Temporal transcriptome analysis of neuronal commitment reveals the preeminent role of the divergent lncRNA biotype and a critical candidate gene during differentiation.

lncRNA genes can be genic or "intergenic". "Genic" RNAs can be further divided into six biotypes. Through genome-wide analysis of a publicly available data set on corticogenesis, we found that the divergent lncRNA (XH) biotype, comprising the lncRNA and the coding gene being in opposite directions in a head-to-head manner, was most prominent during neural commitment. Within this biotype, a coding gene/divergent RNA pair of the BASP1 gene and the uncharacterized RNA loc285696 (hitherto referred as BASP1-AS1) formed a major HUB gene during neuronal differentiation. Experimental validation during the in vitro differentiation of human neural progenitor cells (hNPCs) showed that BASP1-AS1 regulates the expression of its adjacent coding gene, BASP1. Both transcripts increased sharply on the first day of neuronal differentiation of hNPCs, to fall steadily thereafter, reaching very low levels in differentiated neurons. BASP1-AS1 RNA and the BASP1 gene formed a molecular complex that also included the transcription factor TCF12. TCF12 is coded by the DYX1 locus, associated with inherited dyslexia and neurodevelopmental defects. Knockdown of BASP1-AS1, BASP1, or TCF12 impaired the neuronal differentiation of hNPCs, as seen by reduction in DCX and TUJ1-positive cells and by reduced neurite length. There was also increased cell proliferation. A common set of critical genes was affected by the three molecules in the complex. Our study thus identified the role of the XH biotype and a novel mediator of neuronal differentiation-the complex of BASP1-AS1, BASP1, and TCF12. It also linked a neuronal differentiation pathway to inherited dyslexia.

A pilot Indian family-based association study between dyslexia and Reelin pathway genes, DCDC2 and ROBO1, identifies modest association with a triallelic unit TAT in the gene RELN.

Dyslexia is a neurodevelopmental disorder that manifests as a reading disability despite normal intelligence and adequate educational opportunity. Twin and family studies have indicated a genetic component, while genome-wide studies have implicated a number of susceptibility genes, most of which have direct or indirect roles in neuronal migration. Reelin (RELN) has important biological functions facilitating migration of neurons. Polymorphisms in RELN have been implicated in related disorders like autism and schizophrenia but have not been examined in dyslexia. We hypothesized that not only RELN, but its interactors in the neuronal migration pathway may play roles in the etiology of dyslexia. Twenty two functional variants across six RELN signalling genes (RELN, VLDLR, APOER2, DAB1, LIS1 and NDEL1) and two dyslexia candidate genes (DCDC2 and ROBO1) were analyzed for association in twenty six nuclear and three extended families with individuals affected with dyslexia. Univariate association analysis was suggestive of association (puncorrected = 0.01) with rs362746 in RELN which however did not withstand Bonferroni corrections (pcorrected = 0.21). Multimarker tests indicated significant association (p = 0.037), based on which we tested for haplotype associations. Although there were no significant haplotypic associations, we found that a three marker unit with rs3808039 and rs2072403 flanking and independently in linkage disequilibrium with rs362746 was significantly overtransmitted (risk allelic combination - TAT) to dyslexia affected individuals in the sample (p = 0.002). Our results suggest preliminary evidence for a new potential risk variant in the RELN locus for dyslexia.

Ancestral Variations of the PCDHG Gene Cluster Predispose to Dyslexia in a Multiplex Family.

Dyslexia is a heritable neurodevelopmental disorder characterized by difficulties in reading and writing. In this study, we describe the identification of a set of 17 polymorphisms located across 1.9Mb region on chromosome 5q31.3, encompassing genes of the PCDHG cluster, TAF7, PCDH1 and ARHGAP26, dominantly inherited with dyslexia in a multi-incident family. Strikingly, the non-risk form of seven variations of the PCDHG cluster, are preponderant in the human lineage, while risk alleles are ancestral and conserved across Neanderthals to non-human primates. Four of these seven ancestral variations (c.460A>C [p.Ile154Leu], c.541G>A [p.Ala181Thr], c.2036G>C [p.Arg679Pro] and c.2059A>G [p.Lys687Glu]) result in amino acid alterations. p.Ile154Leu and p.Ala181Thr are present at EC2: EC3 interacting interface of γA3-PCDH and γA4-PCDH respectively might affect trans-homophilic interaction and hence neuronal connectivity. p.Arg679Pro and p.Lys687Glu are present within the linker region connecting trans-membrane to extracellular domain. Sequence analysis indicated the importance of p.Ile154, p.Arg679 and p.Lys687 in maintaining class specificity. Thus the observed association of PCDHG genes encoding neural adhesion proteins reinforces the hypothesis of aberrant neuronal connectivity in the pathophysiology of dyslexia. Additionally, the striking conservation of the identified variants indicates a role of PCDHG in the evolution of highly specialized cognitive skills critical to reading.