Pseudogenes

SIGNIFICANCE: Pseudogenes are DNA sequences derived from partial copies, mutated complete copies of functional genes, or normal copies of a gene that has lost its control sequences and therefore cannot be transcribed. They may originate by gene duplication or retrotransposition. They seem to be nonfunctional regions of the genome that may evolve at a maximum rate, free from the evolutionary constraints of natural selection.

Definition and Origin

Pseudogenes are DNA sequences that resemble genes but are not correctly transcribed or translated to a functional polypeptide. If a functional gene is duplicated so that there are two nonhomologous copies of it in the genome, one of the copies can retain the code for the original product, while the other is free from such constraints, since one copy of the gene is sufficient to produce the protein. Because mutations in one copy do not destroy the gene’s function, they may be retained, and the unneeded copy can evolve more quickly. It may change to produce a different, functional polypeptide (and effectively become a new gene), or it may remain nonfunctional as a pseudogene. There are two types of pseudogenes, defined by how they were produced: nonprocessed and processed.

Nonprocessed Pseudogenes

Nonprocessed (or duplicated) arise when a portion of the original gene is duplicated, with portions necessary for proper functioning missing or altered or when the complete original gene is duplicated. They can be identified by the presence of introns and may have mutations in the that prevent transcription or the correct removal of introns, or they may have other mutations (such as premature stop codons) within exons that result in translation of a nonfunctional polypeptide. A series of tandem duplications of a gene can result in clustered gene families, which can include expressed genes, expressed pseudogenes (which are transcribed but produce no functional polypeptide), and nonexpressed pseudogenes that are not transcribed. The alpha-globulin and beta-globulin clusters are examples of such gene families. Other examples of nonprocessed pseudogenes include members of the immunoglobulin (Ig) and gene families.

Processed Pseudogenes

Processed pseudogenes originate from transcribed RNA copies of genes that are copied back to DNA by the reverse transcriptase. Processed pseudogenes are usually integrated into the genome in a different location from the original gene. Reverse transcriptase is an enzyme produced by retroviruses, which have RNA genomes that are reverse transcribed to DNA when the viruses infect host cells. Retrotransposons, which are related to retroviruses, are DNA sequences that transpose or duplicate themselves by reverse transcription of a transcribed RNA copy of the sequence.

Often, retrotransposons will carry along a copy of the surrounding host DNA, resulting in the duplication of that sequence—a processed pseudogene. Because the introns of a gene are removed from the RNA transcript, processed pseudogenes are not exact copies of the original DNA sequence; the introns are missing. Copies of protein-coding genes copied by this mechanism are members of a type of repetitive DNA called LINES (for long interspersed sequences) and exist in multiple copies scattered around the genome, each up to several thousand base pairs in length. Short processed pseudogenes are members of another class of repetitive DNA called SINES (short interspersed sequences of up to several hundred base pairs in length) and result from the retrotransposon-mediated copying of or genes. SINES of this type are sometimes very abundant in genomes because they may have internal promoters, so that they are more easily transcribed, and therefore transposed. The most prominent of SINES are those that are members of the Alu family, which occur an average of once every six thousand base pairs in the human genome.

Pseudogenes and Neutral Evolution

In 2003, Japanese researchers reported the discovery of a mouse pseudogene that is involved in regulating the expression of its related “functional” gene. This discovery suggested that at least some pseudogenes may have important functions. Although pseudogenes are commonly found across genomes, most do not appear to serve any function, and until further research uncovers more functional pseudogenes this assumption appears warranted. Their abundance can be explained by the tendency of duplicated sequences to be further copied. Retrotransposition increases the number of copies of processed pseudogenes, and gene duplication leading to unprocessed pseudogenes favors mechanisms that generate additional copies, leading to clustered gene families. Natural selection does not tend to eliminate these additional copies because their presence does not harm the organism as long as there is at least one functional copy of the original gene. In other words, pseudogenes are selectively neutral.

Because of their selective neutrality, pseudogenes are especially useful for estimating neutral mutation rates in genomes. The predicts that, because of the constraints of selection, functional regions of the genome (such as the exons, or coding sequences, of genes) will evolve more slowly than less critical sequences, such as introns, or nonfunctional sequences like pseudogenes. The number of nucleotide differences between sequences of related species can be used to calculate estimates of evolutionary rates, and such estimates support the neutral theory: the greatest rates of divergence occur within pseudogenes. Using comparisons from several pseudogenes, researchers can establish the baseline neutral mutation rate for a group of species.

Key terms

• intronsnoncoding segments of DNA within a gene that are removed from pre-messenger RNA (pre-mRNA) as a part of the process of producing mature mRNA
• long interspersed sequences (LINES)long repeats of DNA sequences scattered throughout a genome
• neutral theory of molecular evolutionthe theory that most DNA sequence evolution is a result of mutations that are neutral with respect to the fitness of the organism
• retrotransposon (retroposon)a DNA sequence that is transcribed to RNA and reverse transcribed to a DNA copy able to insert itself at another location in the genome
• reverse transcriptasean enzyme, isolated from retroviruses, that synthesizes a DNA strand from an RNA template
• short interspersed sequences (SINES)short repeats of DNA sequences scattered throughout a genome

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