Paralog dispensability shapes homozygous deletion patterns in tumor genomes

• Published in: Molecular systems biology 2023-12, Vol.19 (12), p.e11987-n/a
• Main Authors: De Kegel, Barbara, Ryan, Colm J
• Format: Article
• Language: English
• Subjects: Cancer; Cell Line; Cloning; Consortia; Copy number; copy number variation; dispensability; DNA Copy Number Variations - genetics; Evolutionary genetics; Gene Deletion; Genes; Genomes; Genomic instability; Homozygote; Humans; Mutation; Neoplasms - genetics; paralogs; Proteins; Robustness; Sequence Deletion; Tumor cell lines; Tumor cells; tumor genome evolution; Tumors
• ISSN: 1744-4292; 1744-4292
• DOI: 10.15252/msb.202311987

Genomic instability is a hallmark of cancer, resulting in tumor genomes having large numbers of genetic aberrations, including homozygous deletions of protein coding genes. That tumor cells remain viable in the presence of such gene loss suggests high robustness to genetic perturbation. In model organisms and cancer cell lines, paralogs have been shown to contribute substantially to genetic robustness—they are generally more dispensable for growth than singletons. Here, by analyzing copy number profiles of > 10,000 tumors, we test the hypothesis that the increased dispensability of paralogs shapes tumor genome evolution. We find that genes with paralogs are more likely to be homozygously deleted and that this cannot be explained by other factors known to influence copy number variation. Furthermore, features that influence paralog dispensability in cancer cell lines correlate with paralog deletion frequency in tumors. Finally, paralogs that are broadly essential in cancer cell lines are less frequently deleted in tumors than non‐essential paralogs. Overall, our results suggest that homozygous deletions of paralogs are more frequently observed in tumor genomes because paralogs are more dispensable. Synopsis An analysis of > 10,000 tumor genomes reveals that homozygous deletions of paralog genes are observed more frequently than those of singleton genes. This can be attributed to paralogs being, in general, more dispensable. Analysis of > 10,000 tumor genomes reveals that homozygous deletions of paralogs are observed more frequently than those of singleton genes. Even after accounting for potentially confounding factors that affect copy number variation in tumors, paralogs are more frequently deleted than singletons. Features associated with increased dispensability of paralogs in tumor cell lines are also associated with paralog deletion frequency in tumor genomes. These observations are consistent with a model where paralog deletions are more frequently observed in tumor genomes because paralog genes are, on average, more dispensable. An analysis of > 10,000 tumor genomes reveals that homozygous deletions of paralog genes are observed more frequently than those of singleton genes. This can be attributed to paralogs being, in general, more dispensable.