Pseudogenes are defective copies of functional genes. These may be partial or complete duplicates derived from polypeptide-encoding genes or RNA genes. The DNA sequence of a pseudogene is characteristically very similar to its functional counterpart, but contains variant mutations that render the gene inactive. The functional polypeptide-encoding gene contains an open reading frame, a long stretch of nucleotides that are transcribed and subsequently translated into a series of amino acids uninterrupted by stop codons . In contrast, pseudogenes derived from polypeptide sequences generally are punctuated with stop codons, effectively rendering them incapable of producing a functional protein.
Pseudogenes may also contain frameshift mutations , yielding a change in the reading frame. Additionally, there may be mutations that inactivate regulatory elements or intron-splicing sites. In either case, the duplicated gene may be rendered nonfunctional. Genes and pseudogenes derived from the duplication of an ancestral gene are said to be paralogous.
Gene duplication may occur by a direct increase of DNA content (non-processed) or via an RNA intermediate (processed). Nonprocessed pseudo-genes can arise by unequal crossing over in homologous chromosomes (paired meiotic chromosomes containing the same genetic loci) or unequal sister chromatid exchange (crossover at improperly aligned sequences) after replication in a single chromosome (Figure 1A). Replication slippage also increases DNA content by looping of the synthesized strand during DNA replication, but typically involves short sequence stretches such as microsatellites (short repeated sequences).
A nonprocessed duplicated gene contains the introns and regulatory sequences of the original gene. This yields genetic redundancy, which allows one of the genes to acquire mutations, becoming a nonfunctional pseudo-gene (Figure 2). Occasionally, the duplicated gene acquires mutations yielding a gain-of-function that differs from the original gene (Figure 2). This may allow the evolution of new capabilities in the organism possessing it.
New genes generated by nonprocessed duplication are generally located in the vicinity of the ancestral (original) gene within the genome. However, it is possible that these genes may become separated from each other as a result of major chromosomal rearrangements (such as translocations). Examples of functional and nonfunctional duplicated genes in adjacent locations and on different chromosomes are exhibited by the globin gene superfamily.
Pseudogenes generated via a messenger RNA (mRNA) intermediate demonstrate the features of processed RNA. These genes lack the flanking transcriptional regulatory sequences, do not contain introns, and typically have a polyadenylated 3′ (3-prime) region (adenine-containing nucleotides are added to the mRNA in eukaryotes). These sequences are converted to complementary DNA (cDNA) by the enzyme reverse transcriptase, and then integrated back in the genome at a new location (Figure 1B). These elements, therefore, are not necessarily in the chromosomal vicinity of the original sequence, and are essentially dead on arrival. Processed pseudogenes are also referred to as retropseudogenes.
Processed pseudogenes may also be derived from other RNA genes, such as tRNA (transfer RNA), rRNA (ribosomal RNA), snRNA (small nuclear RNA), and 7SL RNA. Evidence for this phenomenon includes the identification of nonfunctional tRNA genes containing a CCA sequence at the 3′ terminal. CCA is not part of the original DNA sequence, but is enzymatically added to the tRNA molecule following transcription. The gene for 7SL RNA is an integral component of the signal recognition particle complex involved in transmembrane protein transport. The 7SL RNA gene is thought to be the ancestral gene for the primate Alu and rodent B1 retroposons, based on sequence similarities. (Retroposons are a type of transposable genetic element that is found littered throughout the genome.) The Alu element differs from 7SL by having two internal sequence deletions, duplication of the entire sequence, and numerous nucleotide substitutions. At some point in its evolutionary past a 7SL retropseudogene apparently integrated into a highly fortuitous location, as there are about 1.5 million Alu elements in the human genome, accounting for approximately 10 percent of our DNA. Most Alu elements are retropositionally incompetent pseudogenes, hence incapable of generating additional copies. Other retroposons are thought to be derived from processed duplicated tRNA genes (for example, rodent B2 and ID elements).
The globin gene superfamily provides an interesting example of the generation of both functional and nonfunctional duplicated genes (Figure 3). Based on nucleotide sequence data, it appears that a gene duplication occurred about 600 to 800 million years ago, yielding myoglobin and hemoglobin genes. Another duplication of the hemoglobin gene occurred about 500 million years ago, yielding α-globin and β-globin genes. (Adult human hemoglobin contains two α and two β strands.) These are all functional genes, found on three different human chromosomes. The α-globin and β-globin genes further duplicated, yielding both pseudogenes and functional genes. Possession of more than one globin gene provides a selective advantage because it compensates for the variation of oxygen in the prenatal versus postnatal environment.
The α-globin gene cluster consists of three functional genes and three pseudogenes. There is also an additional gene that is expressed but not incorporated into a hemoglobin molecule. In other words, this would be an example of an expressed pseudogene. The β-globin gene complex consists of five functional genes and one pseudogene. Examples of other processed polypeptide-encoding pseudogenes include those derived from actin, ferritin, and glyceraldehyde 3-phosphate dehydrogenase genes.
see also Evolution of Genes; Gene; Gene Families; Hemoglobinopathies; Reading Frame; Replication; RNA; RNA Processing.
David H. Kass
and Mark A. Batzer
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