The 2R hypothesis: an update

doi:10.1016/j.coi.2007.07.009

Current Opinion in Immunology

Volume 19, Issue 5, October 2007, Pages 547-552

https://doi.org/10.1016/j.coi.2007.07.009 Get rights and content

Nearly forty years ago, Susumu Ohno proposed that one or two rounds of whole genome duplication took place close to the origin of vertebrates. The refined version of this proposal, known as the two round (2R) hypothesis, assumes that the genome of jawed vertebrates has been shaped by two rounds of whole genome duplication that took place after the emergence of urochordates and before the radiation of jawed vertebrates. Although this hypothesis has been a focus of heated debate in recent years, it is increasingly supported by genome-wide analysis of key chordate species. The 2R hypothesis has important implications for understanding the evolution of the immune system, including the origin of the major histocompatibility complex and natural killer receptors.

Introduction

In his famous book published in 1970, Susumu Ohno advanced the idea that the vertebrate genome underwent one or two rounds of whole genome duplication (WGD) at the stage of fish or amphibians through a tetraploidization process [1]. This idea was based mainly on the comparison of DNA content (genome size) and karyotypes in various organisms, and the observation that tetraploid species occur naturally in fishes and amphibians. When a gene is duplicated, one of the copies becomes redundant and is allowed to escape from purifying selection. Although such a copy normally accumulates deleterious mutations and is eventually lost, it may acquire a new function on rare occasions. Because WGD affects the organism's entire set of genes simultaneously, it would generate large amounts of genetic raw material that can potentially acquire novel functions. Compared to cumulative gene duplications such as tandem duplications, WGD would enable duplicated genes to co-evolve more efficiently, thus leading to the formation of gene networks required for biological innovations [1].

This influential hypothesis has been a subject of intense debate during the past decade [2, 3]. Some have strongly supported the refined version of Ohno's hypothesis known as the two round (2R) hypothesis, others have argued for only one round of WGD, and still others have rejected the idea of WGD altogether. Here I review the current status of the 2R hypothesis mainly focusing on the developments for the past three years and discuss its relevance for understanding the evolution of the immune system. There is now incontrovertible evidence supporting the 2R hypothesis.

Section snippets

An overview of the 2R hypothesis

Until recently, the most popular form of the hypothesis had assumed two rounds of WGD after the emergence of cephalochordates and before the radiation of jawed vertebrates. However, recent evidence indicates that the urochordate rather than the cephalochordate is the invertebrate most closely related to the vertebrate [4••, 5••]. Hence, the latest version of the 2R hypothesis assumes two rounds of WGD after the emergence of urochordates and before the radiation of jawed vertebrates (Figure 1).

Major histocompatibility complex (MHC)

Because WGD affects the organism's entire set of genes including those with immune functions, the 2R hypothesis has important implications for understanding the evolution of the immune system. An observation that has attracted particular attention in this context is that the MHC is a prototypical region that displays genome paralogy [21] (Figure 2). Indeed, along with the HOX paralogy group (see Glossary), the MHC paralogy group, which involves more than 100 gene families mapping to human

Other paralogons of immunological interest

Du Pasquier et al. [47] recently showed that the human chromosomal region 3q13–q21 is paralogous to 11q23–q25, 1q22–q24, and 21q21–q22. This paralogy group contains several antigen receptor-like immunoglobulin superfamily genes such as those encoding members of nectin, junctional adhesion molecule (JAM), cortical thymocytes marker of Xenopus (CTX), and B7 families. It has been proposed that this paralogy group provided many genes constituting the infrastructure of the adaptive immune system and

Conclusions

In testing the 2R hypothesis, phylogenetic analysis has limited power because it alone cannot prove or disprove WGD; more informative is the arrangement of genes because it can provide definitive evidence for WGD. The distribution of ohnologs in the human genome [17^••] and the genome-wide comparison of gene arrangement between humans and amphioxus strongly support the 2R hypothesis. The ongoing sea lamprey genome project (Washington University, St Louis, MO, USA) is likely to provide additional

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgement

Research in the author's laboratory is supported by Grants-in-Aid for Scientific Research from The Ministry of Education, Culture, Sports, Science and Technology of Japan.

Glossary

Ohnologs: paralogs thought to have emerged close to the origin of vertebrates by WGD.
Paralogons or paralogous regions: chromosomal segments that contain closely linked sets of paralogous genes.
Paralogs or paralogous genes: genes within a single species that belong to the same gene family. The term contrasting with ‘paralogs’ is ‘orthologs’, with the latter referring to genes that diverged by speciation events.
Paralogy group: a set of paralogons derived from a single ancestral region.

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View full text

The 2R hypothesis: an update

Introduction

Section snippets

An overview of the 2R hypothesis

Major histocompatibility complex (MHC)

Other paralogons of immunological interest

Conclusions

References and recommended reading

Acknowledgement

Glossary

Trends Genet

Nature

Trends Genet

Genome Res

Philos Trans R Soc Lond B Biol Sci

Mol Biol Evol

Nature

Immunogenetics

Immunol Rev

Evolution by Gene Duplication

Computational approaches to unveiling ancient genome duplications

Nat Rev Genet

Tunicates and not cephalochordates are the closest living relatives of vertebrates

Nature

Deuterostome phylogeny reveals monophyletic chordates and the new phylum Xenoturbellida

Nature

Genomic analysis of Hox clusters in the sea lamprey Petromyzon marinus

J Exp Zool

Independent Hox-cluster duplications in lampreys

J Exp Zool B Mol Dev Evol

Evidence for independent Hox gene duplications in the hagfish lineage: a PCR-based gene inventory of Eptatretus stoutii

Mol Phylogenet Evol

Major events in the genome evolution of vertebrates: paranome age and size differ considerably between ray-finned fishes and land vertebrates

Proc Natl Acad Sci U S A

Numerous groups of chromosomal regional paralogies strongly indicate two genome doublings at the root of the vertebrates

J Struct Funct Genom

Genomic evolution of Hox gene clusters

Science

The genesis and evolution of homeobox gene clusters

Nat Rev Genet

Extensive genomic duplication during early chordate evolution

Nat Genet

Age distribution of human gene families shows significant roles of both large- and small-scale duplications in vertebrate evolution

Nat Genet

ParaDB: a tool for paralogy mapping in vertebrate genomes

Nucleic Acids Res

Two rounds of whole genome duplication in the ancestral vertebrate

PLoS Biol