内含子的起源与进化牛登科北京师范大学生命科学学院http

1、内含子的起源与进化牛登科北京师范大学生命科学学院http:/ , 58802064What is an intron?Categories of intronsSpliceosomal introns: Major intron, U2-dependent, GTAG; Minor intron, U12-dependent, ATAC. Most of the studies on intron evolution are focused on spliceosomal introns. And in most papers, without further annotation, the

2、term intron means spliceosomal introns.Self splicing introns: Group I and Group II intronstRNA and/or archaeal intronsThe pervasiveness and abundance of introns Except a few nucleomorph genomes(1), all nuclear genomes contains introns. Human has 8 introns/gene; 45% to 55% of the human genome are int

3、rons. The dinoflagellate Symbiodinium minutum has 18.6 introns/gene (2). There are also intron-poor genomes and intronless genes in intron-rich genomes.1.Shoguchi E, et al: Curr Biol 2013, 23: 1399-1408.2.Lane CE, et al. PNAS 104: 19908-19913.Secondary endosymbiosis-NucleomorphJohn MA 2007. Nucleomo

4、rph genomes: structure, function, origin and evolution. BioEssays 29: 392-402.Origin of introns One exon - one function unit, building blocks of genes since the origin of genes Introns have been found in almost all eukaryotic species, but not in prokaryotes (eubacteria and archaebacteria) Intron ear

5、ly theory, Intron late theory.Origin of introns1.Go, M. (1983) Proc. Natl. Acad. Sci. USA 80, 1964-1968.2.Perler, F., et al. (1980) Cell 20, 555-566.3.Sudhof, T. C., et al. (1985) Science 228, 815-822.4.Sudhof, T. C., et al. (1985) Science 228, 893-895.5.Rogers, J. (1985) Nature 315, 458-459.6.Gilbe

6、rt, W. (1985) Science 228, 823-824.7.Henkel, B., et al. (1992) Eur. J. Biochem. 209, 321-328.Origin of introns The occurrence of shared sequences encoded by discrete exons in the LDL receptor gene provides strong evidence in support of Gilberts original hypothesis that introns facilitate the evoluti

7、on of apparently diverse genes by allowing recruitment of exons encoding functional domains. But far from demonstrating the hypothesis.Disputes on the origin of introns Function unit of proteins and exon Protein domain and exon Intron phase：Kannan, et al. MitoCOGs: clusters of orthologous genes from

8、 mitochondria and implications for the evolution of eukaryotes. BMC Evol. Biol. 14, 237 (2014). Exon-shuffling: also early and/or late? 我的博客：生物学家和化学家也是好样的，只要不傻大胆，2012。Exon-shuffling: mechanismsExon retroshuffling. Transcription of an L1 element within gene X bypasses its own weak polyadenylation (pA

9、) signal, instead terminating at the pA signal of the gene. The reverse transcriptase and endonuclease (yellow) encoded by this transcript bind to the poly(A) tail (An) and insert a cDNA copy of the elements RNA (red arrow) into gene Y. This step results in the transduction of exon 4 of gene X into

10、gene Y, creating a new gene. Exon-shuffling: What can we do? How much did the above mechanism contribute to the complexity of vertebrate genomes? Using bioinformatic approaches to analyze the structures of L1 element target site duplications and flanking sequence features. “We provide evidence sugge

11、sting that 15% of full-length L1 elements bear evidence of flanking DNA segment transduction. Extrapolating these findings to the 600,000 copies of L1 in the genome, we predict that the amount of DNA transduced by L1 represents 1% of the genome, a fraction comparable with that occupied by exons.” fr

12、om Pickeral, O. K., et al. 2000 Frequent human genomic DNA transduction driven by LINE-1 retrotransposition. Genome Res. 10: 411415. Many introns exist early in eukaryotic evolution Numerous introns occupy the same position in orthologous genes from distant species. In particular, orthologous genes

13、from humans and A. thaliana share 25% intron positions. The Last Eukaryotic Common Ancestor (LECA) already possessed intron density comparable to that found in modern, moderately intron-rich genomes. The entire line of descent from LECA to mammals was a continuous intron-rich state that would provid

14、e for uninterrupted evolution of the growing repertoire of functional alternative spliced forms. From Rogozin I. et al 2012. Biol. Direct 7: 11. Origin of spliceosomal intronsfrom group II intronsFrom Irimia M, Roy SW 2014. Cold Spring Harb. Perspect. Biol. 6: a016071.Mechanisms of intron lossesFrom

15、 Mourier T, Jeffares DC 2003. Science 300: 1393. 自段文慧 2015. 北京师范大学硕士学位论文From Ma MY, et al. 2015. Biol. Direct 10: 24. Mechanisms of intron lossesMechanisms of intron gainsfrom Yenerall P, Zhou L 2012. Biol. Direct 7: 29 Introner(-Like) Elements are spliceosomal introns that have invaded algal and fu

16、ngal genomes, where they are present in hundreds of near-identical copies in unrelated genes. From Amini ZN et al 2014. PLoS ONE 9. e0129302.Mechanisms of intron gainsAn example of intron gainAn example of intron gainAn example of intron gainPossible functions/effects of introns Alternative splicing

17、 Nesting genes or noncoding RNAs (e.g. MicroRNA), or regulatory motifs Marker for nonsense-mediated decay Splicing of introns interacts with other steps of gene expression from transcription initiation, mRNA export, to mRNA decay and even cytoplasmic localization, translation yield. And References:F

18、edorova L, Fedorov A 2005. Puzzles of the human genome: Why do we need our introns? Curr. Genomics 6: 589-595. Chorev M, Carmel L 2012. The function of introns. Front. Genet. 3: 55Hesselberth JR 2013. Lives that introns lead after splicing. WIREs RNA 4: 677-691.Hube F, Francastel C 2015. Mammalian I

19、ntrons: When the Junk Generates Molecular Diversity. Int J Mol Sci 16: 4429-4452.But also: Doolittle WF, Brunet TDP, Linquist S, Gregory TR 2014. Distinguishing between “function” and “effect” in genome biology. Genome Biol. Evol. 6: 1234-1237.Possible disadvantages of having intronsConsiderable was

20、te of energy during gene expression Delay in obtaining protein products (on average it takes about 45 min for RNA polymerase II to transcribe a 100,000 bp intron)Potential errors in normal splicing, since long introns contain numerous false splicing sitesMutational hazardAnd Attention: Deleterious e

21、ffects are not necessarily strong enough to result in disadvantages (see Huang YF, Niu DK 2008. BMC Evol. Biol. 8: 154.).Mutational hazard of having intronsFackenthal JD, et al. 2012. Hidden dangers: A cryptic exon disrupts BRCA2 mRNA. Clinical Cancer Research 18:4865-4867. Anczukow O, et al. 2012.

22、BRCA2 deep intronic mutation causing activation of a cryptic exon: Opening toward a new preventive therapeutic strategy. Clinical Cancer Research 18:4903-4909.Experimental tests for the effectsNg R, Domdey H, Larson G, Rossi JJ, Abelson J 1985. A test for intron function in the yeast actin gene. Nat

23、ure 314: 183-184.Parenteau J, et al. 2008. Deletion of many yeast introns reveals a minority of genes that require splicing for function. Mol. Biol. Cell 19: 1932-1941. Parenteau J, et al. 2011. Introns within ribosomal protein genes regulate the production and function of yeast ribosomes. Cell 147:

24、 320-331.But yeasts have very few introns, only 5% of the genes have introns.Evolutionary studies on intron presence-absence polymorphismLlopart A et al 2002. Intron presence-absence polymorphism in Drosophila driven by positive Darwinian selection. Proc. Natl. Acad. Sci. USA 99: 8121-8126.Omilian AR et al. 2008. Intron presence-absence polymorphisms in Daphnia. Mol. Biol. Evol. 25: 2129-2139.Li W et al. 2009. Extensive, recent intron gains in Daphnia populations. Science 326: 1260-1262.Brunner PC et al. 2014. Hitchhiking selection is driving intron gain in a pathogenic fungus. Mol. Biol. Evo