Evolution of adaptive immunity from transposable elements combined with innate immune systems

Journal name:
Nature Reviews Genetics
Volume:
16,
Pages:
184–192
Year published:
DOI:
doi:10.1038/nrg3859
Published online

Abstract

Adaptive immune systems in prokaryotes and animals give rise to long-term memory through modification of specific genomic loci, such as by insertion of foreign (viral or plasmid) DNA fragments into clustered regularly interspaced short palindromic repeat (CRISPR) loci in prokaryotes and by V(D)J recombination of immunoglobulin genes in vertebrates. Strikingly, recombinases derived from unrelated mobile genetic elements have essential roles in both prokaryotic and vertebrate adaptive immune systems. Mobile elements, which are ubiquitous in cellular life forms, provide the only known, naturally evolved tools for genome engineering that are successfully adopted by both innate immune systems and genome-editing technologies. In this Opinion article, we present a general scenario for the origin of adaptive immunity from mobile elements and innate immune systems.

At a glance

Figures

  1. Adaptive immune systems of prokaryotes and eukaryotes.
    Figure 1: Adaptive immune systems of prokaryotes and eukaryotes.

    a | The prokaryotic clustered regularly interspaced short palindromic repeat–CRISPR-associated protein (CRISPR–Cas) locus consists of cas genes (blue arrows) that encode different Cas proteins, and CRISPR arrays composed of variable spacers (coloured hexagons) interspersed with direct repeats (red triangles). The leader sequence (grey rectangle) contains a promoter for the transcription of the CRISPR array and marks the end where new spacers are incorporated. Three stages of CRISPR–Cas immunity are depicted. During the adaptation stage, a Cas1–Cas2 heterohexamer uptakes a protospacer from the invading plasmid or viral DNA (green) and incorporates it at the leader-proximal end of the CRISPR array. During the expression stage, the CRISPR array is transcribed, and the transcript is processed into small CRISPR RNAs (crRNAs) by different Cas nucleases in a CRISPR–Cas type-dependent manner. During the interference stage, crRNAs act as guides for the cleavage of invading viral or plasmid DNA or RNA that contains regions complementary to the crRNA. b | Lymphocyte antigen receptor diversification by V(D)J recombination is shown. The variable region of the immunoglobulin heavy chain is assembled by V(D)J recombination from V (variable; purple rectangle), D (diversity; green rectangle) and J (joining; brown rectangle) gene segments. The immunoglobulin light chain is assembled from V and J segments by VJ recombination (not shown). Multiple V, D, J and C (constant region; red rectangles) gene segments are available for recombination in the germline genome. The recombination is carried out by the RAG1–RAG2 recombinase complex and involves two types of recombination signal sequences (RSSs), 23-RSS (red triangles) and 12-RSS (pink triangles), which flank each gene segment. Joining of the DNA ends requires non-homologous end-joining (NHEJ) proteins (not shown). Two rounds of recombination, D to J and V to DJ, produce a VDJ coding joint and two circular molecules (signal joints); the latter do not have any further role and are discarded. Transcription across the VDJ coding joint, followed by splicing, produces the mature transcript of the immunoglobulin heavy chain. Subsequent translation of the transcript, assembly of the heavy chain and association with the light chain (beige rectangles) complete the assembly of the immunoglobulin receptor.

  2. A general scheme of the organization of CRISPR-Cas systems.
    Figure 2: A general scheme of the organization of CRISPR–Cas systems.

    Protein names follow the current nomenclature and classification32. The general functions and the stages of the clustered regularly interspaced short palindromic repeat–CRISPR-associated protein (CRISPR–Cas) immunity are shown on the right; the corresponding proteins in each type of CRISPR–Cas system are shown on the left and are colour coded. Cas9 of Type II CRISPR–Cas is a multifunctional protein involved in several stages of the immune response, including processing of the primary CRISPR transcript into CRISPR RNAs (crRNAs), target binding and target cleavage. Similarly, in Type I and Type III CRISPR–Cas systems, Cas6 is a subunit of the Cascade (CRISPR-associated complex for antiviral defence) complex that is involved in both pre-crRNA processing, as well as target recognition and inactivation. Note that RNase III, which participates in cleavage of Type II CRISPR transcripts, has other roles in the processing of cellular RNA, particularly ribosomal RNA. Csn2 is predicted to be functionally analogous (but not homologous) to Cas4 and participates in spacer acquisition33. HD, histidine–aspartate family nuclease; LS, large subunit; SS, small subunit.

  3. A scenario for the evolution of the CRISPR-Cas system from a casposon, a toxin-antitoxin module and a solo-Cascade innate immune system.
    Figure 3: A scenario for the evolution of the CRISPR–Cas system from a casposon, a toxin–antitoxin module and a solo-Cascade innate immune system.

    Casposon-derived genes are shown as dark blue rectangles, toxin–antitoxin genes are depicted in grey and 'solo-Cascade' (CRISPR-associated complex for antiviral defence) genes are shown in green. A generic organization of a Type III Cascade operon is shown that does not depict any particular genomic locus. Most of the Cascade genes encode proteins that are distinct arrangements of one or two RNA recognition motif (RRM) domains and that might have evolved from a simple double-RRM protein through a series of RRM domain duplications and a fusion with a histidine–aspartate nuclease domain in Cas10 (Ref. 61). Terminal inverted repeats (TIRs) are palindromic, which is reminiscent of the CRISPR unit. polB, family B DNA polymerase; SS, small subunit.

  4. Comparison between TIR, CRISPR and RSS.
    Figure 4: Comparison between TIR, CRISPR and RSS.

    a | Schematic organization of the casposon from Aciduliprofundum boonei T469 (NC_013926, nucleotide coordinates: 380320-389403) is shown at the top, whereas the clustered regularly interspaced short palindromic repeat–CRISPR-associated protein (CRISPR–Cas) system of Thermotoga thermarum DSM 5069 (NC_015707, nucleotide coordinates: 1706198-1717565) is shown at the bottom. cas genes are colour-coded according to the scheme provided in Fig. 2. The alignment of the corresponding casposon terminal inverted repeat (TIR) and CRISPR sequence is shown in the middle. Identical nucleotides are indicated by the black background. b | Predicted secondary structures of the A. boonei casposon TIR (left) and T. thermarum CRISPR repeat (right) are shown. c | Comparison between the Transib TIRs and recombination signal sequences (RSSs) is shown. The Transib5 transposon from Drosophila melanogaster (top) is flanked by TIRs that consist of conserved heptamer and nonamer sequences separated by a variable spacer of either 13 bp (pink triangle) or 23 bp (red triangle). Sequence alignment of the Transib5 TIRs and the consensus recombination recognition sequence (RSS) is depicted. The variable spacers in RSSs are marked by 'n'. The most conserved nucleotides in the RSS heptamer and nonamer, which are necessary for efficient V(D)J recombination, are highlighted by the red background. The RSS and TIR sequences data are derived from Ref. 56. HD, histidine–aspartate family nuclease; polB, family B DNA polymerase.

  5. Comparison of the proposed evolutionary paths to the prokaryotic and eukaryotic versions of adaptive immunity.
    Figure 5: Comparison of the proposed evolutionary paths to the prokaryotic and eukaryotic versions of adaptive immunity.

    Terminal inverted repeats (TIRs) and recombination signal sequences (RSSs) are depicted as triangles. In the case of V(D)J recombination, TIRs and RSSs consist of conserved heptamer and nonamer sequences separated by a variable spacer of either 12 bp (pink triangles) or 23 bp (red triangles). V and J represent variable and joining gene segments of the immunoglobulin (Ig) gene, respectively. The dashed line indicates that RAG1 and RAG2 proteins are not encoded in proximity of the cognate recombination sites. CRISPR–Cas, clustered regularly interspaced short palindromic repeat–CRISPR-associated protein.

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Affiliations

  1. National Center for Biotechnology Information, National Library of Medicine, Bethesda, Maryland 20894, USA.

    • Eugene V. Koonin
  2. Institut Pasteur, Unité Biologie Moléculaire du Gène chez les Extrêmophiles, 25 rue du Docteur Roux, 75015 Paris, France.

    • Mart Krupovic

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  • Eugene V. Koonin

    Eugene V. Koonin is the leader of the Evolutionary Genomics Group at the National Center for Biotechnology Information (NCBI), Bethesda, Maryland, USA. He received his Ph.D. in Molecular Biology in 1983 from the Department of Biology, Moscow State University, Russia, joined the NCBI in 1991 and became a senior investigator in 1996. His group is pursuing several research directions in evolutionary genomics of prokaryotes, eukaryotes and viruses, as well as general problems of evolutionary theory. He is the author of Sequence - Evolution - Function: Computational Approaches in Comparative Genomics, (with Michael Galperin, 2003) and The Logic of Chance: The Nature and Origin of Biological Evolution (2011). He is the founder and Editor-in-Chief (with Laura Landweber and David Lipman) of Biology Direct, an open access, open peer-review journal. Eugene V. Koonin's homepage.

  • Mart Krupovic

    Mart Krupovic is a research scientist in the Department of Microbiology at Institut Pasteur, Paris, France. He obtained his Ph.D. in general microbiology under the supervision of Dennis Bamford at the University of Helsinki, Finland. His research interests include the origin and evolution of viruses, virus–host interactions in bacteria and archaea, and the impact of mobile genetic elements on the evolution of prokaryotic genomes. His ultimate goal is to unravel the complete dimensions and organization of the genetic network that encompasses viruses, plasmids, transposons and all other types of mobile elements. He is Associate Editor of Virus Evolution, a recently launched peer-reviewed journal, and Editorial Board Member for Biology Direct.

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