Three dimensions of the human genome

New algorithm could enable a closer, more accurate way to model genes

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COLUMBIA, Mo.—“DNA is the code of life for all living systems, including people,” states Jianlin “Jack” Cheng, the William and Nancy Thompson Professor in electrical engineering and computer science in the University of Missouri (MU) College of Engineering. “Our tool can help scientists view specific genes and study their interactions, which could help identify factors leading to—and treatment for—various cancers, diseases or disorders.”
The tool that he refers to is an algorithm, created by Cheng and his team, that allowed them to build a high-definition 3D model of the human genome that they believe will transform the way we can identify, diagnose and treat cancer. Among the potential applications, says Cheng, is helping scientists better see the differences between healthy and malignant cells: “We may identify what could cause the cancer to occur and see if there is a way to reverse engineer it.”
Of course, the Human Genome Project has already mapped the single dimension of the human gene system in three major ways: determining the sequence of all the bases in our genome’s DNA; mapping the locations of genes for major sections of all our chromosomes; and producing linkage maps to explore inherited traits (such as those for genetic disease). The 3D model was built using these existing one-dimensional maps, but what makes it so powerful is its ability to bring the interaction between chromosomes within the gene into a clear focus, able to be examined from all angles.
The tool is key breakthrough coming out of MU’s Translational Precision Medicine initiative, which is bringing together industry partners, multiple schools and colleges, and the federal and state government resources to enable precision and personalized medicine. Translational medicine is often referred to as translating scientific discovery from “bench to bedside,” using key research advances to develop applicable clinical therapies. Correspondingly, precision medicine looks at the unique variables in genes, lifestyle and environment for each person and creates drugs, devices and treatments that are customized to the individual being treated.
“Gene interactions are essential for our bodies to function,” Cheng explained. “By visualizing the genes in 3D, and at high-definition, scientists can better visualize these interactions and study long-range interactions that we couldn’t see before. For example, right now scientists might not see the interaction between gene A and gene Y, but with this new tool we can see these two genes are very close to each other because of a process called folding. When the folding malfunctions, it can cause adverse issues, such as diabetes or Alzheimer’s disease.”
A 2018 article in the Journal of Cell Biology details a previous effort to create a three-dimensional picture at the University of Illinois at Urbana-Champaign. That model, created by Yu Chen and Andrew Belmont, is called tyramide signal amplification sequencing (TSA-Seq) that allows the distance of every gene from specific nuclear landmarks to be measured simultaneously. By directing an enzyme—horseradish peroxidase—to specific parts of a nucleus, the resulting molecule, called tyramide, essentially labels any DNA in its vicinity. According to the article, “The closer a gene is to the enzyme, the more it will be labeled, so when researchers subsequently sequence the cells’ DNA, they can calculate how close each gene was to the nuclear structure tagged with horseradish peroxidase.”
The UI team recognized that the technique would need to be improved, but were hopeful that by mapping the relative position of genes within specific cell types, TSA-Seq could help determine how genes change position depending on the health of the cell. “The logic of this nuclear organization remains to be determined, but our model would suggest that chromosome movements of just a few hundred nanometers could have substantial functional significance,” said Belmont in the article.

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