High-resolution Imaging of Entire Human Genome on the Horizon

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by Steve Bryson PhD |

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An $11.2-million, five-year grant has been awarded by the Centers of Excellence in Genomic Science of the National Institutes of Health (NIH) to uncover high-resolution details of the entire human genome. This project should help better understand the genome’s structure and function, as well as provide important clues about the genetic changes underlying diseases such as Prader-Willi syndrome (PWS).

The grant establishes the Center for Genome Imaging (CGI), with half of the funding allotted to Ting Wu, PhD, at Harvard Medical School in Massachusetts. The rest of the grant will be divided between: Nicola Neretti, PhD, at Brown University, in Rhode Island; Erez Lieberman Aiden, PhD, at Baylor College of Medicine, in Texas; and Marc Marti-Renom, PhD, at the Centre Nacional d’Anàlisi Genòmica — Centre for Genomic Regulation in Barcelona, Spain.

The primary goal of the CGI is to develop technologies that will allow the high-resolution imaging, analysis, and modeling of whole genomes to investigate their organization and function as an integrated unit, rather than individual parts.

“When it comes to the genome, the whole is truly greater than the sum of its parts,” Wu said in a Harvard press release. “The structure of the genome underlies both form and function and influences how our genes work.”

The entire genome is critical for the proper formation of egg and sperm, cell division, and the development from an embryo to a fully formed adult. Observing how the genome folds and is packaged during these events, and how abnormalities can occur, could provide insights into how genetic diseases emerge.

“The choreography of cell division with respect to reproduction is extraordinarily complex, with chromosomes pairing and then segregating from each other in unison across the entire genome, like a giant square dance,” said Wu.

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Currently, imaging technologies are limited to observing only a handful of genes at a time. However, genomic processes underlying diseases can involve hundreds, or thousands, of genes across the entire genome.

“As with all phenomena, a better understanding of what happens when things go wrong could give us strategies for how to make things better,” she added.

CGI imaging may reveal the altered chromosomal processes that lead to PWS, caused by the loss of genes (or of their activity) found on a region of chromosome 15, known as the “PWS locus.” These genes regulate growth, intellectual abilities, social behavior, metabolism, and appetite. A lack of these genes leads to symptoms such as weak muscle tone, increased appetite, as well as cognitive and behavioral problems.

Along with the X and Y sex chromosomes, each human cell contains two copies of each chromosome, one from each parent. Normally, some genes on one parental chromosome are active, but silenced on the other chromosome due to a process known as parental imprinting.

In about 60% of PWS cases, genes on chromosome 15 from the father are missing, but inactive on the mother’s chromosome due to parental imprinting. About 35% of cases are caused by maternal uniparental disomy, which occurs when the child inherits two chromosome-15 copies from the mother, but both PWS loci are silent. In a few cases, both chromosomes are intact, but both PWS loci are silent.

Wu aims to analyze high-resolution images of the genome to explore the structural basis for these alterations, which may support the development of PWS therapies or a cure for imprinting-related diseases.

Problems also may occur during cell division, including DNA duplications, deletions, and the movement of DNA segments to different parts of the genome. Errors in chromosomal pairing can result in too many or too few chromosomes in the egg and sperm. Also, chromosome breakage can lead to genetic diseases or cancer.

The high-resolution imaging from the CGI may shed light on these phenomena genome-wide.

Wu described that integrating the information generated from these images with “the tremendous amount of information we know from many other fields” in computer-based analyses is daunting. This is “is why we founded this consortium of four laboratories.”

Each of the four researchers who received grant funding has been developing high-resolution imaging and computational methods, and will provide unique and complementary expertise in genetics, genomics, chromosome mechanics, as well as polymer- and physics-based modeling. The ultimate goal of the CGI is to view the entire human genome at super-high resolution.

“We already know how to look at relatively small subsections of the genome in super-resolution,” said Wu. “The goal now is to innovate on top of our current foundation of technologies so that, soon, we will have a next generation of methods that will, finally, enable us to look at the entire human genome.”