Systematic analysis of complex genetic (GxG, GxGxG) interactions

Today, innumerable genomes (many human ethni groups, other mammals, reptiles, birds, fish, and lower organisms such as worm, fly, sea squirt, sponge, yeast and bacteria) have been sequenced (by means of whole-genome sequencing; WGS), and the precise number of “genes” in the genome of each species has been established. One question now being asked is: “How many genes, and which ones, does an organism absolutely need –– at a minimum –– to sustain growth?” The answer may seem quite straightforward: Just remove all “non-essential genes”, and the organism should be able to continue to survive and grow with the remaining genetic complement. In the yeast Saccharomyces cerevisiae, ~1000 of the ~6000 (~17%) protein-coding genes have been shown to be essential for viability. Theoretically, therefore, one might think that one could remove the other ~5000 non-essential genes, and still have a growing yeast. But that is not what happens.

The reason this does not work –– is that genes interact with each other to drive different traits, including viability and growth; this phenomenon is called epistasis, or gene-gene (GxG) interactions. Authors [see attached article] have now gone one step BEYOND GxG interactions to provide the first systematic analysis of trigenic (GxGxG) interactions in yeast in which three genes are jointly deleted in individual yeast strains in order to ascertain the importance of multi-gene interactions for growth. This study shows that higher-order genetic interactions are common –– which has implications for the interpretation of human gene variants that may interact to affect clinical health and disease.

When two genes were jointly ablated (i.e. GxG interactions between PAIRS of deleted non-essential genes), 10,000 “synthetic lethal interactions” in yeast (synthetic lethal interactions occur when deletion of each individual gene maintains viability and growth, whereas deletion of both genes combined kills the cells). These 10,000 synthetic lethal interactions among non-essential genes involve >3000 genes –– thus revealing their “hidden essentiality.”

Synthetic lethal interactions are only one type of genetic interaction. Generally, GxG interactions are defined when a double mutant confers a phenotype (trait) that is different than expected, based on the phenotype from mutants of each individual gene. Such interactions come in two basic flavors: positive and negative –– where the phenotype of strains harboring positively-interacting gene-pairs is less severe than expected, whereas the phenotype of strains containing negatively-interacting gene-pairs is more severe, with synthetic lethality being the most extreme.

Authors [in present study] constructed ~200,000 yeast triple-mutants and scored negative trigenic (GxGxG) interactions. Trigenic interactions often occurred among functionally-related genes, and essential genes were hubs on the trigenic network. Authors estimate that the global trigenic interaction network is ~100 times as large as the global digenic network. This study therefore highlights the potential for extremely complex genetic interactions to affect the biology of inheritance, including the genotype-to-phenotype relationships. These data further underscore the difficulties with genetic risk prediction (risk of complex diseases, risk of toxicity or cancer caused by an environmental toxicant or mixture of toxicants, risk of drug toxicity, and ability to predict drug efficacy in each holistic individual.

Science 20 Apr 2o18; 360: 283 [rest of pages on internet only] PLUS editorial pp 269–270

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