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Richard Benton - One of the best experts on this subject based on the ideXlab platform.
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Olfactory receptor pseudo-Pseudogenes
Nature, 2016Co-Authors: Lucia L. Prieto-godino, Raphael Rytz, Beno�te Bargeton, J. R. Argüello, Matteo Dal Peraro, Liliane Abuin, Richard BentonAbstract:Drosophila sechellia, a species closely related to the model species Drosophila melanogaster, bypasses a premature stop codon in neuronal cells to express a functional olfactory receptor protein from an assumed pseudogene template. Pseudogenes—genes that have accumulated premature termination codons (PTC)—are considered 'junk' DNA. They may produce regulatory RNAs or small polypeptidic fragments but no functional protein, or so it was thought. Here Richard Benton and colleagues report that the Ir75a pseudogene in Drosophila sechelia encodes a functional olfactory receptor as a consequence of efficient translational read-through of its PTC, exclusively in neurons. The authors go on to identify several other such 'pseudo-Pseudogenes' that act as functional genes despite PTCs, among different olfactory receptor families and various species, which suggests that genome annotation should be reconsidered, especially with respect to PTC-containing disease genes. Pseudogenes are generally considered to be non-functional DNA sequences that arise through nonsense or frame-shift mutations of protein-coding genes1. Although certain pseudogene-derived RNAs have regulatory roles2, and some pseudogene fragments are translated3, no clear functions for pseudogene-derived proteins are known. Olfactory receptor families contain many Pseudogenes, which reflect low selection pressures on loci no longer relevant to the fitness of a species4. Here we report the characterization of a pseudogene in the chemosensory variant ionotropic glutamate receptor repertoire5,6 of Drosophila sechellia, an insect endemic to the Seychelles that feeds almost exclusively on the ripe fruit of Morinda citrifolia7. This locus, D. sechellia Ir75a, bears a premature termination codon (PTC) that appears to be fixed in the population. However, D. sechellia Ir75a encodes a functional receptor, owing to efficient translational read-through of the PTC. Read-through is detected only in neurons and is independent of the type of termination codon, but depends on the sequence downstream of the PTC. Furthermore, although the intact Drosophila melanogaster Ir75a orthologue detects acetic acid—a chemical cue important for locating fermenting food8,9 found only at trace levels in Morinda fruit10—D. sechellia Ir75a has evolved distinct odour-tuning properties through amino-acid changes in its ligand-binding domain. We identify functional PTC-containing loci within different olfactory receptor repertoires and species, suggesting that such ‘pseudo-Pseudogenes’ could represent a widespread phenomenon.
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Olfactory receptor pseudo-Pseudogenes
Nature, 2016Co-Authors: Lucia L. Prieto-godino, Raphael Rytz, Beno�te Bargeton, J. R. Argüello, Matteo Dal Peraro, Liliane Abuin, Richard BentonAbstract:Pseudogenes are generally considered to be non-functional DNA sequences that arise through nonsense or frame-shift mutations of protein-coding genes1. Although certain pseudogene-derived RNAs have regulatory roles2, and some pseudogene fragments are translated3, no clear functions for pseudogene-derived proteins are known. Olfactory receptor families contain many Pseudogenes, which reflect low selection pressures on loci no longer relevant to the fitness of a species4. Here we report the characterization of a pseudogene in the chemosensory variant ionotropic glutamate receptor repertoire5, 6 of Drosophila sechellia, an insect endemic to the Seychelles that feeds almost exclusively on the ripe fruit of Morinda citrifolia7. This locus, D. sechellia Ir75a, bears a premature termination codon (PTC) that appears to be fixed in the population. However, D. sechellia Ir75a encodes a functional receptor, owing to efficient translational read-through of the PTC. Read-through is detected only in neurons and is independent of the type of termination codon, but depends on the sequence downstream of the PTC. Furthermore, although the intact Drosophila melanogaster Ir75a orthologue detects acetic acid—a chemical cue important for locating fermenting food8, 9 found only at trace levels in Morinda fruit10—D. sechellia Ir75a has evolved distinct odour-tuning properties through amino-acid changes in its ligand-binding domain. We identify functional PTC-containing loci within different olfactory receptor repertoires and species, suggesting that such ‘pseudo-Pseudogenes’ could represent a widespread phenomenon.
Deyou Zheng - One of the best experts on this subject based on the ideXlab platform.
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characterization of human pseudogene derived non coding rnas for functional potential
PLOS ONE, 2014Co-Authors: Shira Rockowitz, Herbert M Lachman, Deyou ZhengAbstract:Thousands of Pseudogenes exist in the human genome and many are transcribed, but their functional potential remains elusive and understudied. To explore these issues systematically, we first developed a computational pipeline to identify transcribed Pseudogenes from RNA-Seq data. Applying the pipeline to datasets from 16 distinct normal human tissues identified ∼3,000 Pseudogenes that could produce non-coding RNAs in a manner of low abundance but high tissue specificity under normal physiological conditions. Cross-tissue comparison revealed that the transcriptional profiles of Pseudogenes and their parent genes showed mostly positive correlations, suggesting that pseudogene transcription could have a positive effect on the expression of their parent genes, perhaps by functioning as competing endogenous RNAs (ceRNAs), as previously suggested and demonstrated with the PTEN pseudogene, PTENP1. Our analysis of the ENCODE project data also found many transcriptionally active Pseudogenes in the GM12878 and K562 cell lines; moreover, it showed that many human Pseudogenes produced small RNAs (sRNAs) and some pseudogene-derived sRNAs, especially those from antisense strands, exhibited evidence of interfering with gene expression. Further integrated analysis of transcriptomics and epigenomics data, however, demonstrated that trimethylation of histone 3 at lysine 9 (H3K9me3), a posttranslational modification typically associated with gene repression and heterochromatin, was enriched at many transcribed Pseudogenes in a transcription-level dependent manner in the two cell lines. The H3K9me3 enrichment was more prominent in Pseudogenes that produced sRNAs at pseudogene loci and their adjacent regions, an observation further supported by the co-enrichment of SETDB1 (a H3K9 methyltransferase), suggesting that pseudogene sRNAs may have a role in regional chromatin repression. Taken together, our comprehensive and systematic characterization of pseudogene transcription uncovers a complex picture of how pseudogene ncRNAs could influence gene and pseudogene expression, at both epigenetic and post-transcriptional levels.
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eLS - Pseudogene Evolution in the Human Genome
eLS, 2014Co-Authors: Zhaolei Zhang, Deyou ZhengAbstract:Pseudogenes are those regions in a genome that have sequence similarity to functional genes but have decayed and have no obvious functions. It is estimated that the human genome contains more than 10 000 easily recognisable Pseudogenes and many more fragmented sequences, that arose mainly through one of the following three mechanisms: duplication, retrotranposition and spontaneous loss of function. The majority of the human retrotransposed (i.e. processed) Pseudogenes are primate specific, arising from a burst of retrotransposition activities approximately 45 Ma. Although most of the human Pseudogenes are most likely too degenerated to perform a biological function, ∼20% of them exhibit evidence of transcriptional activity based on data from multiple genomic studies. Furthermore, a handful of pseudogene transcripts have been demonstrated experimentally to gain novel functions as noncoding ribonucleic acids (RNAs), indicating that Pseudogenes could be a reservoir for evolution innovation. Key Concepts: Pseudogenes are prevalent in the human genome and other mammalian genomes. Most human Pseudogenes are from past retrotranspositions occurring before the split of primate from other lineages. Pseudogenes are a good source of DNA sequences for studying genome evolution. Most human Pseudogenes are most likely ‘dead’ but many of them can be transcribed. Some human Pseudogenes have adopted functions as noncoding RNAs. Keywords: pseudogene; human genome; retrotransposition; evolution; noncoding RNAs
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small rnas originated from Pseudogenes cis or trans acting
PLOS Computational Biology, 2009Co-Authors: Xingyi Guo, Zhaolei Zhang, Mark Gerstein, Deyou ZhengAbstract:Pseudogenes are significant components of eukaryotic genomes, and some have acquired novel regulatory roles. To date, no study has characterized rice Pseudogenes systematically or addressed their impact on the structure and function of the rice genome. In this genome-wide study, we have identified 11,956 non-transposon-related rice Pseudogenes, most of which are from gene duplications. About 12% of the rice protein-coding genes, half of which are in singleton families, have a pseudogene paralog. Interestingly, we found that 145 of these Pseudogenes potentially gave rise to antisense small RNAs after examining ∼1.5 million small RNAs from developing rice grains. The majority (>50%) of these antisense RNAs are 24-nucleotides long, a feature often seen in plant repeat-associated small interfering RNAs (siRNAs) produced by RNA-dependent RNA polymerase (RDR2) and Dicer-like protein 3 (DCL3), suggesting that some pseudogene-derived siRNAs may be implicated in repressing pseudogene transcription (i.e., cis-acting). Multiple lines of evidence, however, indicate that small RNAs from rice Pseudogenes might also function as natural antisense siRNAs either by interacting with the complementary sense RNAs from functional parental genes (38 cases) or by forming double-strand RNAs with transcripts of adjacent paralogous Pseudogenes (2 cases) (i.e., trans-acting). Further examinations of five additional small RNA libraries revealed that pseudogene-derived antisense siRNAs could be produced in specific rice developmental stages or physiological growth conditions, suggesting their potentially important roles in normal rice development. In summary, our results show that Pseudogenes derived from protein-coding genes are prevalent in the rice genome, and a subset of them are strong candidates for producing small RNAs with novel regulatory roles. Our findings suggest that Pseudogenes of exapted functions may be a phenomenon ubiquitous in eukaryotic organisms.
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Pseudogenes in the ENCODE regions: Consensus annotation, analysis of transcription, and evolution
Genome Research, 2007Co-Authors: Deyou Zheng, Adam Frankish, Alexandre Reymond, Robert Baertsch, Philipp Kapranov, Siew Woh Choo, Stylianos E. Antonarakis, Michael Snyder, Yijun RuanAbstract:Arising from either retrotransposition or genomic duplication of functional genes, Pseudogenes are “genomic fossils” valuable for exploring the dynamics and evolution of genes and genomes. Pseudogene identification is an important problem in computational genomics, and is also critical for obtaining an accurate picture of a genome’s structure and function. However, no consensus computational scheme for defining and detecting Pseudogenes has been developed thus far. As part of the ENCyclopedia Of DNA Elements (ENCODE) project, we have compared several distinct pseudogene annotation strategies and found that different approaches and parameters often resulted in rather distinct sets of Pseudogenes. We subsequently developed a consensus approach for annotating Pseudogenes (derived from protein coding genes) in the ENCODE regions, resulting in 201 Pseudogenes, two-thirds of which originated from retrotransposition. A survey of orthologs for these Pseudogenes in 28 vertebrate genomes showed that a significant fraction (∼80%) of the processed Pseudogenes are primate-specific sequences, highlighting the increasing retrotransposition activity in primates. Analysis of sequence conservation and variation also demonstrated that most Pseudogenes evolve neutrally, and processed Pseudogenes appear to have lost their coding potential immediately or soon after their emergence. In order to explore the functional implication of pseudogene prevalence, we have extensively examined the transcriptional activity of the ENCODE Pseudogenes. We performed systematic series of pseudogene-specific RACE analyses. These, together with complementary evidence derived from tiling microarrays and high throughput sequencing, demonstrated that at least a fifth of the 201 Pseudogenes are transcribed in one or more cell lines or tissues.
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the ambiguous boundary between genes and Pseudogenes the dead rise up or do they
Trends in Genetics, 2007Co-Authors: Deyou Zheng, Mark GersteinAbstract:Pseudogenes have long been considered to be 'dead', nonfunctional by-products of genome evolution. However, several lines of evidence now show that some Pseudogenes are transcriptionally 'alive', and a few might even have biochemical roles. Therefore, the boundary between genes (often considered to be 'living') and Pseudogenes (often considered to be 'dead') might be ambiguous and difficult to define. Here, we examine the evidence for and against pseudogene functionality, and we argue that the time is ripe for revising the definition of a pseudogene. Furthermore, we suggest a classification system to accommodate Pseudogenes with various levels of functionality.
Lucia L. Prieto-godino - One of the best experts on this subject based on the ideXlab platform.
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Olfactory receptor pseudo-Pseudogenes
Nature, 2016Co-Authors: Lucia L. Prieto-godino, Raphael Rytz, Beno�te Bargeton, J. R. Argüello, Matteo Dal Peraro, Liliane Abuin, Richard BentonAbstract:Drosophila sechellia, a species closely related to the model species Drosophila melanogaster, bypasses a premature stop codon in neuronal cells to express a functional olfactory receptor protein from an assumed pseudogene template. Pseudogenes—genes that have accumulated premature termination codons (PTC)—are considered 'junk' DNA. They may produce regulatory RNAs or small polypeptidic fragments but no functional protein, or so it was thought. Here Richard Benton and colleagues report that the Ir75a pseudogene in Drosophila sechelia encodes a functional olfactory receptor as a consequence of efficient translational read-through of its PTC, exclusively in neurons. The authors go on to identify several other such 'pseudo-Pseudogenes' that act as functional genes despite PTCs, among different olfactory receptor families and various species, which suggests that genome annotation should be reconsidered, especially with respect to PTC-containing disease genes. Pseudogenes are generally considered to be non-functional DNA sequences that arise through nonsense or frame-shift mutations of protein-coding genes1. Although certain pseudogene-derived RNAs have regulatory roles2, and some pseudogene fragments are translated3, no clear functions for pseudogene-derived proteins are known. Olfactory receptor families contain many Pseudogenes, which reflect low selection pressures on loci no longer relevant to the fitness of a species4. Here we report the characterization of a pseudogene in the chemosensory variant ionotropic glutamate receptor repertoire5,6 of Drosophila sechellia, an insect endemic to the Seychelles that feeds almost exclusively on the ripe fruit of Morinda citrifolia7. This locus, D. sechellia Ir75a, bears a premature termination codon (PTC) that appears to be fixed in the population. However, D. sechellia Ir75a encodes a functional receptor, owing to efficient translational read-through of the PTC. Read-through is detected only in neurons and is independent of the type of termination codon, but depends on the sequence downstream of the PTC. Furthermore, although the intact Drosophila melanogaster Ir75a orthologue detects acetic acid—a chemical cue important for locating fermenting food8,9 found only at trace levels in Morinda fruit10—D. sechellia Ir75a has evolved distinct odour-tuning properties through amino-acid changes in its ligand-binding domain. We identify functional PTC-containing loci within different olfactory receptor repertoires and species, suggesting that such ‘pseudo-Pseudogenes’ could represent a widespread phenomenon.
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Olfactory receptor pseudo-Pseudogenes
Nature, 2016Co-Authors: Lucia L. Prieto-godino, Raphael Rytz, Beno�te Bargeton, J. R. Argüello, Matteo Dal Peraro, Liliane Abuin, Richard BentonAbstract:Pseudogenes are generally considered to be non-functional DNA sequences that arise through nonsense or frame-shift mutations of protein-coding genes1. Although certain pseudogene-derived RNAs have regulatory roles2, and some pseudogene fragments are translated3, no clear functions for pseudogene-derived proteins are known. Olfactory receptor families contain many Pseudogenes, which reflect low selection pressures on loci no longer relevant to the fitness of a species4. Here we report the characterization of a pseudogene in the chemosensory variant ionotropic glutamate receptor repertoire5, 6 of Drosophila sechellia, an insect endemic to the Seychelles that feeds almost exclusively on the ripe fruit of Morinda citrifolia7. This locus, D. sechellia Ir75a, bears a premature termination codon (PTC) that appears to be fixed in the population. However, D. sechellia Ir75a encodes a functional receptor, owing to efficient translational read-through of the PTC. Read-through is detected only in neurons and is independent of the type of termination codon, but depends on the sequence downstream of the PTC. Furthermore, although the intact Drosophila melanogaster Ir75a orthologue detects acetic acid—a chemical cue important for locating fermenting food8, 9 found only at trace levels in Morinda fruit10—D. sechellia Ir75a has evolved distinct odour-tuning properties through amino-acid changes in its ligand-binding domain. We identify functional PTC-containing loci within different olfactory receptor repertoires and species, suggesting that such ‘pseudo-Pseudogenes’ could represent a widespread phenomenon.
Kevin V Morris - One of the best experts on this subject based on the ideXlab platform.
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the emerging role of pseudogene expressed non coding rnas in cellular functions
The International Journal of Biochemistry & Cell Biology, 2014Co-Authors: Jessica N Groen, David Capraro, Kevin V MorrisAbstract:Abstract A paradigm shift is sweeping modern day molecular biology following the realisation that large amounts of “junk” DNA”, thought initially to be evolutionary remnants, may actually be functional. Several recent studies support a functional role for pseudogene-expressed non-coding RNAs in regulating their protein-coding counterparts. Several hundreds of Pseudogenes have been reported as transcribed into RNA in a large variety of tissues and tumours. Most studies have focused on Pseudogenes expressed in the sense direction, but some reports suggest that Pseudogenes can also be transcribed as antisense RNAs (asRNAs). A few examples of key regulatory genes, such as PTEN and OCT4, have in fact been reported to be under the regulation of pseudogene-expressed asRNAs. Here, we review what are known about pseudogene expressed non-coding RNA mediated gene regulation and their roles in the control of epigenetic states. This article is part of a Directed Issue entitled: The Non-coding RNA Revolution.
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Not so pseudo anymore: Pseudogenes as therapeutic targets.
Pharmacogenomics, 2013Co-Authors: Thomas C. Roberts, Kevin V MorrisAbstract:Pseudogenes are junk DNA gene remnants generated by inactivating mutations or the loss of regulatory sequences, often following gene duplication or retrotransposition events. These Pseudogenes have previously been considered to be molecular fossils derived from once-coding genes. In many cases, Pseudogenes confer no observable selective advantage to the host organism and may be on a path towards removal from the genome. However, Pseudogenes can also serve as raw material for the exaptation of novel functions, particularly in relation to the regulation of gene expression. Many Pseudogenes are resurrected as noncoding RNA genes, which function in RNA-based gene regulatory circuits. As such, functional Pseudogenes might simply be considered as ‘genes’. Here, we discuss the role of these pseudogene-derived RNAs as regulators of gene expression in the context of human disease. In particular, we consider the manipulation of pseudogene transcripts through the use of antisense oligonucleotides, siRNAs, aptamers o...
Mark Gerstein - One of the best experts on this subject based on the ideXlab platform.
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segmental duplications in the human genome reveal details of pseudogene formation
Nucleic Acids Research, 2010Co-Authors: Ekta Khurana, Philip Cayting, Nicholas Carriero, Chao Cheng, Mark GersteinAbstract:Duplicated Pseudogenes in the human genome are disabled copies of functioning parent genes. They result from block duplication events occurring throughout evolutionary history. Relatively recent duplications (with sequence similarity ≥90% and length ≥1 kb) are termed segmental duplications (SDs); here, we analyze the interrelationship of SDs and Pseudogenes. We present a decision-tree approach to classify Pseudogenes based on their (and their parents’) characteristics in relation to SDs. The classification identifies 140 novel Pseudogenes and makes possible improved annotation for the 3172 Pseudogenes located in SDs. In particular, it reveals that many Pseudogenes in SDs likely did not arise directly from parent genes, but are the result of a multi-step process. In these cases, the initial duplication or retrotransposition of a parent gene gives rise to a ‘parent pseudogene’, followed by further duplication creating duplicated–duplicated or duplicated–processed Pseudogenes, respectively. Moreover, we can precisely identify these parent Pseudogenes by overlap with ancestral SD loci. Finally, a comparison of nucleotide substitutions per site in a pseudogene with its surrounding SD region allows us to estimate the time difference between duplication and disablement events, and this suggests that most duplicated Pseudogenes in SDs were likely disabled around the time of the original duplication.
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small rnas originated from Pseudogenes cis or trans acting
PLOS Computational Biology, 2009Co-Authors: Xingyi Guo, Zhaolei Zhang, Mark Gerstein, Deyou ZhengAbstract:Pseudogenes are significant components of eukaryotic genomes, and some have acquired novel regulatory roles. To date, no study has characterized rice Pseudogenes systematically or addressed their impact on the structure and function of the rice genome. In this genome-wide study, we have identified 11,956 non-transposon-related rice Pseudogenes, most of which are from gene duplications. About 12% of the rice protein-coding genes, half of which are in singleton families, have a pseudogene paralog. Interestingly, we found that 145 of these Pseudogenes potentially gave rise to antisense small RNAs after examining ∼1.5 million small RNAs from developing rice grains. The majority (>50%) of these antisense RNAs are 24-nucleotides long, a feature often seen in plant repeat-associated small interfering RNAs (siRNAs) produced by RNA-dependent RNA polymerase (RDR2) and Dicer-like protein 3 (DCL3), suggesting that some pseudogene-derived siRNAs may be implicated in repressing pseudogene transcription (i.e., cis-acting). Multiple lines of evidence, however, indicate that small RNAs from rice Pseudogenes might also function as natural antisense siRNAs either by interacting with the complementary sense RNAs from functional parental genes (38 cases) or by forming double-strand RNAs with transcripts of adjacent paralogous Pseudogenes (2 cases) (i.e., trans-acting). Further examinations of five additional small RNA libraries revealed that pseudogene-derived antisense siRNAs could be produced in specific rice developmental stages or physiological growth conditions, suggesting their potentially important roles in normal rice development. In summary, our results show that Pseudogenes derived from protein-coding genes are prevalent in the rice genome, and a subset of them are strong candidates for producing small RNAs with novel regulatory roles. Our findings suggest that Pseudogenes of exapted functions may be a phenomenon ubiquitous in eukaryotic organisms.
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pseudofam the pseudogene families database
Nucleic Acids Research, 2009Co-Authors: Ekta Khurana, Philip Cayting, Keihoi Cheung, Nicholas Carriero, Gang Fang, Mark GersteinAbstract:Pseudofam (http://pseudofam.pseudogene.org) is a database of pseudogene families based on the protein families from the Pfam database. It provides resources for analyzing the family structure of Pseudogenes including query tools, statistical summaries and sequence alignments. The current version of Pseudofam contains more than 125000 Pseudogenes identified from 10 eukaryotic genomes and aligned within nearly 3000 families (approximately one-third of the total families in PfamA). Pseudofam uses a large-scale parallelized homology search algorithm (implemented as an extension of the PseudoPipe pipeline) to identify Pseudogenes. Each identified pseudogene is assigned to its parent protein family and subsequently aligned to each other by transferring the parent domain alignments from the Pfam family. Pseudogenes are also given additional annotation based on an ontology, reflecting their mode of creation and subsequent history. In particular, our annotation highlights the association of pseudogene families with genomic features, such as segmental duplications. In addition, pseudogene families are associated with key statistics, which identify outlier families with an unusual degree of pseudogenization. The statistics also show how the number of genes and Pseudogenes in families correlates across different species. Overall, they highlight the fact that housekeeping families tend to be enriched with a large number of Pseudogenes.
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the ambiguous boundary between genes and Pseudogenes the dead rise up or do they
Trends in Genetics, 2007Co-Authors: Deyou Zheng, Mark GersteinAbstract:Pseudogenes have long been considered to be 'dead', nonfunctional by-products of genome evolution. However, several lines of evidence now show that some Pseudogenes are transcriptionally 'alive', and a few might even have biochemical roles. Therefore, the boundary between genes (often considered to be 'living') and Pseudogenes (often considered to be 'dead') might be ambiguous and difficult to define. Here, we examine the evidence for and against pseudogene functionality, and we argue that the time is ripe for revising the definition of a pseudogene. Furthermore, we suggest a classification system to accommodate Pseudogenes with various levels of functionality.
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pseudogene org a comprehensive database and comparison platform for pseudogene annotation
Nucleic Acids Research, 2007Co-Authors: John E Karro, Philip Cayting, Zhaolei Zhang, Paul Harrrison, Nicholas Carriero, Deyou Zheng, Mark GersteinAbstract:The Pseudogene.org knowledgebase serves as a comprehensive repository for pseudogene annotation. The definition of a pseudogene varies within the literature, resulting in significantly different approaches to the problem of identification. Consequently, it is difficult to maintain a consistent collection of Pseudogenes in detail necessary for their effective use. Our database is designed to address this issue. It integrates a variety of heterogeneous resources and supports a subset structure that highlights specific groups of Pseudogenes that are of interest to the research community. Tools are provided for the comparison of sets and the creation of layered set unions, enabling researchers to derive a current ‘consensus’ set of Pseudogenes. Additional features include versatile search, the capacity for robust interaction with other databases, the ability to reconstruct older versions of the database (accounting for changing genome builds) and an underlying object-oriented interface designed for researchers with a minimal knowledge of programming. At the present time, the database contains more than 100 000 Pseudogenes spanning 64 prokaryote and 11 eukaryote genomes, including a collection of human annotations compiled from 16 sources.
