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BIOL 504: Molecular Evolution Gene Duplication Gene duplication Gene duplication is a primary means by which new genes can arise Dr. Erica Bree Rosenblum Gene duplication Types of gene duplication 1) 2) 3) 4) 5) Partial (internal) internal gene duplication Complete gene duplication Partial chromosomal duplication Complete chromosomal duplication Whole genome duplication Exon duplication Gene duplication Principle mechanism for gene duplication is unequal crossing over Unequal crossing over is facilitated by repetitive sequences So gene duplications (particularly those in tandem) can beget more duplications Exon duplication Eukaryotic genes contain many exons Exon duplication can be advantageous by: Neighboring exons are often very similar suggesting history of exon duplications a) Enhancing number of functional or structural domains so the protein can perform existing functions better/faster Exon duplication is major mechanism for gene elongation and evolution of complexity b) Decreasing constraint on one exon copy allowing development of new functions 1 Exon duplication Example: antifreeze genes in fish Freezing of Antarctic ocean ~10-14 MYA Antifreeze glycoprotein gene ~5-14 MYA Many duplication events in short time period likely under strong positive selection Exonization Exons can appear and disappear in processes other than shuffling Exonization: process by which intronic sequence become exons - not very common Pseudoexonization: process by which exon (not whole gene) becomes nonfunctional Gene duplication Gene duplication can result in a copy that: a) becomes a functionless pseudogene (most duplicate genes have a “half-life” of only a few million years) b) retains its original function (these invariant repeats can enable dose effects by allowing more protein production) c) develop a novel function (these variant repeats can create new genes via neofunctionalization) Exon shuffling Exon shuffling can arise from duplication, insertion or deletion Insertion of exons from one gene into another can create mosaic or chimeric proteins Example: tissue plasminogen activator (involved in blood clotting) acquired segments from at least 4 other genes - all at exon/intron borders Gene duplication Rate of duplication of entire genes is only slightly less than the rate at which nucleotide substitutions occur at silent sites Over 250 million years, nearly every gene in a typical eukaryotic genome can be expected to duplicate once So gene duplication can be a major evolutionary consideration Gene duplication Generally people talk about gene copies that develop new constraints because selection is relaxed but… a) This only works if new function can evolve via few substitutions (or it is more likely to become a nonfunctional pseudogene) b) Evidence from tetraploid genomes suggests copies are still under purifying selection c) Functionally distinct copies often arise from positive selection 2 Gene duplication Gene duplication So how does gene duplication lead to new functions? So how does gene duplication lead to new functions? Neofunctionalization Neofunctionalization Masking effects Masking effects Subfunctionalization Subfunctionalization Note that most new gene copies will NOT develop splashy new functions - most will become nonfunctional. Nonfunctionalization or silencing of a gene due to deleterious mutation produces a pseudogene and can result in gene loss Neofunctionalization Neofunctionalization: one copy acquires a beneficial mutation that results in a new function Ancestral polymorphisms can also facilitate neofunctionalization Example: insecticide resistance in mosquito. Acetylcholinesterase enzyme plays essential role in central nervous system. Mutant allele at duplicate gene copy confers insecticide resistance but comes at a fitness cost in insecticide free environments. Maintained at very low frequency in normal populations but linked combo of wildtype and resistant alleles appear in exposed populations. Subfunctionalization Subfunctionalization: partitioning of ancestral gene functions to duplicate genes through complementary loss-of-function mutations in paralogous copies One copy becomes fixed for a mutation that eliminates an essential subfunction, permanently preserving the second copy. Loss of alternate subfunction in second copy then reciprocally preserves the first copy Masking effects Masking effect: duplicate genes have selective advantage associated with their ability to mask the effects of deleterious mutations However in practice there is not much evidence to support this route to new gene functions Gene duplication Model for subfunctionalization Single gene encodes multifunctional protein Gene duplication Each copy specializes for one function 3 Gene duplication Subfunctionalization Lots of evidence for subfunctionalization duplication Studies on polyploid fish repeated show tissue specificity of duplicated enzyme loci degeneration Zebrafish retains 25% of its original gene pairs in functional state complementation subfunctionalization neofunctionalization nonfunctionalization Subfunctionalization Subfunctionalization Lots of evidence for subfunctionalization Quantitative subfunctionalization: when total capacity of both loci is degraded such that their joint presence is needed to fulfill role of ancestral gene Studies on polyploid fish repeated show tissue specificity of duplicated enzyme loci Example: Cytochrome P450 copies, one expressed in ovary and other in brain. Orthologous single-copy gene in tetrapods expressed in both tissues Gene families Gene family: all genes belonging to a certain group of repeated sequences - often lie on the same chromosome Gene family expansions (chytrid fungus) Fungalysin metallopeptidase Serine protease Supergene family: more distantly related gene copies - generally <50% aa similarity 4 Gene family expansions (chytrid fungus) Fungalysin metallopeptidase Serine protease Gene families Can have few or many repeats in a genome Example: rRNA and tRNA genes can exhibit hundreds or thousands of copies and vary by species = Up = Down Bold font: up in sporangia Boxes: up in zoospores Gene families Gene families Evolution of opsins allow wide-range of color detection blue autosomal red X-linked green X-linked Gene families African cichlids have eight opsin genes from rapid multiple duplication events - each opsin codes for distinct visual pigment and positive selection has been detected for most autosome X-linked Human Tricromatic New world monkeys Dicromatic Gene families Further, adaptation to different light environments In turbid lakes (like Lake Victoria) where red light is transmitted more easily, selection on the red-sensitive opsin 5 Gene families Gene duplication and adaptation This all can effect mate choice! Salivary amylase gene (AMY1) and starch consumption Perry et al 2007 Nature Genetics Gene duplication and speciation Ancestral species Gene duplication Geographic isolation and divergent gene silencing Hybridization Other ways of producing new functions In addition to exon shuffling and gene duplication, new genes/proteins can be produced through: 1) Overlapping genes 2) Alternative splicing 3) Intron-encoded and nested genes 4) Functional convergence 5) RNA editing 6) Gene sharing Nonfunctional gametes Other ways of producing new functions Other ways of producing new functions In addition to exon shuffling and gene duplication, new genes/proteins can be produced through: In addition to exon shuffling and gene duplication, new genes/proteins can be produced through: 1) Overlapping genes: DNA segment coding for multiple products using different reading frames, start codons or complementary strands 1) Overlapping genes 2) Alternative splicing 3) Intron-encoded and nested genes 4) Functional convergence 5) RNA editing 6) Gene sharing 2) Alternative splicing: production of different mRNAs from same DNA 3) Intron-encoded and nested genes 4) Functional convergence 5) RNA editing 6) Gene sharing 6 Other ways of producing new functions In addition to exon shuffling and gene duplication, new genes/proteins can be produced through: Other ways of producing new functions In addition to exon shuffling and gene duplication, new genes/proteins can be produced through: 1) Overlapping genes 2) Alternative splicing: production of different mRNAs from same DNA example: doublesex gene in Drosophila alternatively spliced in females (exons 1,2,3,4) and males (exons 1,2,3,5,6) 1) Overlapping genes 2) Alternative splicing 3) Intron-encoded and nested genes: genes inside of introns - either on the same or opposite strand 4) Functional convergence 5) RNA editing 6) Gene sharing Other ways of producing new functions Other ways of producing new functions In addition to exon shuffling and gene duplication, new genes/proteins can be produced through: In addition to exon shuffling and gene duplication, new genes/proteins can be produced through: 1) Overlapping genes 2) Alternative splicing 3) Intron-encoded and nested genes 1) Overlapping genes 2) Alternative splicing 3) Intron-encoded and nested genes 4) Functional convergence 4) Functional convergence: convergent evolution of protein function from unrelated genes 5) RNA editing 6) Gene sharing Other ways of producing new functions 5) RNA editing: posttranslational modification can alter protein product or gene expression 6) Gene sharing Molecular tinkering In addition to exon shuffling and gene duplication, new genes/proteins can be produced through: “Many proteins that were originally considered to be relatively recent evolutionary additions turned out to be derived from ancient proteins… 1) Overlapping genes 2) Alternative splicing 3) Intron-encoded and nested genes 4) Functional convergence 5) RNA editing True novelty is almost unheard of during evolution; rather, preexisting genes and parts of genes are transformed to produce new functions… molecular tinkering…molecular opportunism” 6) Gene sharing: gene acquires and maintains a second function - may require changes in regulation (tissue or developmental timing) 7