Understanding the information in the human genome presents many challenges. While researchers have been able to sequence it, the same sequences or genotype doesn’t always result in the same biological consequences, or phenotype, in different people. Researchers want to know more about how the genetic background - the normal parts of the genome - modulate the impact of other parts of the genome. New work by scientists at the University of Toronto's Donnelly Centre for Cellular and Biomolecular Research has started to tease out the impact of differences in genetic background. The research has been reported in the Proceedings of the National Academy of Sciences (PNAS).
"Genetic background confounds our ability to interpret the information stored in an individual genome," said Professor Brenda Andrews. It also confounds the prognosis of many diseases. The same mutation in the CFTR gene can cause cystic fibrosis in two people. But one of those people might have a disorder with relatively mild symptoms, while the other has a severe disease that disrupts their quality of life significantly.
While we all carry the same genes, any two people might have about three million differences in their genomic sequences. Scientists have looked to simpler organisms with smaller genomes, like yeast, to try to learn more about how the genetic background impacts phenotype.
"Genetic background has the power to make the original phenotype less or more severe," explained study leader Jing Hou, postdoctoral fellow. "This is true for human diseases, and it is also true in yeast which is a very good model to study this."
In this work, Hou compared the effect of gene mutations in two yeast strains, SC and Sigma, that differ genetically by only 0.2 percent, mimicking what might be seen in humans. Previous work by the Boone and Andrews labs and collaborators showed that mutations in 57 genes, or about one percent of the yeast genome, have a different impact in SC versus Sigma. The genetic errors result in death for one or the other, but not both strains. These 57 genes, are 'conditionally lethal' and depend on other genes to modify their effect.
Hou identified the modifier genes by mating the SC and Sigma strains; they could mask the damage and rescue the hybrid yeast progeny.
Hou determined that most conditionally lethal genes can be modified by multiple genes, making the relationships in that network very complex and more challenging to decipher. Some genes only have a single modifier, which is certainly an easier interaction to study. For example, the CYS3 and CYS4 genes help make an essential amino acid, cysteine. In the Sigma strain, CYS3 and CYS4 are conditional-lethal genes, so they die when the gene is gone. The SC strain is ok without those genes though, because the OPT1 gene compensates for their loss. The OPT1 gene is mutated in the Sigma strain; the mutated gene cannot come to the aid of the cell when the CYS genes are lost.
This type of work may one day be possible for understanding interactions in human genes.
"Just based on sequence and the knowledge of this pathway we could predict gene essentiality across the whole species," said Hou. "I think we will be able to predict human risk of disease if we have good enough knowledge of how genes work together in pathways." The studies of human gene interactions are only just beginning, however.
Brenda Andrews is featured in the video above, discussing how we can learn more about connecting phenotype to genotype.