Every cell in the human body, be it liver cell or blood cell or neuron, develops and runs on the same DNA. Mammals, for the most part, have two copies of every gene, a copy inherited from both the mother and the father, providing a handy backup in case one of the two is damaged. But nearly two decades ago, scientists discovered that for a limited number of genes, only one copy is active—the second is turned off by a regulatory process known as genomic imprinting. Scientists have struggled to understand why, from an evolutionary perspective, this process is silencing the reserve copy of essential genes.
“This is important. Mother Nature tells us it’s important because it’s something that evolved hundreds of millions of years ago. If it’s been maintained that long, it’s not a trivial thing,” says Randy Jirtle, an epigenetics researcher at Duke University. “What’s interesting about it is that imprinting results in having only one functional copy of a gene. That makes us more susceptible to disease—one hit can take that gene out. So what’s the advantage?”
Many believe imprinting is a form of epigenetic regulation, or inherited changes in gene expression not due to the DNA itself. [For more about how epigenetics are changing the study of psychiatric disease, see story “Search Widens for Causes of Psychiatric Disorder.”]
Scientists have particularly interested in how these imprinted genes may influence the epigenetics of brain development. In the Aug. 6 issue of Science, researchers from Harvard University demonstrate evidence from mice brains that maternally-inherited genes are favored in the developing brain but then shift preferentially to paternally-inherited genes later in life.
Competition for resources
David Haig, an evolutionary geneticist at Harvard University and one of the co-authors of the Science paper, hypothesizes that imprinting is an age-old genetic conflict for nutrients. When imprinted genes like IGF2, the gene for insulin-like growth factor, are manipulated in mice embryos, researchers see changes in the size of offspring. This led Haig to suggest that imprinting may be a subtle genetic tug-of-war for resources.
Consider this: A mother is sure she is the parent of any offspring she may have. Maternally imprinted genes may work to make sure that all offspring get appropriate resources for survival while leaving enough for the mother herself to make future reproduction possible. But a father has no real way of knowing if he is father of all of a particular mother’s children. The paternally expressed genes may demand more nutrients for the current embryo and help it to grow larger, to help provide an extra advantage over its siblings. Evidence from mouse embryos seems to support this idea, which Haig termed the Conflict Hypothesis.
“Genes of paternal origin make offspring grow larger and demand more resources from the mother,” he says. “But the maternally imprinted genes show preference to the mother’s ability to reproduce in the future and help limit any one offspring from taking too much.”
Beyond development and into the brain
But imprinted genes don’t just impact size. They have also been shown to play a critical role in brain development.
“Imprinting is thought to be involved in brain development and brain function,” says Catherine Dulac, a Howard Hughes Medical Institute researcher based at Harvard and another author on the Science paper. “When scientists have genetically manipulated imprinted genes, the most frequent effect identified relates to embryonic growth. But the second most frequent phenotype identified involves cognitive function.”
Dulac and colleagues were curious about how these genes are influencing brain development over time. And in a genome-wide analysis of mice brains, they found more than 1,300 genes with parent-of-origin effects. What’s more, these genes were expressed in brain areas involved with feeding, mating, and social and motivation behaviors, and showed different effects at different stages in the animal’s life.
“It’s dynamic, not something fixed,” says Dulac, “and a major mode of epigenetic regulation.” Dulac contends that these imprinted genes influence brain development throughout the life span.
Applying imprinting’s effects to humans
Genomic imprinting occurs in all Eutherian mammals, including humans, but which genes are maternally and paternally expressed vary from species to species. Understanding this phenomena in humans could help us to better understand disease, Dulac says, especially those that are seen preferentially in one gender over another. When imprinted genes are not properly regulated, they may result in abnormal brain development.
“Imprinted genes may play a role in different susceptibilities to disease between males and females,” says Dulac. “Think about diseases like autism, schizophrenia, multiple sclerosis, or eating disorders. They have different prevalence in men and women. This could explain why.”
But Jirtle cautions that we still have a lot more to learn before we can understand imprinted genes’ influence on disease. The first step? Identifying all of the genes that are imprinted in the human genome. In the December 2007 issue of Genome Research, Jirtle and colleagues predicted approximately 150 imprinted genes in humans based on a statistical model. But he argues there are likely many more—and all have to be verified in living tissue.
“Once more studies are done in humans, I think it will become clear that the imprinting repertoires (between humans and mice) are greatly different,” he says. “So today’s studies are only the first steps in a big, long process.”
Haig maintains we’re still learning a lot about the evolutionary genetics behind imprinting as we go, however.
“Imprinting suggests that the different genes affecting brain development have different evolutionary goals,” he says. “The resulting behavior, rather than being purely engineering to achieve some end, reflects internal politics in the brain—in certain contexts, we see different sets of genes attempting to modify behavior in conflicting directions. It’s very exciting.”