Supplementary Figure 1 Partial sequence ...

Act pleuropneumonia ser. 5b str. L20 Act pleuropneumoniae ser 6 str. Femo Act pleuropneumonia ser. 5b str. 5b str. L20 Act pleuropneumoniae ser 2 str. 4226 Act pleuropneumoniae ser 2 str. S1536 Act pleuropneumoniae ser 4 str. M62 Actinobacillus Act pleuropneumoniae ser 10 str. D13039 sensu stricto Act pleuropneumoniae ser 12 str. 1096 Act pleuropneumoniae ser 13 str. N273 Act pleuropneumoniae ser 1 str. 4074 Act pleuropneumoniae ser 9 str. CVJ13261 Act pleuropneumoniae ser 11 str. 56153 Act pleuropneumonia ser. 7 str. AP76 Pasteurella pneumotropica Actinobacillus capsulatus Avibacterium paragallinarum Actinobacillus suis H91-0380 Actinobacillus ureae Actinobacillus minor Actinobacillus succinogenes 13 Mannheimia succiniciproducens Pasteurella bettyae Pasteurella multocida 36950 Pasteurella multocida subsp. m Pasteurella dagmatis Mannheimia haemolytica USDA-AR Bibersteinia trehalosi USDA-AR Haemophilus ducreyi 35000HP Haemophilus sputorum Haemophilus parahaemolyticus Haemophilus paraphrohaemolytic Other Haemophilus parasuis SH0165 Pasteurellales Haemophilus somnus 129PT Haemophilus parainfluenzae T3T Haemophilus sp. oral taxon 851 Haemophilus haemolyticus Haemophilus influenzae R2846 Haemophilus influenzae 10810 Haemophilus influenzae Rd KW20 Haemophilus influenzae PittEE Haemophilus influenzae 86-028N Haemophilus influenzae F3047 Haemophilus influenzae F3031 Haemophilus influenzae PittGG Haemophilus pittmaniae Haemophilus aegyptius Aggregatibacter actinomycetemc Aggregatibacter segnis Aggregatibacter aphrophilus NJ Gallibacterium anatis UMN179 Psychromonas ingrahamii 37 Xenorhabdus nematophila Serratia symbiotica Alteromonas sp. SN2 Other Arsenophonus nasoniae Gammaproteo- Sodalis glossinidius str. 'mor bacteria Cronobacter sakazakii ATCC BAA 0/250 Morganella morganii subsp. mor Salmonella enterica Shigella flexneri Citrobacter freundii Escherichia coli

126207889 306860648 126096681 302648616 306856105 306858326 306865081 306869447 306871633 306853881 306862884 306867306 190149698 517167434 517481243 545595425 407692614 491834566 492371309 152977877 52424296 492134420 378775075 15603730 492150615 472334407 470167385 33152293 494789823 491987266 491989861 219870950 113460244 345428882 497184571 491876336 386265268 378696520 16272286 148825382 68248939 319775796 319896667 148827481 494450183 494054052 261867309 493770955 251793350 332289404 119944303 498909906 493761013 333894384 284009170 85058488 156932730 455738312 487688971 491272795 489124323 446148970

368 WLRKLLAWQNDIADSGEIMA ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------D--T----V-----------------DVV---------D--T--S-VI----------------DVV----------------DVV----------------DVV---------A------G-VG ---------H--SN---VVP ---------H--S-A--VVP ---------D--T---------------D--T---------------D--T----V-------E----L----DMV-----------------MVD -----------L-V-SDM----------------SDMVD ----------------DVLD ----------------DVVD ------D--K------DVV---------D--T----V----------D--T----V----------D--T----V----------D--T----V----------D--T----V----------D--T----V----------D--T----VL---------D--T----VL---------D--T----VL---------D--T----VL---------D--T----VL---------D--T---KV----------D--T----VIE ---------D--T----VL---------D--T----V----------D-------V----------D--T----V----------D-L-----VL----I----E-----EDLVD -----I---EEM--T--MLD -----IT--EEM-----MLD ---RI----EEV-E--DMVE -----I---EEM-----MLD ---------EEM-----MLD -----I---EEM-----MLD -----I---EEM-----MLD -----I---EEM-----MLD -----I---EEM-----MLD -----I---EEM-----MLD -----I---EEM-----MLD

A -

412 EMRSQVFDDRVYVFTPKGEVIDLP ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------S---------------------L------------------V------------------R-------L-------------------------------------R----------------------R--------------------------V-----T-I--------------V---L-T----------------V---L-T--------------Q------------------------------------------------------------------------------I----------R------DL---------------------D----I----------R--------------------------V------------------R----------------------R--------------------------V----------------------V---L------------------V---L------------------V---L------------------V---L------------------V---L------------------V---L------------------V---L------------------V---L------------------V---L------------------V---L------------------V---L------------------V---L------------------V---L------------------V---L------------------V---L------------------V---L------------------V--------------------------V----------------------V----------------D-----V----------------D-V---L----------------D-----V----------------D-----V----------------D-V---L----------------D-V---V----------------D-V---V----------------D-V---V----------------D-V---V----------------D-V---V----------------D-V---

Supplementary Figure 1 Partial sequence alignment for GTP pyrophosphokinase. The protein contains 1 aa insertion that is specific for Actinobacillus sensu stricto.

Actinobacillus ureae ATCC 25976 Actinobacillus suis H91-0380 Actinobacillus suis ATCC 33415 Actinobacillus capsulatus Act. pleuropneumonia ser. 3 str. JL03 Act. pleuropneumonia ser. 6 str. Femo Act. pleuropneumonia ser. 2 str. 4226 Act. pleuropneumonia ser. 12 str. 1096 Actinobacillus Act. pleuropneumonia ser. 4 str. M62 sensu stricto Act. pleuropneumonia ser. 2 str. S1536 Act. pleuropneumonia ser. 10 str.D13039 Act. pleuropneumonia ser. 13 str. N273 Act. pleuropneumonia ser. 1 str. 4074 Act. pleuropneumonia ser. 9 str. CVJ13261 Act. pleuropneumonia ser. 11 str. 56153 Act. pleuropneumonia ser. 5b str. L20 Act. pleuropneumonia ser. 7 str. AP76 Actinobacillus minor Actinobacillus succinogenes 13 Mannheimia succiniciproducens Pasteurella bettyae Pasteurella dagmatis Pasteurella multocida subsp. m Pasteurella multocida 36950 Gallibacterium anatis UMN179 Bibersteinia trehalosi USDA-AR Haemophilus ducreyi 35000HP Haemophilus parasuis SH0165 Other Pasteurellales Haemophilus pittmaniae Haemophilus parainfluenzae T3T Haemophilus influenzae F3031 Haemophilus influenzae Rd KW20 Haemophilus influenzae PittGG Haemophilus influenzae 86-028N Haemophilus influenzae R2846 Haemophilus influenzae F3047 Haemophilus influenzae 10810 Haemophilus influenzae PittEE Haemophilus haemolyticus Plesiomonas shigelloides Citrobacter rodentium ICC168 Serratia marcescens FGI94 Morganella morganii subsp. mor Other Enterobacter asburiae LF7a Gammaproteo- Klebsiella oxytoca bacteria Raoultella ornithinolytica B6 0/250 Yersinia pestis Escherichia coli Shigella flexneri Vibrio cholerae O395

322119155 407692608 672592320 517481249 165975838 302651308 302648590 306869420 306858454 306856077 306865053 306871605 306853852 306862854 306867274 126207863 190149672 492378962 152977891 52308100 492141813 492153891 15603307 378775293 332289452 470167686 33152271 219871479 494450103 345429343 319897870 16272627 148827859 68249264 386266588 319775464 378696883 148826678 491864144 499149535 283786321 440228953 455740577 345300129 491003182 481848065 488309597 486207164 491270753 147671420

359 TITGGKLMTYRLMAEWATDLVCKKLNKSDR ----------------T----------------------------T-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------VNKK ----------------------Q---N-KK --------------------------N-KT ---------------------------NAE ---------------------------HAE ---------------------------HAE --------------------I-----HQAE -------------------------G-TE---------------------------VS---------------------------T----------------------------TA---------------------------TA---------------------------TV---------------------------TA---------------------------TA---------------------------TA---------------------------TA---------------------------TA---------------------------TA---------------------------TA----------------------E----TA-----------------S----R---H-AT -------------------A--R--GN-RP ------------------N---E--GV-A-------------------A--A--GITAH --------------Q----A--R--GNTEP -------------------A--R--GN-VP -------------------A--R--GN-VP -------------------K--E--GI-AA -------------------A--R--GN-RP -------------------A--R--GNTRP ---------------------A---GNTQS

L -

400 CSTAERPLPGS -----------------------------------------------------------------------------------------------------------------------------------------------------------------T---------E--D-T----E-SD-T----E--D-V----V--KQA----V--TQ-----V--TQ-----K--KQ-----T-H-------I---CA----V---KA----T--D------T---------T---------V---Q-----V---Q-----V---Q-----V--KQ-----V---QA----V---QA----V---QA----V---Q-----T---K-----V--DT-----T---QA--------E-----V--DK--------DT--------DT-----T--QV-----T--DLA----T--DLA----Q-HL------

Supplementary Figure 2 Partial sequence alignment for anaerobic glycerol-3-phosphate dehydrogenase subunit A. The protein contains 1 aa insertion that is uniquely shared by Actinobacillus sensu stricto.

Haemophilus influenzae PittEE Haemophilus influenzae 22.1-21 Haemophilus influenzae 86-028NP Haemophilus influenzae 3655 Haemophilus influenzae KR494 Haemophilus influenzae R2866 Haemophilus Haemophilus influenzae F3047 Sensu Stricto Haemophilus influenzae 10810 Haemophilus sp. oral taxon 851 Haemophilus haemolyticus M21639 Haemophilus haemolyticus M21127 Haemophilus haemolyticus M19107 Haemophilus haemolyticus M19501 Haemophilus parainfluenzae Pasteurella pneumotropica Haemophilus pittmaniae H. sputorum H. paraphrohaemolyticus Other H. parahaemolyticus Haemophilus H. ducreyi H. parasuis Histophilus somni Act. pleuropneumoniae Act. ureae Act. succinogenes Act. minor Agg. actinomycetemcomitans Other Pasteurellales Agg. segnis Agg. aphrophilus Man. succiniciproducens Man. haemolytica Past. multocida Past. dagmatis Gallibacterium anatis Acinetobacter lwoffii Aliivibrio salmonicida Arsenophonus nasoniae Baumannia cicadellinicola Buchnera aphidicola Citrobacter freundii Congregibacter litoralis Cronobacter turicensis Dickeya dadantii Edwardsiella ictaluri Enterobacter aerogenes Erwinia amylovora Escherichia coli Grimontia hollisae Other Klebsiella oxytoca GammaproteoOceanimonas sp. GK1 bacteria Pantoea agglomerans 0/250 Photorhabdus luminescens Proteus penneri Providencia stuartii Rahnella sp. Y9602 Salmonella enterica Serratia odorifera Shewanella baltica Shigella boydii Sodalis glossinidius Vibrio fischeri Xenorhabdus bovienii Yersinia aldovae Yokenella regensburgei

148825193 144979387 68249130 144985884 543951383 491910936 503292748 505740084 497182876 491862772 491851008 491841414 491847886 503830655 517167701 343519915 359299231 386390298 387772261 33151868 167855425 170719016 307264154 322513554 152978401 257464575 261868195 315634867 251793982 52425815 261492895 383311804 260912696 332288976 262376664 209696105 284008589 94676896 384227506 365103141 88704608 260599325 307129360 238918478 336247240 292486903 377982750 262275021 376381681 374336959 390435428 37527834 226327186 183597880 322831339 213161043 270263179 386340136 187733221 85058229 371493750 290474860 238760057 365847769

34 INDLLPEDAIDPEYYDKLLQTL -----------------------------------------------------------------------------------------------------------------------------------------------------------V--------------------V--------------------V--------------------V--------------------V--------------------L--------------------V--------------------V------------VH-H---ELV-A-QIEDII-MI VH-H---ELV-A-QIEDII-MI VH-H---ELV-A-QIEDII-MI VH-H---ELV-A-QIEDII-MI VH-H---ELV-ADQIEDII-MI V--H----LV-ADQIEDVI-MI VH-H---ELV-A-QIEDII-MI VH-H---ELV-A-QIEDII-MI V--H----LV-TDQIEDII-MI VH-H---ELV-A-QIEDII-MI V--S---ELV-ADQIEDII-MI V--S---ELV-ADQIEDII-MI V--S---ELV-ADQIEDII-MI V--H---ELV-TDQIEDII-MI VH-H---ELV-A-QIEDII-MI V--H---ELV-A-QIEDII-MI V--H---ELV-A-QIEDII-MI V--S----LV-ADQIEDII-MI V--H--DSITES-QIEDII-MV--H---EIV-S-QVEDII-MI V--H----IV-SDQIEDII-MI V-------IV-SDQIEDII-MI V--H----I--S-QI-DII-MI V--H----IV-SDQIEDII-MI V--H----IS--DQVEDII-MI V--H----IV-SDQIEDII-MI V--H----I--SDQIEDII-MI V--H----IV-SDQIEDII-MI V--H----IV-SDQIEDII-MI V--H----IV-SDQIEDII-MI V--H----IV-SDQIEDII-MI V--H----IV-SDQIEDII-MI V--H----IV-SDQIEDII-MI V--H--Q-IV-SDQIEDII-MI V--H----IV-SDQIEDII-MI V--H----IV-SDQIEDII-MI V--H----IV-SDQIEDII-MI V--H----IV-SDQIEDII-MI V--H----IV-SDQIEDII-MI V--H----IV-SDQIEDII-MI V--H----IV-SDQIEDII-MI V--H--A-MV-SDQIEDII-MI V--H----IV-SDQIEDII-MI V--H----IV-SDQIEDII-MI V--H---EIV-S-QVEDII-MI V--H----IV-SDQIEDII-MI V--H----IV-SDQIEDII-MI V--H----IV-SDQIEDII-MI

Q -

75 NDAGIPVLDEAPESDDMML ---------------------------------------------------------------------------------------------------------------------------------------------E-----------------E-----------------E-----------------E-----------------E--H--------------E--H---------P------I- ---------------E--- T-M--Q-FEV--DT-EL-T-M--Q--ET--DT-EL-T-M--K--ET--DT-EL---M--K--ET--DT-EL---M--K--ET--DA--L---M--Q--ESV-DA--L---M--K--ET--DT-EL---M--K--ET--DT-EL---M--Q--ET--DA--LLT-M--Q--ET--DT-EL---M--Q--ET--DA--L---M--Q--ET--DA--L---M--Q--ET--DA--L---M--Q--ES--DA--L---M--Q--EA--DT--LL--M--Q--ES--DA--L---M--Q--ET--DA--L---M--Q--ES--DA--L---V----H-R------T-F --M--K-VET--DA---S--M--Q-ME---DA--LI--M--Q-ME---DA--IL--M----VE---DA--LI--M--Q-ME---DA--LL--M--Q-FEQ--DA--LI--M--Q-ME---DA--LL--M--Q-ME---DA--L---M--Q-ME---DA--L---M--Q-ME---DA--LL--M--Q-VE---DA--L---M--Q-ME---DA--L---M--Q-VET--DA-EL-M --M--Q-ME---DA--LL--M--Q-VEN--DA--L-M --M--Q-VE---DA--L---M--Q-ME---DA--L---M--Q-ME---DA--L---M--Q-ME---DA--LI--M--Q--E---DA--L---M--Q-ME---DA--LL--M--Q-ME---DA--LL--M--R-FE---DA----M --M--Q-ME---DA--L---M--Q-ME---DA--LL--M--K-VET--DA---S--M--Q-ME---DA--L---M--Q--E---DA--L---M--Q-ME---DA--LL-

Supplementary Figure 3 Partial sequence alignment for Aspartate ammonia-lyase. The protein contains 1 aa (glutamine) insertion that is specific for a clade consisting of H. influenzae, H. aegyptius, H. haemolyticus, H. sp. oral taxon 851, H. parainfluenzae, and H. pittmaniae. The remaining Haemophilus species and other Pasteurellales and Gammaproteobacteria species (250 blasts) do not contain the CSI.

Haemophilus Sensu Stricto

Other Haemophilus

Other Pasteurellales

Other Gammaproteobacteria 0/250

Haemophilus influenzae 3655 Haemophilus influenzae R3021 Haemophilus influenzae 10810 Haemophilus influenzae KR494 Haemophilus influenzae PittGG Haemophilus influenzae PittEE Haemophilus influenzae 22.1-21 Haemophilus sp. FF7 Haemophilus influenzae Rd KW20 Pasteurella pneumotropica Haemophilus pittmaniae Haemophilus haemolyticus M19107 Haemophilus haemolyticus M21127 Haemophilus parainfluenzae HK262 Haemophilus parainfluenzae ATCC 33392 Haemophilus parainfluenzae T3T1 Haemophilus aegyptius H. sp. oral taxon 851 H. parasuis H. parahaemolyticus H. sputorum H. paraphrohaemolyticus H. ducreyi Histophilus somni Act. ureae Act. pleuropneumoniae Act. succinogenes Act. minor Agg. segnis Agg. actinomycetemcomitans Agg. aphrophilus Gallibacterium anatis Man. haemolytica Man. succiniciproducens Past. multocida Past. dagmatis Aliivibrio salmonicida Enterobacter cloacae Escherichia coli Grimontia hollisae Pantoea ananatis Pectobacterium carotovorum Photobacterium profundum Photorhabdus luminescens Proteus penneri Providencia stuartii Salmonella enterica Vibrio fischeri Vibrionales bacterium Yersinia rohdei

144986549 491888782 505740607 543997178 500630890 500625845 491882181 692226876 16273272 517167151 494451436 491841549 491853823 491967783 491966042 503831535 494053950 373467219 167854584 387773029 359299851 386389589 33152693 113460378 322514553 190150168 152978693 257465417 315634400 293390251 251792709 332288590 254361623 52425279 15602618 260914246 209809408 311279548 187776147 262273996 291617548 227111338 90412639 37526083 226329945 183599058 168235558 197337488 148981352 238749352

352 DVVLRGVTVVRDGEEI ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------I---KVT ---------I-E--VT ---------I----LT -----------E--VT ---V-----I----VT ---------I----VT --------------LT --------------LT ---------I----VT ---------I----VT ---------I----VT ---------I---KIT ---------I-E--IT ---Q-----I----VT --------------LT ---I-----I-N--VT ---------I----VT ---------I-E--VT ----------KE--VT ---V-----I-E--VT ---I-----I-A--IT ----------K---IT ---I----------VT -T-I-----IKE--IT -E----L--IKE--IT ---I------KE--MT ---I-----I-A--VT ---I-----IKQ--IT ---I-----I---DIT ----------KE--VT ----------KE--VT -T-I------KT--VT

W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W

378 PPAQIQVSAQP ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------APP-------APP-------APP-------APP-------APP-------APP------T -APP-------APP-------APP-------APP-------APP-------APP-------APP-------APP-K-----APP------L -APP-K-----APP-------APP-K-----APP-------APP-------APP-------APP-------APP-----A-APP-------APP-K---A-APP-------APP-------APP-------APP-------APP-------APP-------APP-------

Supplementary Figure 4 Partial sequence alignment for NAD(P) transhydrogenase subunit alpha. This protein region show 1 aa (Tryptophan) deletion that is specific for a clade consisting of H. influenzae, H. aegyptius, H. haemolyticus, H. sp. oral taxon 851, H. parainfluenzae, and H. pittmaniae. The remaining Haemophilus species and other Pasteurellales or Gammaproteobacteria species (250 blasts) do not contain the CSI.

31


Other Haemophilus



Haemophilus influenzae 86-028NP 68249428 Haemophilus influenzae PittGG 148828019 Haemophilus influenzae F3031 319897673 Haemophilus influenzae R3021 144983972 Haemophilus influenzae F3031 317433179 Haemophilus influenzae 10810 378697034 Haemophilus influenzae PittHH 145270132 Haemophilus influenzae HK1212 270317146 Haemophilus influenzae M19501 341949445 Haemophilus influenzae M21127 341950834 Haemophilus influenzae M21639 341956009 Haemophilus haemolyticus 342905181 Haemophilus aegyptius 329122840 Haemophilus parainfluenzae 325579196 Haemophilus pittmaniae 343517839 Haemophilus sp. oral taxon 851 373466532 Pasteurella pneumotropica 2516029750 Haemophilus sputorum 359298516 Haemophilus paraphrohaemolyticus386389927 Haemophilus parahaemolyticus 387772210 Haemophilus parasuis 167855691 Haemophilus ducreyi 33151306 Histophilus somni 113461422 Act. minor 240948013 Act. ureae 322513266 Act. pleuropneumoniae 46143534 Act. succinogenes 152979472 Agg. aphrophilus 251793019 Agg. segnis 315633841 Agg. actinomycetemcomitans 261867504 Man. succiniciproducens 152979472 Man. haemolytica 254362605 Past. dagmatis 260914415 Past. multocida 15602064 Gallibacterium anatis 332288836 Citrobacter koseri 157147874 Cronobacter turicensis 260599495 Dickeya zeae 251788028 Edwardsiella tarda 304557750 Enterobacter aerogenes 336248333 Erwinia billingiae 300715026 Escherichia coli 15804746 Grimontia hollisae 262273031 Klebsiella pneumoniae 206578658 Pectobacterium atrosepticum 50122891 Photobacterium profundum 54310447 Providencia alcalifaciens 212710997 Salmonella enterica 194448129 Serratia odorifera 293393230 Shigella dysenteriae 82779425 Vibrio cholerae 15642653 Vibrionales bacterium 148976863 Xenorhabdus nematophila 300721664 Yersinia pestis 22124529

LREATSVFAVWFCIVLLYGVLCLASNP --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------I-------------------------I-------------------V-----I-------------------------I-------------------------I-------------------------I-------------------V-----IPT---SL--F---IT-GRGT V----AIPT----L------IA-GNGT V----AIPT----L------IS-GNGT ---S---PT----L--F--LV--GNGT I----CIATI---L------IS-GGRH M----AIPSL--SL------I--GQKD V----AIPT----L-----LIS-GNGT V----CLAT----L------IS-GGEG V----CLAT----L---H--IS-GGGS V----A-PT----L------FS--D-T -----ALPT---SL------I--GKAD -----A-PT---SL------I--GKAD V----ALPT---SL------I--GKAD V----A-PT----L------FS--D-T V----CLPT-------F--AVA-SKGT A----AIPTL---L------IS-GNIE A----AIPTL---L------IS-G-LD ---S---PTI---LE-F--LT--GNGT ---G-A-P----S-E-IF-LFA-KHGA ---G---P----S---I--LFA-KHG---G-A-P----S----H--FS-KAG---SSALEN---S---I---FS-KDGA ---G-A-PT---S---I--LFA-KHGA -----ALP-L--SLEMIF-LFA-KNGE ---G-A-P----S-E-IF-LFA-KNG-----VLPLIF-TLC-TF-LGS-VLGE V--G-A-PT---S---I--LFA-KHGA ---G-A-P----S-I-MC-IFA-KNGV----ILPLIF-T-C-TF-LG--VKGM--S---LQ---S-LV----FA-KNG---G-A-P----S-E-IF-LFA-KHGA ---G---P----S---I---FA-KGG---G-A-P----S-E-IF-LFA-KNGV----VLPLIL-TLF-TV-LGS-VKG-----VLPLIL-TVF-TF-LGA-VKG---G---P----SLLV---LFA-KNG---G--IP----SVL-I---FA-K-G-

89

MPG --------------------I-ILV---I-I--

LGILSFIEFLRNPIVVFLNIITLIATLYH -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------D-----------------------------VD--G--------------------M--FD--G--K------------V--------------------------------- H--F------------L------V----FATD-VS-VQ----IVF-L-S-A-I--FDTN-VD--K----II--LVS-A-M-LFDT--VD--K----II--LVS-A-M-LFATT-VG--Q--V--I------G-V-LN -EN--S-SQ--L--I----S-AGL--GLQSD--P--Q----II----A-A-AILN FATD-LT--K--LI-IF-LVS-V-M--LEN--S--Q----FI--V-SIA-L--LDG--S--Q----FI--V-SIA-L--FATD-VG-MQ----MI----S-A-M-LGFVMN--P--Q---I-I---VS-A-L-LGFVM---P--Q--L--I----S-A-L-LGF-A---P--Q-----I----S-A-L-LFATD-VG-MQ----MI----S-A-M-LFTTD-VD--Q--L--I----S-A-M--SFGN--A--------I------G-M-LN SFGN--S--K----II------G-M-LN FDSN-VN--Q--V--I------G-V-LN ESWMG-VG--Q--V--I--L-A-A-A-LESWAG-VG--Q--V--L------L-A-LE-WGH-VG--Q--L-LL---VA-L-AVLA-WE--VA--Q--L-LV----S-LLAVLESWEGYVA--Q-----I--L---A-A-LQSWQA-VAV-QH--MLLI--VA-A-A-LEAWAG-VD--Q--VI-II-L---A-A-LAAWN-WLS-MA--VAIAI--VA-AGS-FESWAGY-G--Q--V--I--L---A-A-LE-WAN-VS--Q--L-LLI--VA-L-AALEAWAGWLS-MS-----V---LA-LGS-FESWAG-VG--S---ILII--V--A---LESWMG-VG--Q--V--I--L---A-A-LDSWVG--G--Q--L-LLI--VA-L-A-LEAWAG-VD--Q--VI-II-L---A-A-LEAWQTWLD-MA--L-IAI-LVA-AGS-FEAWAGWLS-MA---I-GI--VA-LGS-MESWAG-VA--Q----LLI-----L-A-LA-WEG-VS--Q--L-L----L--F-A-L-

Supplementary Figure 5 Partial sequence alignment for Fumarate reductase subunit C. The protein contains 3 aa insertion that is specific for a clade consisting of Haemophilus influenzae, Haemophilus aegyptius, Haemophilus haemolyticus, Haemophilus sp. oral taxon 851, Haemophilus parainfluenzae, and Haemophilus pittmaniae. The remaining Haemophilus species and other Pasteurellales or Gammaproteobacteria species (250 blasts) do not contain the CSI.


Other Haemophilus



Haemophilus influenzae 22.1-21 Haemophilus influenzae PittGG Haemophilus influenzae F3047 Haemophilus influenzae F3031 Haemophilus influenzae KW20 Haemophilus influenzae NT127 Haemophilus influenzae R2866 Haemophilus influenzae PittII Haemophilus influenzae 10810 Haemophilus influenzae PittAA Haemophilus influenzae R2846 Haemophilus influenzae 86-028NP Haemophilus influenzae 3655 Haemophilus influenzae 7P49H1 Haemophilus influenzae 6P18H1 Haemophilus influenzae PittHH Haemophilus influenzae Rd KW20 Haemophilus haemolyticus Haemophilus aegyptius Haemophilus parainfluenzae Haemophilus pittmaniae Pasteurella pneumotropica DSM 21403 Haemophilus sp. oral taxon 851 Haemophilus sputorum Haemophilus parasuis Haemophilus ducreyi Haemophilus paraphrohaemolyticus Haemophilus parahaemolyticus Histophilus somni Act. pleuropneumoniae Act. minor Act. succinogenes Act. ureae Agg. aphrophilus Agg. actinomycetemcomitans Agg. segnis Man. succiniciproducens Man. haemolytica Past. dagmatis Past. multocida Gallibacterium anatis Aeromonas hydrophila Alteromonadales bacterium Ferrimonas balearica Grimontia hollisae Photobacterium damselae Proteus penneri Pseudoalteromonas haloplanktis Pseudoxanthomonas suwonensis Psychromonas ingrahamii Shewanella loihica Shigella dysenteriae Sodalis glossinidius Tolumonas auensis Vibrio angustum Vibrionales bacterium Xanthomonas fuscans Xenorhabdus bovienii Yersinia intermedia

145636352 148827519 319775753 319896709 20178339 260094339 386263423 309750201 378696563 145268169 386265225 68057182 144986822 229810560 229812781 145270517 16272328 142904025 329123594 301155740 343519305 516029676 373467487 359299850 167854979 33152694 386389590 387773034 113460425 307254675 240949393 152978538 322514554 251792921 293390584 315633898 52425783 261493539 260912947 15602181 332289843 117618072 119470463 308050472 262274801 269103289 226328027 332532349 319787464 119945066 127513248 194432193 85059749 237808766 90579380 148979594 294624425 290476021 238795106

17 NIGSAARAMKTMGLTQLCLVSPKS --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------SN-Y-------------------NE-Y-----C --------------S--------V --------------A------------V---------H-----A-QK --------------SR-R--A--Q --------------SN-R--R--N -------------ISH-R--A--Q ----V---------SH-R--E--R --------------N-----A--Q --------------SN-R----LN ----T---------A--------Q ---------------N-Y--A----------------SN-R----LN ---------------D-V--A--Q ---------------D-V--A--Q ----T----------D-V--A--Q --------------AN-Y-----Q ---------------H-R--A--Q --------------SH-Y--A-RQ --------------N--Y--A--Q --------------S--Y-----V -M------------S-MV--D-QA --------------SK-Y--D-AC --------------S--F-AE--V ----------V---KHMV--A-EC ----------V----N-V--D-AC -M--T----------N-YF-N--E --------------SK-Y--D-AC ---A----------SR-V----EK -V-------------K-V--T-EC ----T---------ST-Y-AE--V ----V----------N-W--N-LV ----T---------SN-Y--N-LH --------------S--V--D-VQ ----------V----N-V--D-AC ----------V---S--V--D-QC ---A---------VSR-V--A-ER -M-------------N-Y--N-LV -M--T----------N-Y--N-LV

58 VDEQSYALSAGAENIVKN ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------D-------------------------I--A---DDL-RI----I--A---DD--I-----I--A---AD----------------D---A I---AV--A---KDVLDA I---AI--A---KDVLDP L---AT--A---K--LDP L--DAF------KDLLEP L--DAF------KDLLEG I---AV--A----DV--S P I----Q--A---KDVLDP I---AVS-A---KDVLDR I-A-AV-------DVI-P I---AQ--A---KDVLDG --D-AI--A----DL--S S ----AI--A----DV--S G --D-AI--A----DV--S G I---AV-------DVLRK P L---AE--A---KDVLDA I---AI-------DV--Q P L--HAI-------DVL-Q L PN-E-I------DDV--Q Q P-DNA---A---SDLLAE I-SHAS------SDVLGA P-G--I--A---SDLL-K --G-AI--A---SD-ANE I---AM--A---SD--EK P-SH-I------SDVIGE I-S-AS--A---TDVLGP L-DTA-RR-----DVLDS E I-GK-I------SDVL-A P-G--V--A---SD-L-H K P-S-AI--A---SDVIGK P-A-AI------SD-IGP P--K-T--A---ND-LAE --GHTI--A---ADV-EE ----TL--A---GD-AEA L--DA-RR-----DVLSQ Q P-SH-I------SDVIGK P-S-AI------SDVIG-

Supplementary Figure 6 Partial sequence alignment for Hypothetical tRNA/rRNA methyltransferase. This protein region show 1 aa deletion that is specific for a clade consisting of Haemophilus influenzae, Haemophilus aegyptius, Haemophilus haemolyticus, Haemophilus sp. oral taxon 851, Haemophilus parainfluenzae, and Haemophilus pittmaniae. The remaining Haemophilus species and other Pasteurellales or Gammaproteobacteria species (250 blasts) do not contain the CSI.

197

H. influenzae R3021 H. influenzae 3655 H. influenzae PittAA H. influenzae 22.4-21 H. influenzae 6P18H1 H. influenzae M19107 H. influenzae F3047 H. influenzae M21127 H. influenzae 10810 Haemophilus H. influenzae PittHH Sensu Stricto H. influenzae NT127 H. influenzae R2866 H. influenzae PittII H. aegyptius H. haemolyticus H. pittmaniae H. parainfluenzae H. sp. oral taxon 851 Pasteurella pneumotropica H. paraphrohaemolyticus Other H. parahaemolyticus Haemophilus H. parasuis H. sputorum Histophilus somni Act. succinogenes Act. minor Act. pleuropneumoniae Act. ureae Agg. actinomycetemcomitans Other Agg. aphrophilus Pasteurellales Agg. segnis Man. haemolytica Man. succiniciproducens Past. dagmatis Past. multocida Gallibacterium anatis Arsenophonus nasoniae Citrobacter koseri Cronobacter sakazakii Dickeya dadantii Edwardsiella ictaluri Enterobacter aerogenes Erwinia amylovora Escherichia coli Hafnia alvei Klebsiella oxytoca Other Pantoea ananatis GammaproteoPhotorhabdus asymbiotica bacteria Proteus mirabilis 0/250 Providencia alcalifaciens Rahnella aquatilis Salmonella enterica Serratia marcescens Shigella dysenteriae Sodalis glossinidius Xenorhabdus bovienii Yersinia aldovae Yokenella regensburgei

144984261 144987185 145268512 145273391 229813038 341951493 317449758 341949145 378697101 145269827 260095321 386264654 145272608 329122915 342903547 343517903 345429559 373467991 2516030440 386389256 387772439 167855493 359300234 170718754 152978396 240948719 307254720 322514098 347991576 347813523 315633625 254361022 52307969 260912819 386835057 332289427 284007761 157147175 156935258 307132275 238918850 336248914 292487375 15799947 365837494 376388964 291616445 253990692 227357828 212709386 383188939 56414551 130967 320176707 85058578 290476274 238760030 365848145

ATRSGIETIIAPGNRPNVIADLAYEQNIGTKFIA ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------V -----------------I------------------------------A---V----QKP-------------------S--D--V----DKP----------------------------------------------------------V---H--G-----T-----V-----S-S-E--LV---NGHA--S--L-----V-----S-S-E--LV---NG-A--S--VV -I---V--A--S-E-----FEV-QGAE---R-L-----V-----S-S-E--LV---NGKA--S--LV -----V--------LE---VN---GKD-----VV --------V-------D--T---HGKS-----TV -----V-----S-S-E--LV---NGKE--S--LV -----V--V--S-S-A--LV---NGES--S--LV -----V-----S-S-E--LV---NDVA--S--LV --------------Q----V------P------V --------------QA---V------A-----TV --------------Q----V----D-A-----TV -------------------V----G-A-----SV ---------------E-------HGEA-----TV ---------------S--------GET-------------------------V----G-A-----SV -------------G-K---L---NNLA-----TV -G-A---V---A-DK-----NVLEG-QV----HC -C-A--D----A-SK-G--G-VMAGISA--R-H-G-A----V--A-SK-G--N-VIEGLPV--R-HP -C----DV---A---TG----VINDVSV--R-H-C-A---VV--A-S--G--GEVIDGISV--R-HP -C-A--D----A----D--GHAMEGLPV--C-H-C-A--D----A-S--G--G-AIACNPV--R-H-C-A--D----A-SK-G--G-VMEGISV--L-H-C-A--DV---A-SK-G-VG-VIDGVSV--R-H-C-A--D----A-S--G--G-VMEGVSV--R-H-C-A--DV---A-S-SG--S-VIAGKPV--L-H-G-A--DV-V-A-SKS---S-VIEGNPV--R-HG -G-A--DVV--A-VK-D--SKVIDNEPV--L-HG -G-A--DV---A--K-D--NAVIENIPV--R-YG -C-A-VD----A-SL-G--G-VINGVSV--R-H-C-A--D----S-SK-G--G-VMEGISV--R-H-C-A--DVV--A-SK-G-V--VIEGKPV--R-H-C-A--D----A-SK-G--G-VMEGISV--L-H-N-A---VV--A-GK-G--G-MMAGASV--R-HG -G-A-VDV---A----E-V--VIEGKSV--R-HG -C-A--DVV--A-SQVG----VIDGTPV--R-H-C-A--D----A-S--G--G-VMEGVSV--R-H-

253

H -

QSDRLESRKQWLFAAPSAGIIT -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------A--------------CV-TLH------------------ML- ---------------------- HA-----------------A-------G---------QV-S-V ------G---------QV-S-V -H-KI-G------G--P--T-Y ------G---------QV-S-Y -T---------I----V---VAPEH---------------VVI ------G---------QV-S-------G---------QV-SLV ---C--G---------QV-AL-A-----------------VL-A-----------------VLV -A-----------------VL-A----------Y---------T-K----------------L------------Y---------A----------Y--------PPHAI-----------IT-H-LKTPM-N--R-I-G--L--E-V -ASP--N--R-I-G--P--E--QTP--N--R-I-G--P--E-LETP-----R-I-G--P--E-LQTP--N--R-I-G--P--E-V -ESP--N--R-I-G--P--E-LETP--N--R-I-G--P--ELV -ATP--N--R-I-G--P--E-LETP--N--R-I-G--P--E--ESP--N--R-I-G--P--E--QTP--N--R-I-G--P--E-LASPM-N--R-I-G--P--E-I LKSP--T--R-I-G--V--V-I -KNPM-N--R-I-G--A--DVY METP--N--R-I-G--P--E--ASP--N--R-I-G--P--E-LETP--N--R-I-G--P--E--ATP--N--R-I-G--PG-E--KMP-----R---GP-P--D--ACPM-N--R-I-G--P--E-I LETP--T--R-I-G--P--E--ASP--N--R-I-G--P--E--

Supplementary Figure 7 Partial sequence alignment for Gamma-glutamyl kinase. The protein contains 1 aa (Histidine) insertion that is specific for a clade consisting of H. influenzae, H. aegyptius, H. haemolyticus, H. sp. oral taxon 851, H. parainfluenzae, and H. pittmaniae. The remaining Haemophilus species and other Pasteurellales or Gammaproteobacteria species (250 blasts) do not contain the CSI. Haemophilus ducreyi do not contain the homologue protein.

Haemophilus influenzae HK1212 Haemophilus influenzae 86-028NP Haemophilus influenzae R2846 Haemophilus influenzae KR494 Haemophilus influenzae 3655 Haemophilus influenzae 6P18H1 Haemophilus influenzae 7P49H1 Haemophilus Haemophilus influenzae R2866 Sensu Stricto Haemophilus influenzae 22.1-21 Haemophilus influenzae PittHH Haemophilus aegyptius Haemophilus haemolyticus Haemophilus pittmaniae Haemophilus parainfluenzae Haemophilus sp. oral taxon 851 Pasteurella pneumotropica DSM 21403 Haemophilus parahaemolyticus Other Haemophilus Haemophilus paraphrohaemolyticus Haemophilus parasuis Agg. segnis Agg. aphrophilus Other Agg. actinomycetemcomitans Pasteurellales Past. dagmatis Gallibacterium anatis Cronobacter sakazakii Dickeya dadantii Enterobacter cloacae Enterobacteriaceae bacterium Erwinia pyrifoliae Escherichia coli Other Grimontia hollisae GammaproteoPantoea ananatis bacteria Photorhabdus luminescens 0/250 Serratia odorifera Shigella boydii Vibrio harveyi Xenorhabdus bovienii Yersinia kristensenii

270317394 68250119 386265814 543952153 144986545 229813169 229810271 386264219 144978396 145270596 329123507 342904212 343519865 325578420 373467223 2516029975 387772242 386389687 167856647 315634175 251792472 293390341 260914079 332288876 156933866 271500288 296102444 317491990 259908386 324117609 262275640 291617560 37526065 270262050 320178234 153831886 290475378 238762559

119 GSEGLLKGKKAIVLCAFGGLYDEE --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------F------------P----------------------P-----D------A-C--M---D -P----Q-------AS---M---N -P----------------------P--------------------D-----IT----V-ILTY--I-KDG -P---IT------IL-H--I-KDS -P---I-----V-VL-H--I-KDG -P---------V--A----FHQNQ -P----T----V--A----FHQNQ -P----T----V--A----FHQNQ -P---I-----L-ILTS--IHQGS -PK---PNVPVFAFVTS--E-EGT -P---VT--R----TSR--IHKDT -P---V---R-V--TSR--IHKDT -P---V---R----TSR--IHKDT -P--------VY--TSR--IHKDT -P---I----VV--SSR--IHKDT -P---VT------ITSR--IHKDG --Q---T----LIVTTR--MHVGQ -P---V---R-VI-SSR--IHKDS -P-------QV-I-TSR--IHKDG -P---V---R--I-TSR--IHKGT -P---VT------ITSR--IHKDG -VQ--IE------VTTR---HKDS -P-----N-R----TSR--IHKDN -P---IT--R--I-TSR--IHKDT

159 NLVTQYMKSILGFIGIT -------------------------------------------------------------------------------------------------------------------------------------------------------------------------V-------N--N-L-A--D-V---N--N-L-A----V------------------- --------A----V--LA D-PKL--QTV-N----PT D-AKL--QTV-N----PA D-AKM--QTV-N----PT D---S---A----V--PT D---A-V-T-------SS DI--A-L-M----V--AT D--AA---IM------EF DTMSDWV-QV---V-LS PT D---P-LSLF------ES DV-AP-LRLM------PT D--AP--SLF------DT D---P-LRVF-----LPS D-L-P-LTLF---L-MS PT D---P-LSTF----S-SS DHI-G-L-TV---V--PS D-L-P-V-LF------PS D-LVP-LRLF-S---LPT D--EP-LRLF------PT D---P-LSTF------PT DSM-P-LRTV---V--PT D-I-P-LRTF------N PT D--VP-LRLF-------

Supplementary Figure 8 Partial sequence alignment for ACP phosphodieterase. The protein contains 2 aa deletion that is specific for a clade consisting of Haemophilus influenzae, Haemophilus aegyptius, Haemophilus haemolyticus, Haemophilus sp. oral taxon 851, Haemophilus parainfluenzae, and Haemophilus pittmaniae. The remaining Haemophilus species and other Pasteurellales or Gammaproteobacteria species (250 blasts) do not contain the CSI.

Past. multocida subsp. m str. Pm70 Past. multocida subsp. m str. 3480 Past. multocida subsp. m str. P52VAC Past. multocida subsp. m str. PMTB Past. multocida subsp.m str.VTCCBAA264 Past. multocida subsp. m str. 3480 Past. multocida subsp. gallicida Past. multocida subsp. m str. 3480 Past. multocida subsp. m P1062 Pasteurella Past. multocida subsp. m str. Anand1 sensu stricto Past. multocida subsp. m str. HN06 Past. multocida 1500C Pasteurella multocida RIIF Pasteurella multocida 93002 Pasteurella multocida 671/90 Pasteurella multocida 36950 Pasteurella multocida 1500E Pasteurella multocida 2000 Pasteurella multocida P1933 Pasteurella dagmatis Pasteurella pneumotropica Pasteurella bettyae Mannheimia succiniciproducens Actinobacillus succinogenes 13 Avibacterium paragallinarum Aggregatibacter segnis Aggregatibacter aphrophilus NJ Aggregatibacter actinomycetemc Gallibacterium anatis UMN179 Haemophilus somnus 129PT Haemophilus somnus 2336 Actinobacillus capsulatus Other Pasteurellales Actinobacillus suis H91-0380 Actinobacillus pleuropneumonia Actinobacillus ureae Actinobacillus minor Bibersteinia trehalosi USDA-AR Mannheimia haemolytica USDA-AR Haemophilus parasuis SH0165 Haemophilus parahaemolyticus Haemophilus paraphrohaemolytic Haemophilus ducreyi 35000HP Haemophilus sputorum Haemophilus influenzae 86-028N Haemophilus aegyptius Haemophilus sp. oral taxon 851 Candidatus Regiella insecticol Yersinia rohdei Dickeya dadantii 3937 Plesiomonas shigelloides Enterobacteriaceae bacterium s Other Gammaproteo- Salmonella enterica bacteria Brenneria sp. EniD312 0/250 Serratia marcescens Shewanella sp. W3-18-1 Pantoea sp. GM01 Colwellia psychrerythraea 34H Kosakonia radicincitans

15602400 386834344 401689778 544580593 544580593 385201045 385201045 385201045 557249467 338215897 383310178 512763580 512762374 512757128 512759585 378774244 511371788 512752228 512756828 492146744 517166719 492137292 52425117 152979406 516417163 493769782 251792601 365967873 332288104 113461045 170717619 517481949 407691879 491785160 491831251 492375229 470166787 472333421 219870478 491983005 491988803 33152814 494789029 68250032 494053895 497183028 493756535 490854420 307129908 499151317 440288781 486431237 496405054 491078757 120599623 495162200 71280272 494615276

412 DIRSPEETDEKPLNMENV ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------N--K-D-------------FKSDHH -------H--R-FSL-GY -------H--R-FELAGH ----------N--AL--R -------S--N--QLA-A -------I--N--HI--Q -------I--N--HI--Q -------I-----HI-KQ -------HE-E--QLD-H -------V-D---EISGQ -------V-D---EISGQ ----------T-FSLDG----------A-FSLDG----------A-FSLDG----S-----A-FSLDG-------V----FSL-G----------N-FELDG-------V----FRLDG-------V----FSL-G----------A--ELD-----------A-FKL-G-------M-----VLAQA --------E-S-FTL-G------------FESGTH ----------N-FESGTH ----------N-FESDTH ---A---QE----DLD ---A-D-Q-----KL-GI -----D-Q--R--AL-Q-------EE----VL-G----VD-Q-D---KV-G----VD-Q-D---KV-G---A-D-QE----TLAQA ----ND-QE----QL-Q---A---EEH----I-G----AD-Q-A---AL-G-------EED---ELGD----ID-Q-D---KL-G-

EV EV EV QV KI AM AM TM TI NI NI EV EV EV EV EV NV EV EV EV EV QV TV DV DV EV PV EV EI TV EI DV EI EV EV EV EV DV

446 QLMPFYKLSSQFANLDQ ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------K-----------ST--IQ----------SS--KHL---------ST-PKHL---------GD--IEL----V----GE---------------E--I-L----------E--I-L------G---D--I-L------N---E--LHI------T--PS--I---------H--E--I---------H--E--K------------S--K------------S--K------------S--K------------S--KEL---------GA---I-------NN-GS--KEL---------ST--KEL------NH-G---KEL---------TA--KEL---------TE--IEL------T---H--KVL---------GS--IQ----------GS--IQ----------GS--IQ----------GS--HIL-----R---ST---AI----------D--KSL-----GT--GD--TC-------T--DT--ASL------T--G---VSL------TK-GD--KSL------T--GD--KAL------T--GD--KRI--F--AT---D--K KPLA-----T--GD--KHI------T--GD-VSL------TK-GD---

Supplementary Figure 9 Partial sequence alignment for tRNA s(4)U8 sulfurtransferase. The protein contains 2 aa deletion that is specific for Pasteurella sensu stricto.

Pasteurella multocida 36950 Past. multocida subsp. m str. HN06 Past. multocida subsp. m str. Anand1 Past. multocida subsp. m str. gallicida Past. multocida subsp. m str. Anand1 Past. multocida subsp. m str. 3480 Past. multocida subsp. m str.P52VAC Past. multocida subsp. m str. PMTB Past. multocida subsp. m str.P1062 Past. multocida subsp.m VTCCBAA264 Pasteurella sensu stricto Pasteurella multocida 3695 Pasteurella multocida 1500E Pasteurella multocida 2000 Pasteurella multocida 671/90 Pasteurella multocida 1500C Past. multocida subsp. m str. HB03 Pasteurella multocida 93002 Past. multocida subsp. m str. Pm70 Pasteurella dagmatis Past. dagmatis ATCC 43325 Haemophilus ducreyi Haemophilus sputorum Bibersteinia trehalosi Gallibacterium anatis Haemophilus paraphrohaemolyticus Haemophilus parahaemolyticus Actinobacillus minor Mannheimia haemolytica Actinobacillus capsulatus Actinobacillus pleuropneumoniae Actinobacillus suis Actinobacillus ureae Avibacterium paragallinarum Pasteurella pneumotropica Other Pasteurella bettyae Pasteurellales Actinobacillus succinogenes 13 Mannheimia succiniciproducens Aggregatibacter segnis Aggregatibacter aphrophilus Aggregatibacter actinomycetemc Haemophilus somnus 2336 Haemophilus somnus 129PT Haemophilus sp. oral taxon 851 Haemophilus aegyptius Haemophilus parainfluenzae T3T Haemophilus haemolyticus Haemophilus influenzae 10810 Haemophilus pittmaniae Haemophilus parasuis SH0165 Legionella nagasakiensis Marinobacter sp. ELB17 Acinetobacter sp. NIPH 1847 Moritella sp. PE36 Other Tatlockia micdadei GammaproteoThalassolituus oleivorans MILbacteria Shewanella sp. MR-4 0/250 Psychromonas sp. CNPT3 Idiomarina loihiensis L2TR Candidatus Legionella jeonii Oceanimonas sp. GK1

378775595 383311604 338218483 338219570 401693313 385202348 401688712 544580133 557250232 662151453 356598143 511371593 512753119 512758749 512764075 570283202 512757188 15603214 492150696 260632528 33151282 498362100 575453520 332288995 491991260 386907676 257450706 544866063 517481536 491828212 407693457 322120930 523672791 517168114 492139184 152978358 52424212 493771241 491981671 491778440 170718083 113461773 497180830 327473735 345429100 491864232 378696770 494451577 219871676 209779033 494591722 491370379 492899645 2627466 473829413 113971139 470478469 56461409 4583155 374334872

151 DTVTVNYTGKLPNGEVFDSS ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------K-V------D---RT -----K-V------D---RT -I-IAH-K-T--D-T-------K-H-K-T-VD-S-------K-H-K-T-TD-S-------K---R---ID-TE----V-K-H-K-T--D-T-----M-K-H-K-T--D-T-----I-K-H-K-T----TT------K-H-K-T-TD-T-------K-H-K-T-TD-T-------K-H-K-T-TD-T-------K-H-K-T-TD-T-------K-H-K-T-TD-T-----M-K-H-----AD-T-------K-H----------------K-H-----T--T-----S-K-H--------T-----S-K-H-----T--T-----V-K-H------D-T-------K-H------D-T-----V-K-H------D-T-----R-K-H-----A--K-----R-K-H-----A--K-------K-H--------K-------K-H--------K-------K-H------D-K-------K-H--------K-------K-H--------K-----V-K-H-----AD-K-------K-H-K-T--D-T---------E---R-I-------T E----H---E-L---------K-H-K-Q--D-K---------H---S-LD-S-----V---E-----ID-Q----T -K-L-H-H-T-L--N---------H-H-T-ID-T-------H-H-T-LD-T-----M-E-H-E-T-V------------D---T-LD-Q---TT -V---H---T-VD-TQ----

YE YD YE YK YD YD YD YD YD YD YD YD VQ VE VE VE VE VQ RE HE RE RE VE VE VE VE VE VE YD EK RE YD VE EK VK VE VD YE EK VE

188 RGKPVSFKLNQVVPGWTE -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------H---I------------H---I-------------NE-IELQ-K-LI-A-I--Q-IE---DNLI-A-K--E-IE-Q-S-LI-A-V-NQ-IE-Q-G-LI---V-NA--E-Q-D-LI-A-V-NA--E-Q---LI---I--E-IE-Q-D-LI---I--E-IE-Q---LI---I--E-IE-Q---LI---I--E-IE-Q---LI---I--E-IE-Q---LI---I--E-IE-Q---LI---I--Q-AE------IK-----Q-AE-R-D---K----NQ-AE-M----I------Q-AE-A----I------Q--E-L-D--I------T-AE-P----IK-----T-AE-P----IK-----T-AE-P----IK-----Q-AE------IL-----Q-AE------IL--K--Q--E-Q----IK-----Q--E-Q-D--IK-----Q--E------IK-----Q--E-Q-D--IK-----Q--E-Q-D--IK-----S-AE-------K-----E-IE-Q---LI-A-VT---A----S--I------E----R-D--I------E-IE-P----I------E-AT-A--R-I----T---AT--VS--I------E-IA-G----I------E-IA-P--R-I------E-I-------IK-----E-T--P--R-I----T---AT--VS--I------E-A--P----I-----

Supplementary Figure 10 Partial sequence alignment for FKBP-type peptidyl-prolyl cis-trans isomerase. The protein contains 2 aa deletion that is specific for Pasteurella sensu stricto. .

Pasteurella sensu stricto



Past. multocida subsp. m str. HN06 Past. multocida subsp. m str. Anand1_buffalo Past. multocida subsp. m str. Anand1_poultry Past. multocida subsp. m str. Anand1_poultry Past. multocida subsp. m str. 3480 Past. multocida subsp. m str. HN06 Past. multocida subsp. gallicida X73 Past. multocida subsp. gallicida P1059 Past. multocida subsp.m str.VTCCBAA264 Past. multocida subsp. m str. PMTB Past. multocida subsp. m str. PMTB Past. multocida subsp. m str. HB03 Past. multocida subsp. m str. Pm70 Past. multocida subsp. m str. P52VAC Pasteurella multocida 671/90 Pasteurella multocida 36950 Pasteurella multocida 1500E Pasteurella multocida 93002 Pasteurella multocida P1933 Pasteurella multocida RIIF Pasteurella multocida 1500C Pasteurella dagmatis Pasteurella bettyae Mannheimia succiniciproducens Actinobacillus succinogenes 13 Aggregatibacter aphrophilus NJ Aggregatibacter actinomycetemc Aggregatibacter segnis Gallibacterium anatis UMN179 Actinobacillus suis H91-0380 Actinobacillus ureae Actinobacillus pleuropneumonia Actinobacillus capsulatus Haemohilus ducreyi Actinobacillus minor Haemophilus aegyptius Haemophilus somnus 2336 Haemophilus somnus 129PT Haemophilus influenzae F3031 Haemophilus haemolyticus Haemophilus parainfluenzae T3T Haemophilus pittmaniae Haemophilus sp. oral taxon 851 Haemophilus parahaemolyticus Haemophilus paraphrohaemolytic Haemophilus sputorum Haemophilus parasuis SH0165 Mannheimia haemolytica USDA-AR Bibersteinia trehalosi USDA-AR Pasteurella pneumotropica Avibacterium paragallinarum Dickeya dadantii Ech586 Dickeya zeae Ech1591 Plesiomonas shigelloides Rahnella sp. Y9602 Hafnia alvei Yokenella regensburgei Enterobacter sp. Ag1 Cronobacter malonaticus Aeromonas diversa Pantoea sp. Sc1 Edwardsiella tarda EIB202 Halomonas sp. TD01 Escherichia coli UTI89 Yersinia enterocolitica subsp.

383311492 401692294 338218682 338217898 386835511 380872764 404381296 404381529 662150000 544579597 557250343 570283089 15603497 401688289 512758580 356598033 511370980 512754838 512755327 512761301 512764053 260632372 492142074 52424061 152977962 251793382 491743607 493771023 332289624 407691599 491830899 2494081 517480854 33151282 492378846 327473112 170718618 113461688 319897820 491840026 345429175 494451354 497184927 491983155 491991632 494791543 219871160 472334224 470167928 517168125 516415744 271502355 251787870 499149527 322830931 490192463 493871072 495733328 495054021 491503773 496378765 269140685 497409267 91212916 332163357

173 PASSILDIERKVTAKMRGDL ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------R--------------E-------Q--SVE --------------E--A-S --------------E--A-S -H--------A------DSN -N--------A------DKD -N--------A------DNN -S--------A------AED -----------------E-S -----------------E-S ------E----------E-S -----------------E-G --TC--A------DI--D-S ------E----------AED --------------E--A-N --T--------------AED --T--------------AED --------------E--S-S --------------E--S-S --------------E--S-S --------------E--S-S --------------E--S-S --------------E--S-S --------------A--S-S --------------T--D-S ------E-------E--SED -----------------AED ------E-------Q--A-D --------------E--SAD -----------------DAS ---A----------LS- GG ---A----------LS- GG ---A-----------T-DGS ---A----------LT-SGT ---A---------ELG-SGT ---A---------SLT-SGE ---A---------ELG-SGK ---A----------LT-SGE ---A-------I-E-T-SGT ---A------S--DFT-SGT ---A------R--DL--SGT TS-A----D-----A--SGD -S-A---------TLT-SGE ---A----------AT-SGK

F F F F F F F F F F F F F F F F F F F F F F F F F F F F F L L L L L L L L L L L F L L

245 PIENFGAPLAGSLIPWIDK --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------D----------------T-----A-G---------TD----A-----------TD---TA------------D-----------------D-----------------D----------------T-----A-G---------TD----------------TD----------------TD----------------TD------------------H---------------TT----A-G---------TD----A-G--------STT----A----------STT----A-----------TD----A-G---------TD----A-G---------TD----A-G---------TD----A-G---------T-----A-G---------T-----A-G---------T-----A-G---------TA----A-G---------TA----------------T-----A-G---------TA----A-G---------T-----A-G----------D---T-----------DV----V-----------DV----V------------VD---V------------TD---V----G-------TD---V-----------AVD---V------------VD---V------------VD---V----G-------VD---V-----------T -TD---V------------TD---V------------TD----------L----T -VD---V------------TD---V------------

Supplementary Figure 11 Partial sequence alignment for Aspartate-Semialdehyde Dehydrogenase. The protein contains 1 aa deletion that is specific for Pasteurella sensu stricto. No other species harbor this insert.

Pasteurella dagmatis Pasteurella multocida 671/90 Pasteurella multocida 1500E Pasteurella multocida 1500C Pasteurella multocida 2000 Pasteurella multocida 93002 Pasteurella multocida P1933 Pasteurella multocida RIIF Past. multocida subsp. m str. 3480 Pasteurella Past. multocida subsp. gallicida P1059 sensu stricto Past. multocida subsp. multocida P1062 Past. multocida subsp. m str. Anand1_goat Past. multocida subsp. m str. Anand1_poultry Past. multocida subsp. m str. Pm70 Past. multocida subsp. m str. Pm70 Past. multocida subsp. m str. P52VAC Past. multocida subsp. m VTCCBAA264 Past. multocida subsp. gallicida X73 Past. multocida subsp. m str. HN06 Actinobacillus capsulatus Pasteurella pneumotropica Pasteurella bettyae Mannheimia succiniciproducens Actinobacillus succinogenes 13 Aggregatibacter segnis Aggregatibacter actinomycetemc Aggregatibacter aphrophilus NJ Haemophilus somnus 2336 Haemophilus somnus 129PT Gallibacterium anatis UMN179 Actinobacillus suis H91-0380 Actinobacillus ureae Other Actinobacillus pleuropneumonia Pasteurellales Actinobacillus minor Bibersteinia trehalosi USDA-AR Mannheimia haemolytica USDA-AR Mannheimia haemolytica M42548 Haemophilus parasuis SH0165 Haemophilus sputorum Haemophilus parahaemolyticus Haemophilus paraphrohaemolytic Haemophilus pittmaniae Haemophilus haemolyticus Haemophilus parainfluenzae Haemophilus sp. oral taxon 458 Haemophilus aegyptius Haemophilus influenzae R2866 Cardiobacterium hominis Photobacterium angustum Moritella sp. PE36 Vibrio scophthalmi Other Yersinia ruckeri Gammaproteo- Vibrio rotiferianus bacteria Xenorhabdus nematophila ATCC 1 0/250 Serratia odorifera Teredinibacter turnerae T7901 Morganella morganii subsp. mor Alteromonas macleodii AltDE1

492154065 512760234 511370720 512762880 512751484 512753070 512755610 512761745 386835100 404381029 557250787 338217416 338217905 15603717 12722279 401687889 662151847 404380743 383311110 517482331 517168237 492137572 52424808 152979623 493770012 491712566 251792350 170717339 113460853 332288638 407692534 491832357 491783002 492374701 470167286 472334843 482885659 219870902 494787533 491987197 491993130 494450016 491867161 491966960 545364985 494054377 309751139 490242580 491509629 492900972 491781085 490859449 498133176 300722610 491097500 254787098 455738355 410862588

390 ALLGALVMVKLMLVGNDN ----------------E----------------E----------------E----------------E----------------E----------------E----------------E----------------E----------------E----------------E----------------E----------------E----------------E----------------E----------------E----------------E----------------E----------------E--I---I--N-------G --I---I--N-----G-A ------I------I-GKE --I---I--N-----GEG --V---I--N-----G-G --M------N-----GEH --V---I--N-----G---M------N-----GEH --V---I--N-----G-G --V---I--N-----G-G --V---I--N-----G---I---I--N-------G --I---I--N-------G --V---I--N-------G --I---I--N-----G-G -----II------I-GAD -----I-------I-GVD -----I-------I-GVD --V---I--N-----G-G --I---I--N-----G-E --I---I--N-----G-E --I---I--N-----G-E --T------N-----G-H --V------N-----GEH --M------N-----GEH --M------N-----GEH --V------N-----GEH --I------N-----GEH --F-------F-M--G---V---I---F-MI-GEH -I---I-----MA-GE--V---I---F-MM-G-H ---------NM-ML-GN--V---I---F-MM-DA--F------NM-ML-DE------I--NM-MQ-G-R -------F-N--MM-GEQ --F---I--N--MQ-GE-------F-N--ML-GEQ

YD -------------------

427 SMVITIGKTFADLTGDKW ------------V----------------V----------------V----------------V----------------V----------------V----------------V----------------V----------------V----------------V----------------V----------------V----------------V----------------V----------------V----------------V----------------V----------------V-------KI---S--EA--EY---KI---S--QA--EY---QI--QS--EY--QY---K-------ET--EH---K-------ET--EH---KI--R---EV---D---KI---S--EA--QY---KI--R---EI--ND---KI---S--AA--EY---KI---S--AA--EY---KI---S--AA--EY---KI---S--EA--EY---KI---S--AA--EY---KI---S--AA--EY---KI---S--EA--EY---Q---RS--EF--QS---QI---N--EF--QS---QI---N--EF--QS---KI--QS--QA--EY---KI--RS--HA--EY---KI--RS--HA--EY---KI--RS--HA--EY---KI--R---EI--ND---KI--R---EIS-SN---KI--R---EV--SD---KI--R---EV---D---KI--R---EIS-SN---KI--R---EIS-SN---K---NS--QIA-TN-PIM-T-NA----M-KN-PILI--MA-S--M-TN-PIM-T-RA-SE---TNAP--L---EL-SV--ES-PIM-T-RALS--L-TS-P-FI---AL-AM--EGAP--I--QAL--T--SG-A-AL--QSL-E---AYAP-YI--RSL-GA--ES-A-SV---HM-Y-A-NN-

Supplementary Figure 12 A 2 aa insert in a conserved region of the lactate permease family transporter protein, specific Pasteurella sensu stricto is shown in this figure. No other species harbor this insertion.

Pasteurella dagmatis ATCC 43325 260632997 Pasteurella multocida 93002 512756477 Pasteurella multocida 1500C 512763891 Pasteurella multocida 1500E 511371845 Pasteurella multocida 2000 512750732 Pasteurella multocida P1933 512756520 Pasteurella multocida 671/90 512760522 Pasteurella multocida RIIF 512761903 Pasteurella multocida 36950 378774785 Past. multocida subsp. m str. Pm70 15602011 Past. multocida subsp. m str. HN06 383310759 Past. multocida subsp. m str. 3480 386834751 557251138 Pasteurella Past. multocida subsp. m str. P1062 Past. multocida subsp. m str.P52VAC 401690272 sensu stricto Past. multocida subsp. m str. PMTB 544580907 Past. multocida subsp. m VTCCBAA264 662151314 Past. multocida subsp. m str Anand1_goat 338219119 Past. multocida subsp. m str Anand1_cattle 01701157 Past. multocida subsp. m str Anand1_buffalo 401698941 Past. multocida subsp. m str Anand1_poultry 338216942 Past. multocida subsp. m str 3480 385201454 Past. multocida subsp.gallicida X73 404383534 Past. multocida subsp.gallicida P1059 404383534 Past. multocida subsp. m P1062 557251138 Past. multocida subsp. m str. HB03 570282365 Haemophilus aegyptius 327467404 Avibacterium paragallinarum 516416579 Pasteurella pneumotropica 517168260 Haemophilus pittmaniae 494451856 Pasteurella bettyae 492145430 Mannheimia succiniciproducens 52425717 Actinobacillus succinogenes 13 152979582 Aggregatibacter actinomycetemc 491735876 Aggregatibacter segnis 493768770 Aggregatibacter aphrophilus NJ 251792027 Gallibacterium anatis UMN179 332288548 Haemophilus influenzae 10810 378697366 Other 494451856 Pasteurellales Haemophilus pittmaniae Haemophilus sp. oral taxon 851 497452636 Haemophilus haemolyticus 491875401 Haemophilus parahaemolyticus 491987960 Haemophilus paraphrohaemolytic 491991888 Haemophilus parasuis SH0165 219870395 Haemophilus sputorum 494790961 Actinobacillus pleuropneumonia 126207510 Actinobacillus ureae 491831136 Actinobacillus suis H91-0380 407693004 Actinobacillus minor 492358394 Mannheimia haemolytica USDA-AR 472333002 Bibersteinia trehalosi USDA-AR 470166543

357 VRIGNPLNITGVTHHV --------------L--------------L--------------L--------------L--------------L--------------L--------------L--------------L--------------L--------------L--------------L--------------L--------------L--------------L--------------L--------------L--------------L--------------L--------------L--------------L--------------L--------------L--------------L--------------L---AS------L-DY----S-M----L-DY--V-S------L-DY----S------L-DY--V-Y----S-L-DY--V-Y------L-DY--V-S------L-DY----S------L-DY----S------L-DY--V-S------L-DY-K--T------L-DY---AS------L-DY----S------L-DY----S------L-DY----S------L-DY--V-S----A-L-DY--V------A-L-DY--V--------L-DY--V------E-L-DY--V-Y------L-DY--V-Y------L-DY--V-Y------L-DY--V-Y------L-DY--V-Y------L-DY--V-H------L-DY-

387 E NKPQYSTVLGLLQY - -------------- -------------- -------------- -------------- -------------- -------------- -------------- -------------- -------------- -------------- -------------- -------------- -------------- -------------- -------------- -------------- -------------- -------------- -------------- -------------- -------------- -------------- -------------- --------------R------V-------------V------R------I------R------V----------A-------------A-------------A-------------A--I-------------I----------A--I----------A---------R------V------R------V------R------V------R------V----------A-------------A-----------S-A-------------A-------------A-------------A-------------A-------------A-------F-----A-A-----------A---------

Supplementary Figure 13 A partial sequence alignment of the Cell division protein FtsA depicts the conserved 1 aa insertion shared by Pasteurella sensu stricto.

Aggregatibacter


Aggregatibacter actinomycetemcomitans D11S-1 Aggregatibacter actinomycetemcomitans ANH9381 Aggregatibacter actinomycetemcomitans D7S-1 Aggregatibacter actinomycetemcomitans RhAA1 Aggregatibacter actinomycetemcomitans SC1083 Agg. actinomycetemcomitans serotype a str. A160 Agg. actinomycetemcomitans serotype e str. SCC393 Agg. actinomycetemcomitans serotype b str. S23A Agg. actinomycetemcomitans D11S-1 Agg. actinomycetemcomitans serotype f str. D18P1 Agg. actinomycetemcomitans serotype a str. H5P1 Agg. actinomycetemcomitans serotype c str. SCC2302 Agg. actinomycetemcomitans serotype b str. SCC1398 Agg. actinomycetemcomitans serotype b str. I23C Agg. actinomycetemcomitans serotype c str. D17P-2 Agg. actinomycetemcomitans ANH9381 Agg. actinomycetemcomitans D7S-1 Agg. actinomycetemcomitans Y4 Agg. actinomycetemcomitans serotype c str. AAS4A Agg. actinomycetemcomitans serotype b str. SCC4092 Agg. actinomycetemcomitans HK1651 Aggregatibacter aphrophilus NJ Aggregatibacter aphrophilus NJ8700 Aggregatibacter aphrophilus ATCC 33389 Aggregatibacter aphrophilus F0387 Aggregatibacter segnis Actinobacillus actinomycetemco Actinobacillus ureae Actinobacillus pleuropneumonia Actinobacillus minor Actinobacillus suis H91-0380 Haemophilus sputorum Haemophilus paraphrohaemolytic Haemophilus parahaemolyticus Haemophilus parasuis SH0165 Haemophilus ducreyi 35000HP Mannheimia haemolytica USDA-AR Mannheimia haemolytica M42548 Bibersteinia trehalosi USDA-AR Simonsiella muelleri

261866907 365966720 387121099 359757391 347992294 443549786 348003778 443548871 261412239 348001357 348002279 348004682 348006756 348010515 348656715 365745633 385875591 429155976 443542933 443545908 601111157 251793586 247534982 347814960 353345480 492001274 19911156 491831195 126207537 492365015 407692976 494791298 491991617 491987783 219871549 33151516 472335694 482885642 470167899 488718971

25 FTGFGIGVGVGTTKYKDAK -----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------V--D--------------V--D--------------V--D--------------V--D--------------V---------E-----------------------V-V--DLT-V--DVDG ---V-V--DLT-V---VDG ---L-V--DLT-A---VDG ---V-V--DLT-V--EVDG ---V-V--DLTSA---VDG ---I-VSTDLT-A---ANG ---V-VSADLT-A---VNG ---G---MD-T-----NGD ---M---IDLD-A--TSHG ---I-V--D-T-----VEG ---I-V--D-T-----VEG ---V-V-LDLT-V---NSN ---ASV-TNIE-----IKN

Supplementary Figure 14 A 4 aa deletion in a conserved region of the Outer membrane protein specific is for Aggregatibacter

VKGK VKGK VKGK VKGK IKGK VTGK VTGK LQGK QNGK VKGK VKGK LQGK SISG

64 RISNVDLIADYGIDYGNDFVG ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------N-------------------N-------------------N-------------------N--------------FNH-QNV---------------------QST-PA -VV---M----NQSTGPA -VV---M---DNQSTGPA -VV---M---SN--QSTGPA -VV---M----NQSTGPA -VV---M----NL-QSTGP- -VV---M----NL-QSTGP- -VV---M----NL-QA-GIN FTL--AT---RNLIRKA-PM IVL---M----NL-DSTGPA -VV----EQ--N--DSTGPA -VV----EQ--N--QATGAN FVL--AL----NVLENTR-AV-KG-V-F-M--NL--

Agg. actinomycetemcomitans ANH9381 Agg. actinomycetemcomitans D7S-1 Agg. actinomycetemcomitans serotype b str. I23C Agg. actinomycetemcomitans serotype b str. S23A Agg. actinomycetemcomitans serotype b str. SCC1398 Agg. actinomycetemcomitans serotype b str. A160 Agg. actinomycetemcomitans Y4 Agg. actinomycetemcomitans HK1651 Agg. actinomycetemcomitans serotype b str. SCC4092 Agg. actinomycetemcomitans serotype c str. SCC2302 Agg. actinomycetemcomitans serotype c str. D17P-2 Agg. actinomycetemcomitans serotype c str. AAS4A Aggregatibacter Agg. actinomycetemcomitans serotype d str. I63B Agg. actinomycetemcomitans serotype d str. H5P1 Agg. actinomycetemcomitans serotype d str. D18P1 Agg. actinomycetemcomitans serotype d str.SCC393 Agg. actinomycetemcomitans serotype d str.D17P-3 Agg. actinomycetemcomitans serotype d str. D7S-1 Agg. actinomycetemcomitans D11S-1 Aggregatibacter aphrophilus NJ Aggregatibacter aphrophilus ATCC 33389 Aggregatibacter aphrophilus NJ8700 Aggregatibacter aphrophilus F0387 Aggregatibacter segnis Aggregatibacter segnis ATCC 33393 Haemophilus sp. oral taxon 851 Haemophilus aegyptius Haemophilus influenzae 86-028N Haemophilus parainfluenzae T3T Haemophilus haemolyticus Haemophilus pittmaniae Avibacterium paragallinarum Haemophilus somnus 129PT Haemophilus somnus 2336 Pasteurella pneumotropica Pasteurella dagmatis Pasteurella multocida subsp. m Pasteurella bettyae Others Actinobacillus succinogenes Pasteurellales Mannheimia succiniciproducens Mannheimia haemolytica USDA-AR Bibersteinia trehalosi USDA-AR Actinobacillus capsulatus Actinobacillus pleuropneumonia Actinobacillus ureae Actinobacillus suis H91-0380 Actinobacillus minor Haemophilus parasuis SH0165 Haemophilus ducreyi 35000HP Haemophilus paraphrohaemolytic Haemophilus parahaemolyticus Haemophilus sputorum

365966332 387121526 348008395 443544851 348006394 443550283 429154918 601113024 443547650 348007426 348656671 443541805 347996801 347997479 348002902 348003239 348656236 385876018 261868574 251794002 347813475 247535401 353345600 493770776 315476479 497182424 494053515 68249552 345428924 491853634 494452657 516416005 113460561 170718908 517167578 492150466 15603525 492138635 501021160 52425810 472332644 470166263 517482124 491797892 491836958 407693304 492353241 219871503 33152962 491988454 491985107 494790245

190 220 TVILPTLARHHVNRD DNVKSAVDFCNTMDWG -----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Y----------------------------------A------R---------------------A------R---------------------A------R---------------------A------R---------------------A------R---------------------A------R-------------------E G -SA------R-------------------E G -SA------R-------------------E G -SA------R-------------------E D NSSQ-----RD------------------E G -SD------R-------------------T D -AEQ-GQ--HQ------------------S D NAEQ-----R------------S--Y---T D NIE------RQ-----------S--Y---T D NIE------RQ------------------E D NSEQ-----R-----------------S-H D NSAQ-E---R--L----------------H D HSSQ--I--RH-L---------S------S D -A---SE--RS-------------Q-ADCT D NAAQGVT--RQ-----------S-Q----A D -VQ---A--RA------V--S-S-IAK-KE L TEIQRGEH-Q----------A-S-IAKQKT L SDEQRIQQ-KQ------V--S-S-IAKKKE I -E-QR--E-QG-V----V--S-S-IAKKKE I -E-QR--E-QG------V--S-S-IAKKKE I -EAQR--E-QG------V--S-S-IAKKKE I -DAQR--E-QG------V----S-IAKKK- I -DNQRK-E-QS---------S-S-IAKQK- L TEEQRKFN-EQ------V--N-S-ITKKKA L NEEQR-IA-KQ-L----V----SKIAKQKE L NETERKTQ-QT------V----SKIAKQKA L NETARQAQ-QT------V----SKIAKQK- L AETQRRE--Q--L---

Supplementary Figure 15 A 1 aa deletion in a conserved region of the Multidrug Transporter MurJ protein, specific Aggregatibacter is shown in the figure.

Agg. Actinomycetemcomitans D7S-1 Agg. Actinomycetemcomitans HK1651 Agg. Actinomycetemcomitans D17P-3 Agg. Actinomycetemcomitans Y4 Agg. Actinomycetemcomitans RhAA1 Agg. Actinomycetemcomitans ANH9381 Agg. Actinomycetemcomitans D11S-1 Aggregatibacter Agg. Actinomycetemcomitans erotype Agg. Actinomycetemcomitans erotype Agg. Actinomycetemcomitans erotype Agg. Actinomycetemcomitans erotype Agg. Actinomycetemcomitans erotype Agg. Actinomycetemcomitans erotype Agg. Actinomycetemcomitans erotype Aggregatibacter segnis Haemophilus haemolyticus Haemophilus sp. oral taxon 851 Haemophilus parainfluenzae T3T Other Haemophilus influenzae R2846 Pasteurellales Haemophilus influenzae Rd KW20 Haemophilus influenzae 10810 Haemophilus influenzae F3031 Edwardsiella tarda EIB202 Citrobacter freundii Aliivibrio salmonicida LFI1238 Escherichia coli Shigella boydii Other Hahella chejuensis KCTC 2396 Gammaproteo- Photobacterium damselae bacteria Brenneria sp. EniD312 0/250 Salmonella enterica subsp. ent Cronobacter sakazakii Serratia sp. M24T3 Vibrio mimicus Erythrobacter sp. NAP1

e e e e e f d

str. str. str. str. str. str. str.

SCC393 SCC1398 AAS4A SCC4092 SC1083 D18P1 I63B

387120244 601112307 348655454 429152231 359757161 365967736 261867944 387120244 348006243 443541389 443547308 347993017 348000420 347997013 493769445 491870682 497182862 345429510 386266521 16272688 378696947 319897753 269139415 489928937 209694845 485787518 491148521 83649253 491441018 496403366 197362727 495164111 497321568 491666772 494285496

372 GSLVSLSEFTAFGALSGKITGG ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------G------T-----S---L-SI-N-FGKN -T-----S---L-SI-N-FGKN -T-----S---L-SI-N-FGKN -T-----N---L-S-TN-FGKN -T-----N---L-S-TN-FGKN -T-----N---L-S-TN-FGKN -T-----N---L-S-TN-FGKN ---------STV-S-M-NL-R-------N-STV-S-M-NL-R-------N-STV-S-M-NL-K-------N-STV-S-M-NL-R-------N-STV-S-M-NL-R-------RYSTV-N-M-NL--K -------R-STV-S-M-NL-K-------K-STV-S-M-NLMS-------N-STV-S-M-NL-R-------K-STV-S-M-NLMR-------R-STV-S-M-NL-K-------R-STV-S-M-NL-R---I---R-STV-S-M-NLV--

S -

412 SMTIEGKIAQWVYVSLYR ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------M-----PL-VQ--F--FA-----PL-VQ--F--FA-----PL-VQ--F--FA-----PL-VQ--F--FA-----PL-VQ--F--FA-----PL-VQ--F--FA-----PL-VQ--F--FA-------M---R--RIM-------MV--R--RF--I-----M---R--RI--I-----M---R--RF--I-----M---R--RF--I-----M---R--RF--I-----MV--R--RV--I----VM---R--RF--I-----M---R--RFL-I-----M---R--RF--I-----M---RL-RM--------MV--R--RV--I---A-AV--R--RFI-T----

Supplementary Figure 16 Partial sequence alignment of NADH dehydrogenase, showing the presence of 1 aa insertion that is specific for Aggregatibacter. The homologue of this is protein or the sequence of the region containing insertion is found to be missing in Aggregatibacter aphrophilus

Mannheimia haemolytica USDA-AR M.haemolytica USDA-ARS-USMARC-185 Mannheimia haemolytica D174 Mannheimia haemolytica D171 Mannheimia haemolytica PHL213 Mannheimia haemolytica M42548 Mannheimia haemolytica D193 Mannheimia haemolytica USMARC_2286 M. haemolytica USDA-ARS-USMARC-185 Mannheimia haemolytica M42548 Mannheimia haemolytica D153 Mannheimia Mannheimia haemolytica D38 Mannheimia haemolytica D35 Mannheimia haemolytica MhBrain2012 Mannheimia haemolytica MhSwine2000 M. haemolytica ser. A2 str. OVINE M. haemolytica ser. A2 str. BOVINE M. haemolytica ser. 6 str. H23 M.varigena USDA-ARS-USMARC-1312 M.varigena USDA-ARS-USMARC-1296 M.varigena USDA-ARS-USMARC-1388 M.haemolytica ser. A1/A6 str.PKL10 M.varigena USDA-ARS-USMARC-1261 Mannheimia granulomatis Haemophilus aegyptius Haemophilus pittmaniae Pasteurella pneumotropica Actinobacillus capsulatus Haemophilus influenzae Haemophilus sp. oral taxon 851 Gallibacterium anatis Haemophilus haemolyticus Avibacterium paragallinarum Bibersteinia trehalosi USDA-AR Haemophilus parasuis SH0165 Haemophilus paraphrohaemolytic Haemophilus parahaemolyticus Haemophilus sputorum Other Haemophilus ducreyi 35000HP Pasteurellales Actinobacillus suis H91-0380 Actinobacillus pleuropneumonia Actinobacillus ureae Actinobacillus minor Actinobacillus succinogenes 13 Mannheimia succiniciproducens Pasteurella bettyae Pasteurella dagmatis Pasteurella multocida subsp. m Pasteurella multocida 36950 Aggregatibacter segnis Aggregatibacter aphrophilus NJ Aggregatibacter actinomycetemc Haemophilus somnus 129PT Haemophilus somnus 2336 Haemophilus parainfluenzae T3T Thiomicrospira crunogena XCL-2 Cellvibrio japonicus Ueda107 Francisella philomiragia Vibrio mimicus Rahnella sp. Y9602 Other Aeromonas veronii GammaproteoPseudomonas sp. GM84 bacteria Cronobacter universalis 0/250 Dickeya zeae Ech1591 Xanthomonas campestris pv. cam Hafnia alvei Vibrio sp. HENC-03 Salmonella enterica

472333011 472337351 525663559 523431845 153094058 481063369 528878678 526469516 472261588 481063369 523447566 528825629 528823205 528878382 528876521 261308490 261310843 452086134 575446106 575444080 575446833 589591032 575440375 652755953 494054439 494451972 517168269 517480314 543952514 497452628 332288557 491854538 523673909 470166531 219870386 491991723 491987869 494790980 33151486 407693013 491794283 491831120 492350031 152979591 52425727 492145494 492155823 383310768 378774794 493768749 251792018 491744776 113460499 170718778 345429820 78484908 192360758 490415713 491665840 322834425 491498935 495372865 494980781 251788245 21230195 490196006 497393525 486331335

418 TDDNPRTEDNQKIMADIVKGFSKP -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ES---------------------ENQ -----------N------------K------SQSQ-ET---A--KNM -M-------PI--E---LA-VGDR -T-------PD--E----A---DM ----------T------L---VQV -K------SQNQ-E----A--KNM -K------SQSQ-ES---A--KNM ---------AAA-IN---Q-LDF-K------SQSQ-E----A--KNM ---------PAA--Q--QA--ENV ---------PDV-F---MQ--H----------PDV-FN-VM---R------------------L---ENV --------------V--L---ENV -----------------L---ENV -N-------QH--V-E-MQ--A-----------T------L---VQV ----------A------L---VQV ----------T----N-L---VQV ---------PDV-FN--M---R----------PE--V---TA--ARL ---------RHQ-VQ---A--KR---------HH---Q---V--KQ--------AAE---Q--LL--EDQ --------SAAQ-VQ--LA--EH--------SAAQ-VQ--LA--EH---------HTQ-----L---IH---------HTQ-----L---IN-N----M-EPT------LT--VH--------NPEQ--Q--LT--QQS --------NPEQ--Q--LT--QQS -Q-------PN--E---LT---RM --------LPDA-V---K--MHRS -N----S--PAR-A----R-LNN-E--N-F-SIES-FD--K----H------S-SP-A-V--MLA-LTH------S-EPRA-V---LA-LLDA --------EPAR----M-A-LRD---------P-G-F---RP--A----------PKA-I---LT-MLDA ------S--P-A-VT--LS-LLDA ------G--GDV-V---LR--AR------S-EPRS-----LN-MLDA ------S--PAL--K-MLA-LT---------EPRA-IN--LA-MLDA

TA SA QT EK NT DK EK EK DK NN DK DK KA KA GV DV GI DN EK EK EK KA KN ES EQ SA QH QH QA QA QR SA SA ED -NG DK EL GR AA AD GR GR DA GH AE GQ

473 QQIIHNREEAIKTAIEQAKATDVILIAGKGHE --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------A--T-Q-------------------------A--T-Q-------------------------A--T-Q------------------D------------------------V----------------SI----------V-------------------S----------VG--PD-AQ--QF---S-VEN----------VAL-T--QD--EF-VGG-IEE----------VGL-SD-AQ--EF--QS-QKN-L--------V-V--D--Q---S-----G-K----------VG--PD-AQ--QF---S-VEN----------VG--PD--Q--QF---S-VEN----------AT---Q-KQ-LVY-FAC-N-N----V-----VG--PD--Q--QF---S-VEN----------VA---Q-DF--RY-LSL-QPR--V-------V-TM-I-QY--EQ-----SPK--V-------V-SM-I-QY--EQ--A--EPK----------V-V--D--Q------L---PQ----------V-V--D--Q----T-L---PQ----------V-V--D--Q------L---PQ----------ILV-YD--Q--QH--KH-SSA-L--------V-V--D--Q---------G-K----------V-V--D--Q---------NEK----------V-V--D--Q---------NEK----------V-SM-I-QY--EQ--A--EPK----------V----A--A--CA--QS-AEN----------VN-VYD--Q--R--VQS-VEN----------IKV--D--Q-----VQS-VEN----------VK-L-D--Q--AF-----DPE-T--------VEVC-A-DQ--IQ-LQK-DSD--V-------VEVC-A-DQ--IQ-LQK-DSD--V-------V-V--Q-----A---QS-VEN----------V-V--Q-----A---KS-VEN----------V-V--Q--Q--A---KS-VEN----------V----Q--Q-----LQS-VEN--V-------V----Q--Q-----LQS-VEN--V-------VGV-PD------FT--N-VEN---V------VHVV-D-P---AF--KK-SSH-IVV------CLVLAD-AQ--DF-VQ---PG-LV-------HTF-DS------YT--NS--N----L-----AH-E---FQ-ASY-LQN-G-Q-I--L-----V-E--G-A--VTS--M---ED--V-------V-VE-D-VK--VL-TG--SKQ-I--V-----VDFVAG-GQ--AQL-AS-A-D---VL-----ARVVEG-A--VTN--M--AEN--V-L-----V-V-AG-A--VTS-VM--A-D--V-V-----AIVQRD-AA--HQ--SM-G-D-IV-------A-A-SG-A--VTG--M---PD----V-----AIVQ-D-FK-LSY-L-H-SSQ-I--L-----VRVMEG-A--VTN--M---DN--V--------

Supplementary Figure 17 Partial sequence alignment for UDP-N-acetylmuramoylalanyl-D-glutamate--2,6-diaminopimelate ligase. The protein contains 2 aa deletion that is specific for Mannheimia is shown in the figure. Mannheimia haemolytica ser. A1/A6 str.PKL10 and Mannheimia varigena USDA-ARS-USMARC-1261 lacks this insert.

Mannheimia



Mannheimia haemolytica USDA-AR Mannheimia haemolytica D174 Mannheimia haemolytica D171 Mannheimia haemolytica D153 Mannheimia haemolytica D35 Mannheimia haemolytica USMARC_2286 Mannheimia haemolytica D38 Mannheimia haemolytica D193 Mannheimia haemolytica USMARC_2286 Mannheimia haemolytica M42548 M. haemolytica USDA-ARS-USMARC-185 M. haemolytica serotype 6 str. H23 M. haemolytica M42548 M. haemolytica serotype A1/A6 str. PKL10 M. haemolytica serotype A2 str. OVINE Mannheimia granulomatis Bibersteinia trehalosi USDA-AR Haemophilus parasuis SH0165 Haemophilus ducreyi 35000HP Haemophilus sputorum Haemophilus parahaemolyticus Haemophilus paraphrohaemolytic Actinobacillus suis H91-0380 Actinobacillus ureae Actinobacillus pleuropneumonia Haemophilus pittmaniae Haemophilus parainfluenzae T3T Haemophilus sp. oral taxon 851 Haemophilus influenzae 86-028N Acinetobacter junii Acinetobacter ursingii Xanthomonas sacchari Acinetobacter sp. CIP 70.18 Pseudomonas mendocina Pseudomonas stutzeri ATCC 1758 Pseudoxanthomonas spadix BD-a5 Xanthomonas axonopodis pv. cit Xanthomonas campestris pv. ves Pseudomonas putida KT2440 Serratia plymuthica Alcanivorax pacificus

472333189 525663396 523431632 525702078 528823164 526469350 528826710 528879592 526469350 482887395 472261405 452085964 481065996 589590286 261307780 652757696 470167741 219871186 33151802 494789674 491988280 491992094 407691804 491835981 491785098 494450521 345429902 497182364 68249497 491093379 491131668 498028753 491344899 489337704 339494315 357417720 21243026 78048045 26990029 493362897 496012633

504 RTYDRQSAVDLVK --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------A--------R---K-L-S---FNT-N-I-----Y--IQ-T------TT-G-I------TT-S-I------TT-S-I-----H--IE-T-----H--IE-T-----H--IE-T-----RT--E-I-----RTT-N-I-----KTT-S-I-----KTT-S-I-S---EHSLH---S---EHSLS---S---EH-LE-IA -S---EHSLY---AF--EH-LE---AF--EH-LE---SF--EH-LQ---S----HSLQ--A -S----HSLQ--A -AF--EH-LE---AH--EH-IE-I-A---RH-LT-IR

K -

531 HHVDYHIRETFESA -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------YV------Q-I-FQV-----------QV------L---FQ-------QD-NFIV------QD--FIV------QD--FIV------R---FQ-------L---FQT------L---FQ----L--YD--FIV------QD--FIV------QD--FIV------QD--FIV-------N---M-------KD---Q-------AG------------K---M--------DA--IV-------DA--IV------AG---Q-------AG---Q-------AG---Q--------DA--IV------S AN---QV-V----DD--FLV-------

Supplementary Figure 18 Partial sequence alignment for Glutathione-regulated potassium-efflux system protein is shown in figure. The protein contains 1 aa insertion that is specific for Mannheimia.

Mannheimia



Mannheimia haemolytica USDA-AR Mannheimia haemolytica D35 Mannheimia haemolytica D193 Mannheimia haemolytica M42548 Mannheimia haemolytica D174 Mannheimia haemolytica D171 Mannheimia haemolytica D153 Mannheimia haemolytica USMARC_2286 Mannheimia haemolytica PHL213 Mannheimia haemolytica D38 M. haemolytica Ser. A1/A6 str. PKL10 M. haemolytica ser. A2 str. BOVINE M. haemolytica ser. 6 str. H23 M. haemolytica USDA-ARS-USMARC-183 M. haemolytica USDA-ARS-USMARC-185 M. haemolytica MhSwine2000 M. haemolytica MhBrain2012 M. varigena USDA-ARS-USMARC-183 M. varigena USDA-ARS-USMARC-185 M. varigena USDA-ARS-USMARC-1261 M. varigena USDA-ARS-USMARC-1312 M. varigena USDA-ARS-USMARC-1388 M. varigena USDA-ARS-USMARC-1296 Mannheimia granulomatis Haemophilus ducreyi Avibacterium paragallinarum Actinobacillus capsulatus Pasteurella pneumotropica Bibersteinia trehalosi USDA-AR Haemophilus parasuis SH0165 Haemophilus sputorum Haemophilus parahaemolyticus Haemophilus paraphrohaemolytic Actinobacillus minor Actinobacillus pleuropneumonia Actinobacillus ureae Actinobacillus suis H91-0380 Actinobacillus succinogenes 13 Mannheimia succiniciproducens Pasteurella bettyae Pasteurella dagmatis Pasteurella multocida subsp. m Gallibacterium anatis UMN179 Aggregatibacter actinomycetemc Aggregatibacter segnis Haemophilus somnus 129PT Haemophilus aegyptius Haemophilus influenzae 10810 Haemophilus influenzae F3047 Morganella morganii subsp. mor Xenorhabdus nematophila Brenneria sp. EniD312 Rahnella sp. Y9602 Sodalis glossinidius str. 'mor Alteromonas macleodii str. 'Bl Hafnia alvei Yersinia enterocolitica subsp. Vibrio parahaemolyticus Escherichia coli Salmonella enterica Shimwellia blattae DSM 4481 =

472334521 528823843 528871831 482885978 525664688 525657694 525703384 526468127 153094325 528824437 589590824 261310643 452086460 472258758 472260218 528873636 528877526 472334521 472335981 575441602 575445157 575447863 575443019 652756314 33151743 516417625 517482099 517166617 470167473 219870296 494789007 491986948 491989884 492357411 190150433 491831417 407692764 152979421 52306852 492142581 492155126 383311863 332288840 365966896 493768272 113460531 494053302 378696948 319775311 455737880 498913621 496405590 322834784 85060120 407701965 490196787 386310208 491619082 485767479 486386721 387890936

214 FNKILNSEVIQAAIAEEAKKS -----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------D-LIQLPT-VQ--ED---TK ---L-QLPT-LK--ED---SK L--LIQLPT-VQ--ED---SK ---L-Q-AP-----DD---SK ---L-Q-PA-L---ED----P ---L-Q-PA-L---ED----P ---L-D-AALKK---D--ENK ---L-D---LKK---D--ENK ---L-D-D-LKK---D--ENK ---L-D---LKK---D--ESK ----IQ-PA-K---E----TK ---LIQLSA-VQ--ED---SK ---LIQLPA-VQ--ED---SK ---L-QHPAVLQ--ED--RGK ---L-Q-P--LS---D---SK ---L-Q-P--LE---D---SK ---L-V-SA-LD--KD---AK ---L-V-PT-LD--QD---AK -A-L--N-K-IK---D--ENK ---L-QQP--L---ED---SK ---L-QLP--L---ED---SK ---L-Q-PA-LN---D---SK ---L-Q--A-RR--ED---SK ---L-Q--A-RR--ED---SK ---L-Q--A-RR--ED---SK ---L-K-KA-EK-VED---AK -K-L-A-KA-EK---D-VRSK ---L---KA-KK--DD--RSK ---L-A-KA-EK--ED--RSK ---L-A-KA-EK-VED--RSK -SV-G-DAVRR-----SRSK ---L-S-KA-EK-VED--RSK -K-L-T-KA-EK-V-D--RTK -KRLMK--A-EQ--LD--NSK ---L-A-RA-AK-VED--RSK ---L-A-KA-AR-VED--RSK ---L-A-KA-AK-VED--RSK

KI KI KI NI KS KS KI KI KI KI KI KI KI NM NM NM NI NI KI SI NI RI NI NI NI KI KI KL KI KI KV KI KI DI KI KI KI

252 SPEKARKEAEKIINEIAA ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------L-----------H--------------------PIP---Q-----LD---PL---H---Y--LD----K---QQ-----LD----R---Q---Y--LD---------------MD----L----------LD---------Q-----LE---PL----A--T-MLD---PL----A--A-MLD---------Q-----L-----I----Q-----V-----K---QQ-----LD----K---QQ-----LD---TK----------L-----R-R-HQ-----LK----QAR--Q-----LK----E---TQ--K--LE----E---TQ--K--LD---------Q-----LQ----V----------LD----R---H------LD----K-------Y--LD----I---Q---Y--LD----I---Q---Y--LD----I---Q---Y--LD---TI----QN-VSMM--V---D--KQN-INMLE----H-R-QQN-IALME----H---QQN-IALME----V---QQN-IELME----H---KET-QSY-T----R---QQN-VALME----H---QQN-ITLME---PI-------HA-MD----H---QQN-IALME----H---QQN-IALME----H---QQN-VALME----

Supplementary Figure 19 A 2 aa deletion in a partial sequence alignment of the Glycerol-3-phosphate acyltransferase protein specific for Mannheimia is depicted in the figure.

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