New & Noteworthy
January 20, 2012
As scientists peer ever more deeply into a cell, the picture of how things work becomes more and more complicated. This was true when scientists took a hard look at transcription and gene regulation and found lots of little RNAs scurrying around the cell, regulating genes. And it now appears to be true for what is being translated and how translation is regulated.
In a new study, Brar and coworkers used ribosome profiling to explore what happens in yeast cells during meiosis at the level of translation. What they found was that a whole lot more was being translated (or at the very least gumming up the translation machinery) than anyone expected. They also found that translation is as finely regulated as is transcription.
And this doesn’t just happen in yeast. The same group has also generated similar findings in mice embryos as well. Results with human cells should be right around the corner…
In ribosome profiling, scientists determine what RNAs are contained in a ribosome at a given time point. The basic idea is that they isolate ribosomes, treat them with nucleases and then harvest the associated 30-35 nucleotide long mRNAs. They then sequence all of the isolated RNAs and identify where they came from.
Like lots of biology these days, this technique has only become possible with the advent of cheap, robust sequencing. In fact, the size of these sequences is ideal for modern sequencing techniques.
Researchers in the Weissman lab are finding all sorts of interesting things using this new tool. For example, in meiosis they were better able to determine which proteins are involved at various stages of meiosis, to see how involved “untranslated” mRNA leaders are in translation, and to identify smaller, previously ignored transcripts associated with ribosomes. In this post we’ll just focus on the last point but encourage the reader to learn about the study’s other findings here.
Of Shorter ORFs
Ribosome profiling has revealed that a lot more is being translated in yeast than the standard set of genes identified in the Saccharomyces Genome Database (SGD). For example, Brar and coworkers found that the mRNA of many open reading frames (ORFs) shorter than the usual 250 or so base pairs were associated with the ribosomes. Shorter ORFs like these aren’t routinely thought of as genes and so have not been extensively studied.
However, given how many of these ORFs were associated with ribosomes, scientists probably should start paying more attention now. Even before meiosis, 5% of the ribosomes tested in yeast contained RNAs from these shorter ORFs. Once meiosis kicked in, the number went up to an astonishing 30%.
Since scientists have only just started to focus on them, it isn’t surprising they don’t know how many of these smaller ORFs are translated into smaller peptides. Or what any of these peptides that do get translated might be doing in a cell.
In a recent study, Kondo and coworkers have shown that one of these ORFs is translated into a peptide and proposed it affects how the transcription regulator Shavenbaby works in Drosophila. Work similar to this will need to get underway before we have a good handle on what exactly is going on with these shorter ORFs.
Whatever they turn out to do, these small ORFs will probably change what we consider to be a gene. Again. The cell just keeps getting more and more complicated!
Lengthy but informative lecture on ribosome profiling.
January 14, 2012
Thank you to those who have shared your thoughts and comments about the new site. I am very proud of our new look and all the features it incorporates. For the past year we worked with web design professionals and conducted studies to determine an optimal design for the SGD pages. Since the inception of SGD, the standards for computer-human interfaces and website usability have advanced and we realize that we must embrace these changes in order to reach out to all communities that depend on SGD. The new pages address many previously identified issues and the new design allows the 21,000 weekly users of SGD to more effectively find the information they require. In addition to providing a modern look, the new design greatly decreases the learning curve for new users.
I am delighted that our Search has been enhanced to provide auto-suggest and auto-complete features. The new Search interface gives access to more types of information and facilitates the discovery of huge amounts of information integrated at SGD. Easier access to all the data is also facilitated by recent tool enhancements and data additions. Over the past year several hundred new datasets have been added to the Genomic Browser and we will continue to add new data at about the same rate. This year will also see the addition of new types of data, in particular strain genomic sequence.
I appreciate that change can be difficult. I hope that adjusting to the new site will not be too onerous and, in addition to the data which you are accustomed to getting from the site, you will discover new datatypes useful to you that you may not have realized were contained within SGD. I thank you again for providing me feedback on the new and more powerful SGD and ask that you please continue to send questions and comments to the SGD HelpDesk.
Wishing you all the best in 2012,
J. Michael Cherry, Ph.D.
Associate Professor (Research)
Department of Genetics
Stanford, CA 94305-5120
January 11, 2012
Welcome to SGD’s new look! All of the information and functionality you are familiar with at SGD is still available, but has been repackaged in order to provide better access to data and to provide additional tools and services. One exciting new feature is the SGD blog where we will highlight and discuss research articles and topics. To fully access the updated SGD site, you may need to clear the cache on your browser. We encourage you to explore the new site and send us feedback.
January 4, 2012
Even though it doesn’t have a brain, yeast is teaching us a lot about Alzheimer’s. Researchers are using this simple eukaryote to figure out what previously identified Alzheimer’s-related genes may be doing in humans as well as to identify new genes that might be involved in this terrible disease. Studies like this may even one day help scientists find better treatments.
Alzheimer’s is a form of dementia that hits about 50% of people over 85. The video below has a great summary of the how the disease progresses:
As the video states, plaques and tangles are linked to the memory loss that is associated with Alzheimer’s. Scientists know that the plaques are amyloids of misfolded AΒ peptides and that AΒ peptides that come from the amyloid precursor protein (APP). What they don’t know is how AΒ peptides cause their damage and if it can be stopped. And so far, genome wide association studies (GWAS) in humans have not shed much light on this problem either.
That isn’t to say that GWAS have been a waste of time. They haven’t. These studies have identified a number of alleles of a few genes that impact a person’s risk for ending up with Alzheimer’s. They just haven’t been able to link the build up of plaques with the identified genes. This is where yeast comes in.
Treusch and coworkers created a strain of yeast in which the AΒ peptide was sent to the endoplasmic reticulum. This mimics what happens to the peptide in the cells of Alzheimer’s patients. These yeast grew more slowly and developed protein complexes reminiscent of plaques.
They then added each of 5532 yeast open reading frames to this strain to identify genes that specifically affected its growth rate. Of the 40 different yeast genes they found, two (YAP1802 and INP52) were yeast homologs of human genes (PICALM and SYNJ1) that had already been identified to be important in Alzheimer’s risks. These results validated the screen and gave the researchers the confidence to dive deeper into their results.
The researchers decided to focus on the 12 genes that had very close human homologs. Of these 12 genes, 10 dealt with endocytosis and the cytoskeleton and at least three had been implicated in previous genome wide association studies in humans. Further work by these authors validated four of these genes by showing that they had similar effects on AΒ cell toxicity in the worm model C. elegans.
In one of the most interesting parts of the study, the researchers used the yeast strain to show why the GWAS-identified gene PICALM affects Alzheimer’s patients. Rather than modifying APP trafficking as had been previously proposed, their results support a model where PICALM lessens the impact of misfolded AΒ plaques on the cell.
This study is another example of the awesome power of yeast genetics. Who would have thought that a brainless yeast could teach us so much about Alzheimer’s?