Scientists discover how substitutions are made for injured genes

If there were no bench for second-string players on a football team, who would substitute for tired or injured team members? A team of Weizmann Institute scientists has found that, if the team were made up of genes, they might pull athletes who can play a little football in a pinch from nearby basketball or rugby teams. Their findings were published in the March issue of Nature Genetics.

Dr. Yitzhak (Tzachi) Pilpel and graduate students Ran Kafri and Arren Bar-Even, of the Institute’s Molecular Genetics Department, knew from previous studies that up to 80% of the genes in yeast, a common model for genetics research, have potential stand-ins in various spots around the genome. Though not identical to the original gene, they make a protein that is sufficiently similar to the one it produces to pass muster. Many scientists believed that both genetic substitutes and the main gene were expressed simultaneously so as to supply the organism with needed quantities of proteins. But Pilpel and his team showed that, in fact, when the original gene is up and running, the others are off playing at their own sports. Only when that gene is damaged or deleted, do the substitutes get called onto the “football field,” where they play as they can.

They reached this conclusion after analyzing data from some 40 studies of yeast cells by different research teams around the world. Using bioinformatics techniques (advanced data processing of biological information) to identify patterns and trends in the enormous flux of data supplied by these studies and by the sequencing of the yeast genome, they proposed a “football coach” mechanism that knows when to call up the substitute players.

This “coach” is a feedback mechanism based on the raw materials genes use to make proteins. When a gene is working at full capacity, it will use up most of the raw material available to it, leaving little in its original state. But, if it’s not making sufficient quantities of protein, or producing defective proteins that are missing bits, a relatively larger amount of the raw material will be left over. Raw material that is sitting around activates a special set of proteins called transcription factors, whose job is to turn on genes. The transcription factors then bind to, and activate the substitute genes.

Why have genes to make proteins similar enough to substitute for each other, but dissimilar enough to do it imperfectly? Pilpel’s group proposed that the small variations between exchangeable genes, such as differences in the conditions that cause them to be activated, impart to each a unique function. These differences in function make them sufficiently vital to be preserved by evolution, yet allow them, when necessary, to step in for a gene on a different team as a substitute player.