A research grant from the National Institutes of Health totaling $3,436,466 over four years will enable a Jackson Laboratory research group led by Senior Research Scientist Laura Reinholdt, Ph.D., to develop new data resources and mouse models to better understand Mendelian genetic disorders.
Mendelian genetic disorders are diseases and conditions that occur as a consequence of inheriting certain gene variants from each parent. For example, a child with cystic fibrosis has inherited faulty copies of a specific gene from both his mother and father.
Approximately 20-30 million Americans are affected by Mendelian genetic disorders such as congenital heart disease, congenital bone diseases, inherited skin diseases, hereditary neurological disorders and hereditary cancers.
Over the last several years, sequencing patients’ protein-coding genes — known as whole-exome sequencing — has facilitated molecular diagnosis and as served as a research tool for discovering the fundamental genetic bases for over 100 Mendelian diseases. Whole-exome sequencing is faster, more efficient and less costly than whole-genome sequencing. But despite these advances, the overall success rate for human Mendelian disease gene discovery by whole-exome sequencing is slightly less than 50 percent.
Researchers studying Mendelian and other genetic disorders in mice have new techniques and technologies to create new mouse models; paired with whole-exome sequencing, they have increased the rate of mutation discovery and validation tenfold.
“Still, as in humans,” says Reinholdt, “the success rate for Mendelian disease gene discovery in the mouse is only slightly better than 50 percent.” She says this may be partially accounted for by the existence of regulatory mutations that, residing outside of protein-coding regions, escape detection by exome sequencing.
Moreover, she adds, a significant contributor may also be that exome sequencing alone is not sufficient to reveal the full spectrum of disease-causing mutations regardless of their location in the genome. “We now have the opportunity to employ new genomic technologies that will allow us to move beyond the discovery of single nucleotide mutations. We will be able to efficiently detect mutations that involve larger segments of the genome at scale, including deletions, duplications, insertions and inversions”.
These new genomic technologies are also being employed by human geneticists to advance the success rate of Mendelian disease gene discovery. Dr. Reinholdt’s team is working closely with clinical geneticists to achieve a fully integrated Mendelian disease modeling resource at The Jackson Laboratory.
“With the promise of surmounting past limitations,” Reinholdt says, “our goal is to develop research tools — mouse models and databases — that facilitate exploration and modeling of the full spectrum of mutations that cause Mendelian genetic disorders.”