Thomas W. Glover, Ph.D.
Professor of Human Genetics
Professor of Pediatrics and Communicable Diseases
Professor of Pathology
Our research focuses on the areas of genome instability and the molecular biology of human genetic disease. A longstanding interest is the study of chromosomal fragile sites. These are chromosome loci that are especially sensitive to breakage following replication stress. Our studies of fragile sites have led to our current focus on copy number variants (CNVs). In only the last few years, thousands of normal CNVs spanning tens to hundreds of kb have been found in the human genome where they play important roles in normal genomic variation and evolution. In addition, spontaneous or de novo CNVs are a major cause of genetic and developmental disorders, including mental retardation, autism, schizophrenia, epilepsy, skeletal defects and many others. Despite their importance, there is limited understanding of how most CNVs arise and the risk factors involved. We have found that replication stress, like that leading to fragile site breaks, creates CNVs in human cells. Our current efforts are focused on expanding on these findings to identify the genetic and environmental factors involved in CNVs formation using novel assays both in vitro and in mice in vivo and high-resolution genome analysis approaches.
Our second major interest is Hutchinson-Gilford Progeria (HGP). HGP is characterized by the premature onset of many of the features associated with aging, such as an aged appearance and arteriosclerosis, with death usually before age 15. We were involved in a consortium effort that identified the gene (lamin A/C) responsible for this fascinating disorder, opening the door to functional studies and the identification of therapeutic drug trials. Our current interests include the role of lamin A in genome stability and the identification of genes responsible for related progeroid disorders.
Selected Publications from 134 Peer-Reviewed:
Casper AM, Nghiem P, Arlt MF, Glover TW. ATR regulates fragile site stability. Cell, 111: 779-789, 2002.
Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, Erdos MR, Robbins CM, Moses TY, Berglund P, Dutra A, Pak E, Durkin S, Csoka AB, Boehnke M, Glover TW, Collins FS: Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford Progeria Syndrome. Nature 423: 293-298, 2003.
Glynn MW, Glover TW: Incomplete processing of mutant lamin A in Hutchinson-Gilford progeria leads to nuclear abnormalities, which are reversed by farnesyltransferase inhibition. Hum Mol Genet 14: 2959-2569, 2005.
Durkin SG, Glover TW: Chromosome fragile sites. Annual Review Genetics 41: 2007 Annu Rev Genet 41: 169-192, 2007.
Durkin SG, Ragland RL, Arlt MF, Mulle JG, Warren ST, Glover TW. Replication stress induces tumor-like microdeletions in FHIT/FRA3B. Proc Natl Acad Sci USA 105: 246-251, 2008.
Arlt MF, Mulle JG, Schaibley VM, Ragland RL ,Durkin SL, Warren ST, Glover TW. Replication stress induces genome-wide copy number changes in human cells that resemble polymorphic and pathogenic variants. Am J Hum Genet 84: 339-350, 2009.
Arlt MF, Ozdemir AC, Birkeland SR, Lyons RH, Glover TW, Wilson TE. Comparison of constitutional and replication stress-induced genome structural variation by SNP array and mate-pair sequencing. Genetics. 187:675-683, 2011.
Arlt MF, Ozdemir AC, Birkeland SR,Arlt MF, Ozdemir AC, Birkeland SR, Wilson TE, Glover TW. Hydroxyurea induces de novo copy number variants in human cells. Proc Natl Acad Sci 108:17360–65, 2011.
Arlt MF, Rajendran S, Birkeland SR, Wilson TE, Glover TW. De novo CNV formation in mouse embryonic stem cells occurs in the absence of xrcc4-dependent nonhomologous end-joining. PLos Genetics 8: e1002981, 2012.