1. Using Exons to Define Isoforms in PRO Timothy Danford Novartis Institutes for Biomedical Research PRO / AlzForum Kickoff Meeting Oct. 4, 2011

2. Genes vs. Proteins Gene Transcript Exon Locus Allele Variant SNP Indel Rearrangement Motif Protein Isoform Variant Domain Site Complex Motif Fragment Can we join the worlds of PRO and of Genes, at a finer-grained level than that of “full sequence?”

3. Isoforms in PRO Today PRO v23 (10/2/2011) [Term] id: PR:000010173 name: microtubule-associated protein tau def: "A protein that is a translation product of the MAPT gene or a 1:1 ortholog thereof." [PRO:DNx] comment: Category=gene. Flag=automatic. synonym: "MAPT" EXACT PRO-short-label [] synonym: "neurofibrillary tangle protein" EXACT [] synonym: "paired helical filament-tau" EXACT [] synonym: "PHF-tau" EXACT [] synonym: "MAPTL" RELATED [] synonym: "Mtapt" RELATED [] synonym: "MTBT1" RELATED [] synonym: "TAU" RELATED [] is_a: PR:000000001 ! protein

4. Isoforms in PRO Today PRO v23 (10/2/2011) [Term] id: PR:000026993 name: microtubule-associated protein tau isoform Fetal-tau def: "A microtubule-associated protein tau that is a translation product of some mRNA giving rise to a protein with the amino acid sequence represented by UniProtKB:P10636-2 or a 1:1 ortholog thereof." [PRO:DAN] comment: Category=sequence. synonym: "Fetal-tau" EXACT [] is_a: PR:000010173 ! microtubule-associated protein tau

5. Isoforms in PRO Today PRO v23 (10/2/2011)

6. Isoforms in PRO Today PRO v23 (10/2/2011)

7. Digression: Visual Notation

8. Isoforms in PRO Today PRO v23 (10/2/2011)

9. Isoforms in PRO Today PRO v23 (10/2/2011)

10. Isoforms in PRO Today PRO v23 (10/2/2011)

11. Tau Isoforms Share Functionally-relevant Exons Fetal Tau Adult Tau Slide: Gwen Wong (AlzForum), Image: http://www.med.upenn.edu/cndr/TauSynuclein.shtml “Conserved Protein Domains in Tau Suggest Functional Differences between Protein Isoforms”

12. What Questions Could We Ask of PRO + Genomic Data? Which isoform corresponds to which transcript(s)? Which isoforms share a common feature? – common exons? – common domains? (pfam, interpro, etc.) Which “normal” protein isoforms overlap with SNPs or other genetic variants? – How do protein sites line up to sites on the gene? How do mouse and human proteins correspond?

13. “Which isoform corresponds with which transcript(s)?” Transcript Variant: This variant (4) lacks six internal coding exons, as compared to variant 6. The reading frame is not affected, and the resulting isoform (4) has identical N- and C-termini but lacks five segments, as compared to isoform 6.

14. Define Exons as Parts-of-Proteins

15. Defined class of Isoforms based on has_part and lacks_part to particular exons

16. Integrate Existing Isoforms

17. How is “MAPT Exon 2” defined? Take the “exon” definition from SO:0000147 – “A region of the transcript sequence within a gene which is not removed from the primary RNA transcript by RNA splicing.” Exon number defined relative to the full-length or “canonical” transcript – “An exon that corresponds (aligns) to the second of 13 exons in the full-length MAPT transcript...” Define the part of the protein derived from this portion of the transcript…

18. What Questions Could We Ask of PRO + Genomic Data? Which isoform corresponds to which transcript(s)? Which isoforms share a common feature? – common exons? – common domains? (pfam, interpro, etc.) Which “normal” protein isoforms overlap with SNPs or other genetic variants? – How do protein sites line up to sites on the gene? How do mouse and human proteins correspond?

19. What Questions Could We Ask of PRO + Genomic Data? Which isoform corresponds to which transcript(s)? Which isoforms share a common feature? – common exons? – common domains? (pfam, interpro, etc.) Which “normal” protein isoforms overlap with SNPs or other genetic variants? – How do protein sites line up to sites on the gene? How do mouse and human proteins correspond?

20. What Questions Could We Ask of PRO + Genomic Data? Which isoform corresponds to which transcript(s)? Which isoforms share a common feature? – common exons? – common domains? (pfam, interpro, etc.) Which “normal” protein isoforms overlap with SNPs or other genetic variants? – How do protein sites line up to sites on the gene? How do mouse and human proteins correspond?