The major goal of this research program is to contribute to the establishment of a set of restriction fragment length polymorphisms, to be used in the construction of a human genetic linkage map. Recent work has shown that standard human DNA libraries in bacteriophage lambda vectors appear systematically to be missing a large fraction of human DNA sequences which can be propagated only on hosts with mutations in the recB, recC, and sbcB genes. The results further suggest a possible relationship between lethality and/or instability of sequences in E. coli and polymorphism in the human genome. The major experimental projects are: 1. To test a variety of new hosts, particularly E. coli strains having mutations in various DNA functions, as well as S. cerevisiae (wild type and mutant), in order to identify cloning hosts with improved tolerance of human DNA sequences. 2. To examine sequences acquired through the use of these new cloning hosts and to determine whether as a class, these otherwise lethal and/or unstable sequences are also sites of polymorphism. 3. To elucidate the molecular organization of the highly polymorphic locus D14S1, and to explore the genome for other loci homologous to D14S1 in order to determine whether these are also sites of polymorphism. 4. As new highly polymorphic loci are uncovered, to determine their chromosomal locations, using in situ hybridization and somatic-cell hybrid. To follow the inheritance of the markers in families and, where possible, to determine linkage among RFLPs or between RFLPs and other inherited traits.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Mammalian Genetics Study Section (MGN)
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Massachusetts Institute of Technology
Schools of Arts and Sciences
United States
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Lander, E S; Botstein, D (1987) Homozygosity mapping: a way to map human recessive traits with the DNA of inbred children. Science 236:1567-70
Donlon, T A; Lalande, M; Wyman, A et al. (1986) Isolation of molecular probes associated with the chromosome 15 instability in the Prader-Willi syndrome. Proc Natl Acad Sci U S A 83:4408-12
Brissenden, J E; Page, D C; de Martinville, B et al. (1986) Regional assignments of three polymorphic DNA segments on human chromosome 15. Genet Epidemiol 3:231-9
Wyman, A R; Wertman, K F; Barker, D et al. (1986) Factors which equalize the representation of genome segments in recombinant libraries. Gene 49:263-71
Wertman, K F; Wyman, A R; Botstein, D (1986) Host/vector interactions which affect the viability of recombinant phage lambda clones. Gene 49:253-62
Wyman, A R; Wolfe, L B; Botstein, D (1985) Propagation of some human DNA sequences in bacteriophage lambda vectors requires mutant Escherichia coli hosts. Proc Natl Acad Sci U S A 82:2880-4