Rearrangement in the Hypervariable Region of JC Polyomavirus Genomes Isolated from Patient Samples and Impact on Transcription Factor-Binding Sites and Disease Outcomes
Abstract
:1. Introduction
2. Results
2.1. The Curation of 989 JCPyV NCCR Sequences from Patient Samples
2.2. NCCR Sequences from PML Patients Derived from Urine Samples Were Distinct from Those from CSF, Brain, and Plasma Samples
2.3. The Heterogenicity of NCCR Blocks across Sample Isolation Sites
2.4. Sequences Isolated from Urine Samples Had a Higher Frequency of TFBS That Repress JCPyV Infection, While TFBS That Facilitate JCPyV Infection Were More Frequent in Sequences from Other Tissues
2.5. Highly Variable Number of TFBS in NCCR Viral Isolates from the Brain, Plasma, and CSF, Specifically in Blocks “c” and “d”
2.6. The Number of Forkhead and Homeobox TFBS Were Increased in the “c” Block of Patients with PML
3. Discussion
4. Materials and Methods
4.1. Determining and Visualizing the Blocks of Each NCCR Viral Isolate
4.2. Comprehensive Search for JCPyV NCCR Sequences
4.3. Analysis of Blocks among 989 NCCR Sequences
4.4. Validating the Perl Script to Determine the Accuracy and Precision of Capturing the NCCR and the Individual Blocks
4.5. Cladogram
4.6. Mapping TFBS for Each NCCR Sequence Using the JASPAR Database
4.7. Statistical Analysis of TFBS
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Tissue Source | Primary Disease State | Total | Secondary Disease | Number of Cases |
---|---|---|---|---|
Brain (n = 32) | PML | 26 (81%) | HIV | 11 (34%) |
MS a | 1 (3%) | |||
WAS 1 | 1 (3%) | |||
HIGM 2 | 1 (3%) | |||
N/A | 12 (38%) | |||
JCPyVE 3 | 1 (3%) | H/O Lung Cancer | 1 (3%) | |
GCN b | 1 (3%) | MS | 1 (3%) | |
N/A | 4 (13%) | N/A | 4 (13%) | |
Plasma/serum/PBMC (i.e., blood) (n = 111) | PML | 91 (82%) | HIV | 7 (6%) |
MS | 81 (73%) | |||
N/A | 3 (3%) | |||
Consistent with PML | 7 (6%) | HIV | 7 (6%) | |
N/A | 13 (12%) | HIV | 5 (5%) | |
N/A | 8 (7%) | |||
CSF (n = 217) | PML | 195 (90%) | HIV | 46 (21%) |
HIV/MS | 2 (1%) | |||
RA 4 | 1 (1%) | |||
SLE c | 9 (4%) | |||
MS | 80 (37%) | |||
AML d | 15 (7%) | |||
ALL e | 7 (3%) | |||
CLL f | 4 (2%) | |||
NHL | 4 (2%) | |||
WM 5 | 8 (4%) | |||
Other # | 14 (6%) | |||
N/A | 5 (2%) | |||
Consistent with PML | 6 (3%) | HIV | 6 (3%) | |
Suspected of PML | 14 (6%) | HIV | 2 (1%) | |
MS | 1 (1%) | |||
N/A | 11 (5%) | |||
N/A | 2 (1%) | HIV | 1 (1%) | |
N/A | 1 (1%) | |||
Kidney (n = 2) | JCPyVAN 6 | 2 (100%) | N/A | 2 (100%) |
Kidney; Urine (n = 3) | JCPyVAN 6 | 3 (100%) | N/A | 3 (100%) |
Brain; Kidney (n = 6) | N/A | 6 (100%) | N/A | 6 (100%) |
CSF; Plasma (n = 2) | Consistent with PML | 2 (100%) | HIV | 2 (100%) |
Urine (n = 565) | PML | 78 (14%) | HIV | 4 (1%) |
MS | 74 (13%) | |||
JCPyVAN 6 | 1 (0%) | N/A | 1 (0%) | |
4 (1%) | kidney transplant and subsequent antibody-mediated rejection | 4 (1%) | ||
Healthy | 179 (15%) | N/A | 179 (32%) | |
No PML | 25 (%) | Stable Kidney Transplant | 25 (4%) | |
N/A | 279 (65%) | HIV | 21 (4%) | |
SLE | 8 (1%) | |||
MS | 12 (2%) | |||
RA | 1 (0%) | |||
N/A | 236 (42%) | |||
No tissue reported (n = 50)% | PML | 47 (94%) | HIV | 3 (6%) |
MS | 44 (88%) | |||
N/A | 3 (6%) | N/A | 3 (6%) |
NCCR Block Code | Total # | Number of PML Patient Samples (Total Samples) | |||||
---|---|---|---|---|---|---|---|
CSF | Urine | Blood | Brain | Other | Not Specified | ||
AB----CD-----------------EF | 592 | 35 (36) | 75 (490) | 35 (44) | 1 (2) | 0 (6) | 13 (14) |
AB----C—-E-------------C-EF | 74 | 20 (23) | 1 (1) | 36 (38) | 2 (4) | 0 (1) | 7 (7) |
AB----CD---------------CDEF | 64 | 13 (13) | 2 (50) | 0 (1) | |||
AB----C—-E--B----------C-EF | 28 | 19 (22) | 0 (1) | 2 (3) | 2 (2) | ||
AB----C------------------EF | 22 | 9 (14) | 5 (6) | 2 (2) | |||
AB----C—-E------------FC-EF | 21 | 9 (9) | 10 (10) | 1 (2) | |||
AB----CD-E—-B----------CDEF | 17 | 9 (10) | 0 (1) | 2 (2) | 4 (4) | ||
A-----CD-----------------EF | 13 | 2 (2) | 0 (10) | 0 (1) | |||
AB----CD-E-------------CDEF | 11 | 6 (7) | 0 (1) | 2 (2) | 0 (1) | ||
AB----CD-----CD------EFCDEF | 10 | 10 (10) | |||||
AB----C-------------------F | 10 | 7 (7) | 3 (3) | ||||
AB----CD-EF-B----------CDEF | 10 | 5 (5) | 5 (5) | ||||
AB----C-B--------------C-EF | 10 | 2 (2) | 0 (1) | 0 (2) | 5 (5) | ||
A-----C—-E-A-----------C-EF | 9 | 2 (4) | 2 (2) | 2 (2) | 0 (1) | ||
-B----CD-----------------EF | 8 | 0 (8) | |||||
AB----CD-------------EFCDEF | 7 | 5 (5) | 1 (1) | 1 (1) | |||
AB----C-B--------------CDEF | 5 | 4 (5) | |||||
AB----CD-----------------E- | 4 | 3 (3) | 0 (1) | ||||
A-----CD---------------CDEF | 4 | 2 (2) | 0 (2) | ||||
AB----CD------------------F | 4 | 1 (2) | 0 (1) | 0 (1) | |||
A-----C------------------EF | 4 | 1 (1) | 0 (2) | 0 (1) | |||
AB----C-B----C-E-------C-EF | 4 | 4 (4) | |||||
AB----C-B----CD--------CDEF | 3 | 3 (3) | |||||
AB----CDB--------------CDEF | 3 | 3 (3) | |||||
AB----CD—------------EF-DEF | 3 | 1 (1) | 1 (1) | 1 (1) | |||
A-----C—-E-------------C-EF | 3 | 2 (2) | 0 (1) | ||||
AB----CD---------------CDE- | 3 | 1 (1) | 1 (1) | 1 (1) | |||
AB----C--E--BC-E-B-----C-EF | 2 | 2 (2) | |||||
AB----C--EF-BC-E-B-----C-EF | 2 | 2 (2) | |||||
AB----C-B----C---B-----C-EF | 2 | 1 (1) | 0 (1) | ||||
AB----CD-------------EFC--F | 2 | 2 (2) | |||||
AB----C------------------E- | 2 | 1 (1) | 1 (1) | ||||
AB----CD-----CDEFB-----CDEF | 1 | 1 (1) | |||||
AB----CD-----CDEF--CDEFCDEF | 1 | 1 (1) | |||||
AB----CD-E--B----------CDE- | 1 | 1 (1) | |||||
AB----CD-EF-BCDEFB-----CDEF | 1 | 1 (1) | |||||
AB----CD-EF--CDEF--CDEFCD-- | 1 | 1 (1) | |||||
AB----C--E-A-----B-----C-EF | 1 | 1 (1) | |||||
AB----C--E---C---B-----C-EF | 1 | 1 (1) | |||||
AB----C--E---C-E-B-----C-EF | 1 | 1 (1) | |||||
AB----C--E---C-E---C-E-C-EF | 1 | 1 (1) | |||||
AB----C--E---C-------EFC-EF | 1 | 1 (1) | |||||
AB-E--C--E---C-------E-C-EF | 1 | 1 (1) | |||||
AB---FCD-----------------EF | 1 | 1 (1) | |||||
A----FCD-----------------EF | 1 | 1 (1) | |||||
-B----CD-------------E-CDEF | 1 | 1 (1) | |||||
AB----C--E-------------C--F | 1 | 0 (1) | |||||
AB----C--EF-B----------C-EF | 1 | 0 (1) | |||||
A----FCD---------------CDEF | 1 | 0 (1) | |||||
-BC----------------------EF | 1 | 0 (1) | |||||
AB----CD----B----------C--F | 1 | 1 (1) | |||||
AB----CD---------------CD-F | 1 | 1 (1) | |||||
AB----CD-E--BC-E-B-----CDEF | 1 | 1 (1) | |||||
AB----CD-EF--------CDEFCDEF | 1 | 1 (1) | |||||
AB----C--E---C---B-C-E-C-EF | 1 | 1 (1) | |||||
AB----C--E---------C-E-C-EF | 1 | 1 (1) | |||||
A-----CD---------------CD-F | 1 | 1 (1) | |||||
ABC-B-CD----BCD--B-----C--- | 1 | 1 (1) | |||||
A-----C------------------E- | 1 | 1 (1) | |||||
AB----CD-----------CD-F--E- | 1 | 1 (1) | |||||
AB----CD-------------EF--EF | 1 | 0 (1) | |||||
AB-----D-----------------EF | 1 | 0 (1) | |||||
AB----C--E-A-----------C-EF | 1 | 0 (1) | |||||
A-----CD----B----------CDEF | 1 | 1 (1) | |||||
A-----C--E-A-C-E--A----C-EF | 1 | 0 (1) | |||||
Total | 989 | 195 (217) | 78 (566) | 91 (111) | 26 (32) | 0 (14) | 47 (49) |
Block Letter | Nucleotide Sequence | Maximum Mismatch Value |
---|---|---|
Block “a” | CCTGTATATATAAAAAAAAGGGAAGG | 9 |
Block “b” | AGGGAGGAGCTGGCTAAAACTG | 8 |
Block “c” | GATGGCTGCCAGCCAAGCATGAGCTCATACCTAGGGAGCCAACCAGCTGACAGCC | 27 |
Block “d” | AGAGGGAGCCCTGGCTGCATGCCACTGGCAGTTATAGTGAAACCCCTCCCATAGTCCTTAATCACA | 31 |
Block “e” | AGTAAACAAAGCACAAGG | 1 |
Block “f” | GGAAGTGGAAAGCAGCCAAGGGAACATGTTTTGCGAGCCAGAGCTGTTTTGGCTTGTCACCAGCTGGCCAGT | 31 |
Description of Error | Frequency of Error (%) | Mean (SD) (Block Code or Base Pairs) | % of Error out of the Average Length of the NCCR with Error (SD) |
---|---|---|---|
Block code less than 85% accurate | 13% | 77.7% (±4.2%) | N/A |
Block code greater than 100% (larger blocks from the initial analysis were interpreted as smaller and different block codes) | 6% | 123.5% (±26%) | N/A |
Autogenerated block annotation had nucleotides counted in two sequential blocks, occurring when the start of a block occurs before the end of the previous | 63% | 2.93 (±1.88) | 0.998% (±0.0807%) |
Predicted block lacks at least one base pair that was counted in the manual annotation | 93% | 8.84 (±9.12) | 3.07% (±3.29%) |
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Wilczek, M.P.; Pike, A.M.C.; Craig, S.E.; Maginnis, M.S.; King, B.L. Rearrangement in the Hypervariable Region of JC Polyomavirus Genomes Isolated from Patient Samples and Impact on Transcription Factor-Binding Sites and Disease Outcomes. Int. J. Mol. Sci. 2022, 23, 5699. https://doi.org/10.3390/ijms23105699
Wilczek MP, Pike AMC, Craig SE, Maginnis MS, King BL. Rearrangement in the Hypervariable Region of JC Polyomavirus Genomes Isolated from Patient Samples and Impact on Transcription Factor-Binding Sites and Disease Outcomes. International Journal of Molecular Sciences. 2022; 23(10):5699. https://doi.org/10.3390/ijms23105699
Chicago/Turabian StyleWilczek, Michael P., Aiden M. C. Pike, Sophie E. Craig, Melissa S. Maginnis, and Benjamin L. King. 2022. "Rearrangement in the Hypervariable Region of JC Polyomavirus Genomes Isolated from Patient Samples and Impact on Transcription Factor-Binding Sites and Disease Outcomes" International Journal of Molecular Sciences 23, no. 10: 5699. https://doi.org/10.3390/ijms23105699
APA StyleWilczek, M. P., Pike, A. M. C., Craig, S. E., Maginnis, M. S., & King, B. L. (2022). Rearrangement in the Hypervariable Region of JC Polyomavirus Genomes Isolated from Patient Samples and Impact on Transcription Factor-Binding Sites and Disease Outcomes. International Journal of Molecular Sciences, 23(10), 5699. https://doi.org/10.3390/ijms23105699