PSEUDOGENES: FUNCTIONS AND TYPES - BIOLOGY - 2024

The pseudogenes are ubiquitous and quite abundant sequences in the genomes of living organisms, from animals and plants to bacteria. Historically they were considered as fossils or simply as "junk DNA".

However, today it is known that pseudogenes have regulatory functions, and some can even be transcribed into functional RNA. Its role in regulation can be carried out through the silencing or formation of small RNAs or through changes in the messenger RNA that codes for a certain protein.

Source: Rcrzarg at English Wikipedia

In studies conducted on the human genome, it has been estimated that there are about 20,000 pseudogenes - a number comparable to the sequences that code for proteins.

Certain authors consider it difficult to establish a boundary between a gene and a pseudogene, since on some occasions the non-functionality of genes is not clear. Current knowledge of pseudogenes is shallow and there are still many questions on the subject.

What are pseudogenes?

Pseudogenes are copies of certain genes that have deficient or "damaged" sequences, due to various causes.

These damages occur due to changes in reading frames or premature stop codons. However, these are structurally reminiscent in various aspects of the gene that originated them.

Pseudogenes can be located anywhere in the genome. Retrotransposition processes can cause them to cluster adjacent to their paralogue gene, or to be inserted at a distant location - even on another chromosome.

History

DNA is more complex than it seems. Not all sections of it are protein-coding. That is, not all regions are converted into messenger RNA, which is then translated into a sequence of amino acids - the building blocks of proteins.

With the sequencing of the human genome, it became very clear that only a small portion (about 2%) codes for proteins. Biologists instantly wondered the function of this immense amount of DNA that seems to be unimportant.

For many years, all DNA that did not code for proteins, or noncoding DNA, was - wrongly - considered junk DNA.

These regions include transposable elements, structural variants, duplicate segments, tandem repeating sequences, conserved noncoding elements, functional noncoding RNA, regulatory elements, and pseudogenes.

Today, the term junk DNA has been totally dropped from the literature. Evidence has made it clear that pseudogenes participate as regulatory elements of different cellular functions.

The first pseudogene reported was in 1977 in the DNA of the amphibian Xenopus laevis. From that moment, different pseudogenes began to be reported, in different organisms, including plants and bacteria.

Features

As discussed, pseudogenes are very far from being inactive copies of another gene. Recent studies support the idea that pseudogenes act as regulatory elements in the genome, modifying their "cousins" that code for proteins.

Furthermore, several pseudogenes can be transcribed into RNA, and some show a tissue-specific activation pattern.

The pseudogene transcript can be processed into small interfering RNAs that regulate the coding sequences via RNAi.

A notable discovery was to find that pseudogenes are able to regulate tumor suppressors and certain oncogenes, through the activation of specific microRNAs.

In this valuable finding, it was noted that pseudogenes often lose their regulation during cancer progression.

This fact warrants further investigation into the true scope of the pseudogene's function, to get a better idea of ​​the intricate regulatory network in which they are implicated, and to use this information for medical purposes.

Types of pseudogenes

Processed and unprocessed

Pseudogenes are classified into two broad categories: processed and unprocessed. The latter are divided into a subcategorization into unit and duplicate pseudogenes.

Pseudogenes are produced by the deterioration of genes that originated by duplication in the course of evolution. These "impairments" occur by different processes, be it point mutations, insertions, deletions or changes in the open reading frame.

Loss of productivity or expression due to the aforementioned events results in the production of unprocessed pseudogene. Those of the unitary type are a single copy of a parental gene that becomes non-functional.

Unprocessed pseudogenes and duplicates maintain the structure of a gene, with introns and exons. In contrast, processed pseudogenes originate from retrotransposition events.

Retrotransposition occurs by the reintegration of a cDNA (complementary DNA, which is a reverse copy of a messenger RNA transcript) in a certain area of ​​the genome.

The double-stranded sequence of the processed pseudogene is generated by a single-stranded RNA generated by RNA polymerase II.

Living genes, phantom and dead pseudogenes

Another classification, proposed by Zheng and Gerstein, classifies genes as living genes, ghost pseudogenes, and dead pseudogenes. This classification is based on the functionality of the gene, and on the "life" and "death" of these.

From this perspective, living genes are the genes that code for proteins, and dead pseudogenes are elements in the genome that are not transcribed.

An intermediate state is comprised of phantom pseudogenes, which are classified into three subcategories: exapted pseudogene, piggy-back pseudogene, and dying pseudogene.

Evolutionary perspective

The genomes of organisms also evolve and genes have the property to change and originate de novo. Different mechanisms mediate these processes, among them are gene duplication, gene fusion and fission, lateral gene transfer, etc.

Once a gene originates, it represents a starting point for evolutionary forces to act.

Gene duplication produces a copy where, generally, the original gene retains its function and the copy - which is not under selective pressure to maintain said initial function - can freely mutate and change function.

Alternatively, the new gene can mutate in such a way that it ends up being a pseudogene and loses its function.

References

1. Groen, JN, Capraro, D., & Morris, KV (2014). The emerging role of pseudogene expressed non-coding RNAs in cellular functions. The international journal of biochemistry & cell biology, 54, 350-355.
2. Pink, RC, Wicks, K., Caley, DP, Punch, EK, Jacobs, L., & Carter, DRF (2011). Pseudogenes: pseudo-functional or key regulators in health and disease ?. Rna, 17 (5), 792-798.
3. Poliseno, L., Salmena, L., Zhang, J., Carver, B., Haveman, WJ, & Pandolfi, PP (2010). A coding-independent function of gene and pseudogene mRNAs regulates tumor biology. Nature, 465 (7301), 1033.
4. Tutar Y. (2012). Pseudogenes. Comparative and functional genomics, 2012, 424526.
5. Zheng, D., & Gerstein, MB (2007). The ambiguous boundary between genes and pseudogenes: the dead rise up, or do they ?. Trends in Genetics, 23 (5), 219-224.