Paralog buffering contributes to the variable essentiality of genes in cancer cell lines

What makes a gene essential for cellular survival? In model organisms, such as budding yeast, systematic gene deletion studies have revealed that paralog genes are less likely to be essential than singleton genes and that this can partially be attributed to the ability of paralogs to buffer each other's loss. However, the essentiality of a gene is not a fixed property and can vary significantly across different genetic backgrounds. It is unclear to what extent paralogs contribute to this variation, as most studies have analyzed genes identified as essential in a single genetic background. Here, using gene essentiality profiles of 558 genetically heterogeneous tumor cell lines, we analyze the contribution of paralogy to variable essentiality. We find that, compared to singleton genes, paralogs are less frequently essential and that this is more evident when considering genes with multiple paralogs or with highly sequence-similar paralogs. In addition, we find that paralogs derived from whole genome duplication exhibit more variable essentiality than those derived from small-scale duplications. We provide evidence that in 13–17% of cases the variable essentiality of paralogs can be attributed to buffering relationships between paralog pairs, as evidenced by synthetic lethality. Paralog pairs derived from whole genome duplication and pairs that function in protein complexes are significantly more likely to display such synthetic lethal relationships. Overall we find that many of the observations made using a single strain of budding yeast can be extended to understand patterns of essentiality in genetically heterogeneous cancer cell lines.
Author summary Somewhat surprisingly, the majority of human genes can be mutated or deleted in individual cell lines without killing the cells. This observation raises a number of questions—which genes can be lost and why? Here we address these questions by analyzing data on which genes are essential for the growth of over 500 cancer cell lines. In general we find that paralog genes are essential in fewer cell lines than genes that are not paralogs. Paralogs are genes that have been duplicated at some point in evolutionary history, resulting in our genome having two copies of the same gene—a paralog pair. These paralog pairs are a potential source of redundancy, similar to a car having a spare tire. If this is the case, one might expect that losing one gene from a paralog pair could be tolerated by cells, due to the existence of a 'backup gene', but losing both members would cause cells to die. By analyzing the cancer cell lines we estimate this to be the case for 13–17% of paralog pairs, and that this provides an explanation for why some genes are essential in some cell lines but not others.