As mammals, we inherit equal amounts of genetic material from each parent, sex chromosomes in males aside. However, a study of mice has found that genes inherited from the father are more likely to be expressed, and that genetic diseases can be different depending on which parent they were inherited from. Both findings have implications for the way we should be doing medical research.
A large team of scientists, mostly from the University of North Carolina, studied mice using techniques that allowed them to establish which parent an expressed gene came from. The work, published in Nature Genetics, used Collaborative Cross mice whose high levels of genetic diversity provided a richer sample to study.
They started by looking at imprinted genes, where the gene from one parent is always expressed, rather than expression being based on which form of the gene is dominant. Senior author Professor Fernando Pardo-Manuel de Villena says that these imprinted genes, “can play roles in diseases, depending on whether the genetic mutation came from the father or the mother.”
Before the study, 95 imprinted genes were known, and the total was estimated to lie between one and 200. However, the authors have revealed several thousand more where the gene inherited is more likely to come from a particular parent. While these show statisical tendencies, as opposed to the certainty of what the authors call "classically imprinted genes," their number transforms the phenomenon from a curious anomaly to something of great importance to rodent health. It remains to be seen if the same applies to humans, but even if not, the findings have enormous implications for medical research done on mice, which has relied on the assumption that it is irrelevant which parent a gene comes from.
The team found 3,338 genes where the version inherited from the father appeared more likely to be expressed than the one from the mother, while the equivalent set that favor the maternal line was just 1,631. In many of these genes, the apparent overexpression was likely to be the product of a limited sample size, but the excess of paternal overexpression cannot be explained in this way, indicating that mice are more likely to share genetic characteristics with their fathers than mothers. There was also a tendency for genes to favor the same parent as their neighbors.
“Imagine that a certain kind of mutation is bad,” Pardo-Manuel de Villena says. “If inherited from the mother, the gene wouldn't be expressed as much as it would be if it were inherited from the father. So, the same bad mutation would have different consequences in disease if it were inherited from the mother or from the father."
The genes with a paternal bias may be the most intriguing, but Pardo-Manuel de Villena doesn't want to lose sight of what the study reveals about cis regulatory mutations, variations in DNA that affect the way genes around them are expressed, rather than directly altering protein production. Brain-expressed genes with cis regulatory effects were found to be much more likely to be associated with behavioral changes than those without these regulating capacities. "This type of genetic variation is probably the most important contributor—not to simple Mendelian diseases where there's just one gene mutation [such as cystic fibrosis]—but to much more common and complex diseases, such as diabetes, heart disease, neurological conditions, and a host of others," he says.