Supplementary Information Genome sequencing of ...

Supplementary Information Genome sequencing of 161 Mycobacterium tuberculosis isolates from China identifies genes and intergenic regions associated with drug resistance Hongtai Zhang1,2,14, Dongfang Li3,4,14, Lili Zhao5,6,14, Joy Fleming1,14, Nan Lin7, Ting Wang1, Zhangyi Liu3, Chuanyou Li8, Nicholas Galwey1, Jiaoyu Deng9, Ying Zhou1, Yuanfang Zhu3, Yunrong Gao1, Tong Wang3, Shihua Wang7, Yufen Huang3, Ming Wang1, Qiu Zhong10, Lin Zhou10, Tao Chen10, Jie Zhou11, Ruifu Yang3, Guofeng Zhu12, Haiying Hang1, Jia Zhang1, Fabin Li13, Kanglin Wan5,6, Jun Wang3, Xian-En Zhang2,9 & Lijun Bi1 1

Key Laboratory of Non-coding RNA, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China 2

State Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China 3

BGI-Shenzhen, Shenzhen, China

4

Shenzhen Key Laboratory of Unknown Pathogen Identification, Shenzhen, China

5

National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China 6

State Key Laboratory for Infectious Disease Prevention and Control, Beijing, China

7

College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, China

8

Beijing Chest Hospital, Capital Medical University, Beijing, China

9

State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China 10

Center for Tuberculosis Control of Guangdong Province, Guangzhou, China

11

The 4th Peoples’ Hospital, Foshan City, Guangdong Province, China

12

Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China

13

Heilongjiang Center for Tuberculosis Control and Prevention, Harbin, China

14

These authors contributed equally to this work

Correspondence should be addressed to L.B. ([email protected]), X.E.Z. ([email protected]), J.W. ([email protected]), or K.W. ([email protected])

Nature Genetics: doi:10.1038/ng.2735

DS MDR XDR

Heilongjiang

Xinjiang Liaoning

Inner Mongolia

Beijing

Shaanxi Henan Tibet

Shanghai

Guizhou

Fujian Guangzhou

DS MDR XDR Total

Beijing 4 9 1 14

Fujian 4 12 4 20

Guizhou 4 16 0 20

Henan 1 1 0 2

Liaoning Shanghai 4 5 10 15 3 5 17 25

Shaanxi 4 5 0 9

Tibet 4 23 1 28

Guangzhou 1 3 7 11

Heilongjiang 3 0 2 5

Inner Mongolia 5 0 0 5

Xinjiang 5 0 0 5

Total 44 94 23 161

Supplementary Figure 1 Geographical distribution of the 161 M. tuberculosis isolates analyzed in this study. Isolates were sampled from 12 provinces and municipalities across China. Pie charts show the proportion of drug sensitive (DS; blue), MDR (red) and XDR (green) isolates from each location. Bottom panel: location-specific statistics.

Nature Genetics: doi:10.1038/ng.2735

Lineage 2-specific genes

*

*

-10

I (Lipid transport and metabolism) Q (Secondary metabolites biosynthesis, transport and catabolism) M (Cell wall/membrane/envelope biogenesis) P (Inorganic ion transport and metabolism) C (Energy production and conversion) F (Nucleotide transport and metabolism) N (Cell motility) V (Defense mechanisms) D (Cell cycle control, cell division, chromosome partitioning) J (Translation, ribosomal structure and biogenesis) E (Amino acid transport and metabolism) O (Posttranslational modification, protein turnover, chaperones) T (Signal transduction mechanisms) K (Transcription) G (Carbohydrate transport and metabolism) L (Replication, recombination and repair) S (Function unknown) R (General function prediction only)

-8

-6

-4

-2

0

2

4

Lineage 4-specific genes

*

-6

G (Carbohydrate transport and metabolism) P (Inorganic ion transport and metabolism) R (General function prediction only) E (Amino acid transport and metabolism) N (Cell motility) V (Defense mechanisms) T (Signal transduction mechanisms) U (Intracellular trafficking, secretion, and vesicular transport) H (Coenzyme transport and metabolism) O (Posttranslational modification, protein turnover, chaperones) F (Nucleotide transport and metabolism) M (Cell wall/membrane/envelope biogenesis) J (Translation, ribosomal structure and biogenesis) S (Function unknown) I (Lipid transport and metabolism) Q (Secondary metabolites biosynthesis, transport and catabolism) C (Energy production and conversion) L (Replication, recombination and repair) K (Transcription)

*

-4

-2

0

2

4

Supplementary Figure 2 Distribution of genes containing L2- and L4-specific nsSNPs across COG categories. The x-axis shows the difference in the percentage of genes in each functional class relative to the whole genome. Positive values indicate over-representation of a particular functional class whereas negative values indicate underrepresentation. * pT C->T C->A C->T G->A C->A T->C C->T G->T G->T A->C C->G C->A C->T G->A C->T A->T G->A G->C G->C T->C C->T G->T G->A G->A G->A G->T T->C T->G T->C C->T C->T G->A C->G C->T A->C G->A T->C A->G C->T C->T G->T T->C T->G G->A T->G C->A G->C G->C A->G C->T T->G G->A G->T C->T G->T A->C C->T C->G C->T T->C A->C

Rv0922 Rv0927c-Rv0928 Rv0965c Rv0981 Rv0981 Rv0982-Rv0983 Rv0986 Rv0986 Rv0987 Rv1023 Rv1028c Rv1048c Rv1050 Rv1051c-Rv1052 Rv1072-Rv1073 Rv1076 Rv1091 Rv1099c Rv1159 Rv1161 Rv1168c Rv1181 Rv1183 Rv1186c Rv1214c Rv1217c Rv1217c Rv1227c-Rv1228 Rv1329c Rv1333 Rv1368 Rv1383 Rv1401 Rv1418-Rv1419 Rv1420 Rv1420 Rv1430 Rv1439c Rv1442 Rv1458c Rv1461 Rv1463 Rv1489 Rv1497 Rv1532c Rv1612 Rv1629 Rv1629 Rv1629 Rv1630 Rv1640c Rv1661 Rv1662 Rv1677-Rv1678 Rv1739c Rv1739c Rv1751 Rv1769 Rv1785c Rv1826 Rv1865c Rv1888A Rv1894c-Rv1895 Rv1920 Rv1921c-Rv1922 Rv1925 Rv1934c Rv1936 Rv1938 Rv1956 Rv1999c Rv2000 Rv2047c Rv2059 Rv2079

Nature Genetics: doi:10.1038/ng.2735

NC_000962.2_1028217 NC_000962.2_1034758 NC_000962.2_1076880 NC_000962.2_1097220 NC_000962.2_1097442 NC_000962.2_1099058 NC_000962.2_1102117 NC_000962.2_1102468 NC_000962.2_1102646 NC_000962.2_1145848 NC_000962.2_1151054 NC_000962.2_1172085 NC_000962.2_1173750 NC_000962.2_1175343 NC_000962.2_1197157 NC_000962.2_1201581 NC_000962.2_1217065 NC_000962.2_1227830 NC_000962.2_1285001 NC_000962.2_1288698 NC_000962.2_1299305 NC_000962.2_1317655 NC_000962.2_1322741 NC_000962.2_1329234 NC_000962.2_1357308 NC_000962.2_1361190 NC_000962.2_1361285 NC_000962.2_1370852 NC_000962.2_1498951 NC_000962.2_1501700 NC_000962.2_1541798 NC_000962.2_1556787 NC_000962.2_1577241 NC_000962.2_1593331 NC_000962.2_1594906 NC_000962.2_1595342 NC_000962.2_1606673 NC_000962.2_1617302 NC_000962.2_1620181 NC_000962.2_1643864 NC_000962.2_1647436 NC_000962.2_1651308 NC_000962.2_1678706 NC_000962.2_1688064 NC_000962.2_1733325 NC_000962.2_1811375 NC_000962.2_1831220 NC_000962.2_1831226 NC_000962.2_1831288 NC_000962.2_1834177 NC_000962.2_1849051 NC_000962.2_1877744 NC_000962.2_1885385 NC_000962.2_1902337 NC_000962.2_1967026 NC_000962.2_1967543 NC_000962.2_1980652 NC_000962.2_2003827 NC_000962.2_2023628 NC_000962.2_2072313 NC_000962.2_2112832 NC_000962.2_2138453 NC_000962.2_2142266 NC_000962.2_2172380 NC_000962.2_2173860 NC_000962.2_2177366 NC_000962.2_2185674 NC_000962.2_2187587 NC_000962.2_2191498 NC_000962.2_2202500 NC_000962.2_2244421 NC_000962.2_2245864 NC_000962.2_2294007 NC_000962.2_2315386 NC_000962.2_2337179

nonsyn -syn syn syn -syn syn syn nonsyn syn nonsyn syn --nonsyn syn syn nonsyn syn nonsyn syn nonsyn syn syn syn nonsyn -nonsyn syn nonsyn nonsyn syn -nonsyn nonsyn syn nonsyn nonsyn nonsyn nonsyn nonsyn nonsyn nonsyn nonsyn syn nonsyn nonsyn syn syn syn nonsyn nonsyn -syn nonsyn syn nonsyn nonsyn nonsyn syn syn -nonsyn -nonsyn nonsyn nonsyn nonsyn syn nonsyn nonsyn nonsyn nonsyn nonsyn

G->A C->T C->T C->T C->T G->A G->A C->A G->A A->C C->G C->A G->T C->T T->G A->C C->A G->T A->C G->A G->A C->T A->G G->A T->G G->A C->T T->G G->T G->A C->T T->C G->A G->A G->A T->C G->T G->T C->G T->C G->A A->G A->C A->G C->G G->T A->C A->G C->T A->C C->T A->C T->G A->C C->T C->A G->T A->C C->G C->A A->C C->T C->A A->C A->C C->T A->G G->C G->T C->T G->T C->A T->C C->A C->T

Rv2082 Rv2082 Rv2087-Rv2088 Rv2096c Rv2139 Rv2231c Rv2237-Rv2238c Rv2247 Rv2260 Rv2268c Rv2274c Rv2276 Rv2280 Rv2280 Rv2290 Rv2308 Rv2314c Rv2327 Rv2328 Rv2328 Rv2337c Rv2383c Rv2395-Rv2396 Rv2400c Rv2408 Rv2414c Rv2433c Rv2440c Rv2443 Rv2450c Rv2472 Rv2483c Rv2485c Rv2516c Rv2525c-Rv2526 Rv2562 Rv2564 Rv2573 Rv2578c Rv2621c Rv2629 Rv2644c-Rv2645 Rv2659c-Rv2660c Rv2666 Rv2691 Rv2693c Rv2711 Rv2721c Rv2724c Rv2802c Rv2827c-Rv2828c Rv2831 Rv2837c Rv2864c-Rv2865 Rv2891 Rv2931 Rv2940c Rv2941 Rv2952 Rv2964 Rv3015c Rv3047c Rv3109 Rv3121 Rv3134c Rv3134c Rv3142c-Rv3143 Rv3173c-Rv3174 Rv3181c-Rv3182 Rv3183 Rv3202c Rv3210c Rv3220c Rv3224 Rv3236c

Nature Genetics: doi:10.1038/ng.2735

NC_000962.2_2338810 NC_000962.2_2338811 NC_000962.2_2344246 NC_000962.2_2354791 NC_000962.2_2399734 NC_000962.2_2505085 NC_000962.2_2510350 NC_000962.2_2521428 NC_000962.2_2533377 NC_000962.2_2543395 NC_000962.2_2546684 NC_000962.2_2548700 NC_000962.2_2551576 NC_000962.2_2551577 NC_000962.2_2562644 NC_000962.2_2581052 NC_000962.2_2586076 NC_000962.2_2600260 NC_000962.2_2601576 NC_000962.2_2601760 NC_000962.2_2612256 NC_000962.2_2673818 NC_000962.2_2692100 NC_000962.2_2697489 NC_000962.2_2706663 NC_000962.2_2711722 NC_000962.2_2729058 NC_000962.2_2738274 NC_000962.2_2741209 NC_000962.2_2752122 NC_000962.2_2775361 NC_000962.2_2789798 NC_000962.2_2793810 NC_000962.2_2833329 NC_000962.2_2850631 NC_000962.2_2881974 NC_000962.2_2884068 NC_000962.2_2898522 NC_000962.2_2903439 NC_000962.2_2948230 NC_000962.2_2955957 NC_000962.2_2969197 NC_000962.2_2980861 NC_000962.2_2983873 NC_000962.2_3009834 NC_000962.2_3010993 NC_000962.2_3024021 NC_000962.2_3033189 NC_000962.2_3036826 NC_000962.2_3111476 NC_000962.2_3135606 NC_000962.2_3137736 NC_000962.2_3144623 NC_000962.2_3177452 NC_000962.2_3200282 NC_000962.2_3249025 NC_000962.2_3276703 NC_000962.2_3284855 NC_000962.2_3304966 NC_000962.2_3316955 NC_000962.2_3375165 NC_000962.2_3408150 NC_000962.2_3477942 NC_000962.2_3487108 NC_000962.2_3500149 NC_000962.2_3500243 NC_000962.2_3509626 NC_000962.2_3542049 NC_000962.2_3550347 NC_000962.2_3550789 NC_000962.2_3577497 NC_000962.2_3587446 NC_000962.2_3597249 NC_000962.2_3600576 NC_000962.2_3612813

syn nonsyn -nonsyn nonsyn syn -nonsyn syn syn nonsyn nonsyn nonsyn syn nonsyn nonsyn syn syn nonsyn nonsyn syn nonsyn -nonsyn nonsyn syn nonsyn nonsyn syn nonsyn syn syn nonsyn nonsyn -nonsyn|nonsyn nonsyn syn syn nonsyn nonsyn --stop_syn nonsyn nonsyn syn syn nonsyn syn -nonsyn nonsyn -nonsyn nonsyn nonsyn syn nonsyn nonsyn nonsyn nonsyn syn syn syn syn ---syn nonsyn syn nonsyn syn nonsyn

T->C A->G G->C A->G G->A G->A C->G A->G T->C T->C C->A C->T C->G T->C G->T G->A C->G A->G T->G G->A G->T C->G C->T C->T G->T T->G A->C A->C G->A G->C C->T G->T C->A G->A T->C G->A A->C T->C G->A G->A A->C A->G A->G A->G A->G C->T C->A G->A C->T C->T A->G G->T C->T C->A C->T T->G T->G C->T G->A A->C A->C T->C A->G C->T G->A G->C C->A G->A C->T C->G C->T G->A C->G C->T T->C

Rv3248c Rv3263 Rv3272 Rv3293 Rv3296 Rv3296 Rv3317 Rv3346c-Rv3347c Rv3347c Rv3349c Rv3365c Rv3365c Rv3366 Rv3366 Rv3366-Rv3367 Rv3383c-Rv3384c Rv3395c-Rv3395A Rv3395c-Rv3395A Rv3402c Rv3411c Rv3429 Rv3429 Rv3429 Rv3449 Rv3478 Rv3478 Rv3487c Rv3525c Rv3528c Rv3532-Rv3533c Rv3540c Rv3543c Rv3554 Rv3560c-Rv3561 Rv3579c Rv3590c Rv3590c Rv3598c Rv3610c Rv3616c-Rv3617 Rv3674c Rv3680 Rv3682 Rv3691 Rv3721c Rv3722c Rv3725 Rv3729 Rv3731 Rv3736 Rv3737 Rv3759c Rv3785 Rv3794 Rv3797 Rv3799c Rv3801c Rv3805c Rv3815c Rv3820c Rv3826 Rv3834c Rv3842c Rv3845-Rv3846 Rv3863-Rv3864 Rv3879c Rv3879c Rv3879c-Rv3880c Rv3882c Rv3885c Rv3894c Rv3910 Rv3919c

Nature Genetics: doi:10.1038/ng.2735

NC_000962.2_3628520 NC_000962.2_3643985 NC_000962.2_3653988 NC_000962.2_3674157 NC_000962.2_3678249 NC_000962.2_3680932 NC_000962.2_3704770 NC_000962.2_3743656 NC_000962.2_3743899 NC_000962.2_3754508 NC_000962.2_3775409 NC_000962.2_3775441 NC_000962.2_3778011 NC_000962.2_3778012 NC_000962.2_3778396 NC_000962.2_3798596 NC_000962.2_3811672 NC_000962.2_3811675 NC_000962.2_3821845 NC_000962.2_3830349 NC_000962.2_3847235 NC_000962.2_3847237 NC_000962.2_3847238 NC_000962.2_3870010 NC_000962.2_3894732 NC_000962.2_3895585 NC_000962.2_3906311 NC_000962.2_3962187 NC_000962.2_3964518 NC_000962.2_3970594 NC_000962.2_3979990 NC_000962.2_3981983 NC_000962.2_3993058 NC_000962.2_4001622 NC_000962.2_4022388 NC_000962.2_4032218 NC_000962.2_4032625 NC_000962.2_4041581 NC_000962.2_4050811 NC_000962.2_4056693 NC_000962.2_4115890 NC_000962.2_4120390 NC_000962.2_4122287 NC_000962.2_4133316 NC_000962.2_4166441 NC_000962.2_4167656 NC_000962.2_4170739 NC_000962.2_4179832 NC_000962.2_4182387 NC_000962.2_4186678 NC_000962.2_4189210 NC_000962.2_4205325 NC_000962.2_4231865 NC_000962.2_4243460 NC_000962.2_4252066 NC_000962.2_4254431 NC_000962.2_4262388 NC_000962.2_4267647 NC_000962.2_4280708 NC_000962.2_4284429 NC_000962.2_4301075 NC_000962.2_4308395 NC_000962.2_4314800 NC_000962.2_4319985 NC_000962.2_4340028 NC_000962.2_4357804 NC_000962.2_4359653 NC_000962.2_4359828 NC_000962.2_4362568 NC_000962.2_4368084 NC_000962.2_4378504 NC_000962.2_4397736 NC_000962.2_4407927

syn nonsyn nonsyn nonsyn nonsyn syn nonsyn -syn nonsyn nonsyn nonsyn nonsyn syn ----nonsyn nonsyn nonsyn nonsyn nonsyn nonsyn nonsyn nonsyn nonsyn syn syn -nonsyn syn nonsyn -syn nonsyn syn nonsyn syn -nonsyn nonsyn syn nonsyn syn nonsyn nonsyn nonsyn syn syn syn nonsyn syn syn nonsyn syn nonsyn nonsyn syn nonsyn nonsyn syn nonsyn --nonsyn nonsyn -syn syn nonsyn syn nonsyn

G->A A->C G->A T->A A->C G->A A->G G->A G->A G->C T->C A->C G->A G->T C->T A->G G->T A->G G->T C->T C->T G->T C->T A->G A->G C->T G->A G->A G->A C->G C->G G->A G->A T->C G->A G->A G->T C->T G->A G->T G->C G->C G->T A->T G->A A->G G->C G->C G->C G->A G->T A->G C->A C->T T->C G->A C->T T->C G->A G->A G->C G->A G->A G->C G->C T->G C->T G->A T->G G->C T->C C->T T->G

(2b) L4-specific SNPs Gene/IGR ID Rv0013 Rv0039c Rv0064 Rv0104 Rv0118c Rv0169 Rv0174 Rv0174 Rv0186 Rv0209 Rv0210 Rv0270 Rv0282 Rv0325 Rv0368c Rv0407 Rv0408 Rv0412c Rv0419 Rv0428c Rv0456c Rv0465c Rv0493c Rv0507 Rv0557 Rv0564c-Rv0565c Rv0567-Rv0568 Rv0570 Rv0591 Rv0620 Rv0663 Rv0667 Rv0676c Rv0728c Rv0754-Rv0755c Rv0835 Rv0836c Rv0837c-Rv0838 Rv0845 Rv0862c Rv0872c Rv0918 Rv0945 Rv0969 Rv0982 Rv0987 Rv0990c Rv1023 Rv1026-Rv1027c Rv1040c-Rv1041c Rv1086 Rv1102c Rv1125 Rv1125 Rv1127c Rv1130 Rv1155 Rv1206-Rv1207 Rv1224 Rv1248c Rv1317c Rv1326c Rv1367c Rv1371 Rv1373 Rv1431 Rv1497 Rv1508c Rv1522c Rv1592c Rv1592c Rv1634 Rv1640c

Nature Genetics: doi:10.1038/ng.2735

SNP locus NC_000962.2_15117 NC_000962.2_42281 NC_000962.2_70267 NC_000962.2_123520 NC_000962.2_143207 NC_000962.2_199470 NC_000962.2_206481 NC_000962.2_206484 NC_000962.2_217201 NC_000962.2_249522 NC_000962.2_251575 NC_000962.2_325505 NC_000962.2_342146 NC_000962.2_392261 NC_000962.2_445780 NC_000962.2_491742 NC_000962.2_492150 NC_000962.2_498531 NC_000962.2_505974 NC_000962.2_517358 NC_000962.2_546357 NC_000962.2_555991 NC_000962.2_584171 NC_000962.2_599868 NC_000962.2_648856 NC_000962.2_655986 NC_000962.2_659341 NC_000962.2_662911 NC_000962.2_690450 NC_000962.2_713310 NC_000962.2_757182 NC_000962.2_763031 NC_000962.2_776100 NC_000962.2_820752 NC_000962.2_847995 NC_000962.2_931123 NC_000962.2_932280 NC_000962.2_934230 NC_000962.2_941845 NC_000962.2_960367 NC_000962.2_969762 NC_000962.2_1024346 NC_000962.2_1054784 NC_000962.2_1080192 NC_000962.2_1098523 NC_000962.2_1104690 NC_000962.2_1107940 NC_000962.2_1144585 NC_000962.2_1148259 NC_000962.2_1164336 NC_000962.2_1211369 NC_000962.2_1230778 NC_000962.2_1248382 NC_000962.2_1248936 NC_000962.2_1250340 NC_000962.2_1254562 NC_000962.2_1281771 NC_000962.2_1351172 NC_000962.2_1367484 NC_000962.2_1390763 NC_000962.2_1479085 NC_000962.2_1490905 NC_000962.2_1540141 NC_000962.2_1544255 NC_000962.2_1546703 NC_000962.2_1608276 NC_000962.2_1688300 NC_000962.2_1699849 NC_000962.2_1716472 NC_000962.2_1792777 NC_000962.2_1792778 NC_000962.2_1839759 NC_000962.2_1849609

Mutation type nonsyn nonsyn nonsyn nonsyn nonsyn nonsyn syn syn syn nonsyn nonsyn syn nonsyn stop_nonsyn nonsyn syn nonsyn syn nonsyn nonsyn syn nonsyn nonsyn syn syn --syn syn nonsyn nonsyn syn nonsyn nonsyn -syn stop_nonsyn -nonsyn nonsyn syn nonsyn nonsyn nonsyn nonsyn nonsyn nonsyn nonsyn --nonsyn nonsyn nonsyn syn syn nonsyn nonsyn -nonsyn nonsyn nonsyn nonsyn nonsyn syn nonsyn nonsyn syn nonsyn nonsyn nonsyn syn nonsyn syn

Ancestral baseSample base G->C A->C T->G C->T C->T G->T G->C T->G C->T C->T A->G C->T C->A C->T T->C C->T C->G G->A A->G C->T G->A G->A C->T G->A C->T G->T C->T C->T C->A C->T G->A C->T A->G T->C C->T C->T C->T G->C A->C G->A G->C G->A G->C A->G A->T G->T C->A G->A G->A A->G C->A A->G G->A C->G G->A G->A C->T G->A G->T T->C C->T G->A C->T T->C T->C C->A C->T A->G G->A C->T C->T C->G C->T

Rv1649 Rv1705c Rv1745c Rv1765c Rv1765c Rv1765c Rv1776c-Rv1777 Rv1808 Rv1860-Rv1861 Rv1872c Rv1948c Rv1966 Rv2012-Rv2013 Rv2015c Rv2015c Rv2015c Rv2071c Rv2075c Rv2075c Rv2109c Rv2127 Rv2153c Rv2160c Rv2163c Rv2187 Rv2205c-Rv2206 Rv2340c-Rv2341 Rv2426c Rv2442c-Rv2443 Rv2484c Rv2492 Rv2509 Rv2524c Rv2524c Rv2566 Rv2596 Rv2650c Rv2672 Rv2678c Rv2685 Rv2692 Rv2714 Rv2719c Rv2770c Rv2795c Rv2825c Rv2825c Rv2862c Rv2869c Rv2878c Rv2934 Rv2971 Rv2979c Rv3059 Rv3087 Rv3097c Rv3098c Rv3114 Rv3144c Rv3161c Rv3257c Rv3289c Rv3297 Rv3303c Rv3306c Rv3411c Rv3433c Rv3433c Rv3450c Rv3476c Rv3478-Rv3479 Rv3490 Rv3545c Rv3563 Rv3567c

Nature Genetics: doi:10.1038/ng.2735

NC_000962.2_1859559 NC_000962.2_1931718 NC_000962.2_1971725 NC_000962.2_1998063 NC_000962.2_1998122 NC_000962.2_1998141 NC_000962.2_2010614 NC_000962.2_2050822 NC_000962.2_2108890 NC_000962.2_2122976 NC_000962.2_2199052 NC_000962.2_2209465 NC_000962.2_2260100 NC_000962.2_2262620 NC_000962.2_2262679 NC_000962.2_2262698 NC_000962.2_2328543 NC_000962.2_2331620 NC_000962.2_2331789 NC_000962.2_2369186 NC_000962.2_2388641 NC_000962.2_2413246 NC_000962.2_2421816 NC_000962.2_2425471 NC_000962.2_2448458 NC_000962.2_2470591 NC_000962.2_2619271 NC_000962.2_2723506 NC_000962.2_2740693 NC_000962.2_2791098 NC_000962.2_2807486 NC_000962.2_2825466 NC_000962.2_2841022 NC_000962.2_2847281 NC_000962.2_2886570 NC_000962.2_2925962 NC_000962.2_2975227 NC_000962.2_2988630 NC_000962.2_2994187 NC_000962.2_3003115 NC_000962.2_3010420 NC_000962.2_3027798 NC_000962.2_3031168 NC_000962.2_3079877 NC_000962.2_3104189 NC_000962.2_3133054 NC_000962.2_3133055 NC_000962.2_3174496 NC_000962.2_3180988 NC_000962.2_3189242 NC_000962.2_3266030 NC_000962.2_3326554 NC_000962.2_3335708 NC_000962.2_3420825 NC_000962.2_3454263 NC_000962.2_3466919 NC_000962.2_3467465 NC_000962.2_3480789 NC_000962.2_3510120 NC_000962.2_3530955 NC_000962.2_3638093 NC_000962.2_3670040 NC_000962.2_3681548 NC_000962.2_3690016 NC_000962.2_3693681 NC_000962.2_3830695 NC_000962.2_3851887 NC_000962.2_3851888 NC_000962.2_3871246 NC_000962.2_3893480 NC_000962.2_3895727 NC_000962.2_3909235 NC_000962.2_3984321 NC_000962.2_4005114 NC_000962.2_4008747

nonsyn nonsyn syn nonsyn syn syn -nonsyn -nonsyn nonsyn nonsyn -nonsyn syn syn nonsyn syn nonsyn nonsyn nonsyn nonsyn nonsyn syn nonsyn --syn -nonsyn nonsyn syn nonsyn syn syn nonsyn nonsyn nonsyn syn nonsyn nonsyn nonsyn nonsyn nonsyn syn syn nonsyn nonsyn nonsyn syn syn nonsyn nonsyn nonsyn nonsyn nonsyn syn nonsyn nonsyn nonsyn nonsyn syn syn nonsyn syn syn nonsyn syn syn nonsyn -nonsyn syn nonsyn nonsyn

A->C C->G C->G A->T A->G C->G A->G C->G C->A G->C G->C A->G T->C A->T A->G C->G C->T C->A T->G C->G A->G A->C G->A C->T T->C C->A C->T C->T C->T T->C A->C A->G G->A G->A G->A C->T G->T G->C C->T G->C G->A C->T G->A G->A G->A G->C C->G G->A A->C G->A G->A C->A C->G G->A G->C G->C G->C C->T G->T G->C A->G T->C C->A G->A C->A G->A C->A C->T C->T A->G A->C C->G A->G C->G G->A

Rv3586 Rv3616c-Rv3617 Rv3649 Rv3655c Rv3666c Rv3671c Rv3703c Rv3729 Rv3770c Rv3772 Rv3797 Rv3822 Rv3839 Rv3857c-Rv3858c Rv3888c Rv3898c Rv3898c-Rv3899c Rv3919c Rv3920c-Rv3921c

Nature Genetics: doi:10.1038/ng.2735

NC_000962.2_4028752 NC_000962.2_4056416 NC_000962.2_4089058 NC_000962.2_4095295 NC_000962.2_4107074 NC_000962.2_4112429 NC_000962.2_4145737 NC_000962.2_4179089 NC_000962.2_4215484 NC_000962.2_4217557 NC_000962.2_4251297 NC_000962.2_4287164 NC_000962.2_4313128 NC_000962.2_4329782 NC_000962.2_4372353 NC_000962.2_4383655 NC_000962.2_4384007 NC_000962.2_4407588 NC_000962.2_4408923

nonsyn -nonsyn syn nonsyn nonsyn syn nonsyn nonsyn nonsyn syn syn nonsyn -syn stop_nonsyn -syn --

G->A A->C C->T C->T C->T C->T G->A T->C C->G G->A C->G G->A T->C A->G C->G G->A G->C C->T T->C

(2c) L2.1-specific SNPs Gene/IGR ID Rv0014c Rv0061 Rv0065 Rv0127 Rv0136 Rv0202c Rv0211 Rv0237 Rv0244c Rv0284 Rv0304c Rv0327c Rv0372c Rv0380c Rv0419 Rv0622 Rv0732 Rv0754 Rv0823c Rv0842 Rv0859 Rv0892 Rv0916c-Rv0917 Rv0938 Rv0944 Rv0954 Rv0989c Rv1051c Rv1067c-Rv1068c Rv1073 Rv1123c Rv1147-Rv1148c Rv1172c Rv1346 Rv1391 Rv1523 Rv1529-Rv1530 Rv1547 Rv1552 Rv1557 Rv1589 Rv1707 Rv1891 Rv1894c Rv1934c Rv2329c Rv2341 Rv2357c Rv2528c Rv2561 Rv2563 Rv2579 Rv2688c Rv2744c Rv2821c Rv2826c Rv2839c Rv2842c-Rv2843 Rv2852c Rv2876-Rv2877c Rv2959c Rv3016 Rv3057c Rv3075c Rv3158 Rv3204 Rv3205c Rv3343c Rv3378c Rv3403c Rv3828c Rv3887c Rv3894c Rv3911

Nature Genetics: doi:10.1038/ng.2735

SNP locus NC_000962.2_15890 NC_000962.2_65246 NC_000962.2_71914 NC_000962.2_154990 NC_000962.2_163940 NC_000962.2_239733 NC_000962.2_252900 NC_000962.2_287747 NC_000962.2_294596 NC_000962.2_346693 NC_000962.2_370257 NC_000962.2_393387 NC_000962.2_449194 NC_000962.2_456299 NC_000962.2_505843 NC_000962.2_716025 NC_000962.2_825655 NC_000962.2_846704 NC_000962.2_917596 NC_000962.2_938240 NC_000962.2_955127 NC_000962.2_994382 NC_000962.2_1021776 NC_000962.2_1047873 NC_000962.2_1053912 NC_000962.2_1065793 NC_000962.2_1106614 NC_000962.2_1174655 NC_000962.2_1190472 NC_000962.2_1197567 NC_000962.2_1246500 NC_000962.2_1276232 NC_000962.2_1302482 NC_000962.2_1511460 NC_000962.2_1565566 NC_000962.2_1718152 NC_000962.2_1731293 NC_000962.2_1750386 NC_000962.2_1758588 NC_000962.2_1762216 NC_000962.2_1790479 NC_000962.2_1935437 NC_000962.2_2140076 NC_000962.2_2141368 NC_000962.2_2185009 NC_000962.2_2602454 NC_000962.2_2619799 NC_000962.2_2640807 NC_000962.2_2852598 NC_000962.2_2881542 NC_000962.2_2883217 NC_000962.2_2903643 NC_000962.2_3005014 NC_000962.2_3057256 NC_000962.2_3128345 NC_000962.2_3134017 NC_000962.2_3147511 NC_000962.2_3150049 NC_000962.2_3162021 NC_000962.2_3187987 NC_000962.2_3312401 NC_000962.2_3375807 NC_000962.2_3418386 NC_000962.2_3438664 NC_000962.2_3526873 NC_000962.2_3581476 NC_000962.2_3581967 NC_000962.2_3734189 NC_000962.2_3792765 NC_000962.2_3823194 NC_000962.2_4302926 NC_000962.2_4370678 NC_000962.2_4377999 NC_000962.2_4400839

Mutation type syn syn nonsyn syn nonsyn nonsyn syn nonsyn syn syn syn nonsyn syn nonsyn nonsyn nonsyn nonsyn syn syn syn nonsyn nonsyn -syn nonsyn nonsyn nonsyn nonsyn -nonsyn nonsyn -nonsyn syn syn nonsyn -nonsyn nonsyn nonsyn nonsyn nonsyn nonsyn nonsyn nonsyn syn nonsyn syn nonsyn nonsyn nonsyn nonsyn nonsyn nonsyn nonsyn syn syn -nonsyn -nonsyn nonsyn nonsyn nonsyn nonsyn syn nonsyn nonsyn nonsyn nonsyn nonsyn nonsyn syn syn

Ancestral baseSample base G->A C->T T->C G->T A->G G->T C->T A->C T->G G->T G->C C->T G->A C->G A->G C->T C->A C->T C->A G->C A->C C->T A->G C->T T->C T->G G->T C->T C->T G->C C->T C->A C->T C->T C->T T->C C->G C->T A->G C->G C->G C->T G->A C->T C->T T->G A->C G->A G->C C->G G->C C->A A->G G->A C->G G->T T->G G->T G->C C->T A->C T->C C->T G->C G->T C->T G->C A->T C->A T->C C->G T->C C->A T->C

(2d) L2.2- specific SNPs Gene/IGR ID SNP locus Rv0107c NC_000962.2_128469 Rv0168 NC_000962.2_197705 Rv0373c NC_000962.2_449943 Rv0969 NC_000962.2_1079697 Rv1179c NC_000962.2_1312065 Rv1316c NC_000962.2_1477522 Rv1944c NC_000962.2_2195864 Rv2037c NC_000962.2_2283528 Rv2737c NC_000962.2_3051182 Rv3014c NC_000962.2_3373397 Rv3825c NC_000962.2_4296225 Rv3854c NC_000962.2_4326676

Nature Genetics: doi:10.1038/ng.2735

Mutation type syn nonsyn nonsyn nonsyn nonsyn nonsyn nonsyn nonsyn syn syn syn nonsyn

Ancestral baseSample base C->A G->A C->T G->C A->C C->A G->A C->A C->T G->A G->A G->C

(2e) L2.3-specific SNPs Gene/IGR ID Rv0015c Rv0015c Rv0035 Rv0044c Rv0092 Rv0154c Rv0173 Rv0237 Rv0245 Rv0302 Rv0305c Rv0307c Rv0384c Rv0452 Rv0486 Rv0512 Rv0530 Rv0602c-Rv0603 Rv0676c Rv0691c Rv0855 Rv0858c Rv0858c Rv0890c Rv0932c Rv0987 Rv0988 Rv0988 Rv0991c-Rv0992c Rv0995 Rv1027c Rv1054 Rv1091 Rv1136-Rv1137c Rv1160 Rv1163 Rv1190 Rv1193 Rv1316c Rv1357c-Rv1358 Rv1538c Rv1566c-Rv1567c Rv1640c Rv1769 Rv1821 Rv1823 Rv1835c Rv1837c Rv1888c-Rv1888A Rv1972 Rv1981c-Rv1982c Rv1986 Rv1992c Rv2059 Rv2062c Rv2062c Rv2103c Rv2152c Rv2180c Rv2189c Rv2248 Rv2264c Rv2366c Rv2488c Rv2490c Rv2494 Rv2519 Rv2712c Rv2736c Rv2800-Rv2801c Rv2855 Rv2905 Rv2941

Nature Genetics: doi:10.1038/ng.2735

SNP locus NC_000962.2_17654 NC_000962.2_17657 NC_000962.2_37334 NC_000962.2_48503 NC_000962.2_101539 NC_000962.2_182824 NC_000962.2_204094 NC_000962.2_288260 NC_000962.2_296312 NC_000962.2_364854 NC_000962.2_374353 NC_000962.2_377014 NC_000962.2_460413 NC_000962.2_542514 NC_000962.2_575907 NC_000962.2_605150 NC_000962.2_621598 NC_000962.2_699840 NC_000962.2_776182 NC_000962.2_791249 NC_000962.2_951702 NC_000962.2_954101 NC_000962.2_954468 NC_000962.2_991896 NC_000962.2_1040251 NC_000962.2_1103656 NC_000962.2_1105686 NC_000962.2_1105687 NC_000962.2_1108521 NC_000962.2_1111678 NC_000962.2_1148930 NC_000962.2_1177157 NC_000962.2_1218896 NC_000962.2_1265070 NC_000962.2_1286766 NC_000962.2_1293333 NC_000962.2_1333669 NC_000962.2_1336164 NC_000962.2_1477596 NC_000962.2_1526311 NC_000962.2_1741352 NC_000962.2_1774659 NC_000962.2_1849934 NC_000962.2_2003105 NC_000962.2_2067684 NC_000962.2_2069771 NC_000962.2_2082053 NC_000962.2_2086672 NC_000962.2_2138436 NC_000962.2_2216963 NC_000962.2_2225365 NC_000962.2_2230045 NC_000962.2_2235087 NC_000962.2_2316123 NC_000962.2_2318725 NC_000962.2_2320320 NC_000962.2_2364475 NC_000962.2_2411496 NC_000962.2_2442468 NC_000962.2_2451700 NC_000962.2_2522955 NC_000962.2_2536892 NC_000962.2_2647905 NC_000962.2_2800087 NC_000962.2_2802041 NC_000962.2_2808452 NC_000962.2_2835984 NC_000962.2_3024343 NC_000962.2_3048912 NC_000962.2_3110140 NC_000962.2_3165636 NC_000962.2_3214869 NC_000962.2_3284640

Mutation type nonsyn nonsyn nonsyn syn syn syn syn syn nonsyn nonsyn syn syn syn nonsyn nonsyn syn nonsyn -nonsyn nonsyn nonsyn nonsyn syn nonsyn syn nonsyn nonsyn nonsyn -nonsyn nonsyn nonsyn nonsyn -nonsyn nonsyn syn nonsyn syn -nonsyn -nonsyn syn nonsyn nonsyn nonsyn nonsyn -nonsyn -nonsyn syn nonsyn nonsyn nonsyn nonsyn syn nonsyn syn nonsyn nonsyn nonsyn nonsyn nonsyn nonsyn nonsyn nonsyn nonsyn -syn nonsyn nonsyn

Ancestral baseSample base T->G T->C A->T T->C C->T G->A G->T C->T C->T C->G A->G C->T C->T C->G C->T G->A C->T A->C C->T C->T C->T C->T C->G T->C C->A C->T C->G T->C G->A G->A C->T G->A G->A G->T G->C C->G T->G C->T C->T G->T C->T C->T A->G C->T G->A C->A A->G C->T A->G C->G T->C G->A G->A C->A C->T C->T T->C G->A C->T A->C T->G T->C G->A G->A C->T T->C T->C G->A C->G G->T G->A A->G A->G

Rv3081-Rv3082c Rv3174 Rv3283 Rv3294c Rv3389c Rv3407 Rv3415c Rv3445c Rv3446c Rv3490 Rv3497c Rv3523 Rv3531c Rv3591c Rv3758c Rv3769-Rv3770c Rv3800c Rv3835

Nature Genetics: doi:10.1038/ng.2735

NC_000962.2_3447293 NC_000962.2_3542219 NC_000962.2_3665753 NC_000962.2_3675504 NC_000962.2_3804299 NC_000962.2_3826501 NC_000962.2_3834486 NC_000962.2_3863138 NC_000962.2_3863681 NC_000962.2_3908465 NC_000962.2_3916386 NC_000962.2_3959730 NC_000962.2_3968006 NC_000962.2_4033577 NC_000962.2_4204168 NC_000962.2_4214988 NC_000962.2_4258106 NC_000962.2_4309927

-nonsyn nonsyn syn nonsyn nonsyn syn nonsyn nonsyn nonsyn nonsyn nonsyn nonsyn nonsyn nonsyn -nonsyn nonsyn

T->G G->A G->A G->T G->A C->T T->C G->A C->G A->G G->T T->C A->C A->G T->C G->A G->A T->G

(2f) L4.1-specific SNPs Gene/IGR ID Rv0025-Rv0026 Rv0041 Rv0063 Rv0063 Rv0075 Rv0099 Rv0118c-Rv0119 Rv0175 Rv0238-Rv0239 Rv0248c Rv0286 Rv0360c Rv0368c Rv0378 Rv0405 Rv0435c Rv0512 Rv0530 Rv0573c Rv0617-Rv0618 Rv0647c Rv0650 Rv0696 Rv0756c-Rv0757 Rv0825c Rv0851c Rv0886 Rv0893c Rv0925c-Rv0926c Rv0943c Rv0950c-Rv0951 Rv0959 Rv0987 Rv0987 Rv1003 Rv1074c Rv1097c Rv1130 Rv1181 Rv1182 Rv1217c Rv1222-Rv1223 Rv1229c Rv1248c Rv1250 Rv1286 Rv1292 Rv1366 Rv1445c Rv1447c Rv1459c Rv1461 Rv1480 Rv1493 Rv1518 Rv1520 Rv1548c Rv1552 Rv1595 Rv1619 Rv1715 Rv1726 Rv1737c Rv1768-Rv1769 Rv1845c Rv1848 Rv1857 Rv1894c Rv1938 Rv1956 Rv1991c Rv1992c Rv1996

Nature Genetics: doi:10.1038/ng.2735

SNP locus NC_000962.2_4055993 NC_000962.2_741552 NC_000962.2_851475 NC_000962.2_919420 NC_000962.2_3066099 NC_000962.2_3292987 NC_000962.2_3520977 NC_000962.2_1797312 NC_000962.2_3966059 NC_000962.2_2348855 NC_000962.2_2456256 NC_000962.2_711504 NC_000962.2_2974833 NC_000962.2_2978220 NC_000962.2_300193 NC_000962.2_747169 NC_000962.2_3036437 NC_000962.2_796184 NC_000962.2_84629 NC_000962.2_948322 NC_000962.2_3037917 NC_000962.2_3040001 NC_000962.2_985287 NC_000962.2_1120115 NC_000962.2_3084375 NC_000962.2_109043 NC_000962.2_995419 NC_000962.2_3170166 NC_000962.2_3247928 NC_000962.2_1360212 NC_000962.2_3247929 NC_000962.2_1365818 NC_000962.2_1372301 NC_000962.2_1392921 NC_000962.2_1072076 NC_000962.2_3304970 NC_000962.2_1395684 NC_000962.2_3312069 NC_000962.2_3343150 NC_000962.2_143901 NC_000962.2_3393033 NC_000962.2_1052899 NC_000962.2_1439478 NC_000962.2_3419560 NC_000962.2_350983 NC_000962.2_1447655 NC_000962.2_1538720 NC_000962.2_1198510 NC_000962.2_1624276 NC_000962.2_3559192 NC_000962.2_3583640 NC_000962.2_3608514 NC_000962.2_1625724 NC_000962.2_3643703 NC_000962.2_1644855 NC_000962.2_1647363 NC_000962.2_1671260 NC_000962.2_1684430 NC_000962.2_1710215 NC_000962.2_1711676 NC_000962.2_1061813 NC_000962.2_1751493 NC_000962.2_1758825 NC_000962.2_3704686 NC_000962.2_1819488 NC_000962.2_1942850 NC_000962.2_3713652 NC_000962.2_3751199 NC_000962.2_1952057 NC_000962.2_1965133 NC_000962.2_2002579 NC_000962.2_3751433 NC_000962.2_1318920

Mutation type nonsyn nonsyn -nonsyn nonsyn syn syn nonsyn nonsyn nonsyn nonsyn -syn nonsyn nonsyn nonsyn nonsyn syn nonsyn syn nonsyn nonsyn syn nonsyn -syn nonsyn nonsyn syn syn syn -nonsyn syn nonsyn nonsyn syn ----nonsyn nonsyn syn nonsyn nonsyn nonsyn syn nonsyn -nonsyn syn syn nonsyn syn syn nonsyn syn nonsyn nonsyn -nonsyn nonsyn nonsyn nonsyn syn syn syn nonsyn nonsyn -syn syn

Ancestral baseSample base G->A T->C T->G C->T C->T G->A G->C A->C G->C C->G T->G G->A C->T C->T G->A G->A G->T A->G C->G G->A G->A T->G G->A G->A G->A G->A T->C C->A T->G A->G T->C C->A G->C G->A G->T A->G C->T G->T T->C C->T C->T C->T C->T C->T C->T T->C C->T C->T T->G G->A C->T G->A C->G G->A C->T C->T G->C C->T C->A A->C C->T C->T G->C T->C G->A A->T C->T C->T C->T C->T C->T A->G G->A

Rv1999c Rv2006 Rv2008c Rv2051c Rv2054 Rv2068c Rv2091c Rv2097c Rv2100 Rv2127 Rv2141c Rv2164c Rv2174 Rv2192c Rv2283 Rv2327-Rv2328 Rv2342 Rv2370c-Rv2371 Rv2406c Rv2440c Rv2506 Rv2548 Rv2556c Rv2576c-Rv2577 Rv2586c Rv2590 Rv2597 Rv2616 Rv2626c-Rv2627c Rv2635 Rv2646 Rv2646 Rv2650c Rv2655c Rv2724c Rv2725c Rv2727c Rv2752c Rv2776c-Rv2777c Rv2858c Rv2931 Rv2931 Rv2946c Rv2952 Rv2958c-Rv2959c Rv2985-Rv2986c Rv3032-Rv3033 Rv3059 Rv3153 Rv3191c-Rv3192 Rv3206c Rv3231c Rv3263 Rv3317 Rv3328c Rv3347c Rv3347c Rv3350c Rv3383c-Rv3384c Rv3404c Rv3469c Rv3469c Rv3479 Rv3480c Rv3487c-Rv3488 Rv3503c Rv3529c Rv3529c Rv3551 Rv3562 Rv3566c Rv3610c Rv3616c Rv3630 Rv3635

Nature Genetics: doi:10.1038/ng.2735

NC_000962.2_207304 NC_000962.2_3765430 NC_000962.2_3798665 NC_000962.2_2095529 NC_000962.2_2097368 NC_000962.2_3824390 NC_000962.2_1032674 NC_000962.2_3886203 NC_000962.2_3886878 NC_000962.2_3898775 NC_000962.2_2105029 NC_000962.2_2141192 NC_000962.2_3899045 NC_000962.2_2191657 NC_000962.2_2202582 NC_000962.2_3907451 NC_000962.2_2234475 NC_000962.2_3922214 NC_000962.2_2235930 NC_000962.2_2239303 NC_000962.2_2245075 NC_000962.2_3965965 NC_000962.2_2255190 NC_000962.2_3990402 NC_000962.2_4004036 NC_000962.2_2257835 NC_000962.2_2310038 NC_000962.2_2313206 NC_000962.2_4007564 NC_000962.2_4051823 NC_000962.2_4069743 NC_000962.2_4074738 NC_000962.2_1255487 NC_000962.2_2326024 NC_000962.2_2356012 NC_000962.2_2358916 NC_000962.2_2389986 NC_000962.2_2401509 NC_000962.2_4099481 NC_000962.2_2427471 NC_000962.2_1103786 NC_000962.2_1105102 NC_000962.2_4116773 NC_000962.2_2436247 NC_000962.2_4117614 NC_000962.2_4140319 NC_000962.2_4142063 NC_000962.2_4161581 NC_000962.2_4238963 NC_000962.2_4246508 NC_000962.2_2556092 NC_000962.2_4268928 NC_000962.2_2600689 NC_000962.2_2620500 NC_000962.2_4269375 NC_000962.2_1320675 NC_000962.2_4291593 NC_000962.2_1226129 NC_000962.2_4307886 NC_000962.2_2651706 NC_000962.2_2704416 NC_000962.2_2739131 NC_000962.2_2822255 NC_000962.2_2868925 NC_000962.2_4365784 NC_000962.2_2876703 NC_000962.2_289095 NC_000962.2_4375673 NC_000962.2_438605 NC_000962.2_446437 NC_000962.2_2900706 NC_000962.2_2913091 NC_000962.2_2919828 NC_000962.2_2926654 NC_000962.2_2945342

nonsyn nonsyn -nonsyn nonsyn nonsyn -nonsyn nonsyn nonsyn syn syn nonsyn nonsyn nonsyn -nonsyn nonsyn syn syn nonsyn syn syn syn syn syn nonsyn nonsyn nonsyn nonsyn nonsyn nonsyn syn syn syn syn syn nonsyn -nonsyn nonsyn nonsyn nonsyn syn nonsyn -nonsyn syn syn syn nonsyn syn -nonsyn syn nonsyn -nonsyn syn -nonsyn nonsyn nonsyn syn nonsyn nonsyn -nonsyn syn nonsyn -syn nonsyn nonsyn nonsyn

A->G A->G C->T G->A A->C C->A C->G T->C T->C G->A G->A G->A C->T G->T G->T C->T C->T C->T T->G G->A C->T G->A C->T G->A C->T C->G T->C G->A C->T T->C C->T G->A G->C G->A G->A C->T C->T C->T G->A A->C G->T A->C T->C C->T C->T G->A A->C C->T C->T G->A C->T G->A T->C G->T C->T G->A G->A C->T G->A G->A G->C T->C A->C G->A C->A G->C A->G G->C C->T A->G T->C C->T G->A C->G G->A

Rv3660c-Rv3661 Rv3676 Rv3677c Rv3697c-Rv3698 Rv3699 Rv3717 Rv3792 Rv3794 Rv3806c Rv3806c Rv3823c-Rv3824c Rv3834c Rv3884c Rv3892c

Nature Genetics: doi:10.1038/ng.2735

NC_000962.2_45073 NC_000962.2_2953379 NC_000962.2_2962658 NC_000962.2_455749 NC_000962.2_29641 NC_000962.2_488579 NC_000962.2_524129 NC_000962.2_605161 NC_000962.2_621509 NC_000962.2_666295 NC_000962.2_67570 NC_000962.2_67792 NC_000962.2_2970649 NC_000962.2_2970820

syn -syn nonsyn -nonsyn syn nonsyn syn syn syn syn syn syn

G->A C->A C->T G->A G->A T->C C->G A->C C->T G->C C->T C->T C->T A->G

(2g) L4.2-specific SNPs Gene/IGR ID Rv0006 Rv0009 Rv0058-Rv0059 Rv0065-Rv0066c Rv0101 Rv0106 Rv0159c Rv0173 Rv0182c Rv0206c Rv0213c Rv0234c Rv0235c Rv0236c Rv0258c Rv0284 Rv0316 Rv0335c-Rv0336 Rv0412c Rv0443 Rv0462 Rv0529 Rv0563 Rv0570 Rv0571c Rv0585c Rv0591 Rv0702 Rv0755c Rv0874c Rv0891c-Rv0892 Rv0911 Rv1010 Rv1056-Rv1057 Rv1134-Rv1135c Rv1207 Rv1217c Rv1233c-Rv1234 Rv1245c Rv1257c Rv1266c Rv1282c Rv1341 Rv1355c Rv1382 Rv1388 Rv1396c Rv1428c-Rv1429 Rv1447c Rv1454c Rv1459c Rv1459c Rv1489A-Rv1490 Rv1508c Rv1509-Rv1510 Rv1524 Rv1637c Rv1677 Rv1716 Rv1751 Rv1752-Rv1753c Rv1771 Rv1797 Rv1815-Rv1816 Rv1844c Rv1852 Rv1862 Rv1868 Rv1918c Rv1934c Rv1934c Rv1962c-Rv1963c Rv2006 Rv2024c Rv2033c Rv2038c Rv2048c

Nature Genetics: doi:10.1038/ng.2735

SNP locus NC_000962.2_7892 NC_000962.2_12555 NC_000962.2_63148 NC_000962.2_72268 NC_000962.2_113142 NC_000962.2_125560 NC_000962.2_187439 NC_000962.2_204426 NC_000962.2_213335 NC_000962.2_244550 NC_000962.2_255660 NC_000962.2_280860 NC_000962.2_281316 NC_000962.2_283614 NC_000962.2_310336 NC_000962.2_349200 NC_000962.2_384842 NC_000962.2_400154 NC_000962.2_498557 NC_000962.2_532758 NC_000962.2_552713 NC_000962.2_620029 NC_000962.2_654719 NC_000962.2_661524 NC_000962.2_663803 NC_000962.2_684019 NC_000962.2_690191 NC_000962.2_801697 NC_000962.2_848319 NC_000962.2_973290 NC_000962.2_993566 NC_000962.2_1016101 NC_000962.2_1129926 NC_000962.2_1178823 NC_000962.2_1262172 NC_000962.2_1351724 NC_000962.2_1360209 NC_000962.2_1376886 NC_000962.2_1388246 NC_000962.2_1404949 NC_000962.2_1414767 NC_000962.2_1435763 NC_000962.2_1507626 NC_000962.2_1522856 NC_000962.2_1555801 NC_000962.2_1563717 NC_000962.2_1573660 NC_000962.2_1604835 NC_000962.2_1626656 NC_000962.2_1640474 NC_000962.2_1645599 NC_000962.2_1645802 NC_000962.2_1679273 NC_000962.2_1698581 NC_000962.2_1701247 NC_000962.2_1719757 NC_000962.2_1843658 NC_000962.2_1901924 NC_000962.2_1944107 NC_000962.2_1980871 NC_000962.2_1981605 NC_000962.2_2005932 NC_000962.2_2035893 NC_000962.2_2058203 NC_000962.2_2093998 NC_000962.2_2101009 NC_000962.2_2109694 NC_000962.2_2119297 NC_000962.2_2170568 NC_000962.2_2185888 NC_000962.2_2186054 NC_000962.2_2205511 NC_000962.2_2253701 NC_000962.2_2270100 NC_000962.2_2280668 NC_000962.2_2283866 NC_000962.2_2296042

Mutation type syn syn --nonsyn nonsyn nonsyn nonsyn nonsyn syn syn nonsyn syn nonsyn syn nonsyn nonsyn -nonsyn nonsyn nonsyn syn nonsyn nonsyn nonsyn nonsyn nonsyn nonsyn syn syn -nonsyn nonsyn --syn syn -nonsyn nonsyn syn syn syn nonsyn nonsyn syn nonsyn -nonsyn nonsyn syn nonsyn -nonsyn -syn nonsyn syn nonsyn syn -nonsyn syn -syn nonsyn nonsyn nonsyn nonsyn nonsyn syn -nonsyn nonsyn nonsyn nonsyn nonsyn

Ancestral baseSample base G->A C->T G->T C->G G->A A->G G->C T->C C->G A->G G->A C->T C->T C->T C->T G->A C->T G->A A->C A->C C->G C->T G->A T->C G->A A->G C->T G->A C->T G->A C->T C->G G->C C->T C->T C->T C->T G->T T->C A->C C->A C->T C->T C->T C->T T->C G->T C->A C->T C->T C->T C->T C->A G->C C->T G->T G->A T->C G->A G->C C->G C->T G->T C->T C->T G->C T->C G->A G->C C->T G->A C->T C->G C->T G->A A->C C->G

Rv2067c Rv2087-Rv2088 Rv2090 Rv2094c Rv2101 Rv2129c Rv2158c Rv2164c Rv2178c Rv2184c Rv2198c Rv2247 Rv2255c Rv2269c-Rv2270 Rv2301-Rv2302 Rv2325c Rv2483c Rv2483c Rv2487c Rv2488c Rv2503c Rv2528c Rv2548 Rv2593c Rv2634c Rv2655c Rv2735c Rv2779c-Rv2780 Rv2799 Rv2801c Rv2888c Rv2900c Rv2934 Rv2990c Rv2992c Rv3044 Rv3046c-Rv3047c Rv3062 Rv3105c Rv3159c Rv3190c Rv3215-Rv3216 Rv3232c Rv3322c Rv3350c Rv3350c Rv3399 Rv3409c Rv3452-Rv3453 Rv3459c Rv3505 Rv3506 Rv3528c-Rv3529c Rv3574 Rv3596c Rv3598c Rv3677c Rv3681c Rv3709c Rv3709c Rv3719 Rv3723 Rv3768-Rv3769 Rv3787c Rv3799c Rv3827c Rv3833 Rv3840 Rv3860 Rv3863 Rv3910 Rv3910

Nature Genetics: doi:10.1038/ng.2735

NC_000962.2_2325142 NC_000962.2_2344389 NC_000962.2_2348446 NC_000962.2_2353070 NC_000962.2_2361311 NC_000962.2_2390415 NC_000962.2_2419540 NC_000962.2_2427088 NC_000962.2_2440926 NC_000962.2_2446408 NC_000962.2_2462871 NC_000962.2_2520761 NC_000962.2_2528992 NC_000962.2_2544639 NC_000962.2_2573756 NC_000962.2_2597696 NC_000962.2_2789341 NC_000962.2_2790578 NC_000962.2_2795454 NC_000962.2_2800874 NC_000962.2_2818550 NC_000962.2_2852526 NC_000962.2_2868976 NC_000962.2_2924461 NC_000962.2_2960757 NC_000962.2_2977344 NC_000962.2_3047972 NC_000962.2_3086788 NC_000962.2_3108217 NC_000962.2_3110211 NC_000962.2_3198115 NC_000962.2_3211406 NC_000962.2_3267163 NC_000962.2_3347560 NC_000962.2_3349521 NC_000962.2_3405197 NC_000962.2_3407904 NC_000962.2_3426025 NC_000962.2_3473214 NC_000962.2_3527479 NC_000962.2_3556459 NC_000962.2_3593421 NC_000962.2_3609004 NC_000962.2_3708849 NC_000962.2_3758561 NC_000962.2_3766696 NC_000962.2_3817132 NC_000962.2_3828326 NC_000962.2_3874322 NC_000962.2_3879560 NC_000962.2_3924275 NC_000962.2_3924991 NC_000962.2_3965470 NC_000962.2_4016840 NC_000962.2_4038318 NC_000962.2_4041787 NC_000962.2_4117692 NC_000962.2_4121368 NC_000962.2_4152890 NC_000962.2_4153435 NC_000962.2_4162790 NC_000962.2_4168644 NC_000962.2_4214507 NC_000962.2_4233760 NC_000962.2_4254632 NC_000962.2_4302102 NC_000962.2_4307179 NC_000962.2_4313577 NC_000962.2_4337898 NC_000962.2_4339743 NC_000962.2_4397129 NC_000962.2_4398019

syn -nonsyn syn nonsyn nonsyn nonsyn nonsyn nonsyn nonsyn syn nonsyn syn --syn nonsyn syn syn nonsyn nonsyn nonsyn syn syn nonsyn nonsyn nonsyn -syn nonsyn syn nonsyn nonsyn nonsyn nonsyn nonsyn -nonsyn nonsyn nonsyn nonsyn -nonsyn syn nonsyn nonsyn nonsyn syn -nonsyn nonsyn syn -syn nonsyn nonsyn nonsyn nonsyn syn nonsyn nonsyn nonsyn -syn syn syn nonsyn nonsyn syn nonsyn nonsyn nonsyn

G->A T->A G->C G->A C->T G->A T->C C->T T->G G->A A->G G->A G->A C->T A->C C->T A->C G->A G->A G->A G->A C->G C->G G->A C->T A->C T->G C->T G->T G->A G->A G->A C->T C->T C->G G->T C->G G->A G->C A->C C->A C->T T->G G->A C->T G->A C->T G->C C->T T->C T->C C->T G->A G->A G->A C->T C->G G->A G->A C->T A->G G->A C->A G->A G->A G->A A->G G->A G->A G->A G->T G->A

(2h) 10 genes containing both L2- and L4-specific SNPs Gene ID Rv0104 Rv0663 Rv0987 Rv1023 Rv1497 Rv1640c Rv3411c Rv3729 Rv3797 Rv3919c

Name hypothetical protein atsD Rv0987 eno lipL lysS guaB2 transferase fadE35 gidB

Nature Genetics: doi:10.1038/ng.2735

SNPs L2 nonsyn nonsyn syn nonsyn nonsyn syn nonsyn nonsyn nonsyn nonsyn

Genomic position NC_000962.2_123454 NC_000962.2_757139 NC_000962.2_1102646 NC_000962.2_1145848 NC_000962.2_1688064 NC_000962.2_1849051 NC_000962.2_3830349 NC_000962.2_4179832 NC_000962.2_4252066 NC_000962.2_4407927

L4 nonsyn nonsyn nonsyn nonsyn syn syn syn nonsyn syn syn

Genomic position NC_000962.2_123520 NC_000962.2_757182 NC_000962.2_1104690 NC_000962.2_1144585 NC_000962.2_1688300 NC_000962.2_1849609 NC_000962.2_3830695 NC_000962.2_4179089 NC_000962.2_4251297 NC_000962.2_4407588

Supplementary Table 3 Genes whose density of non-synonymous SNPs in drug-resistant isolates does not fit the Poisson distribution (p