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What are pseudogenes?

Pseudogenes are DNA sequences present in a given population, characterized by close similarities to paralogous genes and non-functionality (Mighell et al., 2000). They contain important defects that make them incapable of producing proteins in transcription and/or translation stages, or in a different scenario, they might produce a protein which is functionally different than the one produced by a normal paralog gene (Gibson, 1994).

Non-functionality in pseudogenes is due to several reasons such as lacking start codons, lacking or having an extra stop codon, and altered sequence or flanking regulatory elements, all of which are necessary in normal genes for conducting proper transcription (Gibson, 1994). It is thought that mutations in pseudogenes are neutral and free from selection, and this is mainly due to the fact that they are, in most cases, located in loci where they do not cause a deleterious effect (Mighell et al., 2000).


Pseudogenes arise by two fundamentally different ways:

1) Retrotransposition:

Retrotransposition is one of the basic processes by which pseudogenes arise. Almost 80% of pseudogenes have been generated in this way (Mighell et al., 2000). A brief description of this process might be helpful to better understand how pseudogenes emerge.

The processed mRNA of functional genes may serve as a template, from which a double stranded DNA, called retrotransposon, is generated (Vanin, 1985). Retrotransposons have the ability to insert themselves into the genomic DNA, a process called retrotransposition. Although typical transposable elements carry functional sequences for the purpose of their insertion, some retrotransposons in humans do not have such sequences. This implies that human cells may possess an intrinsic reverse transcription activity, providing a  necessary tool for generation of pseudogenes (Dhellin et al., 1997).  

Retrotransposition may have different outcomes, depending on the effect of natural selection pressure on the newly arisen phenotype. It could potentially be fatal to the entire organism, if retrotransposed sequences  interrupt genes with crucial functions in life (Mighell et al., 2000). Obviously, with the deletion of organisms carrying the defective gene, the retrotransposed element would not be viable, either. Retrotranspositions occurring in the non-coding regions of genomic DNA, however, are not subjected to the immediate natural selection pressure and survive in the form of non-functional pseudogenes. Transcription does not take place from processed pseudogenes, since they lack the crucial 5’-promoter sequence as well as introns, which may also contain transcription initiation sites. Processed pseudogenes, however, contain 3’- polyadenylation tract and flanking direct repeats, sequences presumably involved in the process of insertion (Mighell et al., 2000).    

Rarely, are retrotransposons maintained as functional, intronless genes. PGK-2 in humans and Amd-2 in mice are the two functional retrotransposed genes corresponding to PGK-1 and Amd-1, respectively. In either case, protein produced by the intronless retrotransposed  gene is highly homologous to the one produced by the original gene (Mighell et al., 2000)

In short, a number of pseudogenes arise by the insertion of retrotransposons in non-coding regions of the genomic DNA. It is very unlikely that processed pseudogenes change the organism’s phenotype, mainly because of two reasons. First they are basically not transcribed and cannot produce proteins, and second, they result from retrotransposition in non-coding regions; hence no pre-existing phenotype is altered. In a few instances, however, retrotransposition gives rise to functional intronless genes.


2) Duplication of genomic DNA:

A less common mechanism for pseudogene generation relies on gene duplication. Gene duplication is a source of genetic diversity which is thought to provide the species with adaptability to the changing environment. All members of a gene family originate from an ancestral gene. Their functionality, however, take on different fates as mutations start to accumulate over time. Some acquire novel adaptive functions in parallel with the environmental changes. Others may maintain their original function, whereas the rest lose their functions and become silent. This last group is, in fact, pseudogenes which have lost their functions either due to conferring a disadvantageous phenotype or due to not giving a selection advantage (Mighell et al., 2000). Hox genes belong to a family of genes with developmental roles and are highly conserved between different species. Two Hox genes have turned into pseudogenes during the evolution of the puffer fish, while they are ubiquitously expressed in other species (Meyer, 1998).  

Sometimes, emergence of pseudogenes by DNA duplication does not result from accumulation of mutations. Rather, the duplicated gene might be defective and non-functional from the very moment that duplication takes place. For instance, yBRCA1 (y denotes pseudogene) arises from a tandem duplication of the 5’-end of the BRCA1 gene. This pseudogene contains only exons 1A, 1B, and 2 of the intact gene, and presumably, has never been functional (Brown et al., 1996).  

In summary, DNA duplication serves as the second most important mechanism through which pseudogenes evolve. DNA duplication gives rise to a series of homologous sequences whose functions are determined by accumulation of mutations as well as natural selection pressure from the environment. Intuitively, those sequences with unfavorable functions are doomed to be silenced into pseudogenes or the organisms cannot survive.


Fig 1: A schematic summary, to be interpreted in conjunction with the text, of the principal issues covered. The width of the arrows gives a rough guide to the relative importance of the different pathways at each level. A: Origin of pseudogenes. The majority of vertebrate pseudogenes are probably derived from functional genes. B: Mechanism of pseudogene formation. The majority of vertebrate pseudogenes are a result of retrotransposition of transcripts derived from genes that encode functional proteins. C: Pseudogene location. Pseudogenes persist in parts of the genome where they do not have a deleterious effect on fitness of the organism. D: Pseudogene fate. Most pseudogenes undergo genetic drift and are never transcribed. By contrast, in some instances there appears to selectional pressures that prevent major changes to the pseudogene sequence. A few pseudogenes are involved in gene conversion and a few can be transcribed. Accordingly, not all pseudogenes are unequivocally functionless. (Re-printed with permission of FEBS Letters and Dr. A.J. Mighell).

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