Bioinformatic analysis of human CNS-expressed ion channels as candidates for episodic nervous system disorders

Abstract

As monogenic forms of episodic nervous system disorders are often caused by ion channel mutations, we looked for features of human central nervous system (CNS) expressed ion channels that further our understanding of those phenotypes. To this end, we compared human ion channels with other CNS-expressed genes, which we categorized according to the existence of transmembrane domains. When looking at the phylogenetic distribution of these genes, we observed an increased percentage of ion channels that exist in vertebrate genomes while missing in invertebrate genomes. Because we hypothesized that this pattern may relate to a more specific expression, we searched for characteristics of ion channels that indicate a tighter expression regulation. We found that ion channels have longer intron and protein sequences, features typical of genes with more specific expression. In addition, ion channels have increased human-rodent conservation around their transcription start site, as indicated by a higher fraction of conserved noncoding regions. This points to a high relevance of mutations that regulate ion channel expression. When we finally asked whether vertebrate-specific diversification is also displayed by non-ion channel genes with important roles in the CNS, we found a similar phylogenetic distribution. This concordant phylogenetic pattern suggests that vertebrate-specific adaptations may account for a large part of the shared genetic basis of episodic CNS disorders, including monogenic and genetically complex disease manifestations. Consequently, this phylogenetic pattern may contribute to the prioritization of candidate genes in human genetic studies of episodic CNS disorders.

Enrichment of HapMap recombination hotspot predictions around human nervous system genes: evidence for positive selection ?

“…35 Accordingly, similar types of CNS genes that are associated with hotspot predictions also had shown genomic characteristics of genes with more tightly regulated expression. 30 If selection intensity would exert an important influence on the distribution of meiotic recombination sites across the human genome, the maintenance of large-scale recombination rates 36 could be the reflection of persistent negative and recurrent positive selection that acts on regulatory sequences located in a wider genomic range around their targets genes. An influence of selection intensity on hotspot activity appears reasonable, because recombination hotspots seem to evolve as sequence-related traits, as shown by their relationship to the CCTCCCT motif 16 and the earlier observation of recombigenic alleles within hotspots.…”

“…Ancestral alleles might be preferentially turned into susceptibility alleles, if encoding the 'conserved core' of the archetypic vertebrate brain. 30,43,44 Such CNS susceptibility genes may differ from other genes in the strength of constraint on sites that neighbor a positively selected allele, as indicated by their stronger sequence conservation. 1 -3,29,30 Therefore, more recombination could be advantageous at these loci.…”

Ion channels and schizophrenia: a gene set-based analytic approach to GWAS data for biological hypothesis testing

“…From an evolutionary perspective, ion channels, relative to most other neuronally expressed proteins, demonstrate a remarkable, and relatively unique, simultaneity of phylogenetic conservation (Anderson and Greenberg 2001; Strong and Gutman 1993; Trimmer and Rhodes 2004), species differentiation (Abernethy and Soldatov 2002; Anderson and Greenberg 2001; Strong and Gutman 1993), structural diversity (Anderson and Greenberg 2001; Ashcroft 2006; Strong and Gutman 1993; Waxman 2000), and developmental and distributional specificity (Abernethy and Soldatov 2002; Anderson and Greenberg 2001; Freudenberg et al 2007; Mechaly et al 2005; Sailer et al 2004; Stocker 2004; Stocker et al 2004; Waxman 2000; Wolfart et al 2001). Together, these qualities support a critical role for ion channels in the functioning and functional specialization of nervous systems, from the most primitive eukaryotes to human beings.…”

“…Together, these qualities support a critical role for ion channels in the functioning and functional specialization of nervous systems, from the most primitive eukaryotes to human beings. In a very compelling bioinformatics analysis of human CNS-expressed ion channels, Freudenberg et al (2007) examined the phylogenetic attributes of human ion channels relative to other CNS-expressed genes (Freudenberg et al 2007). First, they observed that relative to invertebrate, vertebrate genomes had an increased percentage of ion channel genes.…”

Candidate genes for schizophrenia: A survey of association studies and gene ranking

“…Three of them (receptor activity, ion channel activity, and ion transport) seem to be biologically inter-related, for example, ion channelmediated signal processing may depend on receptor activity. The genes encoding ion channels are important in neuronal function and are likely candidates for episodic nervous system disorders [Freudenberg et al, 2007]. The GO term ''amino acid and derivative metabolic process'' is related to metabolic pathways.…”