Abstract
BackgroundTo gain insight into the evolutionary features of the huntingtin (htt) gene in Chordata, we have sequenced and characterized the full-length htt mRNA in the ascidian Ciona intestinalis, a basal chordate emerging as new invertebrate model organism. Moreover, taking advantage of the availability of genomic and EST sequences, the htt gene structure of a number of chordate species, including the cogeneric ascidian Ciona savignyi, and the vertebrates Xenopus and Gallus was reconstructed.ResultsThe C. intestinalis htt transcript exhibits some peculiar features, such as spliced leader trans-splicing in the 98 nt-long 5' untranslated region (UTR), an alternative splicing in the coding region, eight alternative polyadenylation sites, and no similarities of both 5' and 3'UTRs compared to homologs of the cogeneric C. savignyi. The predicted protein is 2946 amino acids long, shorter than its vertebrate homologs, and lacks the polyQ and the polyP stretches found in the the N-terminal regions of mammalian homologs. The exon-intron organization of the htt gene is almost identical among vertebrates, and significantly conserved between Ciona and vertebrates, allowing us to hypothesize an ancestral chordate gene consisting of at least 40 coding exons.ConclusionDuring chordate diversification, events of gain/loss, sliding, phase changes, and expansion of introns occurred in both vertebrate and ascidian lineages predominantly in the 5'-half of the htt gene, where there is also evidence of lineage-specific evolutionary dynamics in vertebrates. On the contrary, the 3'-half of the gene is highly conserved in all chordates at the level of both gene structure and protein sequence. Between the two Ciona species, a fast evolutionary rate and/or an early divergence time is suggested by the absence of significant similarity between UTRs, protein divergence comparable to that observed between mammals and fishes, and different distribution of repetitive elements.
Highlights
To gain insight into the evolutionary features of the huntingtin gene in Chordata, we have sequenced and characterized the full-length htt mRNA in the ascidian Ciona intestinalis, a basal chordate emerging as new invertebrate model organism
In this study we report the characterization of the Ciona intestinalis huntingtin full-length transcript, including the 5' and 3' untranslated regions (UTRs), and the definition of its gene structure using available C. intestinalis genomic sequences
In the CDS we identified a total of 76 polymorphic positions, with nucleotide differences resulting in synonymous (72%) and non-synonymous substitutions (28%, mostly conservative amino acid changes); in the UTRs both nucleotide substitutions and indels were found
Summary
To gain insight into the evolutionary features of the huntingtin (htt) gene in Chordata, we have sequenced and characterized the full-length htt mRNA in the ascidian Ciona intestinalis, a basal chordate emerging as new invertebrate model organism. Huntingtin is a large protein (> 3000 amino acids long in vertebrates), characterized in humans by the presence of an amino-terminal polymorphic polyglutamine (polyQ) tract whose aberrant expansion causes Huntington's Disease (HD), a progressive neurodegenerative disease (page number not for citation purposes). The large dimension of the protein makes its purification extremely problematic and its three dimensional structure remains unsolved. Because of these difficulties, the study of huntingtin function(s) has largely progressed through gene deletion and gene addition studies that have demonstrated that huntingtin is essential for embryonic development [3]. Huntingtin is important for the survival of brain neurons where it controls BDNF (brain-derived neurotrophic factor) production and delivery [5,6,7], axonal transport [8,9] and neuronal gene transcription [3]
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