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  • Review Article
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Congenic mice: cutting tools for complex immune disorders

Nature Reviews Immunology volume 3, pages 243–252 (2003)Cite this article

Key Points

  • In general, autoimmune diseases, which are an important source of disease affecting the adult human population, are under complex genetic control and subject to strong genetic interactions.

  • An improved knowledge of the underlying genetics will provide immunologists with a framework for studying the immune dysregulation that occurs in such diseases.

  • Ascertainment of the number of genes that are involved and their characterization has proven to be difficult in humans, in part because of the clinical and genetic heterogeneity of human populations, and in part because of the underlying intrinsic genetic complexity of autoimmune diseases.

  • Using mouse models of human diseases that are under complex genetic control, such as insulin-dependent diabetes mellitus or systemic lupus erythematosus, can alleviate these problems.

  • Improved methods of genetic analysis, the availability of a draft sequence of the complete mouse genome, annotated complementary DNA libraries and new tools for expression and functional analysis have markedly improved the outlook for such research and emphasized the advantages of mice as a model system.

  • In this review, we provide an overview of the genetic analysis of autoimmune diseases and the crucial role played by congenic and consomic mouse strains in such research, and of current strategies and ongoing efforts to understand autoimmune diseases.

Abstract

Autoimmune diseases are, in general, under complex genetic control and subject to strong interactions between genetics and the environment. Greater knowledge of the underlying genetics will provide immunologists with a framework for study of the immune dysregulation that occurs in such diseases. Ascertaining the number of genes that are involved and their characterization have, however, proven to be difficult. Improved methods of genetic analysis and the availability of a draft sequence of the complete mouse genome have markedly improved the outlook for such research, and they have emphasized the advantages of mice as a model system. In this review, we provide an overview of the genetic analysis of autoimmune diseases and of the crucial role of congenic and consomic mouse strains in such research.

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Figure 1: Selected analytical tools in mouse genetics.
Figure 2: Comparison of classical-breeding and selected-breeding approaches to congenic-strain construction.
Figure 3: Haplotype mapping can help to reduce the size of a congenic candidate region.
Figure 4: The pivotal position occupied by congenic strains in the analysis of complex traits.

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Acknowledgements

We thank our colleagues F. Lepault, F. Colucci, J. Di Santo and C. Boitard for their critical comments on the manuscript.

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  1. Institut Pasteur, Unité Génétique Moléculaire Murine, 25 rue du Docteur Roux, Paris, 75015, France

    Ute C. Rogner & Philip Avner

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Correspondence to Philip Avner.

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DATABASES

LocusLink

GAD

Tim1

TIM1

OMIM

asthma

Bruton's autoimmune syndrome and X-linked agammaglobulinaemia

IDDM

multiple sclerosis

rheumatoid arthritis

SLE

Glossary

INBRED STRAIN

A strain that is essentially homozygous at all genetic loci. In mice, such strains are produced by brother–sister mating for at least 12 sequential generations, or more if other breeding systems are used.

RNA INTERFERENCE

(RNAi). A technique in which the expression of a gene is inhibited when a double-stranded complementary RNA is introduced into the organism.

PENETRANCE

The proportion of affected individuals among carriers of a particular genotype. If all individuals with a disease genotype show the disease phenotype, then the disease is said to be completely penetrant.

HAPLOTYPE

An alternative form of a group of genes, part of a chromosome or a gene complex. The term is applied to groups of genetic loci, whereas the term 'allele' refers to alternative forms of a single gene.

QUANTITATIVE TRAIT LOCI

(QTLs). Loci segregating alleles that have substantial input to the overall phenotype of a trait that is under complex genetic control.

YEAST ARTIFICIAL CHROMOSOME

(YAC). A large genomic fragment of up to 1 Mb in size, containing a centromere, an origin of replication and telomere sequences, that can be cloned into autonomously replicating yeast vectors. The genomic DNA fragments are maintained and propagated in the yeast Saccharomyces cerevisiae as linear chromosomes.

BACTERIAL ARTIFICIAL CHROMOSOME

(BAC). A cloning vector derived from a single-copy F-plasmid of Escherichia coli that carries the F replication and partitioning systems that ensure low copy number and faithful segregation of plasmid DNA to daughter cells. Large genomic fragments can be cloned into such vectors and they are faithfully replicated, which makes BACs useful for constructing genomic libraries.

EPISTASIS

When the phenotype caused by a mutation in one gene is masked or enhanced by a mutation in another gene.

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Rogner, U., Avner, P. Congenic mice: cutting tools for complex immune disorders. Nat Rev Immunol 3, 243–252 (2003). https://doi.org/10.1038/nri1031

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