Dr. Donis-Keller’s early research studies centered on the development of an RNA sequencing method (Donis-Keller et al., 1977) and applications of the method (Rommelaere et al., 1979) while she was a graduate student at Harvard University in the laboratory of Wally Gilbert (who received a Nobel Prize in Medicine in 1979 for his work on developing a DNA sequencing method). While a research scientist at Collaborative Research, Inc., her work focused on the construction of the first genetic linkage map of the human genome (Donis-Keller et al., 1987) and the application of genetic mapping methods to heritable disorders including cystic fibrosis (Knowlton et al., 1985), and neurofibromatosis type 1 (Stephens et al., 1989). During this time her research group also worked developing DNA markers and using them to track the progress of bone marrow transplants (Knowlton et al., 1986).
The development of the human genetic linkage map continued in Dr. Donis-Keller’s research laboratory at Washington University in St. Louis as part of the Human Genome Project sponsored by the National Institutes of Health (NIH/CEPH Collaborators Mapping Group, 1992). New applications of genetic mapping technologies to a variety of heritable disorders including several heritable and sporadic cancers were also initiated. Research on the genetic locus of a form of thyroid cancer, Multiple Endocrine Neoplasia type 2A, led to the identification of the Ret proto-oncogene as the causative agent (Donis-Keller et al., 1993) and to predictive diagnostic tests for the disorder (Wells et al., 1994). Studies in her laboratory determined that another form of thyroid cancer, Multiple Endocrine Neoplasia type 2B was also caused by the Ret proto-oncogene (Carlson et al., 1994). Research in Dr. Donis-Keller’s laboratory on DNA markers for human telomeres, the ends of linear chromosomes, led to the identification and characterization of a large number of telomere-specific DNA markers (Vocero-Akbani et al., 1996) that found numerous clinical and basic research applications (Lengauer et al. 1993). Dr. Donis-Keller’s research group also participated in establishing and maintaining a breast cancer tissue resource for use in research and the development of treatments for the disease (Glass et al., 2001).
Dr. Donis-Keller became interested in studying the viruses of soil bacteria (mycobacteriophages) when she moved to Olin College in Needham, Massachusetts. The overall goal of the research is to learn more about the evolution and diversity of the genomes of mycobacteriophages. Bacteriophages are the most abundant organisms in the biosphere and mycobacteriophages are an ideal resource for undergraduate research since they are readily available from environmental samples and they are not pathogenic to humans. In the laboratory students isolate new phages and characterize them in terms of their morphology, growth characteristics, and their sequence organization. In collaboration with the laboratory of Graham Hatfull and the Pittsburg University Bacteriophage Genome Center, the DNA sequences of the genomes of two Olin phages have been determined thus far and putative gene sequences have been identified and the sequence of one of them has been compared to the panel of phages sequenced in the Hatfull laboratory (Hatfull et al., 2010). Work continues on the characterization of a large panel of phages isolated in the Donis-Keller laboratory and on identification of new bacteriophages.
Representative Donis-Keller Research Literature Citations
RNA Sequencing Method
Donis-Keller, H., A. Maxam and W. Gilbert (1977). Mapping adenines, guanines, and pyrimidines in RNA. Nucleic Acids Research, 4: 2527-2538.
Donis-Keller, H. (1979). Site specific enzymatic cleavage of RNA. Nucleic Acids Research, 7: 179-192.
RNA Sequencing Method Applications
Rommelaere, J., H. Donis-Keller and N. Hopkins (1979). RNA sequencing provides evidence for allelism of determinants of the N-, B-, or NB- tropism of murine leukemia viruses. Cell, 16: 43-50.
Human Genome Map Construction
Donis-Keller, H., P. Green, C. Helms, S. Cartinhour, B. Weiffenbach, K. Stephens, T. P. Keith, D. W. Bowden, D. R. Smith, E. S. Lander, D. Botstein, G. Akots, K. S. Rediker, T. Gravius, V. A. Brown, M. B. Rising, C. Parker, J. A. Powers, D. E. Watt, E. R. Kauffman, A. Bricker, P. Phipps, H. Muller-Kahle, T. R. Fulton, S. Ng, J. W. Schumm, J. C. Braman, R. G. Knowlton, D. F. Barker, S. M. Crooks, S. E. Lincoln, M. J. Daly and J. Abrahamson. (1987). A genetic linkage map of the human genome. Cell, 51(October 23): 319-337.
Mapping Heritable disorders
Knowlton, R. G., O. Cohen-Haguenauer, N. Van Cong, J. Frezal, V. A. Brown, D. Barker, J. C. Braman, J. W. Schumm, L.-C. Tsui, M. Buchwald and H. Donis-Keller (1985). A polymorphic DNA marker linked to cystic fibrosis is located on chromosome 7. Nature, 318: 380-382.
Stephens, K., P. Green, V. M. Riccardi, S. Ng, M. Rsing, D. Barker, J. K. Darby, K. Falls, F. Collins, H. F. Willard and H. Donis-Keller. (1989). Genetic analysis of eight loci tightly linked to neurofibromatosis 1. American Journal of Human Genetics, 44: 13-19.
Applications of DNA Markers to Bone Marrow Transplantation
Knowlton, R. G., V. A. Brown, J. C. Braman, D. Barker, J. W. Schumm, C. Murray, T. Takvorian, J. Ritz and H. Donis-Keller (1986). Use of highly polymorphic DNA probes for genotypic analysis following bone marrow transplantation. Blood, 68(2): 378-385.
Multiple Endocrine Neoplasia Type 2A gene identification
Donis-Keller, H., S. Dou, D. Chi, Katrin M. Carlson, K. Toshima, T. C. Lairmore, J. R. Howe, J. F. Moley, P. F. Goodfellow, and S. A. Wells, Jr. (1993). Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Human Molecular Genetics, 2: 851-856.
Chi, D.D., K. Toshima, H. Donis-Keller, and S. A. Wells, Jr. (1994). Predictive testing for multiple endocrine neoplasia type 2A (MEN 2A) based on the detection of mutations in the RET protooncogene. Surgery, 116: 124-133.
Human Genome Project Mapping Studies
NIH/CEPH Collaborators Mapping Group (1992). A comprehensive genetic linkage map of the human genome. Coordinating editor and senior authorship for maps of chromosomes 2, 6, 7, 8, 12, 14. Science, 258: 67-86 and 148-162.
Multiple Endocrine Neoplasia Type 2B gene identification
Carlson, K. M., S. Dou, D. Chi, N. Scavarda, K. Toshima, C. E. Jackson, S. A. Wells, Jr., P. J. Goodfellow, and H. Donis-Keller (1994). A single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is asociated with multiple endocrine neoplasia type 2B. Proceedings of the National Academy of Science, USA, 91: 1579-1583.
Predictive Diagnostic Testing with DNA Markers for Multiple Endocrine Neoplasia Type 2A
Wells, S. A., Jr., D. D. Chi, K. Toshima, L. P. Dehner, C. M. Coffin, S. B. Dowton, J. L. Ivanovitch, M. K. DeBenedetti, J. F. Moley, and H. Donis-Keller (1994). Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2A. Annals of Surgery, 220: 237-250.
Human Telomere Mapping
Vocero-Akbani, A., C. Helms, J-C. Wang, F. J. Sanjurjo, J. Korte-Sarfaty, R. A. Veile, L. Liu, A. Jauch, A. K. Burgess, A. Hing, M. S. Holt, S. Ramachandra, A. J. Whelan, R. Anker, L. Ahrent, M. Chen, M. R. Gavin, K. Iannantuoni, S. M. Morton, S. D. Pandit, C. M. Read, T. Steinbrueck, C. Warlick, D. A. Smoller, and H. Donis-Keller (1996). Mapping human telomere regions with YAC and P1 clones: Chromosome specific markers for 27 telomeres including 149 STSs and 24 polymorphisms for 14 proterminal regions. Genomics, 36: 492-506.
Applications for Telomere DNA markers
Lengauer, C., M. R. Speicher, S. Popp, A. Jauch, M. Taniwaki, R. Nagaraja, H. Riethman, H. Donis-Keller, M. D’Urso, D. Schlessinger, and T. Cremer (1993). Chromosomal bar codes produced by multicolor fluorescence in situ hybridization with multiple YAC clones and whole chromosome painting probes. Human Molecular Genetics, 2: 505-512.
Breast Cancer Tissue Resource
Glass, A.G., H. Donis-Keller, C. Mies, J. Russo, B. Zehnbauer, S. Taube, and R. Aamodt (2001). The Cooperative Breast Cancer Tissue Resource: archival tissue for the investigation of tumor markers. Clinical Cancer Research, 7: 1843-1849.
Hatfull, G.F., D. Jacobs-Sera, J.G. Lawrence, W.H. Pope, D.A. Russell, C-C. Ko, R.J. Weber, M.C. Patel, K.L. Germane, R.H Edgar, N.N. Hoyte, C.A. Bowman, A.T.Tantoco, E.C. Paladin, M.S. Myers, A.L. Smith, M.S. Grace, T.T. Pham, M.B. O’Brien, A.M. Vogelsberger, A.J. Hryckowian, J.L. Wynalek, H. Donis-Keller, M.W. Bogel, C.L. Peebles, S.G. Cresawn, R.W. Hendrix (2010). Comparative Genomic Analysis of 60 Mycobacteriophage Genomes: Genome clustering, Gene Acquisition and Gene Size. Journal of Molecular Biology, 397(1): 119 – 143.