Open Access Open Badges Research article

Lineage-specific evolution of the vertebrate Otopetrin gene family revealed by comparative genomic analyses

Belen Hurle1, Tomas Marques-Bonet23, Francesca Antonacci3, Inna Hughes4, Joseph F Ryan1, NISC Comparative Sequencing Program15, Evan E Eichler3, David M Ornitz6 and Eric D Green15*

Author Affiliations

1 Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, (50 South Drive), Bethesda, MD (20892), USA

2 Department of Institut de Biologia Evolutiva (UPF/CSIC), (Dr. Aiguader, 88), Barcelona (08003), Spain

3 Department of Genome Sciences and Howard Hughes Medical Institute, University of Washington School of Medicine, (3720 15th Ave NE), Seattle, WA (98195), USA

4 Department of Child Neurology, University of Rochester Medical Center, (601 Elmwood Avenue), Rochester, NY (14642), USA

5 NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, (5625 Fishers Lane), Bethesda, MD (20852), USA

6 Department of Molecular Biology and Pharmacology, Washington University School of Medicine, (660 South Euclid Avenue), St. Louis, MO (63110), USA

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BMC Evolutionary Biology 2011, 11:23  doi:10.1186/1471-2148-11-23

Published: 24 January 2011



Mutations in the Otopetrin 1 gene (Otop1) in mice and fish produce an unusual bilateral vestibular pathology that involves the absence of otoconia without hearing impairment. The encoded protein, Otop1, is the only functionally characterized member of the Otopetrin Domain Protein (ODP) family; the extended sequence and structural preservation of ODP proteins in metazoans suggest a conserved functional role. Here, we use the tools of sequence- and cytogenetic-based comparative genomics to study the Otop1 and the Otop2-Otop3 genes and to establish their genomic context in 25 vertebrates. We extend our evolutionary study to include the gene mutated in Usher syndrome (USH) subtype 1G (Ush1g), both because of the head-to-tail clustering of Ush1g with Otop2 and because Otop1 and Ush1g mutations result in inner ear phenotypes.


We established that OTOP1 is the boundary gene of an inversion polymorphism on human chromosome 4p16 that originated in the common human-chimpanzee lineage more than 6 million years ago. Other lineage-specific evolutionary events included a three-fold expansion of the Otop genes in Xenopus tropicalis and of Ush1g in teleostei fish. The tight physical linkage between Otop2 and Ush1g is conserved in all vertebrates. To further understand the functional organization of the Ushg1-Otop2 locus, we deduced a putative map of binding sites for CCCTC-binding factor (CTCF), a mammalian insulator transcription factor, from genome-wide chromatin immunoprecipitation-sequencing (ChIP-seq) data in mouse and human embryonic stem (ES) cells combined with detection of CTCF-binding motifs.


The results presented here clarify the evolutionary history of the vertebrate Otop and Ush1g families, and establish a framework for studying the possible interaction(s) of Ush1g and Otop in developmental pathways.