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Origin and evolution of the adaptive immune system: genetic events and selective pressures

Key Points

  • The adaptive immune system as defined in humans — which includes antigen receptors generated by recombination-activating gene (RAG)-mediated rearrangement and diversified by members of the AID-APOBEC family; the major histocompatibility (MHC); extensive chemokine and cytokine networks; and secondary lymphoid tissues — arose early in the evolution of jawed vertebrates (in placoderms).

  • The RAG transposon is believed to have invaded an immunoglobulin superfamily exon in early jawed vertebrates. It is thought to have provided a new mechanism for generating antigen receptor diversity and led to the emergence of adaptive immunity.

  • Some features of adaptive immunity are evolutionarily conserved across species and other features show great plasticity, the latter driven by pathogens.

  • Two rounds of whole-genome duplication produced many paralogues (ohnologues) that are essential for the adaptive immune system of jawed vertebrates.

  • Jawless vertebrates have developed an adaptive immune system that employs variable lymphocyte receptors instead of T cell and B cell receptors.

  • Two types of variable lymphocyte receptors — VLRA and VLRB — are expressed on T- and B-like lymphoid cells, respectively, which suggests that the origin of cell-mediated and humoral immunity predates the origin of jawed vertebrates.


The adaptive immune system (AIS) in mammals, which is centred on lymphocytes bearing antigen receptors that are generated by somatic recombination, arose approximately 500 million years ago in jawed fish. This intricate defence system consists of many molecules, mechanisms and tissues that are not present in jawless vertebrates. Two macroevolutionary events are believed to have contributed to the genesis of the AIS: the emergence of the recombination-activating gene (RAG) transposon, and two rounds of whole-genome duplication. It has recently been discovered that a non-RAG-based AIS with similarities to the jawed vertebrate AIS — including two lymphoid cell lineages — arose in jawless fish by convergent evolution. We offer insights into the latest advances in this field and speculate on the selective pressures that led to the emergence and maintenance of the AIS.

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Figure 1: Overview of the evolution of the immune system in deuterostomes.
Figure 2: Antigen receptor proteins and genes in jawed vertebrates.
Figure 3: Two distinct forms of adaptive immunity in vertebrates.
Figure 4: The major histocompatibility complex paralogy group and the neurotrophin paralogy group in the human genome.
Figure 5: A hypothetical model for the origin of the two major forms of adaptive immune system.


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M.F.F. has been funded by the US National Institutes of Health grants AI027877 and RR006603. M.K. has been funded by a KAKENHI grant for the priority area 'Comparative Genomics' from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Corresponding authors

Correspondence to Martin F. Flajnik or Masanori Kasahara.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Figure 1

The HOX paralogy group. (PDF 269 kb)

Supplementary Table 1

Representative Ohnologs mapping to the MHC/neurotrophin- and HOX-paralogons (PDF 207 kb)

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Pre-Ensembl genome database


Somatic hypermutation

Mutation of the variable gene after mature B cells are stimulated. It results in affinity maturation of the antibody response. Like the class switch, it requires activation-induced cytidine deaminase.

Variable–diversity–joining rearrangement

(VDJ rearrangement.) The recombination-activating gene (RAG)-mediated ligation of T cell receptor or B cell receptor variable (V), diversity (D) and joining (J) gene segments during lymphocyte ontogeny, which generates the antigen receptor repertoire.


Also known as antibodies or B cell receptors, they are composed of two identical heavy (H) and light (L) chains that are covalently linked by disulphide bonds. Monomeric immunoglobulins are bivalent, and the binding site is made up of the amino-terminal variable domains of one H and one L chain. The class or isotype of an immunoglobulin is defined by its H chain.

Jawless fish

Primordial vertebrates without jaws, of which the only two extant forms are lampreys and hagfish.

Major histocompatibility complex

A large complex of tightly linked genes, many of which are involved in immunity. It encodes the polymorphic class I and class II molecules, which present antigens in the form of peptides to cytotoxic and helper T cells, respectively.

Jawed vertebrates

Vertebrates from cartilaginous fish to mammals. The first class of vertebrates with jaws, the placoderms, all became extinct.

Mucosal immunity

Immune responses made across epithelial surfaces, such as the gut and lung.

Immunoglobulin new antigen receptor

(IgNAR.) A specialized antibody in sharks that is composed of disulphide-linked heavy chains and no associated light chains.

Translocon organization

An organization of immunoglobulin genes in which there are multiple variable (V), diversity (D) and joining (J) segments upstream of a single constant gene.

Cluster organization

An organization of immunoglobulin genes in which there are single variable (V), diversity (D), joining (J) and constant gene segments, although sometimes two or three diversity segments occur together. Also known as minilocus organization.

Receptor editing

The re-rearrangement of antigen receptor genes to avoid self reactivity in the case of B cells or to express new receptors that can be positively selected in the case of T cells.

Class switch

The rearrangement of an existing variable–diversity–joining (VDJ) exon from the 5′ end of the immunoglobulin M gene to downstream constant (C) genes. Like somatic hypermutation, it requires activation-induced cytidine deaminase.

Major histocompatibility complex restriction

T cell receptors recognize antigens in the form of small peptides ranging from 9–22 amino acids that are bound to major histocompatibility complex (MHC) class I or class II molecules. The T cell receptor recognizes both the MHC protein and the peptide antigen — this is known as 'MHC restriction'.

Complementarity-determining region 3

A loop in the variable (V) region of the B cell receptor and T cell receptor chains that is encoded by the variable–diversity–joining (VDJ) intersection that is generated by recombination-activating gene (RAG)-mediated somatic rearrangement. It is the part of the antigen-binding site that is most diverse in amino acid sequence and length.

Transporter associated with antigen processing

(TAP). A transporter of the ATP-binding cassette superfamily that is involved in the transport of peptides from the cytosol into the lumen of the endoplasmic reticulum. It is a heterodimer composed of TAP1 and TAP2 subunits and has a crucial role in the transport of major histocompatibility complex class I-binding peptides.


A protein that facilitates the binding of peptides to major histocompatibility complex (MHC) class I molecules by forming a bridge between MHC class I molecules and transporter associated with antigen processing (TAP).

Recombination signal sequences

Conserved nucleotide sequences flanking variable (V), diversity (D) and joining (J) segments that are recognized by the recombination-activating gene (RAG) proteins to induce rearrangement.

Immunoglobulin superfamily

Domains of 90–100 amino acids composed of 7–9 β strands forming two sheets, generally stabilized by a disulphide bond. Found in B cell receptor, T cell receptor and major histocompatibility complex molecules.


Paralogues, named after Susumu Ohno, that are thought to have emerged close to the origin of vertebrates by whole-genome duplication.

Paralogy group

A set of paralogons that are derived from a single ancestral region.


(Also known as paralogous genes.) Genes within a single species that belong to the same gene family. In contrast to 'paralogues', 'orthologues' refers to genes that diverged by speciation events.


Chromosomal segments that contain closely linked sets of paralogues. Also known as paralogous regions.


Any substance that can clump particles together.


A family of cytidine deaminases that are involved in the hypermutation of variable–diversity–joining (VDJ) segments, in the immunoglobulin class switch and in defence against viruses. Two members of the family are implicated in generating diversity in variable lymphocyte receptors.

Allelic exclusion

The expression of a single receptor in cells with the potential to express more than two receptors.

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Flajnik, M., Kasahara, M. Origin and evolution of the adaptive immune system: genetic events and selective pressures. Nat Rev Genet 11, 47–59 (2010).

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