Environmental Factor, May 2010, National Institute of Environmental Health Sciences
Chromosome Replication Stress and Health
By Eddy Ball
New findings about genome instability were front and center during a talk at NIEHS presented March 25 by grantee 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/faculty/thomas-w-glover-phd) 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.
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.