Genome Archipelago Model: Clues on Cancer Mutations

The research is highlighted in a paper in a special edition of the International Journal of Molecular Sciences, of which Stachowiak is the guest editor. He is also senior author on the paper.

The study advances a topologically integrated GAM created through the interactions of distant DNA regions and even different chromosomes.

The interactions were mapped by first author Brandon Decker, PhD, a graduate of the genetics, genomics and bioinformatics program and now a postdoctoral associate at the National Institute on Aging (National Institutes of Health) in Bethesda, Maryland.

The interactions led to the formation of topology associated domains (TAD), described as islands of an ever-changing archipelago. The makeover of the TAD islands serves to recruit distinct oncogenic programs during the development of the embryonic stem cells to neurons.

“The genome was considered a library you go to and bring two books together, and you might get some integration; it was not thought to be integrated,” Stachowiak says. “The idea that the genome is integrated in terms of its functionality is a relatively new idea.”

“In our laboratories we found that there are gene programs that change as they go from one stage to another. For instance, in a developmental disorder, schizophrenia, we found that the gene programs are disrupted, disorganized,” Stachowiak adds.

While the TAD islands are dynamically remodeled during cell development, genes of related ontogenic functions — regardless of where they are positioned in the linear genome — are transiently incorporated into the 3D islands, allowing their concerted expression. The islands become hubs of genomic subroutines that underwrite different stages of the cell’s development.

The islands encode development, life, health and disease.

“The genome is an archipelago of constantly changing islands, and when the islands form they provide a blueprint for specific parts of the body, specific functions and so on,” Stachowiak says. “You cannot determine development by simply adding genes. You need to connect those genes into functional domains that will be dictating development.”

“The titles refer to my lifelong inspiration by the travels of Charles Darwin, as he stumbled upon the islands of Galapagos, which turned out to be an instrument of evolution,” Stachowiak adds. “We refer to different islands that form in the cell nucleus and, as we propose, orchestrate ontogenesis.”

The proposed archipelago model helps to explain why functionally-related genes that change chromosomal locations during evolution may maintain co-regulation across diverse evolutionary groups and species. The illumination of their roles in genome structure, remodeling and functional programming offers a key path toward understanding genome programmatic evolution and its aberration in cancer cells.

The archipelago model helps to explain the still puzzling observations that mutations — copy variant changes that occur within nongenic DNA regions (outside protein coding genes) — may lead to complex disorders.

“We’re proposing with some evidence, that when you have a disruption of one small part of DNA the whole topology collapses. If that does, you may have a serious problem, a developmental problem, a developmental disease or cancer, where replacement of a property may not be enough to fix the problem. Because with one small mutation In DNA, a big topilogical structure that incorporates hundreds of genes may become disrupted,” Stachowiak says.

Stachowiak directed the research — funded by grants from the National Science Foundation (CBET-1555720, CBET-1706050 and CBET-2039189) — in collaboration with co-authors Donald Yergeau, PhD, senior research scientist in UB’s New York State Center of Excellence in Bioinformatics and Life Sciences; and Josep M. Jornet, PhD, assistant professor in UB’s Department of Electrical Engineering at the time of the research and now associate professor in the Department of Electrical and Computer Engineering at Northeastern University.

Co-authors from the Jacobs School of Medicine and Biomedical Sciences are:

• Yongho Bae, PhD, assistant professor of pathology and anatomical sciences
• Ewa K. Stachowiak, PhD, assistant professor of pathology and anatomical sciences

Other co-authors are from Northeastern University and the Mossakowski Medical Research Center, Polish Academy of Sciences, in Warsaw, Poland.