The genomic false-shuffle: Maintenance of topological domains in the rearranged gibbon genome

A northern white-cheeked gibbon is swinging across a river that separates different landscapes, inspired by the complex patterns of epigenetic states within the genome.

Large-scale chromosomal rearrangements are a major source of genetic variation and are hallmarks of human disease. However, the mechanisms underlying their occurrence and subsequent fixation are not entirely understood. Lucia Carbone, Ph.D., uses a comparative genomics approach to investigate how specific genomic and epigenetic features lead to chromosomal rearrangements and the outcome of these events on species evolution and pathology. She uses the gibbon genome in her research.

A northern white-cheeked gibbon is swinging across a river that separates different landscapes, inspired by the complex patterns of epigenetic states within the genome.
A northern white-cheeked gibbon is swinging across a river that separates different landscapes, inspired by the complex patterns of epigenetic states within the genome — an arid desert of open chromatin and an impenetrable tropical forest of packed chromatin. Beata Edyta Mierzwa created this illustration for the authors.

The differences in genetic identity between the human genome and the white-cheeked gibbon provide insights into evolutionary consequences of heavy genome reshuffling. The gibbon, an endangered small ape from Southeast Asia, is an exceptionally good model for investigating genomic evolution. It has experienced an unusually high number of chromosomal rearrangements since its (relatively) recent divergence from humans about 17 million years ago, and there is high genetic similarity between humans and gibbons — 96 percent. Additionally, there exists a well-annotated genome for the gibbon, along with a high-resolution identification of evolutionary breaks of synteny with the human genome.

In the July 2018, issue of Genome Research, a team led by Carbone, associate professor in the School of Medicine affiliated with the Oregon National Primate Research Center, reported findings from investigations into these heavily rearranged genome of gibbons. Carbone demonstrated that genome evolution occurs within the constraints of what are called topological associating domains, or TADs.

TADs can be imagined as distinct landscapes — or adjacent rooms — on chromosomes and are separated by strong boundaries that minimize cross-talk between them. Mounting evidence indicates that disruption or deletion of TAD boundaries can be pathogenic — and associated with congenital disorder and cancer as the result of aberrant interactions between genes and regulatory elements of neighboring TADs.

The study shed light on the genetic and epigenetic interplay that shapes genomes during evolution, providing important implications for studies of evolution of chromosomal rearrangements and gene regulation. Specifically, it showed that even during heavy genome shuffling, as the one experienced by the gibbon genome, TAD boundaries remain intact.

Listen to Carbone talk about gibbon conservation, the genomic shuffle and her research on OHSU Week podcast.

Carbone and first author Nathan Lazar’s co-authors include Kimberly A. Nevonen, Thomas J. Meyer and Mariam Okhovat (OHSU), Brendan O’Connell and Richard E. Green (University of California, Santa Cruz), and Christine McCann and Rachel J. O’Neill (University of Connecticut).

The team’s next step is to use an evolutionary approach to identify TAD boundaries that never changed across evolution and test their function by removing them with CRISPR/Cas9.

 

This study was funded by the National Library of Medicine Biomedical Informatics Research Training Program (T15 LM007088, N.H.L, T.J.M.), National Science Foundation (1613856, L.C., M.O., C.M., R.J.O.), National Institutes of Health/ National Center for Research Resources (P51 OD011092, L.C.), Knight Cardiovascular Institute (L.C.), and National Human Genome Research Institute (5U24HG009084, R.E.G.).

Illumina sequencing for the study was performed by the OHSU Massively Parallel Sequencing Shared Resource. The team performed the intensive large-scale data workflows with support from the OHSU ExaCloud Cluster Computational Resource and the Advanced Computing Center.

Resources

Oregon National Primate Research Center researchers to sequence rhesus macaques genomes (OHSU Research News, 2016)

OHSU-led research team first in gibbon DNA sequencing (OHSU Research News, 2014)

Scientist hopes to further sarcoma research with help of tumor from a gibbon (Portland Tribune, 2014)

 

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