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Chromosome Replication Stress and Health

By Eddy Ball
May 2010

Thomas Glover, Ph.D. at the podium
Glover opened his talk by saying, "Our genomes they are a-changin," to underscore the large submicroscopic structural changes that occur continuously in the mammalian genome. (Photo courtesy of Steve McCaw)

Doug Bell, Ph.D. in the audience
Keystone lectures give Intramural scientists with shared research interests, such as NIEHS Environmental Genomics Group head Doug Bell, Ph.D., above, the opportunity to learn about the research of high-profile grantees (Photo courtesy of Steve McCaw)

Lecture host Dan Shaughnessy, right, joined the speaker at the podium
Lecture host Dan Shaughnessy, right, joined the speaker at the podium for questions. (Photo courtesy of Steve McCaw)

Carmen Williams, M.D., Ph.D., with questions for Glover
NIEHS Reproductive Medicine Group headed by Carmen Williams, M.D., Ph.D., above, was one of several in the audience with questions for Glover. (Photo courtesy of Steve McCaw)

New findings about genome instability were front and center during a talk at NIEHS presented March 25 by grantee(http://tools.niehs.nih.gov/portfolio/sc/detail.cfm?appl_id=7817619) Thomas Glover, Ph.D., on "Mechanisms, Consequences, and Environmental Risks for CNV [Copy Number Variation] Mutations in Human Chromosomes."

A professor in the Department of Human Genetics and Department of Pediatrics and Communicable Diseases at the University of Michigan, Glover(http://www.hg.med.umich.edu/facultyprofile.php?id=7) Exit NIEHS is striving to develop a unified theory of the causes and consequences of replication stress in mammalian cells and to determine whether there are predictable pathways of stress-induced DNA damage.

He and his group seek to better understand the potential role of CNV - microscopic deletions and insertions found throughout the genome - in a range of complex human diseases. They are particularly interested in understanding spontaneous or de novo CNVs - those present in an affected individual, but absent in both parents - and their connection to environmental factors.

Genome-wide implications

These de novo CNVs, Glover said, are responsible "much more than we'd expected" for "a surprising number" of diseases, such as mental retardation, autism, developmental defects, and genetic disorders, and copy number alterations are found in cancer cells. "It's almost certain that genetic variations and environmental insults can induce increased risk for new and deleterious CNVs."

Although there are "fragile sites" and "hot spots" in the genome where spontaneous CNVs are common, he noted, "CNVs stagger all across the genome." Investigators have described more than 1,400 CNVs in healthy individuals - a number that is sure to grow with further research - and Glover expects to discover an even greater number in people with complex diseases as he searches for patterns in their occurrence.

Uncovering the mechanisms of environmental stress

As Glover explained, CNVs are an important component of genetic variation, playing a prominent role in phenotypic diversity, complex disease, and evolution. However, despite advances in understanding CNV mechanisms, he concedes, "It's harder to understand how environmental events are involved."

Glover hypothesizes that environmentally induced replication defects and DNA double-strand breaks are two of the major factors leading to CNVs during mitotic cell division in the somatic cells and in cancer cells. His group's goal is developing a high-resolution catalogue of genomic manifestations of two categories of environmental stressors responsible for these two different processes in mammals - induced replication stress, building on previous work with the polymerase inhibitor amphidicolin, using hydroxyurea and folate, and double-strand breaks induced by ionizing radiation or bleomycin.

Glover's talk was hosted by the NIEHS health scientist administrator who manages his America Reinvestment and Recovery Act-funded challenge grant, Dan Shaughnessy, Ph.D. Glover was the sixth speaker in the popular Keystone Science Lecture Seminar Series sponsored each month by the NIEHS Division of Extramural Research and Training.



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