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Gene Prediction

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Gene Prediction Computational Gene Finding Ab initio Methods ComparativeMethods Introduction to Computational Biology; An Evolutionary Approach: Gene Prediction Bernhard Haubold & Thomas Wiehe ICB c 2006 Birkhäuser Verlag Computational Gene Finding Ab initio Methods ComparativeMethods Outline 1 Computational Gene Finding 2 Ab initio Methods Codon Usage Splice Site Detection Exon Chaining 3 Comparative Methods ICB c 2006 Birkhäuser Verlag Computational Gene Finding Ab initio Methods ComparativeMethods What is a Gene? 1 Mendel 1866 2 ≈ 1900: rediscovery of Mendel 3 1913: first gene map 4 1927: Muller: X-rays induce mutations 5 1928: Griffith: transformation with heat-killed cells 6 1944: Avery: Gene ≡ DNA 7 1953: Watson & Crick: B-form DNA 8 1953: Sanger: sequence of insulin 9 1960’s: Nierenberg: Genetic code 10 1960’s/1970’s: Arber/Nathans/Smith: discovery of restriction enzymes & gene cloning 11 1977: Roberts & Sharp: split genes 12 1977: Sanger / Maxam & Gilbert: DNA sequencing ICB c 2006 Birkhäuser Verlag Computational Gene Finding Ab initio Methods ComparativeMethods GenBank Entry for Adh/Adh_dup LOCUS DMADH 4761 bp DNA linear INV 09-MAY-1997 /number=3 DEFINITION D.melanogaster Adh and Adh-dup genes. exon 2660..3100 ACCESSION X78384 /gene="Adh" VERSION X78384.1 GI:483718 /number=4 KEYWORDS ADH gene; Adh-dup gene; polymorphism. gene 3226..4761 SOURCE Drosophila melanogaster. /gene="Adh-dup" ORGANISM Drosophila melanogaster mRNA join(<3226..3321,3748..4152,4204..4761) Eukaryota; Metazoa; Arthropoda; Hexapoda; Insecta; Pterygota; /gene="Adh-dup" Neoptera; Endopterygota; Diptera; Brachycera; Muscomorpha; /note="for sequence comparison with D.simulans see paper" Ephydroidea; Drosophilidae; Drosophila. CDS join(3226..3321,3748..4152,4204..4521) REFERENCE 1 (bases 1 to 4761) /gene="Adh-dup" AUTHORS Kreitman,M. and Hudson,R.R. /note="for sequence comparison with D.simulans see paper" TITLE Inferring the evolutionary histories of the Adh and Adh-dup loci in /codon_start=1 Drosophila melanogaster from patterns of polymorphism and /protein_id="CAA55152.1" divergence /db_xref="GI:483719" JOURNAL Genetics 127 (3), 565-582 (1991) /db_xref="FLYBASE:FBgn0000056" MEDLINE 91200630 /db_xref="SWISS-PROT:P91615" PUBMED 1673107 /translation="MFDLTGKHVCYVADCGGIALETSKVLMTKNIAKLAILQSTENPQ COMMENT See paper for sequence comparison to D. simulans. AIAQLQSIKPSTQIFFWTYDVTMAREDMKKYFDEVMVQMDYIDVLINGATLCDENNID FEATURES Location/Qualifiers ATINTNLTGMMNTVATVLPYMDRKIGGTGGLIVNVTSVIGLDPSPVFCAYSASKFGVI source 1..4761 GFTRSLADPLYYSQNGVAVMAVCCGPTRVFVDRELKAFLEYGQSFADRLRRAPCQSTS /organism="Drosophila melanogaster" VCGQNIVNAIERSENGQIWIADKGGLELVKLHWYWHMADQFVHYMQSNDEEDQD" /db_xref="taxon:7227" exon <3226..3321 /chromosome="2" /gene="Adh-dup" /note="for sequence comparison with D.simulans see paper" /number=1 gene join(1244..1330,1985..2119,2185..2589,2660..3100) intron 3322..3747 /gene="Adh" /gene="Adh-dup" mRNA join(1244..1330,1985..2119,2185..2589,2660..3100) /number=1 /gene="Adh" exon 3748..4152 /note="distal transcript /gene="Adh-dup" for sequence comparison with D.simulans see paper" /number=2 exon 1244..1330 intron 4153..4203 /gene="Adh" /gene="Adh-dup" /number=1 /number=2 intron 1331..1950 exon 4204..4761 /gene="Adh" /gene="Adh-dup" /number=1 /number=3 exon 1985..2119 BASE COUNT 1417 a 1007 c 989 g 1348 t /gene="Adh" ORIGIN /number=2 1 tgtattttcc aattaggtga tagaacttgt gtgcacacac acatatagtt ctatatcaac CDS join(2021..2119,2185..2589,2660..2926) 61 aaacaggttt aagttttatg caaattgaaa gcttatttct tccgcatgct tatctctttc /gene="Adh" 121 cttctcatca tttgtatgca aaaaatacat atgaatttgc agtagcctcc tcccacatca /note="unnamed protein product" 181 tatttaacgc cctatattca aaatttgctc aagaaaatat ttgaaccaaa ttgattttta /codon_start=1 241 gtcaattagt ttttaagtaa ttaagtggag taaacatata caattttatt cttaccaaac /protein_id="CAA55151.1" 301 acatatactc atatattttg aataaataaa taaacaaata tatataaaat ctacgaaatt /db_xref="GI:2077989" 361 ggcaaacaaa ttttaaagca ttatagtatt gccgatttaa ttaatataat taaataatat /db_xref="FLYBASE:FBgn0000055" 421 gtacatgtat taatcttgtg tgcgagcatg ggttaaatct agctgcattc gaaaccgcta /db_xref="SWISS-PROT:P00334" ... .......... .......... .......... .......... .......... .......... /translation="MSFTLTNKNVIFVAGLGGIGLDTSKELLKRDLKNLVILDRIENP 2101 gctcaagcgc gatctgaagg taactatgcg atgcccacag gctccatgca gcgatggagg AAIAELKAINPKVTVTFYPYDVTVPIAETTKLLKTIFAQLKTVDVLINGAGILDDHQI 2161 ttaatctcgt gtattcaatc ctagaacctg gtgatcctcg accgcattga gaacccggct ERTIAVNYTGLVNTTTAILDFWDKRKGGPGGIICNIGSVTGFNAIYQVPVYSGTKAAV 2221 gccattgccg agctgaaggc aatcaatcca aaggtgaccg tcaccttcta cccctatgat VNFTSSLAKLAPITGVTAYTVNPGITRTTLVHKFNSWLDVEPQVAEKLLAHPTQPSLA 2281 gtgaccgtgc ccattgccga gaccaccaag ctgctgaaga ccatcttcgc ccagctgaag CAENFVKAIELNQNGAIWKLDLGTLEAIQWTKHWDSGI" 2341 accgtcgatg tcctgatcaa cggagctggt atcctggacg atcaccagat cgagcgcacc intron 2120..2184 2401 attgccgtca actacactgg cctggtcaac accacgacgg ccattctgga cttctgggac /gene="Adh" 2461 aagcgcaagg gcggtcccgg tggtatcatc tgcaacattg gatccgtcac tggattcaat /number=2 2521 gccatctacc aggtgcccgt ctactccggc accaaggccg ccgtggtcaa cttcaccagc exon 2185..2589 2581 tccctggcgg taagttgatc aaaggaaacg caaagttttc aagaaaaaac aaaactattt /gene="Adh" 2641 gattttataa cacctttaga aactggcccc cattaccggc gtgaccgctt acaccgtgaa /number=3 2701 ccccggcatc acccgcacca ccctggtgca caagttcaac tcctggttgg atgttgagcc intron 2590..2659 2761 ccaggttgct gagaagctcc tggctcatcc cacccagcca tcgttggcct gcgccgagaa /gene="Adh" 2821 gttgtcagtt gcagttcagc agacgggcta acgagtactt gcatctcttc .......... ICB c 2006 Birkhäuser Verlag Computational Gene Finding Ab initio Methods ComparativeMethods Structure of Adh/Adh_dup 1 1000 2000 3000 4000 5000 genomic DNA 5’ 3’ transcription primary transcript splicing mRNA translation protein ICB c 2006 Birkhäuser Verlag Computational Gene Finding Ab initio Methods ComparativeMethods Gene Prediction Algorithms Input: A Query Sequence Gene Prediction Splice Site Profiles Program Codon Usage Table Output: List of coordinates Input: B Query Sequence Subject Sequence(s) Alignment Sequence Similarity Gene Prediction Splice Site Profiles Program Codon Usage Table Output: List of coordinates A: Ab initio; B: comparative ICB c 2006 Birkhäuser Verlag Computational Gene Finding Ab initio Methods ComparativeMethods Gene Models Model 1+: 5’ Single+ 3’ − Model 1−: 3’ Single 5’ Model 2+: 5’ Initial+ Internal+ Final+ 3’ Model 2−: 3’ Final− Internal− Initial− 5’ ICB c 2006 Birkhäuser Verlag Computational Gene Finding Ab initio Methods ComparativeMethods Sensitivity & Specificity sensitivity (Sn): proportion of real elements (coding nucleotides, exons or genes) that have been correctly predicted specificity (Sp): proportion of predicted elements which are correct ICB c 2006 Birkhäuser Verlag Computational Gene Finding Ab initio Methods ComparativeMethods Accuracy at Nucleotide Level TN FN TP FP TN FN TP FN TN Reality Prediction TP: true positive; TN: true negative; FP: false positive; FN: false negative TP(N) Sensitivity: Sn(N)= TP(N)+FN(N) TP(N) Specificity: Sp(N)= TP(N)+FP(N) ICB c 2006 Birkhäuser Verlag Computational Gene Finding Ab initio Methods ComparativeMethods Sensitivity & Specificity 1 0 ≤ Sp ≤ 1; 0 ≤ Sn ≤ 1 2 Ideal prediction program: Sn = Sp = 1 3 Summary measure: Correlation coefficient: TP(N) × TN(N) − FP(N) × FN(N) CC = p(TP(N)+ FP(N))(TN(N)+ FN(N))(TN(N)+ FP(N))(TP(N)+ FN(N)) 4 −1 ≤ CC ≤ 1 5 CC = 1: perfect prediction 6 CC = −1: each coding nucleotide predicted as non-coding & vice versa ICB c 2006 Birkhäuser Verlag Computational Gene Finding Ab initio Methods ComparativeMethods Accuracy at Exon Level true positive: if 5’ & 3’ boundaries predicted correctly false positive: if no overlap with real exon sensitivity: proportion of true positives among true exons specificity: proportion of true positives among predicted exons summary statistic: sensitivity + specificity/2 ICB c 2006 Birkhäuser Verlag Computational Gene Finding Ab initio Methods ComparativeMethods Accuracy at Gene Level true positive 1 all coding exons identified 2 every intron/exon boundary correct 3 all exons included false negative (missed): no exons overlap with any predicted gene false positive (wrong): none of its exons overlapped by any real gene ICB c 2006 Birkhäuser Verlag Computational Gene Finding Ab initio Methods ComparativeMethods Summary Accuracy Measures nucleotide exon gene Sensitivity proportion of cod- proportion of cor- proportion of com- Sn ing nucleotides rectly predicted pletely correctly correctly predicted exons among predicted genes as coding actual exons among actual genes Specificity proportion of proportion of cor- proportion of Sp nucleotides pre- rectly predicted completely cor- dicted as coding exons among all rectly predicted and which are predicted exons genes among all actually coding predicted genes ICB c 2006 Birkhäuser Verlag Computational Gene Finding Ab initio Methods ComparativeMethods Examples Gene Prediction Accuracy Nucleotide Exon Gene Sn Sp Sn Sp FN(E) FP(E) Sn Sp FN(G) FP(G) SG JG (1) 0.89 0.77 0.65 0.49 0.10 0.32 0.30 0.27 0.09 0.24 1.10 1.06 (2) 0.86 0.83 0.58 0.34 0.21 0.47 0.26 0.10 0.14 0.30 1.06 1.11 (3) 0.96 0.92 0.70 0.57 0.08 0.17 0.40 0.29 0.05 0.11 1.17 1.08 (4) 0.97 0.91 0.77 0.55 0.05 0.20 0.44 0.28 0.05 0.13 1.15 1.09 ((5) 0.81 0.86 0.42 0.41 0.24 0.29 0.14 0.12 0.16 0.24 1.23 1.08 (6) 0.97 0.91 0.68 0.53 0.05 0.20 0.35 0.30 0.07 0.15 1.04 1.12 (7) 0.96 0.63 0.63 0.41 0.12 0.50 0.33 0.21 0.05 0.55 1.22 1.06 (1) FGENES, (2) GeneID, (3) GENIE, (4) GENIE EST-version, (5) GRAIL, (6) HMMGENE, and (7) MAGPIE ICB c 2006 Birkhäuser Verlag Computational Gene Finding Ab initio Methods ComparativeMethods
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