Andrew Murray, PhD
Department of Molecular and Cellular Biology, Faculty of Arts and SciencesCo-Director, Bauer Center for Genomics Research
Cellular function and evolution using Saccharomyces cerevisiae
Examining budding yeast (Saccharomyces cerevisiae) from the perspective of both biology and physics, investigate the mechanics of how genetic information is transferred during cell division and mating; characterize yeast evolution as a function of the selective pressure exerted by
Understanding the precise mechanisms behind mitosis and meiosis has relevance for a variety of diseases. There are a number of congenital disorders caused by nondisjunction of the chromosomes, the most common being Down syndrome, where patients have an extra copy of chromosome 21. There are also disorders caused by having 3 copies of chromosomes 8, 9, 13, 16, 18, and 22. Additionally, there are numerous diseases due to the deletion of a chromosomal arm or whole chromosome during meiosis, including Wolf-Hirschhorn syndrome, Cri du chat syndrome, Williams syndrome, and diGeorge syndrome, among others. Nondisjunction can also occur with the X and Y chromosomes, leading to Turner syndrome with just one X chromosome and Klinefelter’s syndrome with an extra X in addition to XY. Many cancers have been linked to translocations of large sections of chromosomes, likely to occur during mitotic nondisjunction. The most well known are various leukemias and lymphomas, as well as Ewing’s sarcoma, synovial sarcoma, and alveolar rhabdomyosarcoma. A greater understanding of the chromosomal segregation machinery would enable researchers to target this machinery in order to prevent and treat the above disorders.
The Murray laboratory’s insight into the evolution and design of cellular networks could have implications far beyond budding yeast. Understanding the mechanics of cellular circuits sheds light on how cells respond to situations of stress and disease development. This could lead to novel therapeutics for chronic diseases, such as diabetes, neurodegenerative disorders, and cancer. Finally, the Murray lab’s work also offers the evolutionary perspective needed to interpret the large quantities of genomic data scientists are currently acquiring from a myriad of species, and this knowledge can be applied to human genetic research as well.
These images represent a yeast cell diving into 4 spores. In the image on the left, where chromosomal segregation is occurring normally, each of the four spores inherits one copy of chromosome IV, marked by GFP at the Lac operator. However, when chromosomes undergo nondisjunction, as in the image on the right, 2 spores end up with 2 chromatids and 2 spores end up with none. However, this effect can be suppressed with an artificial tether or crossovers occurring near the centromere. For more information, see Lacefield, et al., 2007. Nature Genetics. 39(10):1273-7.
Current Research Interests
- Determine how chromosomes mechanically attach to the spindle during mitosis and meiosis.
- Investigate how the spindle checkpoint operates to ensure that chromosomes are appropriately lined up before mitosis proceeds.
- Study how the cytoskeleton and other cellular components are utilized to form a single axis of polarization in mating cells.
- Identify how mutation rate, population size, and signaling pathways induce the evolution of new traits.
Tools and Assays
- Video microscopy
- Genetic manipulation
- Artificial tether
The Murray laboratory focuses on the precise mechanisms that enable a cell to divide its chromosomes evenly to daughter cells during mitosis and meiosis, using yeast (S. cerevisiae) as a model organism to study these processes. The group has examined mutants defective for the spindle checkpoint to study chromosomal segregation and orientation along the axis of polarity in a dividing cell. In addition to using genetic mutants, the lab has elegantly replicated some of their results biomechanically, by attaching an artificial tether to the chromosomes. More recently, the Murray lab has looked at interactions between the kinetochore of the chromosomes and the microtubule machinery of the cell’s cytoskeleton during segregation.
The Murray laboratory’s joint approach utilizing biology and physics has led to several pioneering publications in the field of cellular evolution. They have shown through theoretical and experimental observations the impact of multiple mutations on the rate of evolution in yeast. The laboratory has also designed superior approaches to calculating the mutation rate accurately, and has defined the effective mutation target size for a gene. The Murray group is particularly interested in how a module of genes and proteins controls mating in a population of yeast. To this end, they demonstrated that by inducing simple mutations in the yeast pheromone module, they could convert yeast mating behavior from a graded-response system to a switching system. Different mutations led to different molecular responses and cellular/organismal behaviors. It is possible that yeast cellular circuits evolve quickly to adapt for specific functions in the short-term, yet also re-engineer simply for more long-term adaptations. This finding has broader implications for cellular network dynamics.