New genetic database may help in better understanding Huntington’s

Work may provide 'critical insights' into ancestry-specific diseases: Scientists

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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A close-up view of a DNA strand, shown horizontally, highlights its ribbon-like structure.

Scientists at the University of California, Irvine (UCI) have mapped onto a genetic database nearly a million tandem repeat (TR) expansions — head-to-tail copies of short DNA sequences — to better understand how they’re linked to several human diseases, including Huntington’s.

This work, the team says, may provide “critical insights into the prevalence of ancestry-specific TR disorders.” Among them is Huntington’s, caused by repeats in a sequence of DNA building blocks, which affects an estimated 30,000 people in the U.S.

The genetic database, called TR-gnomAD, was built based on information from 338,963 people of European, African, Hispanic, Asian, and other descent. The goal, according to researchers, is to learn more about how common TR expansions are within each ancestry, and to determine which may be disease-causing.

“The TR-gnomAD advances our ability to determine how certain diseases might affect diverse groups of people based on variations in these mutations among ancestries,” Wei Li, PhD, the study’s senior author and a professor of bioinformatics at UCI School of Medicine, said in a university press release.

“Genetic consulting companies can then develop products to interpret this information and accurately report how certain traits might be linked to different groups of people and diseases,” added Li, who’s also the Grace B. Bell endowed chair at UCI.

The study, “A genome-wide spectrum of tandem repeat expansions in 338,963 humans,” was published as a resource feature in Cell.

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Tandem repeats, or stretches of DNA comprised of two or more contiguous repeats of a small genetic sequence, constitute about 6% of all human genome. The genome is an individual’s complete set of genetic material.

TR expansions, resulting in a higher than normal number of these repeats, are known to cause more than 50 diseases, including Huntington’s.

Huntington’s is specifically caused by an excessive number of CAG repeats, a sequence of three DNA building blocks, in the HTT gene. In healthy people, CAG repeats usually are found 10 to 35 times in a row. In individuals with Huntington’s, they’re copied 40 or more times.

Despite being a major source of genetic variation, genetic databases created to date “have largely overlooked TR expansions,” according to the researchers.

Now, the UCI team sought to provide a resource to better understand how TR expansions function. To do so, the researchers drew on available information from five databases: the UK Biobank; the All of Us Research Program from the National Institutes of Health, in the U.S.; TOPMed, from the National Heart, Lung, and Blood Institute, also in the U.S.; the 1000 Genome Project, from the EMBL’s European Bioinformatics Institute; and the Estonian Biobank, from the University of Tartu Institute of Genomics.

Using genotyping, a technique that can determine differences in an individual’s genetic makeup versus a reference DNA sequence, the researchers identified 910,000 TRs from samples of 338,963 people across 11 populations. A total of 860,000 TRs were of high enough quality to be included in further analyses.

Nearly one-third (30.5%) of the TRs had at least two common alternative forms of different lengths. For example, a short DNA pattern may be repeated 15 times in a row in one group of people but 24 times in another group of people of the same ancestry.

By comparing TRs between different groups of people, it may be possible to determine if certain diseases are more common in certain populations. This could help in diagnosing diseases more accurately and in developing better treatments, according to the team.

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Based on information from 435 people with genetic diseases, including 25 with a Huntington’s diagnosis, the researchers were able to tell common, harmless TR expansions from disease-causing ones.

For example, people who carried more than 30 CAG repeats in the HTT gene were up to about 640 times as likely to develop Huntington’s as those who had fewer copies.

“These results underscore the potential utility of TR-gnomAD as a tool to improve clinical diagnosis,” the researchers wrote, adding that the large spectrum of TR expansions included in the new database may serve as a reference map.

But, according to Li, “although we’ve successfully genotyped a substantial number of TRs, that is still just a fraction of the total number in the human genome.”

“Our next steps will be to prioritize the integration of a greater number of high-quality TR and include more underrepresented ancestries, such as Australian, Pacific Islander and Mongolian, as we move closer to realizing personalized precision medicine,” Li added.

Freely available to the public, TR-gnomAD stands as an invaluable resource for researchers, physicians, and genetic counselors to interpret [tandem repeat] expansions in individuals with genetic diseases.

The scientists noted that the genetic database is already ready for use.

“Freely available to the public, TR-gnomAD stands as an invaluable resource for researchers, physicians, and genetic counselors to interpret TR expansions in individuals with genetic diseases,” the team wrote.