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

Abstract

BackgroundMutations 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.ResultsWe 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.ConclusionsThe 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.

Interchromosomal core duplicons drive both evolutionary instability and disease susceptibility of the Chromosome 8p23.1 region

“…Three of these four chromosomal locations have also been associated with inversion polymorphisms representing some of the largest inversion polymorphisms in the human genome (Giglio et al 2001(Giglio et al , 2002Hurle et al 2011;Ma and Amos 2012). Analysis of primate genomes suggests that such events have occurred recurrently (i.e., the presence of both direct and inverted haplotypes in the bonobo) (Antonacci et al 2009).…”

Structural and functional characterization of an otopetrin family proton channel

“…OTOP1 was also found to play a role in otolith formation in zebrafish through the characterization of the backstroke (bks) mutation that causes a complete absence of otoliths (Hughes et al, 2004; Söllner et al, 2004). Additionally, OTOP2 and OTOP3 represent two main paralogs of OTOP1 in mouse and other mammals (Hurle et al, 2011). While the tissue-specific patterns of expression of OTOP2 and OTOP3 are distinct from OTOP1, their cellular functions remain elusive (Tu et al, 2018; Hurle et al, 2011).…”

RNA sequencing-based analysis of the laying hen uterus revealed the novel genes and biological pathways involved in the eggshell biomineralization

“…Though the function of OTOP2 and OTOP3 remains unknown, Otop1 is postulated to maintain the high concentration of cytosolic calcium in the supporting cells of inner ear during otoconia mineralization in mice 19 . OTOP genes do not necessarily have the same biochemical function as Otop1 20 , however, based on their highly conserved nature between vertebrates and a validated up-streamed expression in laying hens during egg calcification, we hypothesized that OTOP2 has a similar role of regulating intracellular calcium in the uterus for eggshell calcification.…”