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Gene duplications: evolutionary role Liliya Kazantseva A suggestion 35 years ago that gene duplication is a key factor shaping the evolution still attract much attention today. Fate of the duplicated genes Classical view One member of the pair becomes nonfunctional pseudogene. Evidence of transcription of pseudogene. MYLKP1 inhibit the expression of parent gene MYLK. Neofuncionalization Phospholipase A2s in mammals signal transduction, lipid digestion and production of eicosanoids. In snakes (Laticuadata laticuadata) it is important component of the venom: appeared from non toxic gene. Post duplicative divergence accumulation of nonsynonimous mutations positive selection. Subfuncionalization Original gene had two functions. Protein in different tissues Duplication Subfuncionalization by mutations in regulatory region There is a portioning of ancestral functions between duplicated genes. PAX6 is a transcriptional factor. Role in the eye, brain and endocrine pancreas cell development. Mutations absence of eyes and brain abnormalities. In zebrafish is duplicated: Pax6a expressed in brain and retain the regulatory region for brain expression. Pax6b expressed in developing pancreas has a downstream loss of brain elements, while upstream evolved to be pancreas specific. No functional divergence Robustness molecular and morphological diversification (evolutionary innovations) Heart development is controlled by a network of transcriptional factors genes, that have more duplications than in the ancestral. MEF2 myocyte enhancer factor 2 is responsible of the contractile proteins. Vertebrates have 4 copies of the gene. Loss of function no contractile proteins and right ventricle. Multigene family: concerted evolution Duplication Recombination Mutation Gene family must evolve as a block. This model is not able to explain the high diversity. Homogenization of the copies Multigene family: birth and death evolution. The original gene retains its function. The duplicated gene suffers mutations evolve via silent synonymous nucleotide substitutions. Phenotypic spectrum of duplicated genes The copy number increase of AMY1 (human salivary amylase gene) adaptation to high starch diet. The copy number increase of CCL3L1 gene is associated with low susceptibility to HIV infection. Duplication in Charcot – Marie – Tooth disease duplication of PMP22 gene, that encodes major myelin protein. This normally involves enzymes that show little variation in function over gene duplication. MECP2 (methyl – CpG – binding protein 2) is linked in the transcriptional repression. Is involved in Rett syndrome. Parkinson disease: duplication of SNCA (alpha synuclein). Alzheimer disease: duplication of APP (amyloid beta precursor protein). There are many mechanisms that lead to increase in the aggregation, like Down syndrome or mutations in this gene. Conclusions Gene duplications are responsible for the phenotypic variations in the disease. Pathogenic duplications involve dosage sensitive genes with both similar and dissimilar over and underexpression phenotypes, and genes encoding proteins with a propensity to aggregate. References Condrad B, Antonarakis E. Gene duplication: a drive for phenotypic diversity and cause of human disease. Annu Rev Genomics Hum Genet 2007; 8: 17 – 35. Pei B, Sisu C, Frankish A, Howald C, Habegger L, Mu XJ, Harte R, Balasubramanian S, Tanzer A, Diekhans M, Reymond A, Hubbard TJ, Harrow J, Gerstein MB. The GENCODE pseudogene resource. Genome Biol 2012; 13:51. Lynch VJ. Inventing and arsenal: adaptive evolution and neofuncionalization of snake venom phospholipase A2 genes. BMC Dev Biol 2007; 7:2. Kleinjan DA, Bancewicz RM, Gautier P, Dahm R, Schonthaler HB, Damante G, Seawright A, Hever AM, Yeyati PL, van Heyningen V, Coutinho P. Subfunctionalization of duplicated zebrafish pax6 genes by cis – regulatory divergence. PloS Genet 2008; 4(2): e29. Wagner A. Gene duplications, robustness and evolutionary innovations. BioEssays 2008; 30: 367 – 373.