Comparative genomic, transcriptomic, and proteomic reannotation of human herpesvirus 6

Alexander L. Greninger, Giselle M. Knudsen, Pavitra Roychoudhury, Derek J. Hanson, Ruth Hall Sedlak, Hong Xie, Jon Guan, Thuy Nguyen, Vikas Peddu, Michael Boeckh, Meei Li Huang, Linda Cook, Daniel P. Depledge, Danielle M. Zerr, David M. Koelle, Soren Gantt, Tetsushi Yoshikawa, Mary Caserta, Joshua A. Hill, Keith R. Jerome

Research output: Contribution to journalArticle

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Abstract

Background: Human herpesvirus-6A and -6B (HHV-6) are betaherpesviruses that reach >90% seroprevalence in the adult population. Unique among human herpesviruses, HHV-6 can integrate into the subtelomeric regions of human chromosomes; when this occurs in germ line cells it causes a condition called inherited chromosomally integrated HHV-6 (iciHHV-6). Only two complete genomes are available for replicating HHV-6B, leading to numerous conflicting annotations and little known about the global genomic diversity of this ubiquitous virus. Results: Using a custom capture panel for HHV-6B, we report complete genomes from 61 isolates of HHV-6B from active infections (20 from Japan, 35 from New York state, and 6 from Uganda), and 64 strains of iciHHV-6B (mostly from North America). HHV-6B sequence clustered by geography and illustrated extensive recombination. Multiple iciHHV-6B sequences from unrelated individuals across the United States were found to be completely identical, consistent with a founder effect. Several iciHHV-6B strains clustered with strains from recent active pediatric infection. Combining our genomic analysis with the first RNA-Seq and shotgun proteomics studies of HHV-6B, we completely reannotated the HHV-6B genome, altering annotations for more than 10% of existing genes, with multiple instances of novel splicing and genes that hitherto had gone unannotated. Conclusion: Our results are consistent with a model of intermittent de novo integration of HHV-6B into host germline cells during active infection with a large contribution of founder effect in iciHHV-6B. Our data provide a significant advance in the genomic annotation of HHV-6B, which will contribute to the detection, diversity, and control of this virus.

Original languageEnglish
Article number204
JournalBMC Genomics
Volume19
Issue number1
DOIs
Publication statusPublished - 20-03-2018

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Human Herpesvirus 6
Proteomics
Founder Effect
Genome
Infection
Viruses
Geography
Uganda
Herpesviridae
Seroepidemiologic Studies
Firearms
Human Chromosomes
North America
Germ Cells

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Genetics

Cite this

Greninger, A. L., Knudsen, G. M., Roychoudhury, P., Hanson, D. J., Sedlak, R. H., Xie, H., ... Jerome, K. R. (2018). Comparative genomic, transcriptomic, and proteomic reannotation of human herpesvirus 6. BMC Genomics, 19(1), [204]. https://doi.org/10.1186/s12864-018-4604-2
Greninger, Alexander L. ; Knudsen, Giselle M. ; Roychoudhury, Pavitra ; Hanson, Derek J. ; Sedlak, Ruth Hall ; Xie, Hong ; Guan, Jon ; Nguyen, Thuy ; Peddu, Vikas ; Boeckh, Michael ; Huang, Meei Li ; Cook, Linda ; Depledge, Daniel P. ; Zerr, Danielle M. ; Koelle, David M. ; Gantt, Soren ; Yoshikawa, Tetsushi ; Caserta, Mary ; Hill, Joshua A. ; Jerome, Keith R. / Comparative genomic, transcriptomic, and proteomic reannotation of human herpesvirus 6. In: BMC Genomics. 2018 ; Vol. 19, No. 1.
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abstract = "Background: Human herpesvirus-6A and -6B (HHV-6) are betaherpesviruses that reach >90{\%} seroprevalence in the adult population. Unique among human herpesviruses, HHV-6 can integrate into the subtelomeric regions of human chromosomes; when this occurs in germ line cells it causes a condition called inherited chromosomally integrated HHV-6 (iciHHV-6). Only two complete genomes are available for replicating HHV-6B, leading to numerous conflicting annotations and little known about the global genomic diversity of this ubiquitous virus. Results: Using a custom capture panel for HHV-6B, we report complete genomes from 61 isolates of HHV-6B from active infections (20 from Japan, 35 from New York state, and 6 from Uganda), and 64 strains of iciHHV-6B (mostly from North America). HHV-6B sequence clustered by geography and illustrated extensive recombination. Multiple iciHHV-6B sequences from unrelated individuals across the United States were found to be completely identical, consistent with a founder effect. Several iciHHV-6B strains clustered with strains from recent active pediatric infection. Combining our genomic analysis with the first RNA-Seq and shotgun proteomics studies of HHV-6B, we completely reannotated the HHV-6B genome, altering annotations for more than 10{\%} of existing genes, with multiple instances of novel splicing and genes that hitherto had gone unannotated. Conclusion: Our results are consistent with a model of intermittent de novo integration of HHV-6B into host germline cells during active infection with a large contribution of founder effect in iciHHV-6B. Our data provide a significant advance in the genomic annotation of HHV-6B, which will contribute to the detection, diversity, and control of this virus.",
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Greninger, AL, Knudsen, GM, Roychoudhury, P, Hanson, DJ, Sedlak, RH, Xie, H, Guan, J, Nguyen, T, Peddu, V, Boeckh, M, Huang, ML, Cook, L, Depledge, DP, Zerr, DM, Koelle, DM, Gantt, S, Yoshikawa, T, Caserta, M, Hill, JA & Jerome, KR 2018, 'Comparative genomic, transcriptomic, and proteomic reannotation of human herpesvirus 6', BMC Genomics, vol. 19, no. 1, 204. https://doi.org/10.1186/s12864-018-4604-2

Comparative genomic, transcriptomic, and proteomic reannotation of human herpesvirus 6. / Greninger, Alexander L.; Knudsen, Giselle M.; Roychoudhury, Pavitra; Hanson, Derek J.; Sedlak, Ruth Hall; Xie, Hong; Guan, Jon; Nguyen, Thuy; Peddu, Vikas; Boeckh, Michael; Huang, Meei Li; Cook, Linda; Depledge, Daniel P.; Zerr, Danielle M.; Koelle, David M.; Gantt, Soren; Yoshikawa, Tetsushi; Caserta, Mary; Hill, Joshua A.; Jerome, Keith R.

In: BMC Genomics, Vol. 19, No. 1, 204, 20.03.2018.

Research output: Contribution to journalArticle

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AU - Greninger, Alexander L.

AU - Knudsen, Giselle M.

AU - Roychoudhury, Pavitra

AU - Hanson, Derek J.

AU - Sedlak, Ruth Hall

AU - Xie, Hong

AU - Guan, Jon

AU - Nguyen, Thuy

AU - Peddu, Vikas

AU - Boeckh, Michael

AU - Huang, Meei Li

AU - Cook, Linda

AU - Depledge, Daniel P.

AU - Zerr, Danielle M.

AU - Koelle, David M.

AU - Gantt, Soren

AU - Yoshikawa, Tetsushi

AU - Caserta, Mary

AU - Hill, Joshua A.

AU - Jerome, Keith R.

PY - 2018/3/20

Y1 - 2018/3/20

N2 - Background: Human herpesvirus-6A and -6B (HHV-6) are betaherpesviruses that reach >90% seroprevalence in the adult population. Unique among human herpesviruses, HHV-6 can integrate into the subtelomeric regions of human chromosomes; when this occurs in germ line cells it causes a condition called inherited chromosomally integrated HHV-6 (iciHHV-6). Only two complete genomes are available for replicating HHV-6B, leading to numerous conflicting annotations and little known about the global genomic diversity of this ubiquitous virus. Results: Using a custom capture panel for HHV-6B, we report complete genomes from 61 isolates of HHV-6B from active infections (20 from Japan, 35 from New York state, and 6 from Uganda), and 64 strains of iciHHV-6B (mostly from North America). HHV-6B sequence clustered by geography and illustrated extensive recombination. Multiple iciHHV-6B sequences from unrelated individuals across the United States were found to be completely identical, consistent with a founder effect. Several iciHHV-6B strains clustered with strains from recent active pediatric infection. Combining our genomic analysis with the first RNA-Seq and shotgun proteomics studies of HHV-6B, we completely reannotated the HHV-6B genome, altering annotations for more than 10% of existing genes, with multiple instances of novel splicing and genes that hitherto had gone unannotated. Conclusion: Our results are consistent with a model of intermittent de novo integration of HHV-6B into host germline cells during active infection with a large contribution of founder effect in iciHHV-6B. Our data provide a significant advance in the genomic annotation of HHV-6B, which will contribute to the detection, diversity, and control of this virus.

AB - Background: Human herpesvirus-6A and -6B (HHV-6) are betaherpesviruses that reach >90% seroprevalence in the adult population. Unique among human herpesviruses, HHV-6 can integrate into the subtelomeric regions of human chromosomes; when this occurs in germ line cells it causes a condition called inherited chromosomally integrated HHV-6 (iciHHV-6). Only two complete genomes are available for replicating HHV-6B, leading to numerous conflicting annotations and little known about the global genomic diversity of this ubiquitous virus. Results: Using a custom capture panel for HHV-6B, we report complete genomes from 61 isolates of HHV-6B from active infections (20 from Japan, 35 from New York state, and 6 from Uganda), and 64 strains of iciHHV-6B (mostly from North America). HHV-6B sequence clustered by geography and illustrated extensive recombination. Multiple iciHHV-6B sequences from unrelated individuals across the United States were found to be completely identical, consistent with a founder effect. Several iciHHV-6B strains clustered with strains from recent active pediatric infection. Combining our genomic analysis with the first RNA-Seq and shotgun proteomics studies of HHV-6B, we completely reannotated the HHV-6B genome, altering annotations for more than 10% of existing genes, with multiple instances of novel splicing and genes that hitherto had gone unannotated. Conclusion: Our results are consistent with a model of intermittent de novo integration of HHV-6B into host germline cells during active infection with a large contribution of founder effect in iciHHV-6B. Our data provide a significant advance in the genomic annotation of HHV-6B, which will contribute to the detection, diversity, and control of this virus.

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Greninger AL, Knudsen GM, Roychoudhury P, Hanson DJ, Sedlak RH, Xie H et al. Comparative genomic, transcriptomic, and proteomic reannotation of human herpesvirus 6. BMC Genomics. 2018 Mar 20;19(1). 204. https://doi.org/10.1186/s12864-018-4604-2