Output Results of CLIME (Clustering by Inferred Models of Evolution)

Output results of CLIME (CLustering by Inferred Models of Evolution)

Dataset: Num of genes in input gene set: 10 Total number of genes: 20834 Prediction LLR threshold: 0

The CLIME PDF output two sections: 1) Overview of Evolutionarily Conserved Modules (ECMs)

Top panel shows the predefined species tree.

Bottom panel shows the partition of input genes into Evolutionary Conserved Modules (ECMs), ordered by ECM strength (shown at right), and separated by horizontal lines.

Each row show one gene, where the phylogenetic profile indicates presence (blue) or absence (gray) of homologs in each species (column).

Gene symbols are shown at left. Gray color indicates that the gene is a paralog to a higher scoring gene within the same ECM (based on BLASTP E < 1e-3).

2) Details of each ECM and its expansion ECM+

Top panel shows the inferred evolutionary history on the predefined species tree. Branch color shows the gain event (blue) and loss events (red color, with brighter color indicating higher confidence in loss). Branches before the gain or after a loss are shown in gray.

Bottom panel shows the input genes that are within the ECM (blue/white rows) as well as all genes in the expanded ECM+ (green/gray rows). The ECM+ includes genes likely to have arisen under the inferred model of evolution relative to a background model, and scored using a log likelihood ratio (LLR).

PG indicates "paralog group" and are labeled alphabetically (i.e., A, B). The first gene within each paralog group is shown in black color. All other genes sharing sequence similarity (BLAST E < 1e-3) are assigned to the same PG label and displayed in gray. ECM 3 ECM 2 ECM 1 Protein SERPIND1 SERPINC1 PROS1 PROC THBD PLAT HRG F5 F9 F2 Overview ofEvolutionarilyConservedModules(ECMs)

S.moellendorffii Plants S.moellendorffii S.bicolor S.bicolor Z.mays Z.mays O.sativa O.sativa B.distachyon B.distachyon A.lyrata A.lyrata A.thaliana A.thaliana L.japonicus L.japonicus M.truncatula M.truncatula V.vinifera V.vinifera P.trichocarpa P.trichocarpa R.communis R.communis T.trahens T.trahens D.discoideum D.discoideum A.macrogynus A.macrogynus S.punctatus S.punctatus M.globosa M.globosa U.maydis U.maydis C.neoformans C.neoformans P.chrysosporium P.chrysosporium S.commune S.commune C.cinerea C.cinerea L.bicolor L.bicolor S.pombe S.pombe B.fuckeliana B.fuckeliana S.sclerotiorum S.sclerotiorum F.graminearum F.graminearum M.grisea M.grisea N.crassa N.crassa P.anserina P.anserina P.chrysogenum P.chrysogenum A.clavatus A.clavatus A.fumigatus A.fumigatus N.fischeri N.fischeri A.flavus A.flavus A.oryzae A.oryzae A.niger A.niger A.nidulans Fungi A.nidulans U.reesii U.reesii C.immitis C.immitis C.posadasii C.posadasii P.nodorum P.nodorum T.melanosporum T.melanosporum Y.lipolytica Y.lipolytica P.pastoris P.pastoris C.lusitaniae C.lusitaniae D.hansenii D.hansenii M.guilliermondii M.guilliermondii S.stipitis S.stipitis L.elongisporus L.elongisporus C.tropicalis C.tropicalis C.albicans C.albicans C.dubliniensis C.dubliniensis K.lactis K.lactis A.gossypii A.gossypii K.waltii K.waltii L.thermotolerans L.thermotolerans Z.rouxii Z.rouxii V.polyspora V.polyspora C.glabrata C.glabrata S.bayanus S.bayanus S.mikatae S.mikatae S.cerevisiae S.cerevisiae S.paradoxus S.paradoxus S.arctica S.arctica C.owczarzaki C.owczarzaki M.brevicollis M.brevicollis S.rosetta S.rosetta S.mansoni S.mansoni B.malayi B.malayi C.briggsae C.briggsae C.elegans C.elegans D.pulex D.pulex A.pisum A.pisum P.humanus P.humanus A.mellifera A.mellifera N.vitripennis N.vitripennis B.mori B.mori T.castaneum T.castaneum D.melanogaster D.melanogaster D.pseudoobscura D.pseudoobscura A.gambiae A.gambiae A.aegypti A.aegypti

C.quinquefasciatus Metazoa C.quinquefasciatus B.floridae B.floridae T.adhaerens T.adhaerens S.purpuratus S.purpuratus H.magnipapillata H.magnipapillata N.vectensis N.vectensis C.intestinalis C.intestinalis D.rerio D.rerio O.latipes O.latipes F.rubripes F.rubripes T.nigroviridis T.nigroviridis X.tropicalis X.tropicalis G.gallus G.gallus M.gallopavo M.gallopavo O.anatinus O.anatinus M.domestica M.domestica S.scrofa S.scrofa M.musculus M.musculus C.familiaris C.familiaris B.taurus B.taurus H.sapiens H.sapiens Strength 9.4 27.5 16.0 PG A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A SERPINB13 SERPINA11 SERPINB12 SERPINA12 SERPINB10 SERPINA10 SERPINB11 Protein SERPING1 100510292 SERPINB8 SERPINH1 SERPINB1 SERPINB4 SERPINA4 SERPINB3 SERPINA6 SERPINB2 SERPINA7 SERPINA9 SERPINA5 SERPINB6 SERPINA1 SERPINB7 SERPINB5 SERPINA3 SERPINB9 SERPIND1 SERPINC1 SERPINE2 SERPINE3 SERPINE1 SERPINF2 SERPINF1 SERPINI2 SERPINI1 1: Thrombophilia || Num ofECMGenes:2.Predicted84.Strength:16.0 ECM 1,Geneset"Thrombophilia",Page1

Prokaryotes Prokaryotes Last CommonAncestor E.cuniculi E.cuniculi E.histolytica E.histolytica E.dispar E.dispar G.lamblia G.lamblia T.vaginalis T.vaginalis T.brucei T.brucei T.cruzi T.cruzi L.infantum L.infantum L.major L.major 2: Osteogenesis imperfecta || L.braziliensis L.braziliensis T.gondii T.gondii Protists C.hominis C.hominis C.parvum C.parvum B.bovis B.bovis T.annulata T.annulata T.parva T.parva P.knowlesi P.knowlesi P.vivax P.vivax P.falciparum P.falciparum P.chabaudi P.chabaudi P.berghei P.berghei P.yoelii P.yoelii P.tetraurelia P.tetraurelia T.thermophila T.thermophila P.infestans P.infestans 3: Deafness || T.pseudonana T.pseudonana P.tricornutum P.tricornutum C.merolae C.merolae N.gruberi N.gruberi O.lucimarinus O.lucimarinus O.tauri O.tauri C.reinhardtii C.reinhardtii V.carteri V.carteri P.patens P.patens 4: Angioedema S.moellendorffii Plants S.moellendorffii S.bicolor S.bicolor Z.mays Z.mays O.sativa O.sativa B.distachyon B.distachyon A.lyrata A.lyrata A.thaliana A.thaliana L.japonicus L.japonicus M.truncatula M.truncatula V.vinifera V.vinifera P.trichocarpa P.trichocarpa R.communis R.communis T.trahens T.trahens D.discoideum D.discoideum A.macrogynus A.macrogynus S.punctatus S.punctatus M.globosa M.globosa U.maydis U.maydis C.neoformans C.neoformans P.chrysosporium P.chrysosporium S.commune S.commune C.cinerea C.cinerea L.bicolor L.bicolor S.pombe S.pombe B.fuckeliana B.fuckeliana S.sclerotiorum S.sclerotiorum F.graminearum F.graminearum M.grisea M.grisea N.crassa N.crassa P.anserina P.anserina P.chrysogenum P.chrysogenum A.clavatus A.clavatus A.fumigatus A.fumigatus N.fischeri N.fischeri A.flavus A.flavus A.oryzae A.oryzae A.niger A.niger A.nidulans Fungi A.nidulans U.reesii U.reesii C.immitis C.immitis C.posadasii C.posadasii P.nodorum P.nodorum T.melanosporum T.melanosporum Y.lipolytica Y.lipolytica P.pastoris P.pastoris C.lusitaniae C.lusitaniae D.hansenii D.hansenii M.guilliermondii M.guilliermondii S.stipitis S.stipitis L.elongisporus L.elongisporus C.tropicalis C.tropicalis C.albicans C.albicans C.dubliniensis C.dubliniensis

K.lactis K.lactis PRESENCE A.gossypii A.gossypii K.waltii K.waltii

L.thermotolerans L.thermotolerans GAIN Z.rouxii Z.rouxii V.polyspora V.polyspora C.glabrata C.glabrata S.bayanus S.bayanus S.mikatae S.mikatae S.cerevisiae S.cerevisiae S.paradoxus S.paradoxus S.arctica S.arctica C.owczarzaki C.owczarzaki M.brevicollis M.brevicollis S.rosetta S.rosetta

S.mansoni S.mansoni ABSENCE B.malayi B.malayi

C.briggsae C.briggsae LOSS C.elegans C.elegans D.pulex D.pulex A.pisum A.pisum P.humanus P.humanus A.mellifera A.mellifera N.vitripennis N.vitripennis B.mori B.mori T.castaneum T.castaneum D.melanogaster D.melanogaster D.pseudoobscura D.pseudoobscura A.gambiae A.gambiae A.aegypti A.aegypti

C.quinquefasciatus Metazoa C.quinquefasciatus B.floridae B.floridae T.adhaerens

T.adhaerens 0 Log-likelihood RatioScale S.purpuratus S.purpuratus H.magnipapillata H.magnipapillata 10 N.vectensis N.vectensis C.intestinalis C.intestinalis

D.rerio D.rerio 20 O.latipes O.latipes

F.rubripes F.rubripes 30 T.nigroviridis T.nigroviridis X.tropicalis X.tropicalis 40 G.gallus G.gallus M.gallopavo M.gallopavo

O.anatinus O.anatinus 50 M.domestica M.domestica S.scrofa S.scrofa 60 M.musculus M.musculus C.familiaris C.familiaris B.taurus B.taurus H.sapiens H.sapiens LLR 79.2 83.6 83.6 83.8 88.0 88.0 88.0 88.0 88.0 88.0 88.0 88.0 88.0 88.1 88.1 88.1 88.1 88.1 88.1 88.1 88.1 88.1 88.1 88.1 88.1 88.1 88.1 88.1 88.2 88.2 88.2 88.2 88.2 Notes 2 4 3 2 1 1 PG B B B H F H H H H H H H D D C G E C E C F C E E E C D C B B Protein CACNA2D1 SELENBP1 WBSCR17 GALNTL2 GALNTL1 GALNTL4 GALNT11 GALNT12 COL14A1 COL12A1 SLC13A2 NHLRC2 GALNT7 GALNT9 COL6A6 COL6A5 MYOM3 CRISP1 GLIPR2 NIPAL2 SGMS1 SGMS2 EIF2C2 TOR1A PIWIL2 PIWIL3 PIWIL1 PIWIL4 GRIK2 GRID1 GRIA3 ITGAX GRIK3 GRIK4 PI15 1: Dystonia Num ofECMGenes:2.Predicted84.Strength:16.0 ECM 1,Geneset"Thrombophilia",Page2

K.lactis K.lactis PRESENCE A.gossypii A.gossypii K.waltii K.waltii

S.mansoni S.mansoni ABSENCE B.malayi B.malayi

C.quinquefasciatus Metazoa C.quinquefasciatus B.floridae B.floridae T.adhaerens

T.adhaerens 0 Log-likelihood RatioScale S.purpuratus S.purpuratus H.magnipapillata H.magnipapillata 10 N.vectensis N.vectensis C.intestinalis C.intestinalis

D.rerio D.rerio 20 O.latipes O.latipes

F.rubripes F.rubripes 30 T.nigroviridis T.nigroviridis X.tropicalis X.tropicalis 40 G.gallus G.gallus M.gallopavo M.gallopavo

O.anatinus O.anatinus 50 M.domestica M.domestica S.scrofa S.scrofa 60 M.musculus M.musculus C.familiaris C.familiaris B.taurus B.taurus H.sapiens H.sapiens LLR 2.8 2.8 2.8 3.1 3.3 4.0 4.1 4.1 4.2 4.2 4.2 4.2 4.3 5.4 6.1 6.6 7.3 7.8 8.1 9.3 11.2 11.8 12.0 12.0 12.5 14.2 14.4 17.4 17.5 17.6 19.3 24.0 24.6 32.4 50.1 Notes 1 PG I I G C H E E B B B B B B Protein RNASEH1 STARD7 GALNT8 TTC30B TTC30A GRIN3A GRIN2D EIF2C1 EIF2C4 CNTN1 GRIK1 GRIA2 GRIA4 GRIA1 NIPA2 DPP6 1: Ventricularfibrillation Num ofECMGenes:2.Predicted84.Strength:16.0 ECM 1,Geneset"Thrombophilia",Page3

K.lactis K.lactis PRESENCE A.gossypii A.gossypii K.waltii K.waltii

S.mansoni S.mansoni ABSENCE B.malayi B.malayi

C.quinquefasciatus Metazoa C.quinquefasciatus B.floridae B.floridae T.adhaerens

T.adhaerens 0 Log-likelihood RatioScale S.purpuratus S.purpuratus H.magnipapillata H.magnipapillata 10 N.vectensis N.vectensis C.intestinalis C.intestinalis

D.rerio D.rerio 20 O.latipes O.latipes

F.rubripes F.rubripes 30 T.nigroviridis T.nigroviridis X.tropicalis X.tropicalis 40 G.gallus G.gallus M.gallopavo M.gallopavo

O.anatinus O.anatinus 50 M.domestica M.domestica S.scrofa S.scrofa 60 M.musculus M.musculus C.familiaris C.familiaris B.taurus B.taurus H.sapiens H.sapiens LLR 0.0 0.0 1.2 1.6 2.1 2.1 2.4 2.5 2.5 2.5 2.8 2.8 2.8 2.8 2.8 2.8 Notes 1 PG A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A TMPRSS11A TMPRSS11D TMPRSS11B Protein TMPRSS13 TMPRSS7 TMPRSS4 TMPRSS2 CELA2A CELA2B TPSAB1 PRSS56 PRSS42 PRSS57 PRSS45 OVCH1 CTRB2 PRSS2 PRSS3 PRTN3 KLK15 GZMH GZMA PROC CTRC PLAU KLK6 PLAT ST14 ACR HGF F11 F10 F12 F9 F2 1: Thrombophilia || Num ofECMGenes:4.Predicted100.Strength:27.5 ECM 2,Geneset"Thrombophilia",Page1

4: Ichthyosis || O.lucimarinus O.lucimarinus O.tauri O.tauri C.reinhardtii C.reinhardtii V.carteri V.carteri P.patens P.patens

S.moellendorffii Plants S.moellendorffii S.bicolor S.bicolor Z.mays Z.mays O.sativa O.sativa B.distachyon B.distachyon

5: Deafness || A.lyrata A.lyrata A.thaliana A.thaliana L.japonicus L.japonicus M.truncatula M.truncatula V.vinifera V.vinifera P.trichocarpa P.trichocarpa R.communis R.communis T.trahens T.trahens D.discoideum D.discoideum

6: Microphthalmia A.macrogynus A.macrogynus S.punctatus S.punctatus M.globosa M.globosa U.maydis U.maydis C.neoformans C.neoformans P.chrysosporium P.chrysosporium S.commune S.commune C.cinerea C.cinerea L.bicolor L.bicolor S.pombe S.pombe B.fuckeliana B.fuckeliana S.sclerotiorum S.sclerotiorum F.graminearum F.graminearum M.grisea M.grisea N.crassa N.crassa P.anserina P.anserina P.chrysogenum P.chrysogenum A.clavatus A.clavatus A.fumigatus A.fumigatus N.fischeri N.fischeri A.flavus A.flavus A.oryzae A.oryzae A.niger A.niger A.nidulans Fungi A.nidulans U.reesii U.reesii C.immitis C.immitis C.posadasii C.posadasii P.nodorum P.nodorum T.melanosporum T.melanosporum Y.lipolytica Y.lipolytica P.pastoris P.pastoris C.lusitaniae C.lusitaniae D.hansenii D.hansenii M.guilliermondii M.guilliermondii S.stipitis S.stipitis L.elongisporus L.elongisporus C.tropicalis C.tropicalis C.albicans C.albicans C.dubliniensis C.dubliniensis

K.lactis K.lactis PRESENCE A.gossypii A.gossypii K.waltii K.waltii

S.mansoni S.mansoni ABSENCE B.malayi B.malayi

C.quinquefasciatus Metazoa C.quinquefasciatus B.floridae B.floridae T.adhaerens

T.adhaerens 0 Log-likelihood RatioScale S.purpuratus S.purpuratus H.magnipapillata H.magnipapillata 10 N.vectensis N.vectensis C.intestinalis C.intestinalis

D.rerio D.rerio 20 O.latipes O.latipes

F.rubripes F.rubripes 30 T.nigroviridis T.nigroviridis X.tropicalis X.tropicalis 40 G.gallus G.gallus M.gallopavo M.gallopavo

O.anatinus O.anatinus 50 M.domestica M.domestica S.scrofa S.scrofa 60 M.musculus M.musculus C.familiaris C.familiaris B.taurus B.taurus H.sapiens H.sapiens LLR 88.2 88.2 88.2 88.2 88.2 88.2 88.2 88.2 88.2 88.2 88.2 88.2 88.2 88.2 88.2 88.2 88.2 88.2 88.3 88.3 88.3 89.1 91.8 93.9 93.9 93.9 94.3 94.5 94.8 103.9 111.0 Notes 6 5 4 3 1 /2 1 1 1 PG A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A LOC100505597 TMPRSS11E TMPRSS11F Protein TMPRSS15 TMPRSS9 TMPRSS3 TMPRSS5 CELA3A CELA3B PRSS56 PRSS22 PRSS44 PRSS41 PRSS27 PRSS48 OVCH2 PRSS8 TPSG1 CELA1 TPSB2 TPSD1 TPSB2 KLK13 KLK10 KLK11 KLK12 GZMM GZMB GZMK CMA1 CTSG KLK1 KLK5 KLK8 CFD 1: Deafness Num ofECMGenes:4.Predicted100.Strength:27.5 ECM 2,Geneset"Thrombophilia",Page2

K.lactis K.lactis PRESENCE A.gossypii A.gossypii K.waltii K.waltii

S.mansoni S.mansoni ABSENCE B.malayi B.malayi

C.quinquefasciatus Metazoa C.quinquefasciatus B.floridae B.floridae T.adhaerens

T.adhaerens 0 Log-likelihood RatioScale S.purpuratus S.purpuratus H.magnipapillata H.magnipapillata 10 N.vectensis N.vectensis C.intestinalis C.intestinalis

D.rerio D.rerio 20 O.latipes O.latipes

F.rubripes F.rubripes 30 T.nigroviridis T.nigroviridis X.tropicalis X.tropicalis 40 G.gallus G.gallus M.gallopavo M.gallopavo

O.anatinus O.anatinus 50 M.domestica M.domestica S.scrofa S.scrofa 60 M.musculus M.musculus C.familiaris C.familiaris B.taurus B.taurus H.sapiens H.sapiens LLR 88.1 88.1 88.1 88.1 88.1 88.1 88.1 88.1 88.1 88.1 88.1 88.1 88.1 88.1 88.1 88.1 88.1 88.1 88.1 88.1 88.2 88.2 88.2 88.2 88.2 88.2 88.2 88.2 88.2 88.2 88.2 88.2 88.2 88.2 88.2 Notes 1 PG A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A Protein TMPRSS12 TMPRSS6 PRSS36 PRSS12 PRSS46 PRSS21 PRSS50 PRSS55 PRSS58 PRSS33 PRSS38 PRSS43 HGFAC MASP2 ELANE HABP2 KLKB1 CTRB1 PRSS1 TPSB2 CORIN KLK14 MST1 CTRL KLK9 KLK2 KLK3 KLK4 AZU1 KLK7 HPN PLG LPA CFI 1: Pancreatitis || Num ofECMGenes:4.Predicted100.Strength:27.5 ECM 2,Geneset"Thrombophilia",Page3

Prokaryotes Prokaryotes Last CommonAncestor E.cuniculi E.cuniculi E.histolytica E.histolytica E.dispar E.dispar G.lamblia G.lamblia T.vaginalis T.vaginalis T.brucei T.brucei T.cruzi T.cruzi

2: Amelogenesis imperfecta || L.infantum L.infantum L.major L.major L.braziliensis L.braziliensis T.gondii T.gondii Protists C.hominis C.hominis C.parvum C.parvum B.bovis B.bovis T.annulata T.annulata T.parva T.parva P.knowlesi P.knowlesi P.vivax P.vivax P.falciparum P.falciparum P.chabaudi P.chabaudi P.berghei P.berghei P.yoelii P.yoelii P.tetraurelia P.tetraurelia T.thermophila T.thermophila 3: Neutropenia P.infestans P.infestans T.pseudonana T.pseudonana P.tricornutum P.tricornutum C.merolae C.merolae N.gruberi N.gruberi O.lucimarinus O.lucimarinus O.tauri O.tauri C.reinhardtii C.reinhardtii V.carteri V.carteri P.patens P.patens

K.lactis K.lactis PRESENCE A.gossypii A.gossypii K.waltii K.waltii

S.mansoni S.mansoni ABSENCE B.malayi B.malayi

C.quinquefasciatus Metazoa C.quinquefasciatus B.floridae B.floridae T.adhaerens

T.adhaerens 0 Log-likelihood RatioScale S.purpuratus S.purpuratus H.magnipapillata H.magnipapillata 10 N.vectensis N.vectensis C.intestinalis C.intestinalis

D.rerio D.rerio 20 O.latipes O.latipes

F.rubripes F.rubripes 30 T.nigroviridis T.nigroviridis X.tropicalis X.tropicalis 40 G.gallus G.gallus M.gallopavo M.gallopavo

O.anatinus O.anatinus 50 M.domestica M.domestica S.scrofa S.scrofa 60 M.musculus M.musculus C.familiaris C.familiaris B.taurus B.taurus H.sapiens H.sapiens LLR 72.6 72.6 72.7 76.9 77.0 77.1 77.2 77.2 77.2 78.7 78.7 79.0 79.7 79.8 81.4 82.4 82.7 82.7 82.7 82.8 82.8 82.8 82.8 82.9 82.9 83.3 85.2 86.5 87.3 88.1 88.1 88.1 88.1 88.1 Notes 3 2 1 PG A A A B B A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A Protein EFEMP1 EFEMP2 HMCN2 SLMO1 SLMO2 MATN4 PROS1 CCBE1 SUSD1 VLDLR THBS2 THBS3 THBS4 FBLN7 FBLN1 FBLN2 FBLN5 LTBP4 NELL2 ELTD1 NELL1 LTBP3 CD248 UMOD VWCE COMP EMR1 EMR3 THBD GAS6 HEG1 NPNT LDLR CD93 OIT3 1: Thrombophilia || Num ofECMGenes:2.Predicted95.Strength:9.4 ECM 3,Geneset"Thrombophilia",Page1

3: Hypercholesterolemia || T.thermophila T.thermophila P.infestans P.infestans T.pseudonana T.pseudonana P.tricornutum P.tricornutum C.merolae C.merolae N.gruberi N.gruberi O.lucimarinus O.lucimarinus O.tauri O.tauri C.reinhardtii C.reinhardtii V.carteri V.carteri P.patens P.patens

S.moellendorffii Plants S.moellendorffii S.bicolor S.bicolor Z.mays Z.mays O.sativa O.sativa 4: Cutislaxa || B.distachyon B.distachyon A.lyrata A.lyrata A.thaliana A.thaliana L.japonicus L.japonicus M.truncatula M.truncatula V.vinifera V.vinifera P.trichocarpa P.trichocarpa R.communis R.communis T.trahens T.trahens D.discoideum

5: Macular degeneration || D.discoideum A.macrogynus A.macrogynus S.punctatus S.punctatus M.globosa M.globosa U.maydis U.maydis C.neoformans C.neoformans P.chrysosporium P.chrysosporium S.commune S.commune C.cinerea C.cinerea L.bicolor L.bicolor S.pombe S.pombe B.fuckeliana B.fuckeliana S.sclerotiorum S.sclerotiorum F.graminearum F.graminearum M.grisea M.grisea

6: Tooth agenesis || N.crassa N.crassa P.anserina P.anserina P.chrysogenum P.chrysogenum A.clavatus A.clavatus A.fumigatus A.fumigatus N.fischeri N.fischeri A.flavus A.flavus A.oryzae A.oryzae A.niger A.niger A.nidulans Fungi A.nidulans U.reesii U.reesii C.immitis C.immitis

7: Hyperuricemic nephropathy || C.posadasii C.posadasii P.nodorum P.nodorum T.melanosporum T.melanosporum Y.lipolytica Y.lipolytica P.pastoris P.pastoris C.lusitaniae C.lusitaniae D.hansenii D.hansenii M.guilliermondii M.guilliermondii S.stipitis S.stipitis L.elongisporus L.elongisporus C.tropicalis C.tropicalis C.albicans C.albicans C.dubliniensis C.dubliniensis

K.lactis K.lactis PRESENCE A.gossypii A.gossypii K.waltii K.waltii

L.thermotolerans L.thermotolerans GAIN Z.rouxii Z.rouxii 8: Synpolydactyly V.polyspora V.polyspora C.glabrata C.glabrata S.bayanus S.bayanus S.mikatae S.mikatae S.cerevisiae S.cerevisiae S.paradoxus S.paradoxus S.arctica S.arctica C.owczarzaki C.owczarzaki M.brevicollis M.brevicollis S.rosetta S.rosetta

S.mansoni S.mansoni ABSENCE B.malayi B.malayi

C.quinquefasciatus Metazoa C.quinquefasciatus B.floridae B.floridae T.adhaerens

T.adhaerens 0 Log-likelihood RatioScale S.purpuratus S.purpuratus H.magnipapillata H.magnipapillata 10 N.vectensis N.vectensis C.intestinalis C.intestinalis

D.rerio D.rerio 20 O.latipes O.latipes

F.rubripes F.rubripes 30 T.nigroviridis T.nigroviridis X.tropicalis X.tropicalis 40 G.gallus G.gallus M.gallopavo M.gallopavo

O.anatinus O.anatinus 50 M.domestica M.domestica S.scrofa S.scrofa 60 M.musculus M.musculus C.familiaris C.familiaris B.taurus B.taurus H.sapiens H.sapiens LLR 15.9 16.0 16.1 16.7 17.3 18.0 18.1 19.2 20.7 21.0 22.5 24.0 25.6 26.9 28.3 28.5 29.5 29.7 29.9 30.3 31.1 31.8 32.6 32.6 32.9 33.0 33.6 35.4 38.3 39.7 41.7 50.0 53.9 Notes 4 8 4 7 6 4 /5 3 2 1 1 PG A D A A A A E A A A A D A A C A C A A A A C B A A A A Protein ADAMTSL3 ADAMTSL4 ADAMTS12 100509525 ADAMTS2 GALNTL6 SLC17A4 SLC17A7 PRELID1 DCBLD2 GALNT5 GALNT8 ANP32D ZFAND3 CSMD3 MATN1 MATN2 MATN3 ACBD3 DMBT1 FCHO1 APH1A THBS1 EGFL7 EGFL6 EGFL8 USP54 CUBN LITAF PROZ BMP1 LRP8 TLL2 NID2 FST 7: Charcot-Marie-Tooth disease 1: Ehlers-Danlos syndrome || Num ofECMGenes:2.Predicted95.Strength:9.4 ECM 3,Geneset"Thrombophilia",Page2

2: Spondyloepimetaphyseal dysplasia/Spondyloepiphyseal dysplasia/Spondylometaphyseal dysplasia || B.bovis B.bovis T.annulata T.annulata T.parva T.parva P.knowlesi P.knowlesi P.vivax P.vivax P.falciparum P.falciparum P.chabaudi P.chabaudi P.berghei P.berghei P.yoelii P.yoelii P.tetraurelia P.tetraurelia T.thermophila T.thermophila P.infestans P.infestans T.pseudonana T.pseudonana P.tricornutum P.tricornutum C.merolae C.merolae N.gruberi N.gruberi O.lucimarinus O.lucimarinus O.tauri O.tauri C.reinhardtii C.reinhardtii V.carteri V.carteri P.patens P.patens

4: Osteogenesis imperfecta || Y.lipolytica Y.lipolytica P.pastoris P.pastoris C.lusitaniae C.lusitaniae D.hansenii D.hansenii M.guilliermondii M.guilliermondii S.stipitis S.stipitis L.elongisporus L.elongisporus C.tropicalis C.tropicalis C.albicans C.albicans C.dubliniensis C.dubliniensis

K.lactis K.lactis PRESENCE A.gossypii A.gossypii K.waltii K.waltii

L.thermotolerans L.thermotolerans GAIN Z.rouxii Z.rouxii V.polyspora V.polyspora

5: Ectopia lentis|| C.glabrata C.glabrata S.bayanus S.bayanus S.mikatae S.mikatae S.cerevisiae S.cerevisiae S.paradoxus S.paradoxus S.arctica S.arctica C.owczarzaki C.owczarzaki M.brevicollis M.brevicollis S.rosetta S.rosetta

S.mansoni S.mansoni ABSENCE B.malayi B.malayi LOSS

6: Megaloblastic anemia || C.briggsae C.briggsae C.elegans C.elegans D.pulex D.pulex A.pisum A.pisum P.humanus P.humanus A.mellifera A.mellifera N.vitripennis N.vitripennis B.mori B.mori T.castaneum T.castaneum D.melanogaster D.melanogaster D.pseudoobscura D.pseudoobscura A.gambiae A.gambiae A.aegypti A.aegypti

C.quinquefasciatus Metazoa C.quinquefasciatus B.floridae B.floridae T.adhaerens

T.adhaerens 0 Log-likelihood RatioScale S.purpuratus S.purpuratus H.magnipapillata H.magnipapillata 10 N.vectensis N.vectensis C.intestinalis C.intestinalis

D.rerio D.rerio 20 O.latipes O.latipes

F.rubripes F.rubripes 30 T.nigroviridis T.nigroviridis X.tropicalis X.tropicalis 40 G.gallus G.gallus M.gallopavo M.gallopavo

O.anatinus O.anatinus 50 M.domestica M.domestica S.scrofa S.scrofa 60 M.musculus M.musculus C.familiaris C.familiaris B.taurus B.taurus H.sapiens H.sapiens LLR 4.1 4.2 4.2 4.3 4.4 4.7 4.8 4.9 5.0 5.2 5.4 5.7 5.7 5.8 5.8 6.1 6.5 8.1 8.1 8.4 8.6 8.8 8.8 10.0 10.2 11.6 11.9 11.9 12.8 13.2 13.7 14.9 14.9 15.3 15.9 Notes 7 6 5 4 2 /3 1 PG C C C C C C A A A A A A C A A A A A A A E C Protein ADAMTSL1 ADAMTS20 WBSCR17 GALNTL4 GALNTL5 GALNT11 GALNT12 DGAT2L7 FRMPD2 GALNT7 GALNT9 GALNT2 KCTD11 HHIPL1 PAPLN FUCA2 THSD4 LOXL2 LOXL4 LOXL3 LTBP1 AXIN2 EMR2 NUS1 LRP4 FAT2 NID1 1: Sclerosteosis Num ofECMGenes:2.Predicted95.Strength:9.4 ECM 3,Geneset"Thrombophilia",Page3

K.lactis K.lactis PRESENCE A.gossypii A.gossypii K.waltii K.waltii

S.mansoni S.mansoni ABSENCE B.malayi B.malayi

C.quinquefasciatus Metazoa C.quinquefasciatus B.floridae B.floridae T.adhaerens

T.adhaerens 0 Log-likelihood RatioScale S.purpuratus S.purpuratus H.magnipapillata H.magnipapillata 10 N.vectensis N.vectensis C.intestinalis C.intestinalis

D.rerio D.rerio 20 O.latipes O.latipes

F.rubripes F.rubripes 30 T.nigroviridis T.nigroviridis X.tropicalis X.tropicalis 40 G.gallus G.gallus M.gallopavo M.gallopavo

O.anatinus O.anatinus 50 M.domestica M.domestica S.scrofa S.scrofa 60 M.musculus M.musculus C.familiaris C.familiaris B.taurus B.taurus H.sapiens H.sapiens LLR 0.0 0.1 0.1 0.1 0.1 0.1 0.3 0.4 0.5 0.7 0.7 0.7 0.9 0.9 1.0 1.3 1.6 1.9 2.0 2.0 2.1 2.3 2.5 2.6 3.1 3.6 4.0 Notes 1 PG Protein F5 1: Thrombophilia Num ofECMGenes:1.Predicted0 ECM 4,Geneset"Thrombophilia",Page1

K.lactis K.lactis PRESENCE A.gossypii A.gossypii K.waltii K.waltii

S.mansoni S.mansoni ABSENCE B.malayi B.malayi

C.quinquefasciatus Metazoa C.quinquefasciatus B.floridae B.floridae T.adhaerens

T.adhaerens 0 Log-likelihood RatioScale S.purpuratus S.purpuratus H.magnipapillata H.magnipapillata 10 N.vectensis N.vectensis C.intestinalis C.intestinalis

D.rerio D.rerio 20 O.latipes O.latipes

F.rubripes F.rubripes 30 T.nigroviridis T.nigroviridis X.tropicalis X.tropicalis 40 G.gallus G.gallus M.gallopavo M.gallopavo

O.anatinus O.anatinus 50 M.domestica M.domestica S.scrofa S.scrofa 60 M.musculus M.musculus C.familiaris C.familiaris B.taurus B.taurus H.sapiens H.sapiens LLR Notes 1 PG Protein HRG 1: Thrombophilia Num ofECMGenes:1.Predicted0 ECM 5,Geneset"Thrombophilia",Page1

K.lactis K.lactis PRESENCE A.gossypii A.gossypii K.waltii K.waltii

S.mansoni S.mansoni ABSENCE B.malayi B.malayi

C.quinquefasciatus Metazoa C.quinquefasciatus B.floridae B.floridae T.adhaerens

T.adhaerens 0 Log-likelihood RatioScale S.purpuratus S.purpuratus H.magnipapillata H.magnipapillata 10 N.vectensis N.vectensis C.intestinalis C.intestinalis

D.rerio D.rerio 20 O.latipes O.latipes

F.rubripes F.rubripes 30 T.nigroviridis T.nigroviridis X.tropicalis X.tropicalis 40 G.gallus G.gallus M.gallopavo M.gallopavo

O.anatinus O.anatinus 50 M.domestica M.domestica S.scrofa S.scrofa 60 M.musculus M.musculus C.familiaris C.familiaris B.taurus B.taurus H.sapiens H.sapiens LLR Notes 1