Human Subtelomeric WASH Genes Encode a New Subclass of the WASP Family

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Abstract
Subtelomeres are duplication-rich, structurally variable regions of the human genome situated just proximal of telomeres. We report here that the most terminally located human subtelomeric genes encode a previously unrecognized third subclass of the Wiskott-Aldrich Syndrome Protein family, whose known members reorganize the actin cytoskeleton in response to extracellular stimuli. This new subclass, which we call WASH, is evolutionarily conserved in species as diverged as Entamoeba. We demonstrate that WASH is essential in Drosophila. WASH is widely expressed in human tissues, and human WASH protein colocalizes with actin in filopodia and lamellipodia. The VCA domain of human WASH promotes actin polymerization by the Arp2/3 complex in vitro. WASH duplicated to multiple chromosomal ends during primate evolution, with highest copy number reached in humans, whose WASH repertoires vary. Thus, human subtelomeres are not genetic junkyards, and WASH's location in these dynamic regions could have advantageous as well as pathologic consequences. Human subtelomeres are rearrangement-prone regions near chromosome ends. They are concentrations of large, recent interchromosomal duplications. Over half of subtelomeric sequences changed copy number or location since humans and chimpanzee diverged, and subtelomeric content varies greatly among humans. Despite this dynamic activity, subtelomeres contain genes. We report the discovery of genes defining a previously unrecognized third subclass of the Wiskott-Aldrich Syndrome protein (WASP) family within human subtelomeres. The known WASP family members reorganize actin structures in cells in response to various signals, thereby causing cells to change shape and/or move. Representatives of this newly identified subclass, called WASH, exist in many other species, even in Entamoeba and slime mold. Like other WASP family members, WASH colocalizes with actin at the cell periphery and promotes actin polymerization in vitro. Flies lacking WASH die before becoming adults, demonstrating that WASH is critical for survival, and its function is distinct from that of the two other WASP subclasses, Wasp and Scar. Identification of the WASH subclass opens the way for future elucidation of WASH's role in the life cycles of diverse organisms, the implications of human variation in WASH copy number, and the consequences of WASH's location in dynamic telomere-adjacent regions.