Pseudogene 232323 221660636 2008-06-25T14:35:49Z 128.173.82.81 /* Functional pseudogenes? */ Role in transcriptional regulation <!--This article is in US English--> '''Pseudogenes''' are defunct relatives of known [[gene]]s that have lost their [[protein]]-coding ability or are otherwise no longer [[gene expression|expressed]] in the cell.<ref name="vanin_1985">Vanin, E. F. (1985). "Processed pseudogenes: characteristics and evolution." ''Annu Rev Genet'' 19: 253-72. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=3909943 PubMed] </ref> Although they may have some gene-like features (such as [[Promoter]]s, [[CpG island]]s, and [[Splicing (genetics)|splice sites]]), they are nonetheless considered [[function (biology)|nonfunctional]], due to their lack of protein-coding ability resulting from various genetic disablements ([[stop codon]]s, [[frameshift]]s, or a lack of [[transcription (genetics)|transcription]]) or their inability to encode RNA (such as with rRNA pseudogenes). Thus the term, coined in 1977 by Jacq, ''et al.'',<ref name="Jacq_1977">Jacq, C., J. R. Miller, ''et al.'' (1977). "A pseudogene structure in 5S DNA of Xenopus laevis." ''Cell'' 12(1): 109-20.[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=561661 PubMed] </ref> is composed of the prefix ''[[wikt:pseudo-|pseudo]]'', which means ''false'', and the root ''gene'', which is the central unit of [[molecular genetics]]. Because pseudogenes are generally thought of the last stop for genomic material that is to be removed from the genome,<ref name="Zheng"/> they are often labeled as [[junk DNA]]. Nonetheless, pseudogenes contain fascinating biological and [[evolution]]ary histories within their sequences. This is due to a pseudogene's shared ancestry with a functional gene: in the same way that [[Charles Darwin|Darwin]] thought of two species as possibly having a shared [[common ancestor|common ancestry]] followed by millions of years of evolutionary divergence (see [[speciation]]), a pseudogene and its associated functional gene also share a common ancestor and have diverged as separate genetic entities over millions of years. ==Properties of pseudogenes== Pseudogenes are characterized by a combination of '''[[Homology (biology)|homology]]''' to a known gene and '''nonfunctionality'''. That is, although every pseudogene has a [[DNA]] sequence that is similar to some functional gene, they are nonetheless unable to produce functional final products (nonfunctionality).<ref name="mighell_2000">Mighell, A. J., N. R. Smith, ''et al.'' (2000). "Vertebrate pseudogenes." ''FEBS Lett'' 468(2-3): 109-14. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10692568 PubMed] </ref> Pseudogenes are quite difficult to identify and characterize in genomes, because the two requirements of homology and nonfunctionality are implied through sequence calculations and alignments rather than biologically proven. #Homology is implied by sequence identity between the DNA sequences of the pseudogene and parent gene. After [[sequence alignment|aligning]] the two sequences, the percentage of identical [[base pair]]s is computed. A high sequence identity (usually between 40% and 100%) means that it is highly likely that these two sequences diverged from a common ancestral sequence (are homologous), and highly unlikely that these two sequences were independently created (see [[typewriting monkeys]]). #Nonfunctionality can manifest itself in many ways. Normally, a gene must go through several steps in going from a genetic DNA sequence to a fully-functional protein: [[Transcription (genetics)|transcription]], [[pre-mRNA processing]], [[translation (genetics)|translation]], and [[protein folding]] are all required parts of this process. If any of these steps fails, then the sequence may be considered nonfunctional. In high-throughput pseudogene identification, the most commonly identified disablements are [[stop codon]]s and [[frameshift]]s, which almost universally prevent the translation of a functional protein product. #Pseudogenes for RNA genes are often easier to discover. Many RNA genes occur as multiple copy genes, and pseudogenes are identified through sequence identity and location within the region. ==Types and origin of pseudogenes== There are three main types of pseudogenes, all with distinct mechanisms of origin and characteristic features. The classifications of pseudogenes are as follows: #'''Processed''' (or '''retrotransposed''') pseudogenes. In higher eukaryotes, particularly mammals, retrotransposition is a fairly common event that has had a huge impact on the composition of the genome. For example, somewhere between 30% - 44% of the [[human genome]] consists of repetitive elements such as SINEs and LINEs (see [[retrotransposons]]).<ref name="Jurka_2004">Jurka, J. (2004). "Evolutionary impact of human Alu repetitive elements." ''Curr Opin Genet Dev'' 14(6): 603-8.[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15531153 PubMed]</ref><ref name="Dewannieux_2005">Dewannieux, M. and T. Heidmann (2005). "LINEs, SINEs and processed pseudogenes: parasitic strategies for genome modeling." ''Cytogenet Genome Res'' 110(1-4): 35-48. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16093656 PubMed] </ref> In the process of retrotransposition, a portion of the [[messenger RNA|mRNA]] transcript of a gene is spontaneously [[reverse transcription|reverse transcribed]] back into DNA and inserted into chromosomal DNA. Although retrotransposons usually create copies of themselves, it has been shown in an ''in vitro'' system that they can create retrotransposed copies of random genes, too.<ref name="Dewannieux_2003"> Dewannieux, M., C. Esnault, ''et al.'' (2003). "LINE-mediated retrotransposition of marked Alu sequences." ''Nat Genet'' 35(1): 41-8. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12897783 PubMed] </ref> Once these pseudogenes are inserted back into the genome, they usually contain [[Splicing (genetics)|spliced-out introns]] and a [[polyadenylation|Poly-A tail]], two hallmarks features of [[cDNA]]s. However, because they are derived from a mature mRNA product, processed pseudogenes also lack the upstream [[promoters]] of normal genes; thus, they are considered "dead on arrival", becoming non-functional pseudogenes immediately upon the retrotransposition event.<ref name="Graur_1989"> Graur, D., Y. Shuali, ''et al.'' (1989). "Deletions in processed pseudogenes accumulate faster in rodents than in humans." ''J Mol Evol'' 28(4): 279-85. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2499684&dopt=Citation PubMed] [http://scholar.google.com/url?sa=U&q=http://www.springerlink.com/index/K921852G77248424.pdf PDF] </ref> A further characteristic of processed pseudogenes is common truncation of the 5' end relative to the parent sequence, which is a result of the relatively non-processive retrotransposition mechanism that creates processed pseudogenes.<ref name="Pavlicek_2002"> Pavlicek, A., J. Paces, ''et al.'' (2002). "Length distribution of long interspersed nucleotide elements (LINEs) and processed pseudogenes of human endogenous retroviruses: implications for retrotransposition and pseudogene detection." ''Gene'' 300(1-2): 189-94. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12468100 PubMed] </ref> #'''Non-processed''' (or '''duplicated''') pseudogenes. [[Gene duplication]] is another common and important process in the evolution of genomes. A copy of a functional gene may arise as a result of a gene duplication event and subsequently acquire [[mutation]]s that cause it to become nonfunctional. Duplicated pseudogenes usually have all the same characteristics of genes, including an intact [[exon]]-[[intron]] structure and promoter sequences. The loss of a duplicated gene's functionality usually has little effect on an organism's [[fitness (biology)|fitness]], since an intact functional copy still exists. According to some evolutionary models, shared duplicated pseudogenes indicate the evolutionary relatedness of humans and the other primates.<ref name="Max"> Edward E. Max, "Plagiarized Errors and Molecular Genetics: Another Argument in the Evolution-Creation Controversy," [http://www.talkorigins.org/faqs/molgen/] </ref> #'''Disabled''' genes, or '''unitary''' pseudogenes. Various mutations can stop a gene from being successfully transcribed or translated, and a gene may become nonfunctional or deactivated if such a mutation becomes fixed in the population. This is the same mechanism by which non-processed genes become deactivated, but the difference in this case is that the gene was not duplicated before becoming disabled. Normally, such gene deactivation would be unlikely to become fixed in a population, but various population effects, such as [[genetic drift]], a [[population bottleneck]], or in some cases, [[natural selection]], can lead to fixation. The classic example of a unitary pseudogene is the gene that presumably coded the enzyme [[L-gulonolactone oxidase|L-gulono-γ-lactone oxidase]] (GLO) in primates. In all mammals studied besides primates (except guinea pigs), GLO aids in the biosynthesis of [[Ascorbic acid]] (vitamin C), but it exists as a disabled gene in humans and other primates.<ref name="nishikimi"> Morimitsu Nishikimi ''et al.'', "L-gulono-Gamma-Lactone Oxidase, the Key Enzyme for L-Ascorbic Acid Biosynthesis Missing in This Species," ''Journal of Biological Chemistry'' 267 (1992): 21967-21972 </ref><ref name="nishikimi2"> Morimitsu Nishikimi ''et al.'', "Cloning and Chromosomal Mapping of Human Nonfunctional Gene for L-Gulono-Gamma-Lactone Oxidase, the Enzyme for L-Ascorbic Acid Biosynthesis Missing in Man," ''Journal of Biological Chemistry'' 269 (1994): 13685-13688 </ref> Another interesting and more recent example of a disabled gene, which links the deactivation of a [[caspase]] gene (through a [[nonsense mutation]]) to positive selection in humans, can be found in Xue ''et al.'' 2006.<ref name="Xue_2006"> Xue, Y., A. Daly, ''et al.'' (2006). "Spread of an inactive form of caspase-12 in humans is due to recent positive selection." ''Am J Hum Genet'' 78(4): 659-70. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16532395&dopt=Citation PubMed] </ref> Pseudogenes can complicate molecular genetic studies. For example, a researcher who wants to amplify a gene by [[Polymerase chain reaction|PCR]] may simultaneously amplify a pseudogene that shares similar sequences. This is known as PCR bias or amplification bias. Similarly, pseudogenes are sometimes annotated as genes in [[genome]] sequences. Processed pseudogenes often pose a problem for [[gene prediction]] programs, often being misidentified as real genes or exons. It has been proposed that identification of processed pseudogenes can help improve the accuracy of gene prediction methods.<ref name="Van_Baren_Brent_2006"> van Baren, M. J. and M. R. Brent (2006). "Iterative gene prediction and pseudogene removal improves genome annotation." ''Genome Res'' 16(5): 678-85. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16651666 PubMed] </ref> It has also been shown that the parent sequences that give rise to processed pseudogenes lose their coding potential faster than those giving rise to non-processed pseudogenes.<ref name="Zheng"> Deyou Zheng ''et al.'', "Pseudogenes in the ENCODE regions: Consensus annotation, analysis of transcription, and evolution," ''Genome Research'' 17(6) (2007): 839-851 </ref> ==Functional pseudogenes?== Pseudogenes, as defined have no function. However, the classification of pseudogenes in general, relies on the computational analysis of genomic sequences using complex [[algorithm]]s.<ref name="Harrison">Harrison, Paul M., ''et al.'' (2003) "Identification of pseudogenes in the Drosophila melanogaster genome." Nucl. Acids Res. 31(3):1033-7. [http://dx.doi.org/10.1093/nar/gkg169 DOI]</ref> This has led to pseudogenes being incorrectly identified, such as in the case of ''jingwei'', a chimeric gene found in ''[[Drosophila]]'' once thought to be a processed pseudogene. It was subsequently proven to be functional.<ref name="Long">Long, M. and Langley, C. H. (1993) "Natural selection and the origin of ''jingwei'', a chimeric processed functional gene in ''Drosophila''". Science. 260(5104): 91-95. [http://dx.doi.org/10.1126/science.7682012 DOI]</ref> It has been established that quite a few pseudogenes can go through the process of [[Transcription (genetics)|transcription]], either if their own [[promoter]] is still intact or in some cases using the promoter of a nearby gene; this expression of pseudogenes also appears to be tissue-specific.<ref name="Zheng"/> In 2003, Hirotsune ''et al.'' identified a retrotransposed pseudogene whose transcript purportedly plays a ''trans''-regulatory role in the expression of its homologous gene, ''Makorin1'', and suggested this as a general model under which pseudogenes may play an important biological role.<ref name="hirotsune"> Hirotsune, S., N. Yoshida, ''et al.'' (2003). "An expressed pseudogene regulates the messenger-RNA stability of its homologous coding gene." ''Nature'' 423(6935): 91-6. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12721631 PubMed]</ref> Other researchers have since hypothesized similar roles for other pseudogenes.<ref name="svensson_2006"> Svensson, O., L. Arvestad, ''et al.'' (2006). "Genome-wide survey for biologically functional pseudogenes." ''PLoS Comput Biol'' 2(5): e46. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16680195 PubMed] </ref> Hirotsune's report prompted two molecular biologists to carefully review scientific literature on the subject of pseudogenes. To the surprise of many, they found a number of examples in which pseudogenes play a role in gene regulation and expression,<ref name="balakirev">Evgeniy S. Balakirev and Francisco J. Ayala, "Pseudogenes: Are They ‘Junk’ or Functional DNA?" ''Annual Review of Genetics'' 37 (2003): 91-96.</ref> forcing Hirotsune's group to rescind their claim that they were the first to identify pseudogene function.<ref name="hirotsune2">Shinji Hirotsune ''et al.'', "Addendum: An Expressed Pseudogene Regulates the messenger-RNA Stability of Its Homologous Coding Gene," 'Nature' 426 (2003): 100</ref> Furthermore, the original findings of Hirotsune ''et al.'' concerning ''Makorin1'' have recently been strongly contested;<ref name="gray">Gray, T. ''et al.'' (2006). "The putatively functional Mkrn1-p1 pseudogene is neither expressed nor imprinted, nor does it regulate its source gene in trans." ''Proc. Nat. Acad. Sci. USA'' 103(32):12039-44. [http://www.pnas.org/cgi/content/abstract/0602216103v1 Abstract]</ref> thus, the possibility that some pseudogenes could have important biological functions was disputed. Additionally, University of Chicago and University of Cincinnati scientists reported in 2002 that a processed pseudogene called Phosphoglycerate mutase or [http://www.gene.ucl.ac.uk/nomenclature/data/get_data.php?hgnc_id=HGNC:16557 PGAM3] actually produces a functional protein.<ref name="betran">Esther Betrán ''et al.'', "Evolution of the Phosphoglycerate mutase Processed Gene in Human and Chimpanzee Revealing the Origin of a New Primate Gene," 'Molecular Biology and Evolution' 19 (2002): 654-663.</ref> A 2008 publication in Nature discusses that some endogenous siRNAs are derived from pseudogenes, and thus some pseudogenes play a role in regulating protein-coding transcripts ("Endogenous siRNAs from naturally formed dsRNAs regulate transcripts in mouse oocytes" Nature 453 (22) May 2008 pgs 539-544) ==References== <div class="references-small"> <references/> </div> ==External links== * [http://pseudogene.org/ Yale University pseudogene database] * [http://genome.uiowa.edu/pseudogenes/ University of Iowa pseudogene database] * [http://pbil.univ-lyon1.fr/databases/hoppsigen.html Hoppsigen database] (homologous processed pseudogenes) * [http://www.bork.embl-heidelberg.de/Docu/Human_Pseudogenes/ Bork pseudogenes] (published in Torrents ''et al.'' 2003 <sup>[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14656963 PubMed]</sup>) * [http://www.sciam.com/article.cfm?chanID=sa006&colID=1&articleID=000C8CFC-357C-14C0-AFE483414B7F4945 The Real Life of Pseudogenes] (published in Scientific American) ==See also== * [[Molecular evolution]] * [[Retrotransposon]] * [[Retroposon]] [[Category:genetics]] [[de:Pseudogen]] [[es:Seudogén]] [[fr:Pseudogène]] [[he:פסאודוגן]] [[it:Pseudogene]] [[hu:Pszeudogén]] [[ja:偽遺伝子]] [[no:Pseudogen]] [[pl:Pseudogen]] [[sv:Pseudogen]] [[zh:偽基因]]