a form of artificial intelligence called machine learning – was the key to their success.

Duke University scientists have created the first map of imprinted genes throughout the human genome. They give the credit for their success to a modern-day Rosetta stone which is a form of artificial intelligence called machine learning. Imprinted genes are genes whose expression is determined by the parent that contributed them. Four times as many imprinted genes were revealed than had been previously identified. The study is the cover story in the December 3 issue of Genome Research. In classic genetics, children inherit two copies of a gene, one from each parent, and both actively shape how the child develops. But in imprinting, one of those copies is turned off by molecular instructions coming from either the mother or the father. Imprinting information on a gene is believed to happen during the formation of an egg or sperm, and it means that a child will inherit only one working copy of that gene. This is the reason that imprinted genes are so vulnerable to environmental pressures: there is no backup produced if the only functioning copy is damaged or lost. "Imprinted genes have always been something of a mystery, partly because they don't follow the conventional rules of inheritance," says Dr. Randy Jirtle, a genetics researcher in the departments of radiation oncology and pathology at Duke and a senior author of the study. "We're hoping this new road map will help us and others find more information about how these genes affect our health and well-being." Dr. Alexander Hartemink, the other senior author of the study and an assistant professor in Duke's department of computer science, and Philippe Luedi, the first author of the study were responsible for the needed technical savvy. Hartemink and Luedi fed sequence data from two types of genes, those that were known to be imprinted and ones believed not to be imprinted, into a computer and asked it to discover the differences. This approach led to an algorithm, which was able, much like the original Rosetta stone, to decode seemingly impenetrable data, in this case, specific DNA sequences that pointed to the presence of imprinted genes. "We can't say for certain that we identified all of them, but we think we found a large number," says Hartemink, who is also a member of Duke's Institute for Genome Sciences & Policy. Jirtle said "Imprinted genes are unusually vulnerable to pressures in our environment – even what we eat, drink, and breathe. On top of that, epigenetic changes can be inherited. I don't think people realize that." Jirtle had previously shown that Agouti mice, which are normally fat and yellow, when fed certain dietary supplements, would produce brown, normal weight babies. The babies' Agouti genes, the ones responsible for color, were the same as the mother's, yet they looked different. "That's epigenetics in action," says Jirtle. Scientists estimate that imprinted genes comprise about 1 percent of the human genome. Until now only several dozen had been identified. When Jirtle and Hartemink used their new "Rosetta stone", they found 156 new likely imprinted genes, and validated two particularly interesting ones on chromosome 8, where none had been found before. One of the eight, KCNK9, is mostly active in the brain, and is known to cause cancer. KCNK9 may also be linked to bipolar disorder and epilepsy. The second, DLGAP2, is a possible bladder cancer tumor suppressor gene. The experiments needed to confirm that all 156 new genes are truly imprinted and not just statistically likely candidates will be difficult, mostly because gene expression varies from tissue to tissue and most genes turn on and off over time. "We've certainly narrowed the field, but we have a whole lot of work ahead of us."