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Pseudogenes are defunct relatives of known genes that have lost their protein-coding ability or are no longer expressed in the cell. Vanin, E. F. (1985). "Processed pseudogenes: characteristics and evolution." Annu Rev Genet 19: 253-72. PubMed . Although they may 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). Thus the term, coined in 1977 by Jacq et al. Jacq, C., J. R. Miller, et al. (1977). "A pseudogene structure in 5S DNA of Xenopus laevis." Cell 12(1): 109-20.PubMed , is composed of the prefix pseudo, which means false, and the suffix gene, which is the atomic unit of molecular genetics.
Although they are often labeled as Junk DNA, 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 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.
=Overview=
Properties of pseudogenes
Pseudogenes are characterized by a combination of homology to a known gene and nonfunctionality. That is, although every pseudogene has a similar DNA sequence to some functional gene (homology), they are nonetheless unable to produce functional protein products (nonfunctionality) Mighell, A. J., N. R. Smith, et al. (2000). "Vertebrate pseudogenes." FEBS Lett 468(2-3): 109-14. PubMed . 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 aligning the two sequences, the percentage of identical base pairs 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, 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, 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 stop the translation of a functional protein product.
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) Jurka, J. (2004). "Evolutionary impact of human Alu repetitive elements." Curr Opin Genet Dev 14(6): 603-8.PubMedDewannieux, M. and T. Heidmann (2005). "LINEs, SINEs and processed pseudogenes: parasitic strategies for genome modeling." Cytogenet Genome Res 110(1-4): 35-48. PubMed
- 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.
- Disabled genes. 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. An interesting example which links the deactivation of a gene (through a nonsense mutation) to positive selection in humans can be found in Xue et al. 2006
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.
As is frequently the case in molecular biology, one can find unusual examples that challenge any simple definition of a term, and pseudogene is no exception. There is some difference among geneticists concerning the nature of the end product. If the end product is required to be a protein, then some pseudogenes can function as an RNA. See, for example, Hirotsune et al (2003) 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. PubMed discovered a sequence in the human genome that was identified as a pseudogene but apparently has a regulatory function for the homologous protein-coding gene. However, this definition does not allow for tRNA or rRNA pseudogenes, as other geneticists use the term. The mouse Makorin pseudogene also produces a functional product. In 2006, researchers hypothesized two pseudogenes in humans from the Ataxin family, which includes a number of genes related to neurogenerative disorders Svensson, O., L. Arvestad, et al. (2006). "Genome-wide survey for biologically functional pseudogenes." PLoS Comput Biol 2(5): e46. PubMed
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 van Baren, M. J. and M. R. Brent (2006). "Iterative gene prediction and pseudogene removal improves genome annotation." Genome Res 16(5): 678-85. PubMed .
=References=
- Yale University pseudogene database
- University of Iowa pseudogene database
- Hoppsigen database (homologous processed pseudogenes)
- Bork pseudogenes (published in Torrents et al. 2003 PubMed)
=See also=
Pseudogen | Seudogén | Pszeudogén | 偽遺伝子 | Pseudogen | Pseudogen
"Pseudogene"