Abstract
BackgroundDetecting functional variants contributing to diversity of behaviour is crucial for dissecting genetics of complex behaviours. At a molecular level, characterisation of variation in exons has been studied as they are easily identified in the current genome annotation although the functional consequences are less well understood; however, it has been difficult to prioritise regions of non-coding DNA in which genetic variation could also have significant functional consequences. Comparison of multiple vertebrate genomes has allowed the identification of non-coding evolutionary conserved regions (ECRs), in which the degree of conservation can be comparable with exonic regions suggesting functional significance.ResultsWe identified ECRs at the dopamine receptor D4 gene locus, an important gene for human behaviours. The most conserved non-coding ECR (D4ECR1) supported high reporter gene expression in primary cultures derived from neonate rat frontal cortex. Computer aided analysis of the sequence of the D4ECR1 indicated the potential transcription factors that could modulate its function. D4ECR1 contained multiple consensus sequences for binding the transcription factor Sp1, a factor previously implicated in DRD4 expression. Co-transfection experiments demonstrated that overexpression of Sp1 significantly decreased the activity of the D4ECR1 in vitro.ConclusionBioinformatic analysis complemented by functional analysis of the DRD4 gene locus has identified a) a strong enhancer that functions in neurons and b) a transcription factor that may modulate the function of that enhancer.
Highlights
Detecting functional variants contributing to diversity of behaviour is crucial for dissecting genetics of complex behaviours
Examination of the peak of conservation generated showed that a highly homologous sequence to that of the human D4ECR1 was found in 7 other mammalian genomes: Pan troglodytes, Macaca mulatta, Mus musculus, Rattus norvegicus, Cavia porcellus, Echinops telfairi and Canis familiaris
The transcription factor binding sites (TFBS) in the mammalian D4ECR1 sequences were identified by AliBaba 2.1 (Table 1)
Summary
Detecting functional variants contributing to diversity of behaviour is crucial for dissecting genetics of complex behaviours. Comparison of multiple vertebrate genomes has allowed the identification of non-coding evolutionary conserved regions (ECRs), in which the degree of conservation can be comparable with exonic regions suggesting functional significance. The DRD4 gene is involved in the Genome sequencing of diverse vertebrate species has permitted comparisons that reveal strong conservation of non-coding regions (evolutionary conserved regions or ECRs) between distantly related vertebrate species (e.g., between human and mouse or human and fish). Such conservation has been suggested to indicate that a given ECR could act as either a cis regulator of gene expression, alter post-transcriptional modifications or both [1,2]. In vertebrates ECRs have been identified in many genes involved in development [10,11,12] and behaviour [13]
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