Although we inherit equal amounts of genetic mutations from our parents—the mutations that make us who we are and not some other person—we actually use more of the DNA that we inherit from our dads. In this context, “use” refers to the expression of genes, specifically, allelic gene variants.
The bias toward the expression of parental alleles is significant because allelic variants influence complex traits including many diseases—not simple Mendelian diseases, which typically involve just one gene mutation, but complex diseases that involve many genes, such as type 2 diabetes, heart disease, schizophrenia, obesity, and cancers.
The imbalance in gene expression favoring parental alleles was found by researchers at the University of North Carolina Health Care who used mouse models that were designed to account for parent-of-origin effects. Reasoning that genetic regulatory elements are conserved between humans and mice, the researchers decided that a thorough annotation of regulatory elements in mice could aid in characterizing the genetic mechanisms that influence complex human traits.
“We found that the vast majority of genes—about 80%—possessed variants that altered gene expression,” said James Crowley, Ph.D., an assistant professor of genetics at UNC. “And this was when we discovered a new, genome-wide expression imbalance in favor of the dad in several hundred genes. This imbalance resulted in offspring whose brain gene expression was significantly more like their father’s.”
Dr. Crowley was part of a UNC team led by Fernando Pardo-Manuel de Villena, Ph.D., a professor of genetics. Dr. Pardo-Manuel de Villena emphasized that his team’s research opens the door to a new area of exploration in human genetics. “We've known that there are 95 genes that are subject to this parent-of-origin effect. They're called imprinted genes, and they can play roles in diseases, depending on whether the genetic mutation came from the father or the mother,” noted Dr. Pardo-Manuel de Villena. “Now we've found that in addition to them, there are thousands of other genes that have a novel parent-of-origin effect.”
The UNC team published its findings March 2 in Nature Genetics, in an article entitled, “Analyses of allele-specific gene expression in highly divergent mouse crosses identifies pervasive allelic imbalance.”
“We estimate that at least one in every thousand SNPs creates a cis regulatory effect,” wrote the authors. “We also observe two types of parent-of-origin effects, including classical imprinting and a new global allelic imbalance in expression favoring the paternal allele.”
The key to this research is the Collaborative Cross—the most genetically diverse mouse population in the world, which is generated and housed at (and distributed from) UNC. Traditional lab mice are much more limited in their genetic diversity, and so they have limited use in studies that try to home in on important aspects of diseases in humans. The Collaborative Cross bred together various wild type mice to create wide diversity in the mouse genome.
For the current study, Dr. Pardo-Manuel de Villena's team selected three genetically diverse inbred strains of mice that were descended from a subspecies that evolved on different continents. These mice were bred to create nine different types of hybrid offspring in which each strain was used as both father and mother. When the mice reached adulthood, the researchers measured gene expression in four different kinds of tissue, including RNA sequencing in the brain. They then quantified how much gene expression was derived from the mother and the father for every single gene in the genome.
“We now know that mammals express more genetic variance from the father,” asserted Dr. Pardo-Manuel de Villena. “So imagine that a certain kind of mutation is bad. 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.”
These types of genetic mutations across hundreds of genes are hard to study and a major bottleneck to realizing the promises of the post-genome era. But according to Dr. Pardo-Manuel de Villena, “Thanks to the Collaborative Cross, the mouse can be used to model how these genes work and how they impact health and disease in any kind of tissue in the body.”