18.01.14 Pseudogenes Flashcards
Give a definition of a pseudogene.
a DNA sequence that shows a high degree of sequence homology to a functional gene.
What is the typical structure of a pseudogene?
Pseudogenes usually contain multiple exons of a functional gene and harbour inactivating mutations which abolish gene function e.g. truncating mutations and, as such, were generally considered to be non-functional ‘junk DNA’ – however, evidence suggests multiple roles for pseudogenes at the DNA, RNA and protein level (see later).
How common are pseudogenes?
Pseudogenes are common! Human genome predicted to contain 10,000-20,000 pseudogenes (vast majority are processed pseudogenes) and the distribution of pseudogenes per gene is highly uneven – only 10% of human genes have a pseudogene counterpart.
Highly-transcribed genes are more likely to produce processed pseudogenes (the small number of genes encoding ribosomal proteins account for ~20% of all processed pseudogenes).
Why are pseudogenes so common?
- Gene duplication events may be evolutionarily advantageous if they produce new functional gene variants with some kind of selective advantage – pseudogenes may be unsuccessful by-products of this duplication mechanism.
- Pseudogenes are functional and evolutionarily-conserved!
What are the different classes of pseudogenes? Give examples where possible.
Non-processed (duplicated) pseudogenes e.g. SMN1/SMN2, CYP2A1A2/CYP21A1P
Processed (retrotransposed) pseudogenes - UTP14a, UTP14b
Unitary (solitary) pseudogenes
RNA pseudogenes - U6 snRNA has ~800 related pseudogeens
Mitochondrial pseudogenes
Give a description a non-processed (duplicated) pseudogenes.
- A defective gene arising from a copy of genomic DNA sequence (may contain sequence corresponding to promoter, exons, introns).
- Arise via tandem duplication (unequal crossover between homologous chromosomes or unequal sister chromatid exchange within the same chromosome – see S&R, 4th Ed., pg.409).
- Often located close to functional gene counterparts – e.g. SMN1/SMN2, CYP21A2/CYP21A1P, PMS2 pseudogenes, α-globin/β-globin pseudogenes and Class I HLA gene clusters; however, some may be dispersed due to recombination (notably at unstable pericentromeric and subtelomeric regions) – e.g. NF1 pseudogenes.
How do processed (retrotransposed) pseudogenes arise?
A defective gene arising from copying at the cDNA level (contains exonic sequences only).
Arise via retrotransposition – cellular reverse transcriptases (encoded by LINE1 elements) use processed gene transcripts e.g. mRNA to produce cDNA that can then integrate into the genome at a new location – see S&R, 4th Ed, pg. 274 for overview.
What is the structure of processed pseudogenes?
Processed pseudogenes contain sequence corresponding to the exons of the functional gene and lack introns, promoters and regulatory elements and are therefore usually not expressed.
However, there are examples of expressed processed genes that retain some function, known as retrogenes.
What are retrogenes?
Retrogenes are created by chance, when the cDNA copy may be integrated adjacent to a promoter that can drive expression (selective pressure may ensure that the processed gene copy continues to make a functional gene product).
Parental gene and retrogene are often expressed in different ways and often in different cell types.
Retrogenes are often autosomal homologs of X-linked genes thought to be due to their requirement for expression during male meiosis when both X and Y are silenced.
E.g. UTP14a and UTP14c
What makes unitary pseudogenes different from other pseudogenes?
Very rare!
Different to other pseudogenes in that the gene was not duplicated before becoming inactivated (they do not have a genomic counterpart that encodes a fully-functional protein; instead, they arise through spontaneous mutations in protein-coding genes).
Describe mitochondrial pseudogenes.
A defective copy of a mitochondrial gene (but found in the nuclear genome).
Mitochondrial pseudogenes are more abundant than the actual mitochondrial genome!
What is the function of pseudogenes at the DNA level?
- Cause mutation
- Gene conversion
- Parental gene inactivation
- Sequence diversity
- Acquisition of exons (exonisation).
What is the function of pseudogenes at the RNA level?
Sense RNA - microRNA, RNA binding protein, Translation machinery
Antisense RNA - fine-tube corresponding sense transcript, unrelated function to parental gene, acting as a microRNA precursor
What is the function of pseudogenes at the protein level?
- Encode fully functional protein - same/different activity to the functional protein
- Partially functional protein
- Antigenic peptide
Give clinically relevant examples of a pseudogene acting at the DNA level.
Pseudogenes share a high sequence similarity to their parental genes and can therefore elicit function via gene conversion/recombination with their parental homolog.
In some cases, upstream regulatory sequences may affect transcription of the parental gene.
They can interact with other gene loci, leading to alteration in their sequences and/or transcriptional activities.
Pseudogenes may subsequently acquire additional exons. Please see picture below for details.
Clinically-relevant examples
– Gene conversion between PMS2 and its pseudogene leading to inactivation of PMS2.
– Homologous recombination between BRCA1 and its pseudogene leading to a deletion of the BRCA1 promoter.