An evolutionarily conserved mechanism that amplifies the effect of deleterious mutations in osteosarcoma.

Illustrating the molecular consequence of deleterious mutations is essential for bridging the gap between genotype and phenotype. In the cancer field, differential expression of the two alleles on heterozygous sites could directly reflect the effect of a mutation under certain trans environment. We retrieved transcriptomes of osteosarcoma and normal tissues in human and mouse. We defined tumor-specific heterozygous mutations with stringent criteria by considering sequencing depth and ancestral state. We calculated the relative expression of mutated alleles and normal alleles on the missense mutation sites in osteosarcoma. There is a conserved pattern that the mutated alleles have globally higher expression levels than the normal alleles in tumors. In the shared genes with missense mutations in both human and mouse, the relative expression of mutated alleles is highly correlated. Moreover, shared genes are functionally more important than unshared genes, and are enriched in oncogenes. The oncogenic role of mutations in oncogene KMT2A is experimentally verified. We systematically illustrate the deleterious effects of missense mutations by showing the over-expression of mutated alleles. We partially bridge the gap between genotype and phenotype by surmising that the over-expression of the mutated alleles might break the cellular equilibrium and lead to tumorigenesis.