A research team led by the University of California, Irvine has built the first genetic reference maps for short lengths of DNA repeated multiple times that are known to cause more than 50 fatal human diseases, including amyotrophic lateral sclerosis, Huntington’s disease and multiple cancers.
UC Irvine’s Tandem Genome Aggregation Database allows researchers to study how these mutations, called tandem repeat expansions, are connected to diseases, to better understand health disparities and improve clinical diagnosis.
The study, published online today in the journal Cell, presents UC Irvine TR-gnomAD, which addresses a critical gap in current biobanking genome sequencing efforts. Although TR expansions make up about 6 percent of our genome and contribute substantially to complex and pleasant conditions, scientific understanding of them remains limited.
“This innovative project positions UC Irvine as a leader in human and medical genetics by addressing the critical gap in the ability to interpret TR expansions in individuals with genetic disorders,” said Wei Li, the Grace B. Bell Chair and professor of bioinformatics and co-Corresponding author. “TR-gnomAD improves our ability to determine how certain diseases might affect various groups of people based on variations in these mutations among ancestors. Genetic consulting companies can then develop products to interpret this information and accurately report how Certain traits could be related to different groups of people and diseases.”
To create the database, the team used two software tools to analyze genomic data from 338,963 participants across 11 subpopulations. Of the 0.91 million TRs identified, 0.86 million were of high enough quality to be retained for further study. It was also found that 30.5 percent of them had at least two common alternative forms of a gene caused by a mutation located at the same place on a chromosome.
“Although we have successfully genotyped a substantial number of TRs, that is still only a fraction of the total number in the human genome,” Li said. “Our next steps will be to prioritize the integration of a greater number of high-quality TR and include more underrepresented ancestors, such as Australians, Pacific Islanders and Mongolians, as we move closer to realizing personalized precision medicine.” .
UC Irvine team members involved in the research included co-corresponding author and research assistant professor Ya Cui; Wenbin Ye, postdoctoral fellow; Jason Sheng Li, graduate student in biological chemistry; and Eric Vilain, professor of pediatrics and director of the Institute for Clinical and Translational Sciences. Jingi Jessica Le, professor of biostatistics at UCLA, and Dr. Tamer Sallam, vice president and associate professor at the David Geffen School of Medicine at UCLA, also participated.