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Human viruses have codon usage biases that match highly expressed proteins in the tissues they infect

Justin B. Miller

Department of Biology, Brigham Young University, Provo, Utah 84602, USA

E-mail : aa

Ariel A. Hippen

Department of Biology, Brigham Young University, Provo, Utah 84602, USA

Sage M. Wright

Department of Biology, Brigham Young University, Provo, Utah 84602, USA

Caroline Morris

Department of Biology, Brigham Young University, Provo, Utah 84602, USA

Perry G. Ridge

Department of Biology, Brigham Young University, Provo, Utah 84602, USA

DOI: 10.15761/BGG.1000134

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Abstract

It is well-documented that codon usage biases affect gene translational efficiency; however, it is less known if viruses share their host’s codon usage motifs. We determined that human-infecting viruses share similar codon usage biases as proteins that are expressed in tissues the viruses infect. By performing 7,052,621 pairwise comparisons of genes from humans versus genes from 113 viruses that infect humans, we determined which codon usage motifs were most highly correlated. We found that 16 viruses averaged a significant correlation in codon usage with over 500 human genes per viral gene, 58 viruses were highly correlated with an average of at least 100 human genes per viral gene, and 37 viruses were significantly correlated with an average of at least one human gene per viral gene at an alpha level of 7.09 × 10-9 (0.05 alpha / 7,052,621 comparisons). Only two viruses were not highly correlated with an average of one human gene per viral gene. While relatively few of the interactions were previously documented, the high statistical correlations suggest that researchers may be able to determine which tissues a virus is most likely to infect by analyzing codon usage biases.

Key words

codon usage bias, host, human, virus, virus-host interactions

Introduction

Amino acids are encoded by DNA triplets known as codons; however, since there are only 20 canonical amino acids and 64 possible codons, multiple codons encode a single amino acid [1]. The majority of amino acids are encoded by 2-6 different codons. Despite multiple codons encoding a single amino acid, codon usage is not random in most species [2-5]. Various species, including many plant species, E. coli and Drosophila, also maintain DNA triplet preferences, or codon usage biases, over time in both intronic and exonic regions [6-8].

It is generally accepted that non-random mutations occur more frequently at the third position in the codon, and codon bias persists through selection [9,10]. Numerous biological factors create evolutionary pressure to use certain codons. First, an incomplete set of transfer RNAs (tRNAs) or unequal expression of tRNA anticodons within a tissue or species creates pressure for codons with complementary tRNAs available. Second, translational speed may either increase or decrease depending on the codon used, creating pressure to select codons for which translational efficiency matches the needs of the tissue/cell (i.e. suboptimal codons might be preferential to some species for increased translational efficiency, while in other instances suboptimal codons might decrease translational efficiency) [10,11]. Finally, codon usage bias primarily affects the translation of a gene and is a main determinant of gene expression [12].

Recently, significant correlations for codon usage preferences between RNA viruses (e.g. SBV and KV) and their host, the honeybee, were reported [13]. They proposed that such similarities resulted from co-evolution, which typically occurs in a leapfrog fashion (i.e. as the host evolves to combat the parasite, the parasite evolves to adapt to the new conditions).

We aimed to determine whether the same relationship exists between human and viral genes expressed in tissues targeted by the virus. We analyzed 19,482 human proteins, and compared their codon usage biases against 113 viruses that infect human hosts. We found significant correlations for many viral and human proteins, and where tissue information was available, the top correlated human protein was frequently highly expressed in the tissue type targeted by the virus.

Materials and methods

Data collection and cleaning

We used gene annotations from the General Feature Format (GFF) and GFF3 files from the National Center for Biotechnology Information (NCBI) to extract the reference viral and human sequences [14-16]. Since the reference genome is intended to most accurately represent an average individual in a species, we downloaded all reference sequence data, including the corresponding gene annotations, from NCBI. Similar to the methods used by [17], when multiple isoforms were annotated, the longest isoform was always chosen as the representative isoform for that gene, and we removed all genes with any annotated translational exceptions (e.g., translational, unclassified transcription discrepancy, suspected errors, etc.). These filters had only a minor effect on our data because they eliminated less than 5% of the total sequences. All 19,482 sequence accession numbers can be found in the NCBI database by downloading the complete genome annotations for Homo sapiens; the accession numbers for each virus and their highest correlating genes are located in Table S1.

Virus Accession Number

Virus Protein Name

Pearson’s R Correlation Value

P-value

Highest Correlating Protein Accession Number

Protein Common Name

NC_000883

NS1

0.764596741

1.94E-13

NP_002763.2

TMPRSS15

NC_000898

U90

0.931483267

6.40E-29

NP_112561.2

TEX15

NC_001348

ICP4

0.798569441

2.68E-15

NP_787081.2

FAM181B

NC_001352

E1

0.725454272

1.20E-11

NP_037485.2

TMOD4

NC_001354

Pos: 951-2795

0.804857764

1.11E-15

NP_001273387.1

USP7

NC_001355

E1

0.798328333

2.77E-15

NP_940841.1

KBTBD3

NC_001356

E1

0.903438527

1.74E-24

NP_001138663.1

FAM200B

NC_001357

E1

0.805278655

1.05E-15

NP_940841.1

KBTBD3

NC_001405

L1

0.865302979

2.94E-20

NP_001073990.2

RASSF10

NC_001430

Pos: 727-7311

0.837550489

6.34E-18

NP_000123.1

F8

NC_001436

Pr55

0.752880597

7.22E-13

NP_001092872.1

CCNK

NC_001454

L3

0.792140958

6.41E-15

NP_612426.1

KTI12

NC_001457

Pos: 5345-6895

0.859158203

1.06E-19

NP_061854.1

DNAJC10

NC_001458

Pos: 822-2678

0.847795937

9.88E-19

NP_001273176.1

RALGPS2

NC_001460

E1B

0.806525776

8.74E-16

NP_001116801.1

ZBTB1

NC_001472

Pos: 742-7290

0.800822126

1.96E-15

NP_005224.2

EPHA3

NC_001488

Pos: 807-2108

0.748225962

1.19E-12

NP_001073882.3

NOBOX

NC_001490

Pos: 629-7168

0.891321462

5.65E-23

NP_002175.2

IL6ST

NC_001526

L1

0.807134439

8.00E-16

NP_942089.1

MAP4K5

NC_001531

Pos: 961-2781

0.852165343

4.29E-19

NP_079114.3

THNSL1

NC_001576

Pos: 791-2836

0.785723092

1.48E-14

NP_899059.1

RAB27A

NC_001583

Pos: 878-2794

0.787008282

1.26E-14

NP_940841.1

KBTBD3

NC_001586

Pos: 850-2778

0.799660538

2.31E-15

NP_940841.1

KBTBD3

NC_001587

Pos: 5430-7016

0.749586507

1.03E-12

NP_057654.2

ERGIC2

NC_001591

E1

0.845045382

1.65E-18

NP_078787.2

HAUS3

NC_001593

L1

0.744112558

1.84E-12

NP_001167579.1

ZBED6

NC_001595

Pos: 5798-7315

0.770647823

9.56E-14

NP_001273644.1

AGTPBP1

NC_001596

E1

0.844374112

1.86E-18

NP_940841.1

KBTBD3

NC_001612

Pos: 751-7332

0.842341207

2.70E-18

NP_001116105.1

CPS1

NC_001617

Pos: 619-7113

0.86771873

1.74E-20

NP_002175.2

IL6ST

NC_001664

IE1

0.893813269

2.86E-23

NP_653091.3

CASC5

NC_001676

Pos:828-2729

0.787967453

1.11E-14

NP_940841.1

KBTBD3

NC_001690

E1

0.855417316

2.26E-19

NP_001092688.1

RAD51AP2

NC_001691

E1

0.876751214

2.23E-21

NP_940841.1

KBTBD3

NC_001693

E1

0.894934035

2.10E-23

NP_940841.1

KBTBD3

NC_001716

IE1

0.927833476

3.03E-28

NP_001073973.2

RBM44

NC_001722

Pos: 1103-2668

0.737893765

3.50E-12

NP_002408.3

MKI67

NC_001781

L

0.876166171

2.56E-21

NP_065982.1

KIAA1586

NC_001796

Pos: 8646-15347

0.903986563

1.47E-24

NP_065982.1

KIAA1586

NC_001798

UL39

0.904920752

1.10E-24

NP_036567.2

SHC2

NC_001802

Pr55

0.78047161

2.89E-14

NP_001093866.1

C2orf73

NC_001806

UL30

0.90801467

4.15E-25

NP_055778.2

SBNO2

NC_001897

Pos: 703-7242

0.890389641

7.26E-23

NP_001017975.3

HFM1

NC_001943

Pos: 86-4380

0.830734096

2.04E-17

NP_114161.3

SPATA16

NC_002645

Pos: 293-12550

0.774229507

6.22E-14

NP_000099.2

DLD

NC_003266

L4

0.898683268

7.19E-24

NP_009115.2

NISCH

NC_003443

L

0.839684044

4.35E-18

NP_004645.2

USP9Y

NC_003461

L

0.866879002

2.09E-20

NP_065982.1

KIAA1586

NC_004104

E1

0.68207836

5.44E-10

NP_899059.1

RAB27A

NC_004148

L

0.867913209

1.67E-20

NP_065982.1

KIAA1586

NC_004295

VP1

0.773099678

7.13E-14

NP_114414.2

EIF2A

NC_004500

E1

0.880929983

8.18E-22

NP_004645.2

USP9Y

NC_005134

E1

0.851299523

5.07E-19

NP_001138663.1

FAM200B

NC_005147

Pos: 21507-22343

0.820880135

1.01E-16

NP_064506.3

UGGT2

NC_005831

Pos: 287-20475

0.750091303

9.77E-13

NP_037471.2

ALG6

NC_006273

IE1

0.87654333

2.35E-21

NP_055478.2

KDM4A

NC_006577

Pos: 22942-27012

0.756094354

5.07E-13

NP_852607.3

LRRC70

NC_007018

ORF2

0.774104535

6.31E-14

NP_005112.2

MED13

NC_007026

Pos: 828-2486

0.704735964

8.08E-11

NP_001024.1

RRM1

NC_007027

Pos: 94-1698

0.746908872

1.37E-12

NP_002717.3

PREP

NC_007455

VP1

0.768556356

1.22E-13

NP_803875.2

PKHD1L1

NC_007605

BALF5

0.934931283

1.36E-29

NP_620124.1

RHOT2

NC_008188

E1

0.85042555

6.00E-19

NP_940841.1

KBTBD3

NC_008189

E1

0.781785258

2.45E-14

NP_000305.3

PTEN

NC_009333

ORF75

0.91780911

1.47E-26

NP_002891.1

RBP3

NC_009334

BALF5

0.935906758

8.64E-30

NP_620124.1

RHOT2

NC_009996

Pos: 616-7050

0.834124398

1.15E-17

NP_004939.1

DSC1

NC_010329

E1

0.908048024

4.10E-25

NP_940841.1

KBTBD3

NC_010810

Pos: 956-7837

0.825974666

4.46E-17

NP_004939.1

DSC1

NC_010956

L4

0.884411516

3.44E-22

NP_009115.2

NISCH

NC_011202

L1

0.825443151

4.86E-17

NP_787072.2

EXOC8

NC_011203

L4

0.84556954

1.50E-18

NP_009115.2

NISCH

NC_011800

Pos: 1892-2533

0.744847797

1.71E-12

NP_056526.3

GLTSCR1

NC_012042

VP1

0.776501461

4.72E-14

NP_005424.1

YES1

NC_012213

E1

0.843291298

2.27E-18

NP_001138663.1

FAM200B

NC_012485

E1

0.883809966

4.00E-22

NP_940841.1

KBTBD3

NC_012486

E1

0.902494945

2.32E-24

NP_001138663.1

FAM200B

NC_012564

VP1

0.783191043

2.05E-14

NP_002899.1

REL

NC_012729

NS2

0.805392124

1.03E-15

NP_001073932.1

DYNC2H1

NC_012798

Pos: 139-6480

0.82589364

4.52E-17

NP_057190.2

SCFD1

NC_012801

Pos: 750-7124

0.824196863

5.94E-17

NP_001191195.1

GABRA4

NC_012802

Pos: 748-7128

0.834958942

9.94E-18

NP_001161829.1

PLA2G7

NC_012950

Pos: 21445-22281

0.818600204

1.44E-16

NP_064506.3

UGGT2

NC_012959

Pos: 22707-24845

0.842896843

2.44E-18

NP_009115.2

NISCH

NC_012986

Pos: 719-7831

0.755617438

5.35E-13

NP_004215.2

GPR50

NC_013035

E1

0.900330229

4.44E-24

NP_940841.1

KBTBD3

NC_014185

E1

0.928268261

2.53E-28

NP_940841.1

KBTBD3

NC_014952

E1

0.879231256

1.24E-21

NP_940841.1

KBTBD3

NC_014953

E1

0.904630266

1.21E-24

NP_940841.1

KBTBD3

NC_014954

E1

0.895597619

1.74E-23

NP_940841.1

KBTBD3

NC_014955

E1

0.905343727

9.67E-25

NP_940841.1

KBTBD3

NC_014956

E1

0.903382032

1.77E-24

NP_940841.1

KBTBD3

NC_015150

Pos: c5026-4790, c4437-2632

0.897789054

9.32E-24

NP_060862.3

C4orf21

NC_015630

Pos: 381-1076

0.54440122

3.32E-06

NP_689786.2

RASEF

NC_016157

Pos: 817-2640

0.919910732

6.78E-27

NP_940841.1

KBTBD3

NC_017993

Pos: 805-2610

0.859261423

1.04E-19

NP_940841.1

KBTBD3

NC_017994

E1

0.868341489

1.52E-20

NP_940841.1

KBTBD3

NC_017995

Pos: 714-2546

0.883104334

4.77E-22

NP_001138663.1

FAM200B

NC_017996

Pos: 717-2534

0.881915256

6.42E-22

NP_940841.1

KBTBD3

NC_017997

Pos; 703-2502

0.825068761

5.16E-17

NP_112561.2

TEX15

NC_019023

E1

0.864842857

3.24E-20

NP_940841.1

KBTBD3

NC_019843

orf1ab

0.777846368

4.00E-14

NP_079265.2

PGAP1

NC_020890

large T antigen

0.894050364

2.68E-23

NP_001017975.3

HFM1

NC_021483

E1

0.858044662

1.34E-19

NP_001092688.1

RAD51AP2

NC_021568

Pos: 279-13433, 13433-21514

0.731131014

6.89E-12

NP_066012.1

METTL14

NC_021928

Pos: c5033-4821, c4421-2508

0.8986358

7.29E-24

NP_065982.1

KIAA1586

NC_022095

L1

0.818922205

1.37E-16

NP_001273644.1

AGTPBP1

NC_022518

Pos: 6451-8550

0.801092218

1.89E-15

NP_001121143.1

LIFR

NC_022892

E1

0.856537918

1.81E-19

NP_065982.1

KIAA1586

NC_023874

Pos: 161-997

0.720321018

1.95E-11

NP_060146.2

GIN1

NC_023891

E1

0.88293482

4.98E-22

NP_940841.1

KBTBD3

NC_023984

Pos: 1362-7727

0.837884709

5.98E-18

NP_036434.1

LPHN2

NC_024694

Pos: 1 - 1113

0.676628221

8.40E-10

NP_054860.1

CNTNAP2

Table S1. A comprehensive list of the 113 viruses with their highest correlating protein, accompanied by the Pearson’s r correlation and the respective p-value. Bolded rows were found to be insignificant. Unnamed viral proteins are designated by their position numbers in the following format— Pos: start position-stop position.

Codon usage correlation values

To determine if there was a correlation between human and viral codon usage biases, we performed a Pearson’s r correlation test with discrete codon usage counts by comparing total codon usage counts in human and viral coding sequences (CDS). We used Pearson’s r because it uses a product-moment correlation coefficient that is used to determine the correlation between two variables with different units or different magnitudes [18]. Since gene lengths can vary greatly between genes, and genes do not contain all codons, the assumptions for most statistical tools would not be adequately met using the raw data. Furthermore, the high number of zero codon usage counts in some genes meant that a percentage comparison of codon usages using a traditional t-test was unfeasible, even with a transformation. We chose an implementation of Pearson’s r from the package SciPy in Python version 2.7 because Pearson’s r is robust to variations in sequence sizes as well as zero values. Using Pearson’s r, we graphed a linear regression and calculated the R2 coefficients of determination and p-values by plotting the discrete codon counts from each gene within each virus against each human gene. Next, we ranked the correlation of codon usage between viral and human genes from highest to lowest. We corrected for multiple tests using a Bonferroni correction; the significance threshold used was 7.09 × 10-9 (0.05/7,052,621 total comparisons). We obtained the highest correlations when the viral and human protein codon usage motifs were most similar.

Human tissue comparisons

We determined which proteins were expressed in each human tissue by querying each highly correlated human protein against the Human Protein Atlas [19,20]. We checked the top correlating human proteins for each virus (113 total proteins) to determine in which tissues they were most highly expressed. While many proteins were expressed in low levels throughout the body, we were most concerned with high expression areas, and only the high expression areas were compared in this study.

Results

Of the 113 viruses analyzed, we found that on average, each viral gene in 16 viruses was significantly correlated with more than 500 human proteins (Table S2). Of the remaining 97 viruses, 58 were significantly correlated with at least 100 human proteins per viral gene, and 37 were significantly correlated with at least one human gene per viral gene on average at a p-value <7.09 × 10-9. Only two viruses, Human papillomavirus type 90 (NC_004104) and Human gyrovirus type 1 (NC_015630) were not significantly correlated with the codon usage of at least one human gene per viral gene, on average.

 Virus Accession Number

Virus Name

Virus Protein Name

Protein Accession Number

Protein Name

Correlation %

P-value

NC_009334

Human herpesvirus 4

BALF5

NP_620124.1

RHOT2

93.6

8.64E-30

NC_007605

Human herpesvirus 4 (wild type)

BALF5

NP_620124.1

RHOT2

93.5

1.36E-29

NC_000898

Human herpesvirus 6B

U90

NP_112561.2

TEX15

93.1

6.40E-29

NC_014185

Human papillomavirus 121

E1

NP_940841.1

KBTBD3

92.8

2.53E-28

NC_001716

Human herpesvirus 7

IE1

NP_001073973.2

RBM44

92.8

3.03E-28

NC_016157

Human papillomavirus 126

Pos: 817-2640

NP_940841.1

KBTBD3

92.0

6.78E-27

NC_009333

Human herpesvirus 8

ORF75

NP_002891.1

RBP3

91.8

1.47E-26

NC_010329

Human papillomavirus 88

E1

NP_940841.1

KBTBD3

90.8

4.10E-25

NC_001806

Human herpesvirus 1

UL30

NP_055778.2

SBNO2

90.8

4.15E-25

NC_014955

Human papillomavirus 132

E1

NP_940841.1

KBTBD3

90.5

9.67E-25

Table 1. Here we report the top-ten codon usage bias correlations (Pearson’s r values) between a virus and a human protein with their respective p-values (all under 10-25), demonstrating that viruses and proteins in their host (humans) share high codon biases. Unnamed viral proteins are designated by their position numbers in the following format— Pos: start position-stop position.

Virus Accession Number

Number of Genes in Virus

Number of Highly Correlating Genes in Humans

Number of Highly Correlating Human Proteins per Viral Protein

NC_015630

3

0

0

NC_004104

7

4

0.57

NC_012986

1

1

1

NC_001436

6

7

1.17

NC_024694

4

13

3.25

NC_001488

6

27

4.5

NC_011800

6

28

4.67

NC_007026

2

15

7.5

NC_005831

6

47

7.83

NC_001722

9

91

10.11

NC_001352

7

91

13

NC_023874

2

32

16

NC_001595

6

104

17.33

NC_001357

8

152

19

NC_001454

34

655

19.26

NC_006577

8

165

20.63

NC_021568

2

50

25

NC_001576

7

221

31.57

NC_001587

6

219

36.5

NC_001348

73

2843

38.95

NC_001593

7

331

47.29

NC_000883

6

317

52.83

NC_019843

11

582

52.91

NC_001355

9

478

53.11

NC_001460

36

1950

54.17

NC_001583

6

328

54.67

NC_001676

7

391

55.86

NC_001526

8

456

57

NC_008189

6

353

58.83

NC_001802

10

629

62.9

NC_002645

8

613

76.63

NC_001586

6

517

86.17

NC_015150

5

435

87

NC_007027

1

93

93

NC_011202

38

3637

95.71

NC_007455

4

392

98

NC_001781

11

1079

98.09

NC_017997

7

691

98.71

NC_001354

11

1096

99.64

NC_012950

12

1268

105.67

NC_005147

9

970

107.78

NC_012042

4

438

109.5

NC_004500

7

787

112.43

NC_013035

7

837

119.57

NC_008188

6

720

120

NC_004295

6

747

124.5

NC_022095

6

750

125

NC_012564

4

555

138.75

NC_004148

9

1314

146

NC_001405

38

5628

148.11

NC_000898

104

15694

150.9

NC_012485

7

1083

154.71

NC_006273

169

26217

155.13

NC_001664

88

13960

158.64

NC_012213

5

801

160.2

NC_003461

10

1706

170.6

NC_003266

38

7275

191.45

NC_001798

77

14790

192.08

NC_022892

6

1160

193.33

NC_010956

38

7500

197.37

NC_017993

7

1382

197.43

NC_001690

7

1464

209.14

NC_021483

7

1467

209.57

NC_001596

7

1470

210

NC_014953

7

1498

214

NC_012959

36

7762

215.61

NC_001591

6

1327

221.17

NC_014952

7

1601

228.71

NC_011203

39

9069

232.54

NC_001531

8

1903

237.88

NC_012729

5

1212

242.4

NC_003443

7

1720

245.71

NC_020890

5

1235

247

NC_010329

7

1744

249.14

NC_012486

7

1768

252.57

NC_001691

7

1771

253

NC_023891

7

1843

263.29

NC_001356

7

1844

263.43

NC_021928

7

1879

268.43

NC_005134

7

1893

270.43

NC_014956

7

1894

270.57

NC_001796

8

2167

270.88

NC_016157

7

1969

281.29

NC_001457

7

1980

282.86

NC_014954

7

1981

283

NC_014955

7

2051

293

NC_017994

7

2061

294.43

NC_014185

7

2076

296.57

NC_009333

86

26437

307.41

NC_001458

7

2182

311.71

NC_001693

7

2316

330.86

NC_001806

77

26054

338.36

NC_019023

6

2070

345

NC_017996

7

2500

357.14

NC_007018

2

769

384.5

NC_001716

86

33651

391.29

NC_017995

7

2784

397.71

NC_001943

2

1088

544

NC_022518

1

592

592

NC_001472

1

753

753

NC_007605

95

85227

897.13

NC_009334

80

82905

1036.31

NC_001612

1

1133

1133

NC_009996

1

1157

1157

NC_001617

1

1193

1193

NC_010810

1

1223

1223

NC_012802

1

1408

1408

NC_001490

1

1423

1423

NC_012798

1

1437

1437

NC_023984

1

1453

1453

NC_012801

1

1482

1482

NC_001430

1

1720

1720

NC_001897

1

1918

1918

Average

15.74

4161.41

303.36

Total

1779

470239

34279.52

Table S2. A comprehensive list of the 113 viruses with the number of genes in the virus, the number of highly correlating human genes, and the number of highly correlating human proteins per viral protein. Viruses are ordered in accending order based on the number of highly correlating human genes per viral gene.

The viruses listed in Table 1 have the highest Pearson r correlation values of all comparisons made, with their codon usages strongly correlating to their host codon usages (p-value<10-25). Four of the top 10 correlations in Table 1 belong to the group of 16 viruses that strongly correlate to over 500 human proteins per viral gene on average, and the rest of them belong to the group of 58 with significant correlations with at least 100 human genes significantly correlating to each viral gene, on average. Overall, the average correlation of the 113 viruses with the top hit from each virus was 83.1%, meaning about 83% of the codon usage bias in the virus also existed in the human host protein. Each viral protein strongly correlated to an average of 303 human genes.

To demonstrate the strong correlations in codon usage bias, we plotted codon usage for several representative viral proteins compared to the human protein with the strongest correlation (Figure 1).

<p><strong>Figure 1. Codon counts. </strong>Four of the highest correlating virus-protein pairs found in Table 1 are displayed. We plotted codon counts for the viral protein (X-axis) against the human protein&rsquo;s codon counts (Y-axis). Each graph has 64 points, each representing a codon. Points near the top right are used at a higher rate than points near the bottom left. The line represents the result of a best-fit linear model, indicating that there is a strong correlation--as protein codon usage increases, so does the codon usage count of the respective virus. Residual plots of the linear regression were also analyzed and appear to fit the assumptions of the model. (A) displays RHOT2 vs HHV-4 (correlation of 93.6%), (B) shows TEX15 vs HHV-6B (correlation of 93.1%), (C) shows KBTBD3 vs HPV-121 (correlation of 92.8%), and (D) displays RBM44 vs HHV-7 (correlation of 92.8%). See Table 1 for more information on these pairs.</p>

Finally, we analyzed the correlations of codon usage biases for human proteins expressed in tissues infected by a specific virus. With the exception of sexually transmitted diseases (STDs), tissue information was incomplete for many viruses, and further exacerbating this problem is that many human proteins expressed in a specific tissue were also expressed in many other tissues. We report all known tissue information in Table S3, and in Table 2 list representative viruses with their highest correlating protein and affected tissues.

Discussion

The high number of proteins significantly correlated with each virus suggests that humans and human-host viruses share similar codon usage biases. For example, each of the 80 Human herpesvirus 4 (HHV-4, NC_009334) genes significantly correlated with 1 to 10,012 human genes with a median of 8,290 highly correlated human genes and an average of 1,036 highly correlated human genes. HHV-4 was previously identified as having a similar codon usage bias to its host cells [21,22], which may provide insights into the efficient proliferation of HHV-4, since it can more readily utilize host tRNA machinery in the tissue types it infects. Indeed, HHV-4 (commonly known as mononucleosis or “the kissing disease”) is one of the most common viruses known to infect humans, with almost 90% of adults having antibodies suggesting previous HHV-4 infection [22]. Herpesviruses overtake host translational machinery through virion host shutoff (vhs), which limits the expression of host mRNA [23], and through the degradation of host mitochondrial DNA [24], although some herpesvirus strains act differently [25]. Our data suggest that herpesvirus is able to co-opt the translational apparatus of the infected cell by closely matching codon usage biases. The virus is able to use existing tRNAs in the cell, which are not being used by the cell due to vhs.

Furthermore, viruses such as HPV-90 (NC_004104) and Human gyrovirus 1 (NC_015630) with fewer correlating proteins typically occur less frequently in human populations. Although limited data exist for the prevalence of HPV-90 in the general population, in general it presents a very low risk to the general population [26,27]. Human gyrovirus 1, which is identical to the Chicken Anemia Virus, is relatively rare and the effects of the virus still remain largely unknown, although it may affect the apoptosis pathway [28,29].

Human-host viruses appear to target tissues where the correlating human protein also has high expression. Although many viruses analyzed were not clearly annotated as infecting a particular human tissue, the viruses with documented tissue interactions were always highly correlated with a protein that was highly expressed in that tissue. For instance, HPV-128 correlates most with the human protein TIGD4, which is mainly expressed in the genitalia. In addition, other STDs were strongly correlated with proteins that were also mainly expressed in genitalia (Table 2, Table S3). We note that viruses tend to share the same codon usage biases as at least one protein that is highly expressed in the disease targeted area, further emphasizing our conclusion that viral and host codon usage biases are highly correlated.

Accession Number

Virus Name

Virus Protein

Correlating Human Protein

Protein’s Expression Location

NC_004500

HPV 92

E1

MSH4

Testis

NC_022095

HPV 179

L1

HLTF

Testis

NC_014952

HPV 128

E1

TIGD4

Testis, vagina

NC_001691

HPV 50

E1

TEX15

Testis

NC_001405

HPV 18

L1

MRC2

Soft tissue, testis, endometrium

NC_001354

HPV 41

USP7

SLC12A2

Digestive tract, breast, placenta

NC_000898

HHV 6

U90

ELTD1

Gallbladder, breast, smooth muscle

NC_019023

HPV 166

E1

OTOGL

Cervix, testis

NC_009334

HHV 4

BALF5

SPTB

Epididymis

NC_010329

HPV 88

E1

RAD51AP2

Seminal Vesicle, Fallopian Tube

NC_004500

HPV 92

E1

USP9Y

Prostate

Table 2. A selection of viral proteins and their top correlating human proteins, along with the human protein’s documented area of expression. These results show that viral codon usage biases highly correlate with the codon usage biases of human proteins that are found within tissues that the viruses are known to promote symptomatic issues.

Virus Accession Number

Highest Correlating Human Protein Accession Number

Region(s) Where Human Protein is Most Highly Expressed

NC_000883

NP_002763.2

Stomach glandular cells

NC_000898

NP_112561.2

Testis, urinary tract, and brain

NC_001348

NP_787081.2

Myocytes in heart muscle, lateral ventricle, cerebral cortex,

hippocampus

NC_001352

NP_037485.2

Myocytes in skeletal muscle, and glandular cells in the stomach.

NC_001354

NP_001273387.1

Liver, pancreas, digestive tract, male reproductive system, endocrine

NC_001355

NP_940841.1

Skeletal muscle, smooth muscle, epidermal cells, hepatocytes in liver

NC_001356

NP_001138663.1

GI-tract, gallbladder, and the blood and immune system

NC_001357

NP_940841.1

Smooth muscle cells

NC_001405

NP_001073990.2

Stomach, kidney, fallopian tube,

NC_001430

NP_000123.1

Adipocytes of soft tissue, placenta, tubule cells in the kidney

NC_001436

NP_001092872.1

Hematopoietic cells in bone marrow, glandular cells in the stomach

NC_001454

NP_612426.1

Glandular cells of the GI tract, urinary tract cells, adrenal glands

NC_001457

NP_061854.1

Glandular cells of the epididymis and the endometrium

NC_001458

NP_001273176.1

Testis.

NC_001460

NP_001116801.1

Kidney, testis, stomach, esophagus, vagina, skin, lung, and heart

NC_001472

NP_005224.2

Low expression everywhere

NC_001488

NP_001073882.3

No information found

NC_001490

NP_002175.2

Stomach cells, prostate, kidney, liver, pancreas, heart muscle

NC_001526

NP_942089.1

Female reproductive system

NC_001531

NP_079114.3

Stomach

NC_001576

NP_899059.1

Stomach and rectum

NC_001583

NP_940841.1

Smooth muscle cells

NC_001586

NP_940841.1

Smooth muscle cells

NC_001587

NP_057654.2

Heart muscle cells, and some GI-tract cells.

NC_001591

NP_078787.2

Stomach

NC_001593

NP_001167579.1

GI-tract and female reproductive system

NC_001595

NP_001273644.1

Testis

NC_001596

NP_940841.1

Smooth muscle cells

NC_001612

NP_001116105.1

Stomach and liver

NC_001617

NP_002175.2

Stomach cells, prostate, kidney, liver, pancreas, heart muscle

NC_001664

NP_653091.3

Testis

NC_001676

NP_940841.1

Smooth muscle cells

NC_001690

NP_001092688.1

Male reproductive system

NC_001691

NP_940841.1

Smooth muscle cells

NC_001693

NP_940841.1

Smooth muscle cells

NC_001716

NP_001073973.2

Testis

NC_001722

NP_002408.3

Blood, immune system

NC_001781

NP_065982.1

Seminal vesicle in men, and the breast in women

NC_001796

NP_065982.1

Seminal vesicle in men, and the breast in women

NC_001798

NP_036567.2

Varied expression everywhere

NC_001802

NP_001093866.1

Male reproductive system and GI-tract

NC_001806

NP_055778.2

Liver cells, skeletal muscle, cerebral cortex, endocrine glands, lung

NC_001897

NP_001017975.3

Lung cells and skeletal muscles

NC_001943

NP_114161.3

Testis and cerebellum

NC_002645 NC_003266

NP_000099.2 NP_009115.2

Nearly everywhere, except skin

   

Skin, gallbladder, cerebellum, heart muscle, adrenal gland, bronchus

NC_003443

NP_004645.2

Prostate

NC_003461

NP_065982.1

Seminal vesicle in men, and the breast in women

NC_004104

NP_899059.1

Stomach and rectum

NC_004148

NP_065982.1

Seminal vesicle in men, and the breast in women

NC_004295

NP_114414.2

Skin

NC_004500

NP_004645.2

Prostate

NC_005134

NP_001138663.1

GI-tract, gallbladder, and the blood and immune system

NC_005147

NP_064506.3

Testis and the brain

NC_005831

NP_037471.2

Both male and female reproductive systems

NC_006273

NP_055478.2

Stomach, testis, and brain

NC_006577

NP_852607.3

Hippocampus, heart muscle, parathyroid gland

NC_007018

NP_005112.2

Bone marrow, and testis

NC_007026

NP_001024.1

Testis, lymph nodes, and lateral ventricles

NC_007027

NP_002717.3

GI-tract, and endometrium in women

NC_007455

NP_803875.2

Spleen and bone marrow

NC_007605

NP_620124.1

Stomach, placenta, skeletal muscle, and cerebral cortex

NC_008188

NP_940841.1

Smooth muscle cells

NC_008189

NP_000305.3

Cerebral cortex

NC_009333

NP_002891.1

No information found

NC_009334

NP_620124.1

Stomach, placenta, skeletal muscle, and cerebral cortex

NC_009996

NP_004939.1

highest expression in the skin keratinocytes

NC_010329

NP_940841.1

Smooth muscle cells

NC_010810

NP_004939.1

Skin keratinocytes

NC_010956

NP_009115.2

Skin, gallbladder, cerebellum, heart muscle, adrenal gland, bronchus

NC_011202

NP_787072.2

Adrenal gland, cerebellum, stomach, and placenta

NC_011203

NP_009115.2

Skin, gallbladder, cerebellum, heart muscle, adrenal gland, bronchus

NC_011800

NP_056526.3

Medium/high expression everywhere

NC_012042

NP_005424.1

Testis, stomach, and placenta

NC_012213

NP_001138663.1

GI-tract, gallbladder, blood and immune system

NC_012485

NP_940841.1

Smooth muscle cells

NC_012486

NP_001138663.1

GI-tract, gallbladder, blood and immune system

NC_012564

NP_002899.1

Blood, immune system, women reproductive system, and GI-tract

NC_012729

NP_001073932.1

GI-tract

NC_012798

NP_057190.2

Pancreas, testis, kidney, and placenta

NC_012801

NP_001191195.1

Cerebral cortex

NC_012802

NP_001161829.1

Appendix, prostate, placenta, lymph node, and spleen

NC_012950

NP_064506.3

Testis and the brain

NC_012959

NP_009115.2

Skin, gallbladder, cerebellum, heart muscle, adrenal gland, bronchus

NC_012986

NP_004215.2

Kidney and smooth muscle tissue

NC_013035

NP_940841.1

Smooth muscle cells

NC_014185

NP_940841.1

Smooth muscle cells

NC_014952

NP_940841.1

Smooth muscle cells

NC_014953

NP_940841.1

Smooth muscle cells

NC_014954

NP_940841.1

Smooth muscle cells

NC_014955

NP_940841.1

Smooth muscle cells

NC_014956

NP_940841.1

Smooth muscle cells

NC_015150

NP_060862.3

No information available

NC_015630

NP_689786.2

GI-tract and urinary tract

NC_016157

NP_940841.1

Smooth muscle cells

NC_017993

NP_940841.1

Smooth muscle cells

NC_017994

NP_940841.1

Smooth muscle cells

NC_017995

NP_001138663.1

GI-tract, gallbladder, blood and immune system

NC_017996

NP_940841.1

Smooth muscle cells

NC_017997

NP_112561.2

Low expression everywhere

NC_019023

NP_940841.1

Smooth muscle cells

NC_019843

NP_079265.2

Testis, placenta and parathyroid gland

NC_020890

NP_001017975.3

Lung cells and skeletal muscles

NC_021483

NP_001092688.1

Stomach, male reproductive system, and skin

NC_021568 NC_021928

NP_066012.1 NP_065982.1

Testis and stomach

   

Seminal vesicle in men, and the breast in women

NC_022095

NP_001273644.1

Testis

NC_022518

NP_001121143.1

Male reproductive tissue and in the heart

NC_022892

NP_065982.1

Seminal vesicle in men, and the breast in women

NC_023874

NP_060146.2

Tonsil, stomach, and pancreas

NC_023891

NP_940841.1

Smooth muscle cells

NC_023984

NP_036434.1

Skeletal and smooth muscle, tonsils, small intestine, colon

NC_024694

NP_054860.1

Cerebral cortex

Table S3. A comprehensive list of where the highest correlating human protein with respect to a human-infecting virus is most highly expressed.

Highly expressed genes have codon biases that utilize highly abundant tRNAs in order for optimal translational and transcriptional speed [12,13,30-33]. The Human Adenovirus E (NP_009115.2), which causes respiratory illness, has an 89.9% codon usage correlation with the NISCH gene, which is mainly expressed in the bronchus. Since NISCH is highly expressed in the tissues that the adenovirus normally infects, the virus is able to take advantage of its codon usage bias similarities with the host proteins to rapidly proliferate and infect additional hosts.

There are other possibilities for the observed shared codon usage biases. For example, co-evolution may have contributed to the appearance of such strong codon bias correlations, in which the host and the virus evolve at similar rates in order to either combat or maintain parasitic infection [34]. Since viruses have smaller genomes, they can selectively evolve more rapidly toward being similar to a preferred host.

While co-evolution and the abundance of optimal tRNAs are thought to allow greater viral spread, determining the exact cause of this correlation remains unexplored. Our extensive analysis of codon usage determined that a strong correlation in codon usage bias exists between human-host viruses and proteins expressed in the human tissues that they infect. Future research should focus on the causes of these correlations.

Authorship and contributorship

JM and PR conceived the idea. JM oversaw all aspects of the project. AH developed the comparison algorithms and ran the comparisons. CM and SW conducted literature searches and wrote sections of the paper. JM and PR were primarily responsible for editing the manuscript. PR mentored the project.

Acknowledgements

We also appreciate Mark Ebbert and Samantha Jensen who provided expert suggestions for the project flow and design.

Funding information

We appreciate the contributions of Brigham Young University and the Fulton Supercomputing Laboratory in supporting our research.

Competing interests

The authors declare that they have no competing interests.

Availability of data and material

All data are freely available from the NCBI database at ftp://ftp.ncbi.nlm.nih.gov/

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Editorial Information

Editor-in-Chief

Article Type

Research Article

Publication history

Received: June 10, 2017
Accepted: July 24, 2017
Published: July 27, 2017

Copyright

© 20107 Miller JB. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation

Miller JB (2017) Human viruses have codon usage biases that match highly expressed proteins in the tissues they infect. Biomed Genet Genomics 2: DOI: 10.15761/BGG.1000134

Corresponding author

Perry G. Ridge

Department of Biology, Brigham Young University, Provo, Utah 84602, USA.

 Virus Accession Number

Virus Name

Virus Protein Name

Protein Accession Number

Protein Name

Correlation %

P-value

NC_009334

Human herpesvirus 4

BALF5

NP_620124.1

RHOT2

93.6

8.64E-30

NC_007605

Human herpesvirus 4 (wild type)

BALF5

NP_620124.1

RHOT2

93.5

1.36E-29

NC_000898

Human herpesvirus 6B

U90

NP_112561.2

TEX15

93.1

6.40E-29

NC_014185

Human papillomavirus 121

E1

NP_940841.1

KBTBD3

92.8

2.53E-28

NC_001716

Human herpesvirus 7

IE1

NP_001073973.2

RBM44

92.8

3.03E-28

NC_016157

Human papillomavirus 126

Pos: 817-2640

NP_940841.1

KBTBD3

92.0

6.78E-27

NC_009333

Human herpesvirus 8

ORF75

NP_002891.1

RBP3

91.8

1.47E-26

NC_010329

Human papillomavirus 88

E1

NP_940841.1

KBTBD3

90.8

4.10E-25

NC_001806

Human herpesvirus 1

UL30

NP_055778.2

SBNO2

90.8

4.15E-25

NC_014955

Human papillomavirus 132

E1

NP_940841.1

KBTBD3

90.5

9.67E-25

Table 1. Here we report the top-ten codon usage bias correlations (Pearson’s r values) between a virus and a human protein with their respective p-values (all under 10-25), demonstrating that viruses and proteins in their host (humans) share high codon biases. Unnamed viral proteins are designated by their position numbers in the following format— Pos: start position-stop position.

Accession Number

Virus Name

Virus Protein

Correlating Human Protein

Protein’s Expression Location

NC_004500

HPV 92

E1

MSH4

Testis

NC_022095

HPV 179

L1

HLTF

Testis

NC_014952

HPV 128

E1

TIGD4

Testis, vagina

NC_001691

HPV 50

E1

TEX15

Testis

NC_001405

HPV 18

L1

MRC2

Soft tissue, testis, endometrium

NC_001354

HPV 41

USP7

SLC12A2

Digestive tract, breast, placenta

NC_000898

HHV 6

U90

ELTD1

Gallbladder, breast, smooth muscle

NC_019023

HPV 166

E1

OTOGL

Cervix, testis

NC_009334

HHV 4

BALF5

SPTB

Epididymis

NC_010329

HPV 88

E1

RAD51AP2

Seminal Vesicle, Fallopian Tube

NC_004500

HPV 92

E1

USP9Y

Prostate

Table 2. A selection of viral proteins and their top correlating human proteins, along with the human protein’s documented area of expression. These results show that viral codon usage biases highly correlate with the codon usage biases of human proteins that are found within tissues that the viruses are known to promote symptomatic issues.

Virus Accession Number

Virus Protein Name

Pearson’s R Correlation Value

P-value

Highest Correlating Protein Accession Number

Protein Common Name

NC_000883

NS1

0.764596741

1.94E-13

NP_002763.2

TMPRSS15

NC_000898

U90

0.931483267

6.40E-29

NP_112561.2

TEX15

NC_001348

ICP4

0.798569441

2.68E-15

NP_787081.2

FAM181B

NC_001352

E1

0.725454272

1.20E-11

NP_037485.2

TMOD4

NC_001354

Pos: 951-2795

0.804857764

1.11E-15

NP_001273387.1

USP7

NC_001355

E1

0.798328333

2.77E-15

NP_940841.1

KBTBD3

NC_001356

E1

0.903438527

1.74E-24

NP_001138663.1

FAM200B

NC_001357

E1

0.805278655

1.05E-15

NP_940841.1

KBTBD3

NC_001405

L1

0.865302979

2.94E-20

NP_001073990.2

RASSF10

NC_001430

Pos: 727-7311

0.837550489

6.34E-18

NP_000123.1

F8

NC_001436

Pr55

0.752880597

7.22E-13

NP_001092872.1

CCNK

NC_001454

L3

0.792140958

6.41E-15

NP_612426.1

KTI12

NC_001457

Pos: 5345-6895

0.859158203

1.06E-19

NP_061854.1

DNAJC10

NC_001458

Pos: 822-2678

0.847795937

9.88E-19

NP_001273176.1

RALGPS2

NC_001460

E1B

0.806525776

8.74E-16

NP_001116801.1

ZBTB1

NC_001472

Pos: 742-7290

0.800822126

1.96E-15

NP_005224.2

EPHA3

NC_001488

Pos: 807-2108

0.748225962

1.19E-12

NP_001073882.3

NOBOX

NC_001490

Pos: 629-7168

0.891321462

5.65E-23

NP_002175.2

IL6ST

NC_001526

L1

0.807134439

8.00E-16

NP_942089.1

MAP4K5

NC_001531

Pos: 961-2781

0.852165343

4.29E-19

NP_079114.3

THNSL1

NC_001576

Pos: 791-2836

0.785723092

1.48E-14

NP_899059.1

RAB27A

NC_001583

Pos: 878-2794

0.787008282

1.26E-14

NP_940841.1

KBTBD3

NC_001586

Pos: 850-2778

0.799660538

2.31E-15

NP_940841.1

KBTBD3

NC_001587

Pos: 5430-7016

0.749586507

1.03E-12

NP_057654.2

ERGIC2

NC_001591

E1

0.845045382

1.65E-18

NP_078787.2

HAUS3

NC_001593

L1

0.744112558

1.84E-12

NP_001167579.1

ZBED6

NC_001595

Pos: 5798-7315

0.770647823

9.56E-14

NP_001273644.1

AGTPBP1

NC_001596

E1

0.844374112

1.86E-18

NP_940841.1

KBTBD3

NC_001612

Pos: 751-7332

0.842341207

2.70E-18

NP_001116105.1

CPS1

NC_001617

Pos: 619-7113

0.86771873

1.74E-20

NP_002175.2

IL6ST

NC_001664

IE1

0.893813269

2.86E-23

NP_653091.3

CASC5

NC_001676

Pos:828-2729

0.787967453

1.11E-14

NP_940841.1

KBTBD3

NC_001690

E1

0.855417316

2.26E-19

NP_001092688.1

RAD51AP2

NC_001691

E1

0.876751214

2.23E-21

NP_940841.1

KBTBD3

NC_001693

E1

0.894934035

2.10E-23

NP_940841.1

KBTBD3

NC_001716

IE1

0.927833476

3.03E-28

NP_001073973.2

RBM44

NC_001722

Pos: 1103-2668

0.737893765

3.50E-12

NP_002408.3

MKI67

NC_001781

L

0.876166171

2.56E-21

NP_065982.1

KIAA1586

NC_001796

Pos: 8646-15347

0.903986563

1.47E-24

NP_065982.1

KIAA1586

NC_001798

UL39

0.904920752

1.10E-24

NP_036567.2

SHC2

NC_001802

Pr55

0.78047161

2.89E-14

NP_001093866.1

C2orf73

NC_001806

UL30

0.90801467

4.15E-25

NP_055778.2

SBNO2

NC_001897

Pos: 703-7242

0.890389641

7.26E-23

NP_001017975.3

HFM1

NC_001943

Pos: 86-4380

0.830734096

2.04E-17

NP_114161.3

SPATA16

NC_002645

Pos: 293-12550

0.774229507

6.22E-14

NP_000099.2

DLD

NC_003266

L4

0.898683268

7.19E-24

NP_009115.2

NISCH

NC_003443

L

0.839684044

4.35E-18

NP_004645.2

USP9Y

NC_003461

L

0.866879002

2.09E-20

NP_065982.1

KIAA1586

NC_004104

E1

0.68207836

5.44E-10

NP_899059.1

RAB27A

NC_004148

L

0.867913209

1.67E-20

NP_065982.1

KIAA1586

NC_004295

VP1

0.773099678

7.13E-14

NP_114414.2

EIF2A

NC_004500

E1

0.880929983

8.18E-22

NP_004645.2

USP9Y

NC_005134

E1

0.851299523

5.07E-19

NP_001138663.1

FAM200B

NC_005147

Pos: 21507-22343

0.820880135

1.01E-16

NP_064506.3

UGGT2

NC_005831

Pos: 287-20475

0.750091303

9.77E-13

NP_037471.2

ALG6

NC_006273

IE1

0.87654333

2.35E-21

NP_055478.2

KDM4A

NC_006577

Pos: 22942-27012

0.756094354

5.07E-13

NP_852607.3

LRRC70

NC_007018

ORF2

0.774104535

6.31E-14

NP_005112.2

MED13

NC_007026

Pos: 828-2486

0.704735964

8.08E-11

NP_001024.1

RRM1

NC_007027

Pos: 94-1698

0.746908872

1.37E-12

NP_002717.3

PREP

NC_007455

VP1

0.768556356

1.22E-13

NP_803875.2

PKHD1L1

NC_007605

BALF5

0.934931283

1.36E-29

NP_620124.1

RHOT2

NC_008188

E1

0.85042555

6.00E-19

NP_940841.1

KBTBD3

NC_008189

E1

0.781785258

2.45E-14

NP_000305.3

PTEN

NC_009333

ORF75

0.91780911

1.47E-26

NP_002891.1

RBP3

NC_009334

BALF5

0.935906758

8.64E-30

NP_620124.1

RHOT2

NC_009996

Pos: 616-7050

0.834124398

1.15E-17

NP_004939.1

DSC1

NC_010329

E1

0.908048024

4.10E-25

NP_940841.1

KBTBD3

NC_010810

Pos: 956-7837

0.825974666

4.46E-17

NP_004939.1

DSC1

NC_010956

L4

0.884411516

3.44E-22

NP_009115.2

NISCH

NC_011202

L1

0.825443151

4.86E-17

NP_787072.2

EXOC8

NC_011203

L4

0.84556954

1.50E-18

NP_009115.2

NISCH

NC_011800

Pos: 1892-2533

0.744847797

1.71E-12

NP_056526.3

GLTSCR1

NC_012042

VP1

0.776501461

4.72E-14

NP_005424.1

YES1

NC_012213

E1

0.843291298

2.27E-18

NP_001138663.1

FAM200B

NC_012485

E1

0.883809966

4.00E-22

NP_940841.1

KBTBD3

NC_012486

E1

0.902494945

2.32E-24

NP_001138663.1

FAM200B

NC_012564

VP1

0.783191043

2.05E-14

NP_002899.1

REL

NC_012729

NS2

0.805392124

1.03E-15

NP_001073932.1

DYNC2H1

NC_012798

Pos: 139-6480

0.82589364

4.52E-17

NP_057190.2

SCFD1

NC_012801

Pos: 750-7124

0.824196863

5.94E-17

NP_001191195.1

GABRA4

NC_012802

Pos: 748-7128

0.834958942

9.94E-18

NP_001161829.1

PLA2G7

NC_012950

Pos: 21445-22281

0.818600204

1.44E-16

NP_064506.3

UGGT2

NC_012959

Pos: 22707-24845

0.842896843

2.44E-18

NP_009115.2

NISCH

NC_012986

Pos: 719-7831

0.755617438

5.35E-13

NP_004215.2

GPR50

NC_013035

E1

0.900330229

4.44E-24

NP_940841.1

KBTBD3

NC_014185

E1

0.928268261

2.53E-28

NP_940841.1

KBTBD3

NC_014952

E1

0.879231256

1.24E-21

NP_940841.1

KBTBD3

NC_014953

E1

0.904630266

1.21E-24

NP_940841.1

KBTBD3

NC_014954

E1

0.895597619

1.74E-23

NP_940841.1

KBTBD3

NC_014955

E1

0.905343727

9.67E-25

NP_940841.1

KBTBD3

NC_014956

E1

0.903382032

1.77E-24

NP_940841.1

KBTBD3

NC_015150

Pos: c5026-4790, c4437-2632

0.897789054

9.32E-24

NP_060862.3

C4orf21

NC_015630

Pos: 381-1076

0.54440122

3.32E-06

NP_689786.2

RASEF

NC_016157

Pos: 817-2640

0.919910732

6.78E-27

NP_940841.1

KBTBD3

NC_017993

Pos: 805-2610

0.859261423

1.04E-19

NP_940841.1

KBTBD3

NC_017994

E1

0.868341489

1.52E-20

NP_940841.1

KBTBD3

NC_017995

Pos: 714-2546

0.883104334

4.77E-22

NP_001138663.1

FAM200B

NC_017996

Pos: 717-2534

0.881915256

6.42E-22

NP_940841.1

KBTBD3

NC_017997

Pos; 703-2502

0.825068761

5.16E-17

NP_112561.2

TEX15

NC_019023

E1

0.864842857

3.24E-20

NP_940841.1

KBTBD3

NC_019843

orf1ab

0.777846368

4.00E-14

NP_079265.2

PGAP1

NC_020890

large T antigen

0.894050364

2.68E-23

NP_001017975.3

HFM1

NC_021483

E1

0.858044662

1.34E-19

NP_001092688.1

RAD51AP2

NC_021568

Pos: 279-13433, 13433-21514

0.731131014

6.89E-12

NP_066012.1

METTL14

NC_021928

Pos: c5033-4821, c4421-2508

0.8986358

7.29E-24

NP_065982.1

KIAA1586

NC_022095

L1

0.818922205

1.37E-16

NP_001273644.1

AGTPBP1

NC_022518

Pos: 6451-8550

0.801092218

1.89E-15

NP_001121143.1

LIFR

NC_022892

E1

0.856537918

1.81E-19

NP_065982.1

KIAA1586

NC_023874

Pos: 161-997

0.720321018

1.95E-11

NP_060146.2

GIN1

NC_023891

E1

0.88293482

4.98E-22

NP_940841.1

KBTBD3

NC_023984

Pos: 1362-7727

0.837884709

5.98E-18

NP_036434.1

LPHN2

NC_024694

Pos: 1 - 1113

0.676628221

8.40E-10

NP_054860.1

CNTNAP2

Table S1. A comprehensive list of the 113 viruses with their highest correlating protein, accompanied by the Pearson’s r correlation and the respective p-value. Bolded rows were found to be insignificant. Unnamed viral proteins are designated by their position numbers in the following format— Pos: start position-stop position.

Virus Accession Number

Number of Genes in Virus

Number of Highly Correlating Genes in Humans

Number of Highly Correlating Human Proteins per Viral Protein

NC_015630

3

0

0

NC_004104

7

4

0.57

NC_012986

1

1

1

NC_001436

6

7

1.17

NC_024694

4

13

3.25

NC_001488

6

27

4.5

NC_011800

6

28

4.67

NC_007026

2

15

7.5

NC_005831

6

47

7.83

NC_001722

9

91

10.11

NC_001352

7

91

13

NC_023874

2

32

16

NC_001595

6

104

17.33

NC_001357

8

152

19

NC_001454

34

655

19.26

NC_006577

8

165

20.63

NC_021568

2

50

25

NC_001576

7

221

31.57

NC_001587

6

219

36.5

NC_001348

73

2843

38.95

NC_001593

7

331

47.29

NC_000883

6

317

52.83

NC_019843

11

582

52.91

NC_001355

9

478

53.11

NC_001460

36

1950

54.17

NC_001583

6

328

54.67

NC_001676

7

391

55.86

NC_001526

8

456

57

NC_008189

6

353

58.83

NC_001802

10

629

62.9

NC_002645

8

613

76.63

NC_001586

6

517

86.17

NC_015150

5

435

87

NC_007027

1

93

93

NC_011202

38

3637

95.71

NC_007455

4

392

98

NC_001781

11

1079

98.09

NC_017997

7

691

98.71

NC_001354

11

1096

99.64

NC_012950

12

1268

105.67

NC_005147

9

970

107.78

NC_012042

4

438

109.5

NC_004500

7

787

112.43

NC_013035

7

837

119.57

NC_008188

6

720

120

NC_004295

6

747

124.5

NC_022095

6

750

125

NC_012564

4

555

138.75

NC_004148

9

1314

146

NC_001405

38

5628

148.11

NC_000898

104

15694

150.9

NC_012485

7

1083

154.71

NC_006273

169

26217

155.13

NC_001664

88

13960

158.64

NC_012213

5

801

160.2

NC_003461

10

1706

170.6

NC_003266

38

7275

191.45

NC_001798

77

14790

192.08

NC_022892

6

1160

193.33

NC_010956

38

7500

197.37

NC_017993

7

1382

197.43

NC_001690

7

1464

209.14

NC_021483

7

1467

209.57

NC_001596

7

1470

210

NC_014953

7

1498

214

NC_012959

36

7762

215.61

NC_001591

6

1327

221.17

NC_014952

7

1601

228.71

NC_011203

39

9069

232.54

NC_001531

8

1903

237.88

NC_012729

5

1212

242.4

NC_003443

7

1720

245.71

NC_020890

5

1235

247

NC_010329

7

1744

249.14

NC_012486

7

1768

252.57

NC_001691

7

1771

253

NC_023891

7

1843

263.29

NC_001356

7

1844

263.43

NC_021928

7

1879

268.43

NC_005134

7

1893

270.43

NC_014956

7

1894

270.57

NC_001796

8

2167

270.88

NC_016157

7

1969

281.29

NC_001457

7

1980

282.86

NC_014954

7

1981

283

NC_014955

7

2051

293

NC_017994

7

2061

294.43

NC_014185

7

2076

296.57

NC_009333

86

26437

307.41

NC_001458

7

2182

311.71

NC_001693

7

2316

330.86

NC_001806

77

26054

338.36

NC_019023

6

2070

345

NC_017996

7

2500

357.14

NC_007018

2

769

384.5

NC_001716

86

33651

391.29

NC_017995

7

2784

397.71

NC_001943

2

1088

544

NC_022518

1

592

592

NC_001472

1

753

753

NC_007605

95

85227

897.13

NC_009334

80

82905

1036.31

NC_001612

1

1133

1133

NC_009996

1

1157

1157

NC_001617

1

1193

1193

NC_010810

1

1223

1223

NC_012802

1

1408

1408

NC_001490

1

1423

1423

NC_012798

1

1437

1437

NC_023984

1

1453

1453

NC_012801

1

1482

1482

NC_001430

1

1720

1720

NC_001897

1

1918

1918

Average

15.74

4161.41

303.36

Total

1779

470239

34279.52

Table S2. A comprehensive list of the 113 viruses with the number of genes in the virus, the number of highly correlating human genes, and the number of highly correlating human proteins per viral protein. Viruses are ordered in accending order based on the number of highly correlating human genes per viral gene.

Virus Accession Number

Highest Correlating Human Protein Accession Number

Region(s) Where Human Protein is Most Highly Expressed

NC_000883

NP_002763.2

Stomach glandular cells

NC_000898

NP_112561.2

Testis, urinary tract, and brain

NC_001348

NP_787081.2

Myocytes in heart muscle, lateral ventricle, cerebral cortex,

hippocampus

NC_001352

NP_037485.2

Myocytes in skeletal muscle, and glandular cells in the stomach.

NC_001354

NP_001273387.1

Liver, pancreas, digestive tract, male reproductive system, endocrine

NC_001355

NP_940841.1

Skeletal muscle, smooth muscle, epidermal cells, hepatocytes in liver

NC_001356

NP_001138663.1

GI-tract, gallbladder, and the blood and immune system

NC_001357

NP_940841.1

Smooth muscle cells

NC_001405

NP_001073990.2

Stomach, kidney, fallopian tube,

NC_001430

NP_000123.1

Adipocytes of soft tissue, placenta, tubule cells in the kidney

NC_001436

NP_001092872.1

Hematopoietic cells in bone marrow, glandular cells in the stomach

NC_001454

NP_612426.1

Glandular cells of the GI tract, urinary tract cells, adrenal glands

NC_001457

NP_061854.1

Glandular cells of the epididymis and the endometrium

NC_001458

NP_001273176.1

Testis.

NC_001460

NP_001116801.1

Kidney, testis, stomach, esophagus, vagina, skin, lung, and heart

NC_001472

NP_005224.2

Low expression everywhere

NC_001488

NP_001073882.3

No information found

NC_001490

NP_002175.2

Stomach cells, prostate, kidney, liver, pancreas, heart muscle

NC_001526

NP_942089.1

Female reproductive system

NC_001531

NP_079114.3

Stomach

NC_001576

NP_899059.1

Stomach and rectum

NC_001583

NP_940841.1

Smooth muscle cells

NC_001586

NP_940841.1

Smooth muscle cells

NC_001587

NP_057654.2

Heart muscle cells, and some GI-tract cells.

NC_001591

NP_078787.2

Stomach

NC_001593

NP_001167579.1

GI-tract and female reproductive system

NC_001595

NP_001273644.1

Testis

NC_001596

NP_940841.1

Smooth muscle cells

NC_001612

NP_001116105.1

Stomach and liver

NC_001617

NP_002175.2

Stomach cells, prostate, kidney, liver, pancreas, heart muscle

NC_001664

NP_653091.3

Testis

NC_001676

NP_940841.1

Smooth muscle cells

NC_001690

NP_001092688.1

Male reproductive system

NC_001691

NP_940841.1

Smooth muscle cells

NC_001693

NP_940841.1

Smooth muscle cells

NC_001716

NP_001073973.2

Testis

NC_001722

NP_002408.3

Blood, immune system

NC_001781

NP_065982.1

Seminal vesicle in men, and the breast in women

NC_001796

NP_065982.1

Seminal vesicle in men, and the breast in women

NC_001798

NP_036567.2

Varied expression everywhere

NC_001802

NP_001093866.1

Male reproductive system and GI-tract

NC_001806

NP_055778.2

Liver cells, skeletal muscle, cerebral cortex, endocrine glands, lung

NC_001897

NP_001017975.3

Lung cells and skeletal muscles

NC_001943

NP_114161.3

Testis and cerebellum

NC_002645 NC_003266

NP_000099.2 NP_009115.2

Nearly everywhere, except skin

   

Skin, gallbladder, cerebellum, heart muscle, adrenal gland, bronchus

NC_003443

NP_004645.2

Prostate

NC_003461

NP_065982.1

Seminal vesicle in men, and the breast in women

NC_004104

NP_899059.1

Stomach and rectum

NC_004148

NP_065982.1

Seminal vesicle in men, and the breast in women

NC_004295

NP_114414.2

Skin

NC_004500

NP_004645.2

Prostate

NC_005134

NP_001138663.1

GI-tract, gallbladder, and the blood and immune system

NC_005147

NP_064506.3

Testis and the brain

NC_005831

NP_037471.2

Both male and female reproductive systems

NC_006273

NP_055478.2

Stomach, testis, and brain

NC_006577

NP_852607.3

Hippocampus, heart muscle, parathyroid gland

NC_007018

NP_005112.2

Bone marrow, and testis

NC_007026

NP_001024.1

Testis, lymph nodes, and lateral ventricles

NC_007027

NP_002717.3

GI-tract, and endometrium in women

NC_007455

NP_803875.2

Spleen and bone marrow

NC_007605

NP_620124.1

Stomach, placenta, skeletal muscle, and cerebral cortex

NC_008188

NP_940841.1

Smooth muscle cells

NC_008189

NP_000305.3

Cerebral cortex

NC_009333

NP_002891.1

No information found

NC_009334

NP_620124.1

Stomach, placenta, skeletal muscle, and cerebral cortex

NC_009996

NP_004939.1

highest expression in the skin keratinocytes

NC_010329

NP_940841.1

Smooth muscle cells

NC_010810

NP_004939.1

Skin keratinocytes

NC_010956

NP_009115.2

Skin, gallbladder, cerebellum, heart muscle, adrenal gland, bronchus

NC_011202

NP_787072.2

Adrenal gland, cerebellum, stomach, and placenta

NC_011203

NP_009115.2

Skin, gallbladder, cerebellum, heart muscle, adrenal gland, bronchus

NC_011800

NP_056526.3

Medium/high expression everywhere

NC_012042

NP_005424.1

Testis, stomach, and placenta

NC_012213

NP_001138663.1

GI-tract, gallbladder, blood and immune system

NC_012485

NP_940841.1

Smooth muscle cells

NC_012486

NP_001138663.1

GI-tract, gallbladder, blood and immune system

NC_012564

NP_002899.1

Blood, immune system, women reproductive system, and GI-tract

NC_012729

NP_001073932.1

GI-tract

NC_012798

NP_057190.2

Pancreas, testis, kidney, and placenta

NC_012801

NP_001191195.1

Cerebral cortex

NC_012802

NP_001161829.1

Appendix, prostate, placenta, lymph node, and spleen

NC_012950

NP_064506.3

Testis and the brain

NC_012959

NP_009115.2

Skin, gallbladder, cerebellum, heart muscle, adrenal gland, bronchus

NC_012986

NP_004215.2

Kidney and smooth muscle tissue

NC_013035

NP_940841.1

Smooth muscle cells

NC_014185

NP_940841.1

Smooth muscle cells

NC_014952

NP_940841.1

Smooth muscle cells

NC_014953

NP_940841.1

Smooth muscle cells

NC_014954

NP_940841.1

Smooth muscle cells

NC_014955

NP_940841.1

Smooth muscle cells

NC_014956

NP_940841.1

Smooth muscle cells

NC_015150

NP_060862.3

No information available

NC_015630

NP_689786.2

GI-tract and urinary tract

NC_016157

NP_940841.1

Smooth muscle cells

NC_017993

NP_940841.1

Smooth muscle cells

NC_017994

NP_940841.1

Smooth muscle cells

NC_017995

NP_001138663.1

GI-tract, gallbladder, blood and immune system

NC_017996

NP_940841.1

Smooth muscle cells

NC_017997

NP_112561.2

Low expression everywhere

NC_019023

NP_940841.1

Smooth muscle cells

NC_019843

NP_079265.2

Testis, placenta and parathyroid gland

NC_020890

NP_001017975.3

Lung cells and skeletal muscles

NC_021483

NP_001092688.1

Stomach, male reproductive system, and skin

NC_021568 NC_021928

NP_066012.1 NP_065982.1

Testis and stomach

   

Seminal vesicle in men, and the breast in women

NC_022095

NP_001273644.1

Testis

NC_022518

NP_001121143.1

Male reproductive tissue and in the heart

NC_022892

NP_065982.1

Seminal vesicle in men, and the breast in women

NC_023874

NP_060146.2

Tonsil, stomach, and pancreas

NC_023891

NP_940841.1

Smooth muscle cells

NC_023984

NP_036434.1

Skeletal and smooth muscle, tonsils, small intestine, colon

NC_024694

NP_054860.1

Cerebral cortex

Table S3. A comprehensive list of where the highest correlating human protein with respect to a human-infecting virus is most highly expressed.

<p><strong>Figure 1. Codon counts. </strong>Four of the highest correlating virus-protein pairs found in Table 1 are displayed. We plotted codon counts for the viral protein (X-axis) against the human protein&rsquo;s codon counts (Y-axis). Each graph has 64 points, each representing a codon. Points near the top right are used at a higher rate than points near the bottom left. The line represents the result of a best-fit linear model, indicating that there is a strong correlation--as protein codon usage increases, so does the codon usage count of the respective virus. Residual plots of the linear regression were also analyzed and appear to fit the assumptions of the model. (A) displays RHOT2 vs HHV-4 (correlation of 93.6%), (B) shows TEX15 vs HHV-6B (correlation of 93.1%), (C) shows KBTBD3 vs HPV-121 (correlation of 92.8%), and (D) displays RBM44 vs HHV-7 (correlation of 92.8%). See Table 1 for more information on these pairs.</p>