Abstract
BackgroundPseudogenes are an integral component of the human genome. Little attention, however, has so far been paid to the phenomenon that some pseudogenes are transcriptionally active. Recently, we demonstrated that the human ortholog of the rodent testis-specific ATP-binding cassette (ABC) transporter Abca17 is a ubiquitously transcribed pseudogene (ABCA17P). The aim of the present study was to establish a complete inventory of all ABC transporter pseudogenes in the human genome and to identify transcriptionally active ABC transporter pseudogenes. Moreover, we tested the hypothesis that a regulatory interdependency exists between ABC transporter pseudogenes and their parental protein coding equivalents.ResultsSystematic bioinformatic analysis revealed the existence of 22 ABC transporter pseudogenes within the human genome. We identified two clusters on chromosomes 15 and 16, respectively, which harbor almost half of all pseudogenes (n = 10). Available information from EST and mRNA databases and RT-PCR expression profiling indicate that a large portion of the ABC transporter pseudogenes (45%, n = 10) are transcriptionally active and some of them are expressed as alternative splice variants. We demonstrate that both pseudogenes of the pseudoxanthoma elasticum gene ABCC6, ABCC6P1 and ABCC6P2, are transcribed. ABCC6P1 and ABCC6 possess near-identical promoter sequences and their tissue-specific expression profiles are strikingly similar raising the possibility that they form a gene-pseudogene dual transcription unit. Intriguingly, targeted knockdown of the transcribed pseudogene ABCC6P1 resulted in a significant reduction of ABCC6 mRNA expression levels.ConclusionThe human genome contains a surprisingly small number of ABC transporter pseudogenes relative to other known gene families. They are unevenly distributed across the chromosomes. Importantly, a significant portion of the ABC transporter pseudogenes is transcriptionally active. The downregulation of ABCC6 mRNA levels by targeted suppression of the expression of its pseudogene ABCC6P1 provides evidence, for the first time, for a regulatory interdependence of a transcribed pseudogene and its protein coding counterpart in the human genome.
Highlights
Pseudogenes are an integral component of the human genome
The human genome contains 22 ATP-binding cassette (ABC) transporter pseudogenes To identify homologs of human ABC transporters, we performed a genome-wide search based on the sequences of the known 48 human and the five murine ABC transporter genes, for which no orthologous counterpart as yet have been documented in the human genome (Abca14Abca17,Abcg3)
The ABC transporter pseudogenes we identified could be assigned to all seven subfamilies, ABC A- ABC G (Table 1)
Summary
Pseudogenes are an integral component of the human genome. Little attention, has so far been paid to the phenomenon that some pseudogenes are transcriptionally active. Pseudogenes are defined as non-functional sequences that are present in the genome with high similarity to one or more paralogous genes. This lack of function is a result of either failure of transcription or translation, or production of a protein that differs in function from the protein encoded by the functional gene [5]. Pseudogenes are thought to arise either by gene duplication and subsequent degeneration of the duplicated gene or by retroposition of a reversely transcribed mRNA of the paralogous gene into the genome. The latter are intronless and referred to as "processed" pseudogenes [6]
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