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.
Highlights
Human chromosome termini are unusual in their sequence content and frequency of structural rearrangement
We show that MGC52000 encodes a new member of the Wiskott-Aldrich Syndrome Protein (WASP) family and is conserved from Entamoeba to human
We report the discovery of genes defining a previously unrecognized third subclass of the Wiskott-Aldrich Syndrome protein (WASP) family within human subtelomeres
Summary
Human chromosome termini are unusual in their sequence content and frequency of structural rearrangement. Their ends are capped with telomeres that protect chromosomes against degradation and fusion [1] and that can exert a silencing effect on nearby genes [2,3]. Patchworks of large DNA segments duplicated on various subsets of chromosomes lie just proximal of telomeres [4]. These subtelomeric regions comprise less than 0.1% of the human genome, but account for over 40% of interchromosomal duplicates in the genome assembly that formed since human and chimpanzee diverged. No essential gene has yet been identified within human subtelomeres
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