Absence of Pathogenicity in Non-Human Primates of Mutations Related to Retinoblastoma in Humans

The tumor suppressor, Human Retinoblastoma Susceptibility Gene (RB1) plays a prominent role in normal development, gene transcription, DNA replication, repair, and mitosis, and its complete biallelic dysfunction in retinoblasts is the main cause of retinoblastoma in humans. Comparisons between the reference, human RB1 coding region with its counterparts in 19 non-human primates showed that several RB1 alterations accompanying retinoblastoma in the human were present in several non-human primates without apparent pathological effects. Comparative analyses of molecular data were most useful for tracing the evolution of RB1, identifying the polarity of mutational events, the physico-chemical effects conferred by amino acid substitutions, and the number of codons under selection. These historic reconstructions indicated that several RB1 mutations found in retinoblastoma in the human were presumably atavistic, accounting for evolutionary regressions. Moreover, some same-sense RB1 mutations, despite specifying for the same amino acids, were probably ancient adaptations that took place in our evolutionary lineage.