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Paper 3: PSZO103: Genetics and, Evolution, Unit 2: Molecular Genetics, 2.2.1 Multi-gene Families and, Types:, b) Pseudogenes, c) Selfish gene

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Introduction, A pseudogene is a sequence of nucleotide that, resembles the genuine gene but does not specify a, functional RNA or protein,, In some cases a gene loses its function and, becomes a pseudogene because the change in its, nucleotide sequence due to mutation.

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• Pseudogenes are ubiquitous and abundant in, genomes., • Pseudogenes were once called “genomic fossils”, and treated as “junk DNA” several years., • Nevertheless, it has been recognized that some, pseudogenes play essential roles in gene, regulation of their parent genes, and many, pseudogenes are transcribed into RNA

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Types of Pseudogenes, Pseudogenes can be categorized in two forms:, A. Unprocessed -Unprocessed pseudogenes can, also be subcategorized as unitary and, duplicated, B. Processed

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A) Unprocessed pseudogenes, When a gene undergoes changes in nucleotide, sequence due to mutation it becomes nonfunctional. Once pseudogene become nonfunctional it will degrade through accumulation of, more mutations and it will no longer show, similarities with the functional gene. Such, pseudogenes are called unprocessed pseudogenes., They are of 2 types• Duplicated pseudogenes, • Unitary pseudogenes

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a) Duplicated pseudogenes, • They arise when a member of multigene family, is inactivated by mutation, • The effects are not deleterious as other genes in, family are active and function specified by, pseudogene is not lost, • Pseudogene in one species is homolog of, pseudogene in other species, • E.g δ globin gene is active in human but, pseudogene in mice

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b)Unitary pseudogenes, • They also arise from mutation but not a member of, multigene family therefore the resulting loss of, function is not compensated by other genes, • They are rare as loss of function can be lethal and if, death occurs it cannot contribute to evolutionary, lineage, • Unitary pseudogenes that appear in genome are the, ones whose loss of function can be tolerated by cells, • There are less than 50 unitary pseudogenes in human, genome, • E.g. Ascorbic acid synthesizing gene in humans is, pseudogene

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Processed pseudogenes, • It is derived from mRNA of gene by synthesis of, cDNA which subsequently reinserts in genome., • It does not contain introns from parent genes, • It also lacks nucleotide sequence immediately, upstream of the parent gene which is the region in, which the signals used to switch on expression are, located, • Thus processed gene are not expressed and remain, inactive, • This occurs either due to retroviral infection or, retroposon activity when active reverse, transcriptase is present in cell

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• The two subtypes of processed pseudogenes, arei. Truncated pseudogenes- lacking sequences, from one end of complete gene, ii. Fragment pseudogenes- short isolated regions, from within genes

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• Approx. 20,000 pseudogene are present in, human. Ribosomal protein comprises a large, family of peudogene with approx. 2000 copies., More than 2/3 of human ribosomal, pseudogenes are found in Chimpanzee genome, and dozen are shared with rodents.

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“unitary” pseudogenes, • A unique subfamily of unprocessed pseudogenes are described by, Zhang et al. Formation of nonduplicated unprocessed pseudogenes is, named “unitary” pseudogenes [7]. In unitary type of pseudogenes, a, single copy parent gene becomes nonfunctional. Unprocessed and, duplicated pseudogenes keep their intron-exon structure. Processed, pseudogenes are formed through retrotransposition., Retrotransposition occurs by reintegration of a cDNA, a reverse, transcribed mRNA transcript, into the genome at a new location. The, double-stranded sequences of processed pseudogenes are generated, from single-strand RNA by RNA polymerase II rather than the RNA, polymerase III. Therefore, processed pseudogenes lack introns, 5′, promoter sequence, and have flanking direct repeats and 3′, polyadenylation tag. The overall distribution of most pseudogenes is, completely random, duplicated, and processed pseudogenes are found, in the same or on different chromosome of their parent genes., • Duplication of DNA segments explains the generation of gene families, from a common ancestral gene. The dynamic nature of genome cause, changes in its composition with time.

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c) Selfish gene, Selfish genetic elements, (historically also referred to, as selfish genes, ultra-selfish, genes, selfish DNA, parasitic, DNA, genomic outlaws) are, genetic segments that can, enhance their own, transmission at the expense, of other genes in the genome,, even if this has no or a, negative effect on, organismal fitness.

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Concept of Selfish gene, • Early observations of selfish genetic elements were, made almost a century ago, but the topic did not get, widespread attention until several decades later., • Inspired by the gene-centred views of evolution, popularized by George Williams and Richard Dawkins, two papers were published back-to-back in Nature in, 1980—by Leslie Orgel and Francis Crick and Ford, Doolittle and Carmen Sapienza respectively., • These papers emphasized that ‘genes can spread in a, population regardless of their effect on organismal, fitness as long as they have a transmission advantage’

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It considers evolution by natural selection as a, process involving two separate entities:, i) replicators -entities that produce faithful copies, of themselves, usually genes, ii) vehicles or interactors- entities that interact, with the ecological environment, usually, organisms., Since organisms are temporary occurrences,, present in one generation and gone in the next,, genes (replicators) are the only entity faithfully, transmitted from parent to offspring.

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Examples of selfish genetic elements, • Segregation distortersSome selfish genetic elements manipulate the, genetic transmission process to their own, advantage, and so end up being overrepresented, in the gametes

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Some elements can, preferentially be transmitted, in egg cells as opposed to, polar bodies during meiosis,, where only the former will be, fertilized and transmitted to, the next generation. Gene, that can manipulate the odds, of ending up in the egg rather, than the polar body will have, a transmission advantage,, and will increase in frequency, in a population.

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• Homing endonucleases, A phenomenon closely related to segregation, distortion is homing endonucleases., These are enzymes that cut DNA in a sequencespecific way, and those cuts, generally double, strand breaks, are then “healed” by the regular, DNA repair machinery.

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Homing endonucleases, , Homing endonucleases, insert themselves into the, genome at the site, homologous to the first, insertion site, resulting in a, conversion of a heterozygote, into a homozygote bearing a, copy of the homing, endonuclease on both, homologous chromosomes., This gives homing, endonucleases an allele, frequency dynamics rather, similar to a segregation, distortion system, and, generally unless opposed by, strong countervailing selection,, they are expected to go to, fixation in a population.

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• Transposable elements,  Transposable elements (TEs) include a wide variety of DNA, sequences that all have the ability to move to new, locations in the genome of their host.,  Transposons do this by a direct cut-and paste mechanism,, whereas retrotransposons need to produce an RNA, intermediate to move.,  TEs have been referred to as selfish genetic elements, because they have some control over their own, propagation in the genome.,  Most random insertions into the genome appear to be, relatively innocuous, but they can disrupt critical gene, functions with devastating results.

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For example, TEs have been linked to a variety, of human diseases, ranging from cancer to, haemophilia., TEs that tend to avoid disrupting vital functions, in the genome tend to remain in the genome, longer, and hence we are more likely to find them, in innocuous locations.