Mysteries of the fission yeast genome bubble to the surface
Fission yeast is an essential model for studying how cells grow and divide and for untangling the mysteries of chromosomes, but, in terms of efforts to read out its DNA, it has lagged behind budding yeast, a distant cousin on the fungal tree of life. Budding yeast is more familiar to most people – it is used in making beer and baking bread – and has been studied much more extensively, but fission yeast is biologically more complex and more similar to animals, including humans, in many important cellular ways.
In a Science paper published online on April 21, a team of researchers led by scientists at University of Massachusetts Medical School (UMMS) and the Broad Institute give this model organism more evolutionary context and offer new, genomic tools to the community of scientists who use fission yeast to better understand cellular biology. In the process of comparing the four known species of fission yeast, the researchers made some unusual and intriguing discoveries about the fission yeasts’ genetic makeup and the activity of their genes.
“When we look at the genome of any organism, we find new mysteries to plumb,” said Chad Nusbaum, one of the paper’s senior authors and co-director of the Broad’s Genome Sequencing and Analysis Program. “This has been such a rewarding project. There’s so much there.”
Nusbaum worked closely with Nicholas Rhind, a cell biologist at UMMS and Aviv Regev, a core member at the Broad Institute. Each brought expertise in genome sequencing, fission yeast biology, and functional genomics, respectively, to bear on the project. “We all had very nicely balanced, complementary interests and abilities,” said Nusbaum. “It was a much more exciting outcome because we did it all together.”
One of the interesting discoveries that emerged from the study centers on centromeres. When cells divide, one of the essential players that can determine a successful or failed division is the centromere. Sitting at the intersection of the two arms of a chromosome, the centromere acts like a fastener, holding two copies of the chromosome together until it is time for each to be pulled apart into the newly forming cells. A faulty centromere, like a broken clasp, means that the copies cannot pull apart correctly and cells may receive the wrong number of chromosomes. Centromeres tend to be littered with transposons – mobile, repetitive stretches of DNA that can “jump” around the genome. Transposons are found in a variety of organisms and are a normal part of the fabric of a chromosome.
The researchers discovered that the species of fission yeast that they studied had very odd centromeres; one species had centromeres made up almost entirely of transposons, while two other species had centromeres devoid of these mobile elements. These latter species still have repeated stretches, but these stretches appear to be stuck in place.
“If you squint, at arms length, they sort of look the same,” Rhind said of the repeated stretches. “But when you look up close, they are not transposons. They don’t move. They don’t transpose.”
Centromeres work the same way in the different fission yeast species, even though their composition and what regulates them is entirely different. “It’s as though you have a car and you put a completely different engine in it and it still works just fine,” said Nusbaum. Just as swapping out a gas engine for a diesel engine requires a different fuel, spark plugs, and other changes, these very different centromeres require different kinds of controls. “There are implications of this switch so many things have to change.”
In addition to sequencing the organisms’ genomes, the researchers also looked at gene expression under different conditions and developed new software tools to generate this kind of data. Regev, an assistant professor at MIT, an early career scientist at the Howard Hughes Medical Institute, and one of senior authors on the paper, said that analyzing not only what the sequence is but also how genetic components function gives the paper an extra dimension.
“We’ve made an effort to go after functional data,” said Regev. “We’ve taken the extra step to do functional analysis and show how these pieces work in the different genomes to give a really in-depth view of things like the centromere.”
Another intriguing finding from the study has to do with the way that fission yeast cells reproduce. These cells can grow and divide continuously or they can mate, sharing DNA with another yeast cell through a process known as meiosis. Researchers have studied the meiotic program for years and have observed that certain genes are ratcheted up during this process. Rhind, Regev, Nusbaum, and their colleagues noticed something quite unusual about the way that some of these meiotic genes were being transcribed or copied from DNA. DNA has two strands and usually RNA is copied from the “sense” strand, but in this case a small number of genes, many of which are involved in meiosis, were copied from the opposite strand (called the “antisense” strand). The researchers hypothesized that this may be a mechanism that allows fission yeast to switch from one way of reproducing to another.
“It looks like it’s a belt and suspenders approach,” said Rhind, the paper’s first author. “Not only do you turn off the sense transcript, you also antisense transcribe [the gene] in a way that if any sense transcripts are made, somehow the antisense transcription further represses the expression of those genes.”
The researchers do not yet understand the mechanism at work here, but hope that these findings will whet other scientists’ investigative appetites.
“That was really the motivation behind this project: to produce datasets with the assumption that there would be new and interesting things to find,” said Rhind, who studies DNA replication in fission yeast. “It was gratifying to find so many of these things that we hope will be followed up by people in the field.”