Lan et al. Manfredonia et al.Huston et al.D

SC

IS.2

Lan et al. vs.Manfredonia et al.

Lan et al. vs.Huston et al.

Huston et al. vs.Manfredonia et al.

sim

ilarit

y (m

FMI)

S.3

Comparison to purely computational models

Comparison of TRS structures (RNAz)

RNAz ContraFold

Agr

eem

ent (

%)

0

20

40

60

80

100

Includes edgesExcludes edges

Comparison with high confidenceContraFold

020406080100

Genome-wide comparison with RNAz

% AgreementRNAz prediction not available

Comparison with high P-valueRNAz

3a3' UTR

EM6S 7a7b8NORF1b

NSP13NSP12NSP3 NSP5

ORF1a

AAAAAA...L

0 2000015000100005000 2990325000

S.4A B

C

FED

In-cell model consistency

0

20

40

60

80

100

NormalizationTop 5% vs. Top 10%

Max Distance120nt vs. 350ntA

gree

men

t (%

)

TRS-L TRS-ORF3a TRS-E TRS-M0

20

40

60

80

100

Prediction 1Prediction 2

Region of comparison

Agr

eem

ent (

%)

Agr

eem

ent (

%)

0

20

40

60

80

100

Region of comparison

0

20

40

60

80

100

Agr

eem

ent (

%)

Region of comparison1 32 1 32 54

3a3' UTR

EM6S 7a7b8N

HelicaseRNA-dependentRNA polymerase

ORF1b

NSP13NSP12NSP3 NSP5

ORF1a

3CLprotease

Papain-likeprotease

AAAAAA...L

0 2000015000100005000 2990325000

Continuous stretch of open bases (>=14)Continuous stretch of paired bases (>=10)

Structured regions and accessible regions across the genome S.5A

G

U

U

CUC

U A AAC

G

A

A

C U U

A C U AAACGAACA A U

GUUUGUUU U U C

21560

C A C

A

U

A

A

A

C

G

A

ACU

UA U

GGA

U

U

U

G

U

U

U

A

U

G A G

25400

U G

A

U

G

A

G

U

A

CGA

AC U

UAU

G

U

A

C

U

C

A

U

U C G

26240

C U

UCU

G

G

U

C

U

A

A

A

C

G

A

A

C

U

A

AAU

AU U

AUA

U

U

A

G

U

U

UUUC

UG

U

U

U

G

G

AA

C

UUU

A

A U U

26480

A U C A A

G

G

A

C

C

U

GC

CUA

AA G A A

AU C A C U G U U G C U A C A U

C AC G A A C G C U U U C

UU A U

UAC

AAAU

UGGGAGCUUCG

CAGCGUGUAGCAGGUGA

CUC

A

G

G

U

U

U

U G C U

27040

27080

C A C G C

C

U

A

AAC

G

A

A

C

AU

G

AA

A UU

U

CU

U

G

U

U

UUC

U

U

A

G

G A

27879

G U

A

U

C

AUG

A

C

G

U

UC

GU

GU

UGUU

UU

AG

AUU

U C AU

CU

AA

A CGA

AC A

AA

C UAA

A

A

U

G

U

C

U

G

A

U

A A U

28240

TRS-B: ORF6

TRS-B: ORF3a

TRS-B: E

TRS-B: S

TRS-B: N

TRS-B: ORF8TRS-B: M

TRS-L

21551 21575

61 77

2540925378

2625726229

26461 26516

2710427003

27019

2828528223

28268

27917

B

TRS-BTRS-BTRS-L

Structures at the TRS-L and TRS-B

R = -0.330S.6

index start end length1 128 149 222 505 528 243 726 756 314 823 837 155 926 939 146 1071 1089 197 1304 1321 188 1330 1359 309 1377 1399 2310 1421 1438 1811 1573 1598 2612 1610 1636 2713 1919 1939 2114 2385 2398 1415 2435 2458 2416 2550 2568 1917 2667 2682 1618 2801 2819 1919 2901 2918 1820 3116 3129 1421 3258 3273 1622 3349 3371 2323 3647 3662 1624 3668 3683 1625 3733 3818 8626 3863 3883 2127 4101 4122 2228 4264 4307 4429 4580 4608 2930 4619 4645 2731 4702 4715 1432 4826 4846 2133 4877 4897 2134 5020 5036 1735 5297 5311 1536 5382 5399 1837 5522 5535 1438 5647 5662 1639 5688 5715 2840 5773 5795 2341 5933 5949 1742 5955 5969 15

S. Table 1`

43 6058 6090 3344 6103 6145 4345 6307 6325 1946 6346 6362 1747 6390 6403 1448 6505 6532 2849 6538 6554 1750 6567 6589 2351 6622 6640 1952 6697 6736 4053 6771 6785 1554 6925 6973 4955 7010 7025 1656 7073 7092 2057 7146 7193 4858 7214 7229 1659 7260 7280 2160 7391 7404 1461 7511 7536 2662 7547 7567 2163 7590 7603 1464 7690 7716 2765 7725 7743 1966 8075 8095 2167 8128 8143 1668 8290 8327 3869 8336 8349 1470 8379 8392 1471 8459 8472 1472 8523 8537 1573 8556 8576 2174 8621 8647 2775 8669 8690 2276 8766 8779 1477 8800 8822 2378 8906 8942 3779 8957 8992 3680 9096 9117 2281 9131 9158 2882 9187 9224 3883 9281 9294 1484 9527 9546 2085 9555 9569 15

86 9624 9680 5787 9913 9931 1988 10006 10030 2589 10067 10096 3090 10157 10174 1891 10440 10456 1792 10500 10536 3793 10551 10614 6494 10754 10781 2895 10912 10927 1696 11040 11082 4397 11118 11131 1498 11165 11230 6699 11560 11577 18100 11728 11742 15101 11755 11772 18102 11814 11830 17103 11910 11928 19104 11957 11970 14105 12014 12027 14106 12055 12129 75107 12173 12220 48108 12281 12309 29109 12314 12330 17110 12484 12498 15111 12619 12635 17112 12665 12696 32113 12741 12766 26114 12775 12791 17115 12881 12928 48116 12967 12988 22117 13052 13065 14118 13327 13347 21119 13723 13736 14120 13912 13957 46121 13990 14005 16122 14056 14070 15123 14170 14185 16124 14405 14418 14125 14642 14690 49126 14819 14841 23127 14861 14889 29128 14900 14915 16

129 14926 14942 17130 15139 15156 18131 15196 15213 18132 15236 15272 37133 15459 15472 14134 15498 15514 17135 15560 15573 14136 15695 15720 26137 15801 15818 18138 15902 15918 17139 16199 16213 15140 16297 16312 16141 16419 16434 16142 16592 16607 16143 16712 16737 26144 16761 16775 15145 16787 16805 19146 16938 16954 17147 16990 17026 37148 17273 17294 22149 17491 17504 14150 17515 17538 24151 17561 17593 33152 17651 17667 17153 17739 17796 58154 17822 17853 32155 17875 17898 24156 18008 18052 45157 18102 18115 14158 18151 18180 30159 18219 18260 42160 18321 18360 40161 18371 18384 14162 18415 18436 22163 18471 18486 16164 18531 18546 16165 18789 18802 14166 18918 18937 20167 18965 18991 27168 19003 19018 16169 19046 19065 20170 19249 19271 23171 19569 19593 25

172 19601 19615 15173 19623 19664 42174 19861 19876 16175 19883 19899 17176 20003 20023 21177 20092 20161 70178 20198 20213 16179 20230 20253 24180 20403 20443 41181 20652 20667 16182 20693 20708 16183 20794 20835 42184 20947 21008 62185 21123 21147 25186 21235 21248 14187 21304 21317 14188 21478 21501 24189 21573 21752 180190 21855 21868 14191 21949 21974 26192 22115 22137 23193 22153 22170 18194 22390 22405 16195 22442 22459 18196 22547 22573 27197 22611 22624 14198 22736 22750 15199 23010 23047 38200 23079 23135 57201 23155 23168 14202 23306 23324 19203 23395 23409 15204 23414 23460 47205 23590 23607 18206 23626 23641 16207 23655 23695 41208 23705 23725 21209 23910 23934 25210 23960 23973 14211 23984 23999 16212 24095 24108 14213 24165 24184 20214 24235 24250 16

215 24270 24304 35216 24337 24353 17217 24361 24384 24218 24490 24503 14219 24633 24647 15220 24888 24911 24221 24985 25008 24222 25015 25032 18223 25133 25148 16224 25408 25439 32225 25546 25563 18226 25579 25592 14227 25703 25719 17228 25798 25816 19229 25823 25836 14230 26198 26224 27231 26508 26531 24232 26722 26742 21233 26862 26886 25234 26902 26919 18235 27128 27148 21236 27289 27302 14237 27363 27408 46238 27546 27560 15239 27669 27692 24240 27751 27777 27241 27800 27828 29242 27869 27882 14243 27997 28012 16244 28142 28163 22245 28333 28346 14246 28431 28455 25247 28688 28711 24248 28721 28754 34249 28767 28781 15250 29004 29025 22251 29074 29089 16252 29110 29133 24253 29155 29178 24254 29307 29320 14255 29488 29502 15256 29614 29628 15257 29658 29673 16

258 29786 29800 15259 29824 29844 21