Phylogenetic analysis of ribonuclease H domains suggests a late, chimeric origin of LTR retrotransposable elements and retroviruses
Open accessAbstract
We have conducted a phylogenetic analysis of the Ribonuclease HI (RNH) domains present in Eubacteria, Eukarya, all long-term repeat (LTR)-bearing retrotransposons, and several late-branching clades of non-LTR retrotransposons. Analysis of this simple yet highly conserved enzymatic domain from these disparate sources provides surprising insights into the evolution of eukaryotic retrotransposons. First, it indicates that the lineage of elements leading to vertebrate retroviruses acquired a new RNH domain either from non-LTR retrotransposons or from a eukaryotic host genome. The preexisting retroviral RNH domain degenerated to become the tether (connection) domain of the reverse transcriptase (RT)–RNH complex. Second, it indicates that all LTR retrotransposons arose in eukaryotes well after the origin of the non-LTR retrotransposons. Because of the younger age of the LTR retrotransposons, their complex structure, and the absence of any prokaryotic precursors, we propose that the LTR retrotransposons originated as a fusion between a DNA-mediated transposon and a non-LTR retrotransposon. The resulting two-step mechanism of LTR retrotransposition, in which RNA is reverse transcribed away from the chromosomal target site, rather than directly onto the target site, was probably an adaptation to the uncoupling of transcription and translation in eukaryotic cells.
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Ribonuclease H belongs to the retroviral integrase superfamily.
“Structurally, RNH belongs to the retroviral integrase superfamily [19,23,24]”
From Retroviral RNase H: structure, mechanism, and inhibition (2021) · cites this paper as [19]
The section on vertebrate retroviruses reacquiring their RNH domain describes a structural fold and catalytic features shared by RNH and retroviral integrases. It does not classify RNH as a member of a retroviral integrase superfamily, so the structural connection is supported but the stated membership is not. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThe connection, ribonuclease H, and integrase domains share a similar RNH-like fold consisting of a five-stranded beta-sheet with alpha-helices.
“the connection, RNH, and IN domains that are encoded in retroviral Pol (Figure 1a) share a similar RNH-like fold, a five stranded β–sheet with α–helices [19,23,24]”
From Retroviral RNase H: structure, mechanism, and inhibition (2021) · cites this paper as [19]
Experimental — accuracy not yet measuredThe active-site histidine is not conserved in LTR retrotransposons.
“Interestingly, the His residue is not conserved in the LTR retrotransposons [19].”
From Retroviral RNase H: structure, mechanism, and inhibition (2021) · cites this paper as [19]
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- Authors
- Malik, H. S., & Eickbush, T. H.
- Affiliations
- Fred Hutch Cancer Center (US)
- ORCID
- Malik, Harmit S.
- Venue
- Genome Research
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2001-07-01
- Volume
- 11
- Issue
- 7
- Pages
- 1187-1197
- ISSN
- 1088-9051 (ISSN-L)
- 1549-5469
- OpenAlex
- W2166752015
- Semantic Scholar
- 20853baf5fec3bca1e2fc1f8504e2b198ad89ab8
- Cited by
- 248
- References
- 67
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 8 · 2023: 2 · 2022: 4 · 2021: 18 · 2020: 5 · 2019: 7 · 2018: 5 · 2017: 12 · 2016: 7 · 2015: 15 · 2014: 5 · 2013: 12 · 2012: 12
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genome Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation (9974606, GM-29009)
- Helen Hay Whitney Foundation
- National Institutes of Health (MCB-9974606, 5r01gm029009-21, GM29009)
- National Institute of General Medical Sciences (GM29009)
- Topics
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Keywords
- LTR retrotransposons, non-LTR retrotransposons, retroviral evolution, reverse transcriptase, phylogenetic analysis
- MeSH terms
- Amino Acid Sequence, Animals, Humans, Models, Molecular, Molecular Sequence Data, Phylogeny, Recombinant Fusion Proteins, Retroviridae, Viral Proteins, Sequence Alignment, Ribonuclease H, Protein Structure, Tertiary, Retroelements, Terminal Repeat Sequences, Catalytic Domain, Amino Acid Motifs
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