New & Noteworthy
Crowdsourcing Genetic Disease
February 28, 2013
Remember when sequencing the human genome was going to help us better understand and treat complex diseases like Type 2 diabetes or Parkinson’s? Well, ten years later, we’re still waiting.
Looks like we need more people in our GWAS if we are ever going to figure out the genetics behind complex diseases and traits.
Sure we’ve made some progress. Using genome wide association studies (GWAS), scientists have uncovered markers here and there that explain a bit about how a genetic disease is inherited. But despite a seemingly never-ending stream of these assays, scientists simply can’t explain all of the genetics behind most of these diseases.
So now scientists need to try to explain this missing heritability. If they can find out why they aren’t getting the answers they need from GWAS, then maybe they can restructure these assays to give better results.
As usual, when things get dicey genetically, scientists turn to the yeast Saccharomyces cerevisiae to help sort things out. And in a new study out in Nature, Bloom and coworkers have done just that.
In this study, they mated a laboratory and a wine strain of yeast to get 1,008 test subjects from their progeny. They extensively genotyped each of these 1008 and came up with a colony size assay that allowed them to determine how well each strain grew under various conditions. They settled on 46 different traits to study genetically.
What they found was that none of these traits was determined by a single gene. In fact, they found that each of the 46 different traits had between 5 and 29 different loci associated with it, with a median of 12 loci. This tells us that at least in yeast, many genetic loci each contribute a bit to the final phenotype. And if this is true in people, it could be a major factor behind the missing heritability in GWAS.
If a trait is dependent on many genetic loci that each have a small effect, then researchers need large populations in order to tease them out. In fact, when Bloom and coworkers restricted their population to 100 strains, they could only detect a subset of the genetic loci. For example, the number of loci went from 16 to 2 when they looked at growth in E6 berbamine.
So it may be that scientists are missing loci in GWAS because there are simply too few participants in their assays. If true, then the obvious answer is to increase the size of the populations being studied. Thank goodness DNA technologies get cheaper every year!
Of course as the authors themselves remind us, we do need to keep in mind that humans are a bit more complex than yeast. There may be other reasons that we aren’t turning up the genetic loci involved in various traits. It may be that we can’t as accurately measure the phenotypes in humans or that human traits are more complicated than the yeast ones studied. Another possibility is that in humans, there are more rare alleles that can contribute to a given trait. These would be very hard to find in any population studies like GWAS.
Still, this study at the very least tells us that larger populations will undoubtedly uncover more loci involved in human disease. Thank you again yeast.
Yeast with Dementia
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?
Simple explanation of the genetics of Alzheimer’s
More information about Alzheimer’s
Tags: alzheimer's > amyloid > APP > model organism > PICALM > plaque > yeast
