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

Linardopoulou, Elena V.; Parghi, Sean S; Friedman, Cynthia; Osborn, Gregory E.; Parkhurst, Susan M.; Trask, Barbara J.

doi:10.1371/journal.pgen.0030237

Cited by 187 publications

(175 citation statements)

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“…One possibility may be that this protein family, similar to other studied proteins corresponding to core duplicons (e.g., TBC1D3), plays a role in regulating cell signaling, growth, and proliferation during development (Wainszelbaum et al 2008;Stahl and Wainszelbaum 2009). It is also intriguing that our cell transfection studies suggest that LRRC37 may play a role in the formation of filipodia protrusions similar to what has been reported for other gene families that have expanded in the human lineage (Linardopoulou et al 2007;Guerrier et al 2009). A critical step forward will be accurately assessing genetic variation, including copy number changes of these and other duplicate genes with respect to human phenotypes (Sudmant et al 2010;Alkan et al 2011a).…”

Section: Resultssupporting

confidence: 79%

Evolutionary dynamism of the primate LRRC37 gene family

et al. 2012

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Core duplicons in the human genome represent ancestral duplication modules shared by the majority of intrachromosomal duplication blocks within a given chromosome. These cores are associated with the emergence of novel gene families in the hominoid lineage, but their genomic organization and gene characterization among other primates are largely unknown. Here, we investigate the genomic organization and expression of the core duplicon on chromosome 17 that led to the expansion of LRRC37 during primate evolution. A comparison of the LRRC37 gene family organization in human, orangutan, macaque, marmoset, and lemur genomes shows the presence of both orthologous and species-specific gene copies in all primate lineages. Expression profiling in mouse, macaque, and human tissues reveals that the ancestral expression of LRRC37 was restricted to the testis. In the hominid lineage, the pattern of LRRC37 became increasingly ubiquitous, with significantly higher levels of expression in the cerebellum and thymus, and showed a remarkable diversity of alternative splice forms. Transfection studies in HeLa cells indicate that the human FLAG-tagged recombinant LRRC37 protein is secreted after cleavage of a transmembrane precursor and its overexpression can induce filipodia formation.

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Section: Resultssupporting

confidence: 79%

Evolutionary dynamism of the primate LRRC37 gene family

et al. 2012

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“…1B). On human 15qter, genes L-T are supplanted by WASH3P, a member of a recently identified family of subtelomeric genes (Linardopoulou et al 2007). Complete and partial forms of WASH are duplicated at multiple chromosome ends in primates; the intact form spans blocks 1 and 2, and the partial form includes only block 1 (Fig.…”

Section: Structural Changes In 15q Subsequent To the Fission Eventmentioning

confidence: 99%

“…Complete and partial forms of WASH are duplicated at multiple chromosome ends in primates; the intact form spans blocks 1 and 2, and the partial form includes only block 1 (Fig. 2) (Linardopoulou et al 2007). WASH sequence is not detected by FISH at the 15q subtelomere in gorilla, chimpanzee, or orangutan (Fig 2; Supplemental Table 2) (Linardopoulou et al 2007), suggesting that this gene was appended to 15qter in the human lineage.…”

Section: Structural Changes In 15q Subsequent To the Fission Eventmentioning

confidence: 99%

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Comparative sequence analysis of primate subtelomeres originating from a chromosome fission event

Rudd

Endicott²,

Friedman³

et al. 2008

Genome Res.

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Subtelomeres are concentrations of interchromosomal segmental duplications capped by telomeric repeats at the ends of chromosomes. The nature of the segments shared by different sets of human subtelomeres reflects their high rate of recent interchromosomal exchange. Here, we characterize the rearrangements incurred by the 15q subtelomere after it arose from a chromosome fission event in the common ancestor of great apes. We used FISH, sequencing of genomic clones, and PCR to map the breakpoint of this fission and track the fate of flanking sequence in human, chimpanzee, gorilla, orangutan, and macaque genomes. The ancestral locus, a cluster of olfactory receptor (OR) genes, lies internally on macaque chromosome 7. Sequence originating from this fission site is split between the terminus of 15q and the pericentromere of 14q in the great apes. Numerous structural rearrangements, including interstitial deletions and transfers of material to or from other subtelomeres, occurred subsequent to the fission, such that each species has a unique 15q structure and unique collection of ORs derived from the fission locus. The most striking rearrangement involved transfer of at least 200 kb from the fission-site region to the end of chromosome 4q, where much still resides in chimpanzee and gorilla, but not in human. This gross structural difference places the subtelomeric defect underlying facioscapulohumeral muscular dystrophy (FSHD) much closer to the telomere in human 4q than in the hybrid 4q-15q subtelomere of chimpanzee.[Supplemental material is available online at www.genome.org. The sequence data from this study have been submitted to GenBank under accession nos. AC188481, AC183330, AC150715, AC149242, AC148620, AC148535, AC173434, AC186245, AC205763, AC150448, AC183669, AC197422.]Subtelomeres are composed of interchromosomally duplicated sequences situated near the ends of chromosomes just proximal of telomeric repeats (Mefford and Trask 2002). Roughly half of the subtelomeric sequence in the human genome has moved or changed copy number since human and chimpanzee diverged (Linardopoulou et al. 2005). Due to this recent change, most subtelomeric duplications show variation in chromosomal location and copy number in the human population. Assays of the content of subtelomeres in other primates by fluorescence in situ hybridization (FISH) have revealed significant differences among species (Kingsley et al. 1997;Trask et al. 1998;Martin et al. 2002;van Geel et al. 2002b;Linardopoulou et al. 2005). However, no study has yet traced the evolution of a given subtelomere in primates by comparative analyses at the sequence level.The evolution of subtelomeres is "reticulate" (Jackson et al. 2005;Huson and Bryant 2006). Recurrent shuffling of material among ends makes it difficult to distinguish structures that are identical by descent from the shared presence (or absence) of particular sequences. Gene conversion-like transfers between duplicated segments can obfuscate the timing of the original duplication. In order to reconstru...

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“…Recently, another highly conserved WASP family member, WASH (Wiskott-Aldrich syndrome protein and SCAR homolog) was identified (13). WASH exists in a multiprotein complex termed the SHRC (WASH regulatory complex), which is comprised of FAM21, SWIP, strumpellin, and CCDC53 (14)(15)(16).…”

mentioning

confidence: 99%

WASH Knockout T Cells Demonstrate Defective Receptor Trafficking, Proliferation, and Effector Function

Piotrowski

Gomez

Schoon

et al. 2013

Molecular and Cellular Biology

107

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WASH is an Arp2/3 activator of the Wiskott-Aldrich syndrome protein superfamily that functions during endosomal trafficking processes in collaboration with the retromer and sorting nexins, but its in vivo function has not been examined. To elucidate the physiological role of WASH in T cells, we generated a WASH conditional knockout (WASHout) mouse model. Using CD4 Cre deletion, we found that thymocyte development and naive T cell activation are unaltered in the absence of WASH. Surprisingly, despite normal T cell receptor (TCR) signaling and interleukin-2 production, WASHout T cells demonstrate significantly reduced proliferative potential and fail to effectively induce experimental autoimmune encephalomyelitis. Interestingly, after activation, WASHout T cells fail to maintain surface levels of TCR, CD28, and LFA-1. Moreover, the levels of the glucose transporter, GLUT1, are also reduced compared to wild-type T cells. We further demonstrate that the loss of surface expression of these receptors in WASHout cells results from aberrant accumulation within the collapsed endosomal compartment, ultimately leading to degradation within the lysosome. Subsequently, activated WASHout T cells experience reduced glucose uptake and metabolic output. Thus, we found that WASH is a newly recognized regulator of TCR, CD28, LFA-1, and GLUT1 endosome-to-membrane recycling. Aberrant trafficking of these key T cell proteins may potentially lead to attenuated proliferation and effector function.

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

Cited by 187 publications

References 50 publications

Evolutionary dynamism of the primate LRRC37 gene family

Evolutionary dynamism of the primate LRRC37 gene family

Comparative sequence analysis of primate subtelomeres originating from a chromosome fission event

WASH Knockout T Cells Demonstrate Defective Receptor Trafficking, Proliferation, and Effector Function

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