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pseudogene

 
Dictionary: pseu·do·gene   (sū'də-jēn') pronunciation
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n.
A defective segment of DNA that resembles a gene but cannot be transcribed.


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Genetics Encyclopedia: Pseudogenes
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Pseudogenes are defective copies of functional genes. These may be partial or complete duplicates derived from polypeptide-encoding genes or RNA genes. The DNA sequence of a pseudogene is characteristically very similar to its functional counterpart, but contains variant mutations that render the gene inactive. The functional polypeptide-encoding gene contains an open reading frame, a long stretch of nucleotides that are transcribed and subsequently translated into a series of amino acids uninterrupted by stop codons. In contrast, pseudogenes derived from polypeptide sequences generally are punctuated with stop codons, effectively rendering them incapable of producing a functional protein.

Pseudogenes may also contain frameshift mutations, yielding a change in the reading frame. Additionally, there may be mutations that inactivate regulatory elements or intron-splicing sites. In either case, the duplicated gene may be rendered nonfunctional. Genes and pseudogenes derived from the duplication of an ancestral gene are said to be paralogous.

Nonprocessed Pseudogenes

Gene duplication may occur by a direct increase of DNA content (non-processed) or via an RNA intermediate (processed). Nonprocessed pseudo-genes can arise by unequal crossing over in homologous chromosomes (paired meiotic chromosomes containing the same genetic loci) or unequal sister chromatid exchange (crossover at improperly aligned sequences) after replication in a single chromosome (Figure 1A). Replication slippage also increases DNA content by looping of the synthesized strand during DNA replication, but typically involves short sequence stretches such as microsatellites (short repeated sequences).

A nonprocessed duplicated gene contains the introns and regulatory sequences of the original gene. This yields genetic redundancy, which allows one of the genes to acquire mutations, becoming a nonfunctional pseudo-gene (Figure 2). Occasionally, the duplicated gene acquires mutations yielding a gain-of-function that differs from the original gene (Figure 2). This may allow the evolution of new capabilities in the organism possessing it.

New genes generated by nonprocessed duplication are generally located in the vicinity of the ancestral (original) gene within the genome. However, it is possible that these genes may become separated from each other as a result of major chromosomal rearrangements (such as translocations). Examples of functional and nonfunctional duplicated genes in adjacent locations and on different chromosomes are exhibited by the globin gene superfamily.

Processed Pseudogenes

Pseudogenes generated via a messenger RNA (mRNA) intermediate demonstrate the features of processed RNA. These genes lack the flanking transcriptional regulatory sequences, do not contain introns, and typically have a polyadenylated 3′ (3-prime) region (adenine-containing nucleotides are added to the mRNA in eukaryotes). These sequences are converted to complementary DNA (cDNA) by the enzyme reverse transcriptase, and then integrated back in the genome at a new location (Figure 1B). These elements, therefore, are not necessarily in the chromosomal vicinity of the original sequence, and are essentially dead on arrival. Processed pseudogenes are also referred to as retropseudogenes.

Processed pseudogenes may also be derived from other RNA genes, such as tRNA (transfer RNA), rRNA (ribosomal RNA), snRNA (small nuclear RNA), and 7SL RNA. Evidence for this phenomenon includes the identification of nonfunctional tRNA genes containing a CCA sequence at the 3′ terminal. CCA is not part of the original DNA sequence, but is enzymatically added to the tRNA molecule following transcription. The gene for 7SL RNA is an integral component of the signal recognition particle complex involved in transmembrane protein transport. The 7SL RNA gene is thought to be the ancestral gene for the primate Alu and rodent B1 retroposons, based on sequence similarities. (Retroposons are a type of transposable genetic element that is found littered throughout the genome.) The Alu element differs from 7SL by having two internal sequence deletions, duplication of the entire sequence, and numerous nucleotide substitutions. At some point in its evolutionary past a 7SL retropseudogene apparently integrated into a highly fortuitous location, as there are about 1.5 million Alu elements in the human genome, accounting for approximately 10 percent of our DNA. Most Alu elements are retropositionally incompetent pseudogenes, hence incapable of generating additional copies. Other retroposons are thought to be derived from processed duplicated tRNA genes (for example, rodent B2 and ID elements).

Pseudogene Examples

The globin gene superfamily provides an interesting example of the generation of both functional and nonfunctional duplicated genes (Figure 3). Based on nucleotide sequence data, it appears that a gene duplication occurred about 600 to 800 million years ago, yielding myoglobin and hemoglobin genes. Another duplication of the hemoglobin gene occurred about 500 million years ago, yielding α-globin and β-globin genes. (Adult human hemoglobin contains two α and two β strands.) These are all functional genes, found on three different human chromosomes. The α-globin and β-globin genes further duplicated, yielding both pseudogenes and functional genes. Possession of more than one globin gene provides a selective advantage because it compensates for the variation of oxygen in the prenatal versus postnatal environment.

The α-globin gene cluster consists of three functional genes and three pseudogenes. There is also an additional gene that is expressed but not incorporated into a hemoglobin molecule. In other words, this would be an example of an expressed pseudogene. The β-globin gene complex consists of five functional genes and one pseudogene. Examples of other processed polypeptide-encoding pseudogenes include those derived from actin, ferritin, and glyceraldehyde 3-phosphate dehydrogenase genes.

Bibliography

Brown, Terence A. Genomes. New York: John Wiley & Sons, 1999.

Li, Wen-Hsiung. Molecular Evolution. Sunderland, MA: Sinauer Associates, 1997.

Strachan Tom, and Andrew P. Read. Human Molecular Genetics, 2nd ed. New York:John Wiley & Sons, 1999.

—David H. Kass and Mark A. Batzer

Biology Q&A: What is a pseudogene?
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As genes are copied and transposed, mutations may occur that make the copies nonfunctional. This is thought to be the origin of pseudogenes, which resemble actual genes but which, while stable, do not produce a polypeptide.

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Veterinary Dictionary: pseudogene
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A nonfunctional DNA sequence, nearly homologous to a functional gene.

Wikipedia: Pseudogene
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Pseudogenes are defunct relatives of known genes that have lost their protein-coding ability or are otherwise no longer expressed in the cell.[1] Although some do not have introns or promoters (these pseudogenes are copied from mRNA and incorporated into the chromosome and are called processed pseudogenes)[2], most have some gene-like features (such as promoters, CpG islands, and splice sites), they are nonetheless considered nonfunctional, due to their lack of protein-coding ability resulting from various genetic disablements (stop codons, frameshifts, or a lack of transcription) or their inability to encode RNA (such as with rRNA pseudogenes). Thus the term, coined in 1977 by Jacq, et al.,[3] is composed of the prefix pseudo, which means false, and the root gene, which is the central unit of molecular genetics.

Because pseudogenes are generally thought of as the last stop for genomic material that is to be removed from the genome,[4] they are often labeled as junk DNA. Nonetheless, pseudogenes contain fascinating biological and evolutionary histories within their sequences. This is due to a pseudogene's shared ancestry with a functional gene: in the same way that Darwin thought of two species as possibly having a shared 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.

Contents

Properties of pseudogenes

Pseudogenes are characterized by a combination of 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).[5] 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.

  1. Homology is implied by sequence identity between the DNA sequences of the pseudogene and parent gene. After aligning the two sequences, the percentage of identical base pairs is computed. A high sequence identity (usually between 40% and close to 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).
  2. 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, pre-mRNA processing, 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 codons and frameshifts, which almost universally prevent the translation of a functional protein product.
  3. 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:

  1. 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).[6][7] In the process of retrotransposition, a portion of the mRNA transcript of a gene is spontaneously 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.[8] Once these pseudogenes are inserted back into the genome, they usually contain a poly-A tail, and usually have had their introns spliced out; these are both hallmark features of cDNAs. 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.[9] 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.[10]
  2. 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 mutations 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, 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.[11]
  3. 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-gulono-γ-lactone oxidase (GULO) in primates. In all mammals studied besides primates (except guinea pigs), GULO aids in the biosynthesis of Ascorbic acid (vitamin C), but it exists as a disabled gene (GULOP) in humans and other primates.[12][13] Another interesting and more recent example of a disabled gene, which links the deactivation of the caspase 12 gene (through a nonsense mutation) to positive selection in humans.[14]

Pseudogenes can complicate molecular genetic studies. For example, a researcher who wants to amplify a gene by 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.[15]

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.[4]

Functional pseudogenes?

By definition, pseudogenes lack a function. However, the classification of pseudogenes generally relies on computational analysis of genomic sequences using complex algorithms.[16] This has led to the incorrect identification of pseudogenes. For example the functional, chimeric gene jingwei in Drosophila was once thought to be a processed pseudogene. [17]

It has been established that quite a few pseudogenes can go through the process of 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.[4] 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.[18] Other researchers have since hypothesized similar roles for other pseudogenes.[19] 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,[20] forcing Hirotsune's group to rescind their claim that they were the first to identify pseudogene function.[21] Furthermore, the original findings of Hirotsune et al. concerning Makorin1 have recently been strongly contested;[22] 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 3 (PGAM3P) actually produces a functional protein.[23]

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.[24]

References

  1. ^ Vanin EF (1985). "Processed pseudogenes: characteristics and evolution". Annu. Rev. Genet. 19: 253–72. doi:10.1146/annurev.ge.19.120185.001345. PMID 3909943. 
  2. ^ Evolutionary Analysis Fourth Edition, Freeman Scott, Herron John C.
  3. ^ Jacq C, Miller JR, Brownlee GG (September 1977). "A pseudogene structure in 5S DNA of Xenopus laevis". Cell 12 (1): 109–20. doi:10.1016/0092-8674(77)90189-1. PMID 561661. 
  4. ^ a b c Zheng D, Frankish A, Baertsch R, Kapranov P, Reymond A, Choo SW, Lu Y, Denoeud F, Antonarakis SE, Snyder M, Ruan Y, Wei CL, Gingeras TR, Guigó R, Harrow J, Gerstein MB (June 2007). "Pseudogenes in the ENCODE regions: consensus annotation, analysis of transcription, and evolution". Genome Res. 17 (6): 839–51. doi:10.1101/gr.5586307. PMID 17568002. 
  5. ^ Mighell AJ, Smith NR, Robinson PA, Markham AF (February 2000). "Vertebrate pseudogenes". FEBS Lett. 468 (2-3): 109–14. doi:10.1016/S0014-5793(00)01199-6. PMID 10692568. 
  6. ^ Jurka J (December 2004). "Evolutionary impact of human Alu repetitive elements". Curr. Opin. Genet. Dev. 14 (6): 603–8. doi:10.1016/j.gde.2004.08.008. PMID 15531153. 
  7. ^ Dewannieux M, Heidmann T (2005). "LINEs, SINEs and processed pseudogenes: parasitic strategies for genome modeling". Cytogenet. Genome Res. 110 (1-4): 35–48. doi:10.1159/000084936. PMID 16093656. 
  8. ^ Dewannieux M, Esnault C, Heidmann T (September 2003). "LINE-mediated retrotransposition of marked Alu sequences". Nat. Genet. 35 (1): 41–8. doi:10.1038/ng1223. PMID 12897783. 
  9. ^ Graur D, Shuali Y, Li WH (April 1989). "Deletions in processed pseudogenes accumulate faster in rodents than in humans". J. Mol. Evol. 28 (4): 279–85. doi:10.1007/BF02103423. PMID 2499684. 
  10. ^ Pavlícek A, Paces J, Zíka R, Hejnar J (October 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. doi:10.1016/S0378-1119(02)01047-8. PMID 12468100. 
  11. ^ Max EE (2003-05-05). "Plagiarized Errors and Molecular Genetics". TalkOrigins Archive. http://www.talkorigins.org/faqs/molgen/. Retrieved 2008-07-22. 
  12. ^ Nishikimi M, Kawai T, Yagi K (October 1992). "Guinea pigs possess a highly mutated gene for L-gulono-gamma-lactone oxidase, the key enzyme for L-ascorbic acid biosynthesis missing in this species". J. Biol. Chem. 267 (30): 21967–72. PMID 1400507. http://www.jbc.org/cgi/content/abstract/267/30/21967. 
  13. ^ Nishikimi M, Fukuyama R, Minoshima S, Shimizu N, Yagi K (May 1994). "Cloning and chromosomal mapping of the human nonfunctional gene for L-gulono-gamma-lactone oxidase, the enzyme for L-ascorbic acid biosynthesis missing in man". J. Biol. Chem. 269 (18): 13685–8. PMID 8175804. http://www.jbc.org/cgi/content/abstract/269/18/13685. 
  14. ^ Xue Y, Daly A, Yngvadottir B, Liu M, Coop G, Kim Y, Sabeti P, Chen Y, Stalker J, Huckle E, Burton J, Leonard S, Rogers J, Tyler-Smith C (April 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. doi:10.1086/503116. PMID 16532395. 
  15. ^ van Baren MJ, Brent MR (May 2006). "Iterative gene prediction and pseudogene removal improves genome annotation". Genome Res. 16 (5): 678–85. doi:10.1101/gr.4766206. PMID 16651666. 
  16. ^ Harrison PM, Milburn D, Zhang Z, Bertone P, Gerstein M (February 2003). "Identification of pseudogenes in the Drosophila melanogaster genome". Nucleic Acids Res. 31 (3): 1033–7. doi:10.1093/nar/gkg169. PMID 12560500. 
  17. ^ Long M, Langley CH (April 1993). "Natural selection and the origin of jingwei, a chimeric processed functional gene in Drosophila". Science (journal) 260 (5104): 91–5. doi:10.1126/science.7682012. PMID 7682012. 
  18. ^ Hirotsune S, Yoshida N, Chen A, Garrett L, Sugiyama F, Takahashi S, Yagami K, Wynshaw-Boris A, Yoshiki A (May 2003). "An expressed pseudogene regulates the messenger-RNA stability of its homologous coding gene". Nature 423 (6935): 91–6. doi:10.1038/nature01535. PMID 12721631. 
  19. ^ Svensson O, Arvestad L, Lagergren J (May 2006). "Genome-wide survey for biologically functional pseudogenes". PLoS Comput. Biol. 2 (5): e46. doi:10.1371/journal.pcbi.0020046. PMID 16680195. 
  20. ^ Balakirev ES, Ayala FJ (2003). "Pseudogenes: are they "junk" or functional DNA?". Annu. Rev. Genet. 37: 123–51. doi:10.1146/annurev.genet.37.040103.103949. PMID 14616058. 
  21. ^ Hirotsune S, Yoshida N, Chen A, Garrett L, Sugiyama F, Takahashi S, Yagami K, Wynshaw-Boris A, Yoshiki A (November 2003). "Addendum: An Expressed Pseudogene Regulates the messenger-RNA Stability of Its Homologous Coding Gene". Nature 426 (100): 100. doi:10.1038/nature02094. PMID 12721631. 
  22. ^ Gray TA, Wilson A, Fortin PJ, Nicholls RD (August 2006). "The putatively functional Mkrn1-p1 pseudogene is neither expressed nor imprinted, nor does it regulate its source gene in trans". Proc. Natl. Acad. Sci. U.S.A. 103 (32): 12039–44. doi:10.1073/pnas.0602216103. PMID 16882727. 
  23. ^ Betrán E, Wang W, Jin L, Long M (May 2002). "Evolution of the phosphoglycerate mutase processed gene in human and chimpanzee revealing the origin of a new primate gene". Mol. Biol. Evol. 19 (5): 654–63. PMID 11961099. http://mbe.oxfordjournals.org/cgi/content/abstract/19/5/654. 
  24. ^ Watanabe T, Totoki Y, Toyoda A, Kaneda M, Kuramochi-Miyagawa S, Obata Y, Chiba H, Kohara Y, Kono T, Nakano T, Surani MA, Sakaki Y, Sasaki H (May 2008). "Endogenous siRNAs from naturally formed dsRNAs regulate transcripts in mouse oocytes". Nature 453 (7194): 539–43. doi:10.1038/nature06908. PMID 18404146. 

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Dictionary. The American Heritage® Dictionary of the English Language, Fourth Edition Copyright © 2007, 2000 by Houghton Mifflin Company. Updated in 2009. Published by Houghton Mifflin Company. All rights reserved.  Read more
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