In eucaryotic organisms, haploid gametes are generated from diploid cells during meiosis. In the first meiotic division, homologous chromosomes migrate to opposite poles of the cell (disjoin). In organisms as diverse as Saccharomyces cerevisiae and Homo sapiens, crossovers between the homologous chromosomes ensure correct meiosis I segregation by holding the pair together until anaphase I when they move apart. An undefined activity, referred to as the chiasma binder, probably enables crossovers to hold homologous chromosomes together. Meiosis is carried out with considerable fidelity and errors are usually lethal. In humans, a number of disorders, including Down's syndrome, are caused by segregation errors in meiosis I. The long term objective of the research described here is to elucidate the mechanisms by which homologous chromosomes are segregated in meiosis I. These experiments will be carried out in the yeast, S. cerevisiae, where it is possible to study meiosis using artificial chromosomes. These model molecules offer the advantages that they mimic the behavior of natural chromosomes but have precisely defined structures and are easily modified to meet specific experimental needs. Most importantly, they carry no essential genes. Therefore, cells which have lost them through meiotic errors are viable and can be analyzed. The experiments in this proposal are designed to accomplish four specific aims. First, these experiments will test the hypothesis that specialized DNA sequence elements are required to mediate homologous pairing and/or crossing-over. Second, they will test the model that intertwining of sister chromatids provides chiasma binder activity. A strategy for identifying sequences with chiasma binder activity will also be presented. A system capable of correctly segregating nonrecombined artificial chromosomes in yeast has recently been described. This system may be utilized to increase the fidelity of meiosis by correctly distributing pairs of natural chromosomes that have failed to recombine. The third goal of these experiments will be to test this hypothesis. The final experimental section describes a strategy for identifying mutants in this system, and cloning the affected genes. The goal here is to acquire a set of mutant strains and cloned genes which can be used as tools to examine how this system functions in yeast and whether it is common to other organisms.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM040452-01
Application #
3297989
Study Section
Genetics Study Section (GEN)
Project Start
1988-07-01
Project End
1993-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
1
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Tufts University
Department
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02111
Malkova, A; Ross, L; Dawson, D et al. (1996) Meiotic recombination initiated by a double-strand break in rad50 delta yeast cells otherwise unable to initiate meiotic recombination. Genetics 143:741-54
Ross, L O; Rankin, S; Shuster, M F et al. (1996) Effects of homology, size and exchange of the meiotic segregation of model chromosomes in Saccharomyces cerevisiae. Genetics 142:79-89
Ross, L O; Maxfield, R; Dawson, D (1996) Exchanges are not equally able to enhance meiotic chromosome segregation in yeast. Proc Natl Acad Sci U S A 93:4979-83
Flatters, M; Maxfield, R; Dawson, D (1995) The effects of a ring chromosome on the meiotic segregation of other chromosomes in Saccharomyces cerevisiae. Mol Gen Genet 249:309-16
Flatters, M; Dawson, D (1993) SID1-1: a mutation affecting meiotic sister-chromatid association in yeast. Genetics 134:423-33
Ross, L O; Treco, D; Nicolas, A et al. (1992) Meiotic recombination on artificial chromosomes in yeast. Genetics 131:541-50