You might resemble or act more like your mother, but a first-of-its-kind study reveals that mammals are genetically more like their dads. Specifically, the research shows that although we inherit equal amounts of genetic materials from our parents – i.e., the mutations that make us who we are instead of some other person – we actually “use” more of the DNA that we inherit from our fathers.
The paper, “Analyses of allele-specific gene expression in highly divergent mouse crosses identifies pervasive allelic imbalance,” was published online March 2 in the journal Nature Genetics. Drs. Fernando Pardo-Manuel de Villena, and Patrick Sullivan, both professors of genetics, were the co-principal investigators.
Several faculty members and students of the UNC Gillings School of Public Health made significant contributions to this project. Dr. Fei Zou, professor of biostatistics, was a senior co-author. Co-first authors included Dr. Wei Sun, associate professor of genetics and biostatistics, and Mr. Vasyl Zhabotynsky, Doctor of Public Health candidate in biostatistics.
Dr. Zou, Dr. Sun and Mr. Zhabotynsky, together with members of their statistical team, Mr. Kyungsu Kim and Mr. James Xenakis, both doctoral students in biostatistics, provided research support by developing and applying a suitable statistical model and performing data analyses. A paper detailing their statistical methodology was published last February in Genetics.
“The success of this project was due in part to the novelty and soundness of our statistical methods,” Dr. Zou said.
The knowledge of how genes are passed from parents to child has wide implications for the study of human disease, especially when using mammalian research models. For instance, in many mouse models created for the study of gene expression related to disease, researchers typically don’t take into account whether specific genetic expression originates from mothers or fathers. The UNC research, however, shows that inheriting a mutation has different consequences in mammals depending on whether the genetic variant is inherited from the mother or father.
These genetic mutations show up in many common but complex diseases such as type-2 diabetes, heart disease, schizophrenia, obesity and cancers. Studying them in genetically diverse mouse models that take parent-of-origin into account will give scientists more precise insights into the underlying causes of disease and the creation of therapeutics or other interventions.
The key to this research is the Collaborative Cross – the most genetically diverse mouse population in the world, which is generated, housed and distributed from UNC. Traditional lab mice are much more restricted in their genetic diversity, 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 mice to create wide diversity in the mouse genome. This helps scientists study diseases that involve various levels of genetic expression across many different genes.
“The Collaborative Cross and the expertise we have at UNC allow us to look at different gene expression for every gene in the genome of every kind of tissue,” said Dr. Pardo-Manuel de Villena, who directs the Collaborative Cross.
For the Nature Genetics study, his team selected three genetically diverse strains of mice descended from subspecies that evolved on different continents. The 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 and quantified how much gene expression was derived from the mother and the father for every single gene in the genome.
They found that the vast majority of genes – about 80 percent – possessed variants that altered gene expression. This revealed a new, genome-wide expression imbalance in favor of the father in several hundred genes.
“We now know that mammals express more genetic variance from the father,” said 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 cause a major bottleneck to realizing the promises of the post-genome era. Thanks to the Collaborative Cross, mice can be better used to model how genes work and how they impact health and disease.