How ‘junk DNA’ influences blood pressure

Dark Genetic DNA Mutation Concept

SickKids researchers have discovered how non-coding genome variants influence the regulation of blood pressure genes, potentially contributing to the early detection and treatment of hypertension. This groundbreaking study not only sheds light on cardiovascular genomics research, but also suggests a framework applicable to other genetic conditions.

SickKids scientists assign function to the non-coding genome and shed light on the genetics of hypertension.

Scientists at the Hospital for Sick Children (SickKids) are digging deep into the non-coding genome to unravel the complex genetics that underlie blood pressure regulation and hypertension (high blood pressure) – the leading cause of

“This research unveils, for the first time, the complex link between how noncoding genome variants affect genes associated with blood pressure and hypertension.”
dr. Philip Maas

While the human genome includes coding and non-coding elements A research team led at SickKids by Genetics and Genome Biology program scientist Dr. Philipp Maass sought to understand how these variants likely regulate blood pressure genes and, in doing so, describe the regulatory processes in the genome for regulation of blood pressure genes. Their findings, recently published in the journal Cell genomics, offer compelling insight into how these genetic sequences influence the regulation of genes associated with high blood pressure.

“This research unveils, for the first time, the complex link between how non-coding genome variants affect genes associated with blood pressure and hypertension,” Maass says. “What we have created is a kind of functional map of blood pressure gene regulators that can not only inform future investigations of cardiovascular genomics, but also presents a framework that can be applied to study other genetic conditions. .”

Analysis of thousands of genetic variants finds link to blood pressure regulation

Although it constitutes 98% of our genetic material, the non-coding genome does not actively produce proteins. Instead, non-coding sequences regulate coding genes in various ways.

While more traditional genome-wide association studies (GWAS) are used to identify associations between genetic traits and specific diseases, they are unable to describe how genetic variants act and influence neighboring genes. GWAS findings have informed much research on the function of variants in the coding genome, but very little has extended to include variants on non-coding regions of the genome.

Maass and his team used SickKids’ Massly Parallel Reporter Assay (MPRA) technology and the computational expertise of Dr. Marta Melé of the Barcelona Supercomputing Center to examine non-coding genome genetic variants at scale and identify how they likely regulate blood pressure. arterial. Genoa. Leveraging the stem cell expertise of Dr. James Ellis, Senior Scientist in the Developmental and Stem Cell Biology program, the team was able to study the genetic variants of heart cells relevant to humans.

The study, which screened more than 4,600 genetic variants with high-throughput technology, represents one of the largest endeavors to date in studying and assigning function to the non-coding genome. Surprisingly, Maass notes, the analysis revealed high densities of variants located at genes related to blood pressure regulation.

“With the increasing adoption of whole genome sequencing, we can find thousands of new variants in a single genome,” says co-author Dr. Seema Mital, Cardiologist, Senior Scientist in the Genetics and Genome Biology Program and Chief Scientist, Ted Rogers Center for Heart Research and Head of Cardiovascular Research at SickKids. “Discerning which variants may be linked to disease has the potential to improve the utility of genome sequencing in the clinical setting.”

Findings could inform precision medicine approaches for cardiovascular health

For the research team, uncovering the function of these genetic variants is an important step toward the future of Precision Child Health, a movement by SickKids to provide individualized care for each patient. They hope that information about these variants and their role in blood pressure regulation could one day be used to help clinicians predict which children might develop high blood pressure and offer appropriate interventions earlier.

“The variants we have characterized in the noncoding genome could be used as genomic markers for hypertension, laying the groundwork for future genetic research and potential therapeutic targets for cardiovascular disease.”

dr. Philip Maas

Beyond the impact on cardiac care, the findings may also inform similar approaches to other conditions with an underlying genetic component.

“Our research has allowed us to peer into the ‘dark matter’ of our DNA, revealing information that could be used as a roadmap to explore the genomic architecture behind various genetic traits. By combining different genomic, biochemical and computational methodologies, this innovative approach holds promise for redefining our understanding of the regulatory role played by the non-coding genome in children’s health,” says Maass, Canada Research Chair coding. Mechanisms of disease.

Reference: “Systematic characterization of regulatory variants of blood pressure genes” by Winona Oliveros, Kate Delfosse, Daniella F. Lato, Katerina Kiriakopoulos, Milad Mokhtaridoost, Abdelrahman Said, Brandon J. McMurray, Jared WL Browning, Kaia Mattioli, Guoliang Meng , James Ellis, Seema Mital, Martha Mele and Philipp G. Maass, May 24, 2023, Cell genomics.
DOI: 10.1016/j.xgen.2023.100330

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