Early Origin and Evolution of the Angelman Syndrome Ubiquitin Ligase GeneUbe3a.
The humanUbe3agene encodes an E3 ubiquitin ligase and exhibits brain-specific genomic imprinting. Genetic abnormalities that affect the maternal copy of this gene cause the neurodevelopmental disorder Angelman syndrome (AS), which is characterized by severe mental retardation, speech impairment, seizure, ataxia and some unique behavioral phenotypes. In this review article, I highlight the evolution of theUbe3agene and its imprinting to provide evolutionary insights into AS. Recent comparative genomic studies have revealed thatUbe3ais most phylogenetically similar toHECTD2among the human HECT (homologous to the E6AP carboxyl terminus) family of E3 ubiquitin ligases, and its distant evolutionary origin can be traced to common ancestors of fungi and animals. Moreover, a gene more similar toUbe3athanHECTD2is found in a range of eukaryotes from amoebozoans to basal metazoans, but is lost in later lineages. Unlike in mice and humans,Ube3aexpression is biallelic in birds, monotremes, marsupials and insects. The imprinting domain that governs maternal expression ofUbe3awas formed from non-imprinted elements following multiple chromosomal rearrangements after diversification of marsupials and placental mammals. Hence, the evolutionary origins ofUbe3adate from long before the emergence of the nervous system, although its imprinted expression was acquired relatively recently. These observations suggest that exogenous expression and functional analyses of ancientUbe3aorthologs in mammalian neurons will facilitate the evolutionary understanding of AS.
Graduate School of Science and Engineering and Brain and Body System Science Institute, Saitama UniversitySaitama, Japan; RIKEN Brain Science InstituteWako, Japan.
Masaaki
M
Sato
HECT domain; autism; brain evolution; developmental disorder; genomic imprinting; intellectual disability; synapse