Our laboratory investigates the chromosomal processes underlying meiosis and sexual reproduction. Meiosis is the specialized cell division that produces the gamete cells, such as sperm and eggs, that will fuse during fertilization. We are particularly interested in the extensive programmed chromosome breakage that occurs as part of meiosis in essentially all sexual species. This process is necessary for accurate chromosome inheritance and fertility, but if breaks are repaired incorrectly, it can also lead to harmful chromosome rearrangements and birth defects. Our goal is to understand the mechanisms controlling meiotic chromosome break formation in order to shed light on the molecular safeguards that protect genome integrity from one generation to the next.
Our model system is the sexually reproducing baker’s yeast, Saccharomyces cerevisiae.
The rules of chromosome break distribution
Although meiotic chromosome breaks can occur practically anywhere in the genome, some regions are much more likely to break than others. The non-random distribution of breaks is observed as defined hotspots and coldspots, and also as broad hot and cold regions that can span substantial fractions of a chromosome (Figure 1). We are particularly interested in the latter large-scale mechanisms driving meiotic break distribution. Using our own microarray technology to monitor break distribution across the entire yeast genome, we have identified many genomic regions in which chromosome breakage is actively induced or suppressed, and are in the process of defining the molecular mechanisms that govern the large-scale breakage constraints of meiotic chromosomes.
Figure 1. Meiotic chromosome break distribution.
(a) Breaks on spread yeast chromosomes (blue) detected by immunostaining against the break repair protein Rad51 (green). (b) Distribution of chromosome breaks along yeast chromosome 3 as measured using microarrays. Arrowheads indicate the strongest break hotspots.
The developmental program of break formation
Meiotic break formation is not only controlled through its distribution along chromosomes, but also through its timing within the meiotic program. Temporal regulation is important to avoid conflicts with processes such as chromosome duplication, which would jeopardize chromosome integrity. The mechanisms that provide communication and coordination between meiotic processes are collectively referred to as checkpoint mechanisms. Our work has identified several key meiotic checkpoint enzymes, most of which have clear counterparts in humans, and we aim to understand the complete network of coupling mechanisms that help embed chromosome breakage in the step-by-step execution of meiosis.