Chromosomes are organelles that maintain genetic order inside living cells. Problems in chromosome structure and function are detected as a normal process of aging and chromosome problems are a signature of numerous disease states including cancer and genetic syndromes like Downs. A chromosome is not just DNA, but a structure organized by a complex mixture of structural proteins, sequence-specific proteins, enzymes, and small RNA's. These components work together to facilitate reactions like transcription of ribosomal RNA and mRNA, DNA replication, and homologous recombination. In addition to encoding signals for transcription and replication, chromosomes also move to specific cellular locations. Our lab studies the cellular mechanisms that govern chromosome movement using biochemical and genetic methods. One way to study DNA movement in E. coli and Salmonella typhimurium is to use site specific recombination. This method combines specially marked chromosomes with controlled expression of site specific recombinases from yeast (Flp) and the transposon (Tn3 resolvase) to measure how frequently two segments of DNA touch. Experiments show that log phase bacteria have about 400 (10 kb) domains with most boundaries occurring at random with respect to DNA sequence. Two enzymes that influence domain structure are DNA gyrase and Topoisomerase IV. Viruses that grow in bacteria are sensitive to this structure, and when bacteriophage Mu replicates it transposes from one domain to another. Understanding the folding and movement of DNA molecules in vivo is critical for progress in understanding a wide range of topics in molecular genetics, including mechanics of recombination, replication, transcription and chromosome segregation. Current projects in the lab involve microarrays and strategies to identify special mechanisms in transcription that restrict chromosome movement in about 3% of the DNA.
Patrick Higgins completed undergraduate studies at Wichita State University. He obtained a Ph.D. degree in the Department of Microbiology from the University of Chicago (1976). He was appointed to the faculty of the University of Wyoming in 1979 and moved to Birmingham in 1984, where he is a full Professor of Biochemistry and Molecular Genetics and Co-Director of the Howell Heflin Center for Human Genetics. His research is supported through grants from the NIH, NSF, American Cancer Society, and the Parke Davis Corporation