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Alternative Splicing A very short introduction (in plants)

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1 Alternative Splicing A very short introduction (in plants)

2 Alternative Splicing The exons and introns of a particular gene get shuffled to create multiple isoforms of a particular protein First demonstrated in the late 1970’s in adenovirus Fairly well characterized in animals (at least somewhat better than in plants) Contributes to protein diversity Affects mRNA stability

3 One Gene / One Enzyme One Gene / One Polypeptide “One Gene / One set of connected transcripts” 1940’s ’s Ensembl- What is a gene, post-ENCODE? History and updated definition Genome Res :

4 Alternative splicing in metazoans Alternative splicing is well characterized in animals In humans, the vast majority of genes have multiple spliceforms Estimates of up to 80% of human genes are alternatively spliced Estimating rates of alternative splicing in mammals and invertebrates. NATURE GENETICS VOLUME 36 | NUMBER 9 | SEPTEMBER 2004 The Alternative Splicing Gallery (ASG): bridging the gap between genome and transcriptome Nucleic Acids Research, 2004, Vol. 32, No. 13 Human splicing statistics

5 Alternative splicing in disease By virtue of its widespread involvement in most of the genomic landscape, AS is important in almost all gene families AS (or mis-splicing) is a very important component of genetic diseases

6 Mechanisms of splicing

7 E1E2I2E4E3I1 E1E2E3E4 Pre-mRNA Spliced mRNA Genome

8 Alternative splicing of RuBisCo was one of the first examples of AS in plants “The data presented here demonstrate the existence of alternative splicing in plant systems, but the physiological significance of synthesizing two forms of rubisco activase remains unclear. However, this process may have important implications in photosynthesis. if these polypeptides were functionally equivalent enzymes in the chloroplast, there would be no need for the production of both polypeptides, and alternative splicing of the rubisco activase mRNA would likely become a dispensable process.” The majority of AS events have not been functionally characterized

9 E1E2I1 Pre-mRNA 5’ Splice Site 3’ Splice Site Reddy, S.N. Annu. Rev. Plant Biol : In Arabidopsis out 1470 of 1588 predicted splice sites follow the canonical (GT…AG, CG…AG, AT…AC )consensus sites. (The Plant Journal (2004) 39, 877–885 Intron retention is a major phenomenon in alternative splicing in Arabidopsis)

10 I1 Pre-mRNA 5’ Splice Site 3’ Splice Site E1E2 m7Gm7G UTR AAA...AA Mature mRNA - Alternative splicing can effect the entire pre-mRNA transcript (UTRs included) ATG SS - Alternative splicing can also alter start codons or lead to premature termination codons E2UTRE1UTR

11 There are 5 main types of splicing Constitutive (familiar/ “normal”) Alternative Donor site Alternative Acceptor site Alternative position Exon Skipping Intron retention E1E2 m7Gm7G UTR AAA...AA

12 E1E2I2E4E3I1 E1E2E3E4 Constitutive splicing Pre-mRNA Spliced mRNA Genome

13 E1E2I1 E1E2I1E1 E2 Alternative donor site (AltD) Pre-mRNA Spliced mRNA

14 E1E2I1 E1E2I1E2 E1E2 Alternative acceptor site (AltA) Pre-mRNA Spliced mRNA

15 E1E2I1 E1E2 E1E2 I1 Alternative Position (AltP) Pre-mRNA Spliced mRNA

16 E1E3 E1E3 I1I2E2 I1I2E2 E1E3 Exon skipping (ExonS) Pre-mRNA Spliced mRNA

17 E1E2I1 E1E2I1 E1 Intron retention (IntronR) Pre-mRNA Spliced mRNA

18 How prevalent are these alternative spliceforms? AS typeEvents (%)Genes (%)Events (%)Genes (%) AltD845 (10.2)724 (3.3)1,642 (11.3)990 (3.2) AltA1,810 (21.9)1,452 (6.7)2,201 (15.1)1,698 (5.5) AltP308 (3.7)200 (0.9)921 (6.3)562 (1.8) ExonS666 (8.1)379 (1.8)2,004 (13.8)999 (3.2) IntronR4,635 (56.1)3,094 (14.3)7,774 (53.5)4,513 (14.6) Total8,2644,707 (21.8)14,5426,568 (21.2) Genomewide comparative analysis of alternative splicing in plants PNAS May 2, 2006 vol. 103 no ,641 genes and Arabidopsis and 30,917 genes in rice were interrogated for Alternative splicing events. An estimated 1/5 th of plant genes undergo alternative splicing

19 AS typeArabidopsisRiceMaizeHuman AltD3%11%5%42% AltA18%22% 24% ExonS38%34%38%25% IntronR41%33%35%9% Genome-wide analyses of alternative splicing in plants: Opportunities and challenges Genome Res : Alternative splicing is far less common in plants - In humans up to 80% of genes undergo AS (compared to ~20% in plants) - The types of AS varies across species - Intron retention is the most common type of AS in plants

20 Reddy, S.N. Annu. Rev. Plant Biol : The plant spliceosome is less well characterized than metazoan mechanisms. - Plants share similar splice site configurations with animals, but there are significant differences in intron size and composition

21 How are AS events detected? Splicing in disease: disruption of the splicing code and the decoding machinery. doi: /nrg2164 High-througput detection is largely based on microarray data provided by cDNA and EST data PCR based assays

22 Biological importance of AS So far, AS has been implicated in a number of biologically important roles including: - Splicing - Transcriptions - Flowering regulation - Disease resistance - Enzymatic activity A database of AS genes is available at

23 Some examples: Disease resistance in tobacco - In tobacco, the N gene confers resistance to Tobacco Mosaic Virus (TMV) - There are two alternative transcripts N s and N L (short and long) - N L lacks 13 of the 14 LRRs that make are a part of the N s protein - Infection with TMV causes N L to become more abundant after infection - Expression of N s in transgenic plants does not confer TMV resistance

24 Some examples: Jasmonate signaling in Arabidopsis Jasmonate (plant hormone) is involved in cell division and growth, reproduction as well as defense against insects, pathogens, and abiotic stress. AS isoforms (10.4 and 10.3) result in various phenotypic effects (e.g. male sterility, insensitivity to jasmonate inhibition of root growth, etc.)

25 Some examples: Jasmonate signaling in Arabidopsis The JAZ10.3 isoform results in a premature stop codon in the D exon. The JAZ10.4 (AltD) isoform results in a truncation of the D exon, which leads to the elimination of an important domain (Jas).

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