Endogenization and excision of human herpesvirus 6 in human genomes

Liu, Xiaoxi; Kosugi, Shunichi; Koide, Rie; Kawamura, Yoshiki; Ito, Jumpei; Miura, Hiroki; Matoba, Nana; Matsuzaki, Motomichi; Fujita, Masashi; Kamada, Anselmo Jiro; Nakagawa, Hidewaki; Tamiya, Gen; Matsuda, Koichi; Murakami, Yoshinori; Kubo, Michiaki; Aswad, Amr; Sato, Kei; Momozawa, Yukihide; Ohashi, Jun; Terao, Chikashi; Yoshikawa, Tetsushi; Parrish, Nicholas F.; Kamatani, Yoichiro

doi:10.1371/journal.pgen.1008915

Cited by 25 publications

(15 citation statements)

References 64 publications

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“…While these approaches mark a giant leap forward for genomics, challenges remain regarding the reproducibility of read lengths, high error rates, and low coverage (difficulty in obtaining overlapping sequencing reads). This was exemplified by a recent study that used ONT to sequence the iciHHV-6−host junction ( 32 ). Although successful, it is important to note that only two reads were obtained across a relatively small junction of 1.3 kb.…”

Section: Discussionmentioning

confidence: 97%

Unbiased optical mapping of telomere-integrated endogenous human herpesvirus 6

Wight

Aimola

Aswad

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Next-generation sequencing technologies allowed sequencing of thousands of genomes. However, there are genomic regions that remain difficult to characterize, including telomeres, centromeres, and other low-complexity regions, as well as transposable elements and endogenous viruses. Human herpesvirus 6A and 6B (HHV-6A and HHV-6B) are closely related viruses that infect most humans and can integrate their genomes into the telomeres of infected cells. Integration also occurs in germ cells, meaning that the virus can be inherited and result in individuals harboring the virus in every cell of their body. The integrated virus can reactivate and cause disease in humans. While it is well established that the virus resides in the telomere region, the integration locus is poorly defined due to the low sequence complexity (TTAGGG)n of telomeres that cannot be easily resolved through sequencing. We therefore employed genome imaging of the integrated HHV-6A and HHV-6B genomes using whole-genome optical site mapping technology. Using this technology, we identified which chromosome arm harbors the virus genome and obtained a high-resolution map of the integration loci of multiple patients. Surprisingly, this revealed long telomere sequences at the virus−subtelomere junction that were previously missed using PCR-based approaches. Contrary to what was previously thought, our technique revealed that the telomere lengths of chromosomes harboring the integrated virus genome were comparable to the other chromosomes. Taken together, our data shed light on the genetic structure of the HHV-6A and HHV-6B integration locus, demonstrating the utility of optical mapping for the analysis of genomic regions that are difficult to sequence.

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Section: Discussionmentioning

confidence: 97%

Unbiased optical mapping of telomere-integrated endogenous human herpesvirus 6

Wight

Aimola

Aswad

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Germline-integrated HHV-6 has been reported in some of the same datasets analyzed here [ 32 ], however we recently described another form of integrated HHV-6 in which a single HHV-6 direct repeat (DR) is present (termed “solo-DR”). The solo-DR form presumably reflects recombination between the two DR regions present in the full-length integrated HHV-6 genome leading to excision of the unique portion of the viral genome [ 12 ]. Abundant HHV-6 reads were present in 18 datasets ( Table 1 and Figs 3A and S6 ), suggesting that these subjects likely have chromosomally-integrated copies of HHV-6.…”

Section: Resultsmentioning

confidence: 99%

“…In addition to retroviruses, sequences from ancient relatives of Borna disease virus, an RNA-only virus, were horizontally acquired in the haplorrhine lineage [10]. Human herpesviruses 6A and 6B, double stranded DNA viruses, have also been horizontally transferred to some human genomes during the holocene [11][12][13]. These observations show that viruses acquired during the lifespan of an individual organism, including humans, have sometimes contributed to the genetic material passed on to their offspring, seemingly in violation of Weismann's proposed barrier between soma and germline [14].…”

Section: Introductionmentioning

confidence: 99%

Virus-derived variation in diverse human genomes

2021

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Acquisition of genetic material from viruses by their hosts can generate inter-host structural genome variation. We developed computational tools enabling us to study virus-derived structural variants (SVs) in population-scale whole genome sequencing (WGS) datasets and applied them to 3,332 humans. Although SVs had already been cataloged in these subjects, we found previously-overlooked virus-derived SVs. We detected non-germline SVs derived from squirrel monkey retrovirus (SMRV), human immunodeficiency virus 1 (HIV-1), and human T lymphotropic virus (HTLV-1); these variants are attributable to infection of the sequenced lymphoblastoid cell lines (LCLs) or their progenitor cells and may impact gene expression results and the biosafety of experiments using these cells. In addition, we detected new heritable SVs derived from human herpesvirus 6 (HHV-6) and human endogenous retrovirus-K (HERV-K). We report the first solo-direct repeat (DR) HHV-6 likely to reflect DR rearrangement of a known full-length endogenous HHV-6. We used linkage disequilibrium between single nucleotide variants (SNVs) and variants in reads that align to HERV-K, which often cannot be mapped uniquely using conventional short-read sequencing analysis methods, to locate previously-unknown polymorphic HERV-K loci. Some of these loci are tightly linked to trait-associated SNVs, some are in complex genome regions inaccessible by prior methods, and some contain novel HERV-K haplotypes likely derived from gene conversion from an unknown source or introgression. These tools and results broaden our perspective on the coevolution between viruses and humans, including ongoing virus-to-human gene transfer contributing to genetic variation between humans.

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“…CC-BY 4.0 International license made available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is chromosome ends (Aswad et al, 2021;Greninger et al, 2018;Kawamura et al, 2017;Liu et al, 2018;Liu et al, 2020;Miura et al, 2018;Tweedy et al, 2016;Zhang et al, 2017). For example, iciHHV-6B is commonly found integrated into the telomere on the short arm of chromosome 17 (17p) in populations of European descent and iciHHV-6A is commonly found in the long arm of chromosome 22 (22q) in Japan.…”

Section: Introductionmentioning

confidence: 99%

“…For example, iciHHV-6B is commonly found integrated into the telomere on the short arm of chromosome 17 (17p) in populations of European descent and iciHHV-6A is commonly found in the long arm of chromosome 22 (22q) in Japan. Integration sites have been determined in a variety of studies by one or a combination of the following methods: Fluorescent in situ hybridisation (FISH); PCR amplification from subterminal sequences adjacent to human telomeres (subtelomere) into the viral genome; inverse PCR and comparison with known subtelomere sequences; long-read sequencing; optical genome mapping (Daibata et al, 1999;Huang et al, 2014;Luppi et al, 1998;Nacheva et al, 2008) (Aswad et al, 2021;Greninger et al, 2018;Kawamura et al, 2017;Liu et al, 2020;Miura et al, 2018;Tweedy et al, 2016;Wight et al, 2020;Zhang et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Variation in Human Herpesvirus 6B telomeric integration, excision and transmission between tissues and individuals

Wood

Veal

Neumann

et al. 2021

Preprint

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Human herpesviruses 6A and 6B (HHV-6A/6B) are ubiquitous pathogens that persist lifelong in latent form and can cause severe conditions upon reactivation. They are spread by community-acquired infection of free virus (acqHHV6A/6B) and by germline transmission of inherited chromosomally-integrated HHV-6A/6B (iciHHV-6A/6B) in telomeres. We exploited a hypervariable region of the HHV-6B genome to investigate the relationship between acquired and inherited virus and revealed predominantly maternal transmission of acqHHV-6B in families. Remarkably, we demonstrate that some copies of acqHHV-6B in saliva from healthy adults gained a telomere, indicative of integration and latency, and that the frequency of viral genome excision from telomeres in iciHHV-6B carriers is surprisingly high and varies between tissues. In addition, newly formed short telomeres generated by partial viral genome release are frequently lengthened, particularly in telomerase-expressing pluripotent cells. Consequently, iciHHV-6B carriers are mosaic for different iciHHV-6B structures, including circular extra-chromosomal forms that have the potential to reactivate. Finally, we show transmission of an HHV-6B strain from an iciHHV-6B mother to her non-iciHHV-6B son. Altogether we demonstrate that iciHHV-6B can readily transition between telomere-integrated and free virus forms.

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Endogenization and excision of human herpesvirus 6 in human genomes

Cited by 25 publications

References 64 publications

Unbiased optical mapping of telomere-integrated endogenous human herpesvirus 6

Unbiased optical mapping of telomere-integrated endogenous human herpesvirus 6

Virus-derived variation in diverse human genomes

Variation in Human Herpesvirus 6B telomeric integration, excision and transmission between tissues and individuals

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