1 Dr. Erica Bree Rosenblum Molecular Evolution Gene Duplication Gene duplication is a primary means by which new genes can arise Gene duplication Types of gene duplication 1) Partial (internal) internal gene duplication 2) Complete gene duplication 3) Partial chromosomal duplication 4) Complete chromosomal duplication 5) Whole genome 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 Gene duplication Eukaryotic genes contain many exons Neighboring exons are often very similar suggesting history of exon duplications Exon duplication is major mechanism for gene elongation and evolution of complexity Exon duplication Exon duplication can be advantageous by: a) Enhancing number of functional or structural domains so the protein can perform existing functions better/faster b) Decreasing constraint on one exon copy allowing development of new functions Exon duplication2 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 Exon duplication Exon shuffling can arise from duplication, insertion or deletion Insertion of exons from one gene into another can create mosaic or chimeric proteins Exon shuffling Example: tissue plasminogen activator (involved in blood clotting) acquired segments from at least 4 other genes - all at exon/intron borders 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 Exonization Rate of duplication of entire genes is only slightly less than the rate at which nucleotide substitutions occur at silent sites Gene duplication 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 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) 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 Gene duplication3 So how does gene duplication lead to new functions? Neofunctionalization Masking effects Subfunctionalization Gene duplication So how does gene duplication lead to new functions? Neofunctionalization Masking effects Subfunctionalization Gene duplication 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: one copy acquires a beneficial mutation that results in a new function Neofunctionalization 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 wild-type and resistant alleles appear in exposed populations. Masking effect: duplicate genes have selective advantage associated with their ability to mask the effects of deleterious mutations Masking effects However in practice there is not much evidence to support this route to new gene functions Subfunctionalization: partitioning of ancestral gene functions to duplicate genes through complementary loss-of-function mutations in paralogous copies Subfunctionalization 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 Model for subfunctionalization Gene duplication Single gene encodes multifunctional protein Each copy specializes for one function Gene duplication4 Gene duplication duplication degeneration subfunctionalization neofunctionalization nonfunctionalization complementation Lots of evidence for subfunctionalization Studies on polyploid fish repeated show tissue specificity of duplicated enzyme loci Subfunctionalization Zebrafish retains 25% of its original gene pairs in functional state Lots of evidence for subfunctionalization Studies on polyploid fish repeated show tissue specificity of duplicated enzyme loci Subfunctionalization Example: Cytochrome P450 copies, one expressed in ovary and other in brain. Orthologous single-copy gene in tetrapods expressed in both tissues Quantitative subfunctionalization: when total capacity of both loci is degraded such that their joint presence is needed to fulfill role of ancestral gene Subfunctionalization Gene family: all genes belonging to a certain group of repeated sequences - often lie on the same chromosome Gene families Supergene family: more distantly related gene copies - generally <50% aa similarity Gene family expansions (chytrid fungus) Fungalysin metallopeptidase Serine protease5 = Up = Down Bold font: up in sporangia Boxes: up in zoospores Fungalysin metallopeptidase Serine protease Gene family expansions (chytrid fungus) 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 Gene families Evolution of opsins allow wide-range of color detection blue autosomal red X-linked green X-linked Gene families Human New world monkeys Tricromatic Dicromatic autosome Gene families X-linked African cichlids have eight opsin genes from rapid multiple duplication events -