Large-scale genetic repeat variations contribute to height and other human traits

Credit: Suzanna Hamilton, Broad Communications

A new study has found that certain genetic changes involving long repeat sequences in the human genome can affect a variety of health-related traits.

Geneticists are studying how differences in DNA sequences between individuals affect individuals over the past decade Disease risk And other properties are primarily focused on one type of variation, the one-letter modification. Today, new research reveals how larger genetically modified organisms significantly contribute to human traits.

In this study by researchers at the Broad Institute of MIT and Harvard, Brigham and Women’s Hospital, and Harvard Medical School, genetic alterations called tandem variable number repeats (VNTRs) were associated with about 20 characteristics, including the waist and curl of the hair. It turned out to be strongly related. , And the risk of heart and kidney disease. VNTRs are sections of the genome that vary in length from 7 to thousands of base pairs and are repeated over and over in different individuals.

The team expected connections between the VNTR and the traits, but were surprised at the power of those connections. “The VNTR that we studied ultimately became the largest or second-largest genomic contributor to the trait,” said an associate professor at Harvard Medical School and associate member of the Broad Institute, co-author of the study. said Po-Ru Loh. .. “It was a real surprise.”

The result is, ChemistryPaving the way for a deeper genetic understanding of how genetics affect human traits and diseases, and also presents new ways for scientists to study repeated genetic mutations on a larger scale. ..

Presentation of VNTRS

The role of larger genomic changes such as VNTR has been studied over the past decade. Because VNTRs are larger and more complex changes, the usual methods used to study genetic variation overlook the contribution of VNTRs to human traits.

To address this issue, Loh’s lab developed a new tool to analyze human exome sequencing data and examine potential VNTRs. Together with Steve McCarroll, a member of the Broad’s Institute, director of genome neurobiology at the Stanley Center for Psychiatry in Broad and professor at Harvard Medical School, they evaluated the human genome. They assessed whether these VNTR length variations were associated with traits by studying the genetics data of approximately 415,000 UK Biobank participants.

Researchers have found that the five VNTRs contribute to a number of properties, often showing strong associations that have not been reported before. One of the VNTRs was in the LPA gene, which encodes a lipoprotein (a) and is associated with a risk of cardiovascular disease. The team’s analysis analyzed how this VNTR, along with other LPA variants, accounted for 90% of genetic mutations at the lipoprotein level (a).

The team also found that the VNTR of the ACAN gene, which encodes a component of cartilage, is related to height. The VNTR length difference for this gene appears to alter the height by up to 3.2 cm. “Our results show that these VNTRs can have very strong effects,” said Bob Handsaker, researcher and lead co-author of the study at McCarroll Labs. “There is more evidence that these complex regions of the genome are really important and may require further research.”

One of the limitations of this study is that the population of UK Biobank is predominantly of European origin. The authors stress that data from a more diverse cohort needs to be investigated to learn more about the role of large-scale genetic alterations such as VNTR. It is also important to study the DNA of a sick person. “It would be very interesting to explore the VNTRs in other cohorts rich in specific biological findings, such as specific diseases,” said a postdoctoral researcher and lead co-author of the study in Loh’s lab. Ronen Mukamel said.

In addition, all 118 VNTRs studied by the researchers were found in the protein coding region of the genome. They say studying VNTRs in other regions of the genome, such as non-coding regions that regulate gene expression, is also essential to understanding how VNTRs affect human characteristics. ..

The team hopes their research will give other researchers a chance to dig deeper into VNTR. “We’ve really only scratched the surface,” Loh said. “There are many more. ”

Under-studied mutations have a significant impact on gene expression

For more information:
Ronen E. Mukamel et al, repetitive polymorphisms encoding proteins strongly shape various human phenotypes. Chemistry.. Online September 23, 2021. DOI: 10.1126 / science.abg8289

Provided by
Broad Institute at MIT and Harvard

Quote: Large Scale Genetic Repeat Mutations, Height and Other Obtained from on Sep 24, 2021 Contributes to human characteristics ( September 24, 2021) .html

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