Comparative Genomics Reveals Recurrent Loss of Autophagy-Related 9B (ATG9B) in Amniotes

Background/Objectives: Autophagy is an evolutionarily conserved intracellular degradation mechanism that is regulated by a set of autophagy-related (ATG) proteins. The only transmembrane protein among ATGs is the lipid scramblase ATG9, which exists in the form of two paralogs, ATG9A and ATG9B, in humans and other vertebrates. Methods: Here, we analyzed human and murine skin transcriptome and proteome datasets for the expression of ATG9 paralogs and performed comparative genomics to determine their conservation during the evolution of amniotes (mammals and sauropsids). Results: The expression of ATG9B, but not of ATG9A, is enriched in differentiated epidermal keratinocytes and in skin appendages of humans and mice. In contrast to the conservation of ATG9A in all major clades of amniotes, ATG9B has been lost in at least three phylogenetic lineages. Cetaceans, which have unique skin adaptations to aquatic life, harbor mutations that disrupt the open reading frame of ATG9B. Many or all species of turtles (Testudines) and crocodilians (Crocodylia) have entirely lost the ATG9B gene. Conclusions: ATG9B has undergone independent pseudogenization or gene loss in different subgroups of amniotes. In mammalian species that have retained the gene, its expression pattern indicates functions of ATG9B in the skin and skin appendages.