April 09, 2012
Genomic scientists are quickly being overwhelmed by all of the data they are generating. As trillions of A’s, T’s, C’s and G’s come pouring out of sequencers all over the world, how is anyone going to make sense of it all?
One idea is to use yeast to quickly figure out what effect certain differences have on a gene’s function. Now this won’t be that useful for differences outside of genes or in genes that aren’t shared by yeast and humans. But that still leaves an awful lot of SNPs that we might be able to better understand using the awesome power of yeast genetics.
In the most recent issue of GENETICS, Mayfield and coworkers use yeast to study a large number of variants in the human cystathione-beta synthase (CBS) gene. They chose this gene because it is involved in the metabolic disease homocystinuria, different variants respond to treatment in unpredictable ways, and it can substitute for the yeast homolog, CYS4.
The hope was that they would be able to group CBS variants based on their phenotype in yeast and that this would let them predict which treatments would work for novel variants. They were definitely able to group variants based on phenotype. Time will only tell whether they can use this to better treat patients who come into the clinic with novel variants of the gene.
They looked at 84 known alleles of CBS that affected an amino acid with a single base pair change (81 were from homocystinuria patients). They grouped these alleles based on growth phenotypes in yeast under varying conditions. For example, they determined how well each grew in the absence of glutathione. Only those alleles that were still functional would support growth. They also varied the amount of glutathione, looked at the effect of heme and vitamin B6, studied metabolite profiles with mass spectroscopy and so on.
From this they were able to group many of the alleles in clinically meaningful ways. This means that when a novel allele comes up in a patient, they can screen it in this yeast assay to see if it falls within a known group. At least 38 never before seen missense mutations have been found in the CBS gene since 2010 and undoubtedly new ones will keep appearing as more DNA is sequenced.
The study also revealed alleles that were more difficult to interpret in this assay. For example, some alleles known to cause disease did not affect yeast growth. This might mean that their particular mutation needs something human and/or patient specific to manifest itself or that the enzyme function is fine but something else is wrong.
This study provided a powerful proof of principle. The next step will be to see how well it works in practice and if any patients can benefit.
Benjamin deals with his homocystinuria
by D. Barry Starr, Ph.D., Director of Outreach Activities, Stanford Genetics