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Pseudogene

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Pseudogenes are dysfunctional relatives of 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 (premature 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. We can define a pseudogene operationally as a fragment of nucleotide sequence that resembles a known protein domain's but with stop codons or frameshifts mid-domain. 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.

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 protein products.[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 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 Convergent evolution).
  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.

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] However, occasionally these insertions contribute exons to existing genes and usually via alternatively spliced transcripts.[10] 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.[11]
  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.[12] If Pseudogenization it is due to gene duplication, it usually occurs in the first few million years after the gene duplication provided the gene is not been subjected to any selection pressure.[13] The functional redundancy will be generated by gene duplication and mostly it is of course not advantageous to carry two identical genes, and mutations that disrupts either structure or function of any one of the two genes are not deleterious and will not be removed through selection process. As a result, that gene that has been mutated gradually becomes a pseudogene and will be either unexpressed or functionless. This kind of evolutionary fate is shown by population genetic modeling[14][15] and also by genome analysis.[13][16] These pseudogenes according to evolutionary context will either be deleted or become so distinct from the parental genes so that they will be no more identifiable. Relatively young pseudogenes can be recognizable due to their sequence similarity.[17]
  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.[18][19] 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.[20]

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.[21]

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.[22] 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.[23]

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 (MKRN1) (see also RING finger domain and ubiquitin ligases), and suggested this as a general model under which pseudogenes may play an important biological role.[24] Other researchers have since hypothesized similar roles for other pseudogenes.[25] A bioinformatics analysis has shown that processed pseudogenes can be inserted into introns of annotated genes and be incorporated into alternatively spliced transcripts.[10] 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,[26] forcing Hirotsune's group to rescind their claim that they were the first to identify pseudogene function.[27] Furthermore, the original findings of Hirotsune et al. concerning Makorin1 have recently been strongly contested;[28] 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.[29]

Two 2008 publications in Nature discuss that some endogenous siRNAs are derived from pseudogenes, and thus some pseudogenes play a role in regulating protein-coding transcripts.[30][31] In June 2010, Nature published an article showing the mRNA levels of tumour suppressor PTEN and oncogenic KRAS is affected by their pseudogenes PTENP1 and KRAS1P. This discovery demonstrated an miRNA decoy function for pseudogenes and identified their transcripts as biologically active units in tumor biology; thus attributing a novel biological role to expressed pseudogenes, as they can regulate coding gene expression, and reveal a non-coding function for mRNAs in disease progression.[32]

Resurrection of a pseudogene?

The duplicated pseudogenic DNA can be resurrected to a functional protein in certain cases as a rare or occasional evolutionary event and may enable sampling of more sequence space for a protein or protein family.[17] The pseudogenes or parts of pseudogenes may be re-utilized once they have been drifted randomly without being subjected to selection pressure for certain period of evolution. Koch, for the first time, postulated an idea about such “untranslatable intermediates” in the evolution of protein.[33] Occasionally this mechanism may yield a shorter evolutionary route to another desirable or favorable evolutionary energetic minimum although one would generally expect it to produce unviable or unfavorable leaps in sequence space. A longer time will be available to search sequence space by the pseudogene resurrection, but it is believed that it rarely brings in to existence the proteins with new functions. The repair of lesions could be achieved by the reinsertion of a deleted segment, the removal (in frame) of an inserted segment, or other events that are likely to be improbable like gene conversion. Conversion of a pseudogene with a functional gene as a donor might improve the probability of pseudogene reactivation provided enough of the pseudogene sequence must be preserved throughout the course to maintain the benefits of expanding the sequence space explored after duplication.[34]

There are several examples that can be used to support such resurrection. The Bovine Seminal Ribonuclease, which was been laid dormant for about 20 million years as a pseudogene, appears to have been resurrected into a functional gene. It is believed that the event called gene conversion may be the cause of such resurrection.[35] The large group of pseudogenes for olfactory receptors (ORs) in metazoans, where 60% of the ORs in the human genome are pseudogenic, are resurrectable may be due to gene conversion events. In a cluster of ORs which contains 16 OR genes and 6 OR pseudogenes on chromosome 17 is appeared to be subjected to many number (20) of gene conversion events over the course of primate evolution.[36] These gene conversion events in OR gene clusters may aid to bring diversity in binding capability at the odorant binding site.[36] Finally, the resurrection of a pseudogene also led to the diversity of immunoglobulin heavy chain variable-region gene segments in the chicken which appears to be brought by the gene conversion event of a single functional gene with more than 80 pseudogenic gene segments.[37]

The era of molecular paleontology is exciting and is just beginning. Just now the surface of the pseudogene strata is barely scratched and if we drill deeper, we can identify many more number of pseudogenes with more surprises. The data mining process of large scale identification of pseudogenes is very dynamic. The very ancient and decayed pseudogenes are escaping from detection although the recently generated pseudogenes are readily identified by the current techniques which are heavily based on the sequence comparison to well characterized genes. Characterization of pseudogenes will be improved as well since the sequence and annotation of the human genome itself are refined and updated. Recent clues like all pseudogenes are not dead have been plotted and some possibilities of pseudogene resurrection- a dead gene become a living one and makes a functional protein exist with the evidence.[38]

In addition to the seminal ribonuclease enzyme, the other incidents like slight differences in the pseudogene complements of individual people have also been found. For instance, in most people the olfactory receptor pseudogenes are dead but in few they are intact and functional genes. Some studies also suggested that however that in yeast, certain cell surface protein pseudogenes are resurrected due to stressful new environment challenged the organism. The two processed pseudogenes called the rat RC9 cytochrome c pseudogene[39] and the mouse L 32 ribosomal protein pseudogene rpL32-4A are implied to be potentially functional.[40] From the recent experiments, they found that in a bacterial genome a considerable segment of the intergenic regions are actively transcribed.[41] From the ENCODE project, scientists have found about 20% of the TARS were produced from previously unidentified ‘potential unborn genes’ which says that there are functional pseudogenes inside these regions.[42] To make sure that do the pseudogenes are transcribed in to RNA and to ascertain their functionality the studies on mouse oocyte are very useful where the small interfering RNAs (siRNAs) derived from pseudogene are found to be functional in regulating gene expression.[43] Some pseudogenes are dead yet with some functions strengthen the fact that they are not ‘junk DNA”. With the embedded picture of genome annotation the real evolutionary history of pseudogenes will be revealed out in the near future of research.

See also

References

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