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Strategies for mapping and cloning quantitative trait genes in rodents

Key Points

  • Many quantitative phenotypes of biomedical interest can be modelled in rodents, and the chromosomal locations of the genetic variants that contribute to phenotypic variation can be identified by crosses between inbred strains. Unfortunately, it has proved extremely difficult to find the genes that underlie this variation. In the past few years, several novel methods and resources have become available that might make quantitative trait loci (QTL) cloning more tractable.

  • A number of problems must be overcome if QTL cloning is to become routine. First, the methods that are used must be able to tackle QTLs that contribute to only a small percentage of the variation of a phenotype. Second, it is unlikely that genes will be identified by the presence of unambiguous sequence features. Third, many QTLs that are detected in an inbred-strain cross are due to multiple, physically linked small effects.

  • New methods for QTL mapping include the use of chromosome substitution strains (CSSs), the proposed Collaborative Cross, probabilistic ancestral haplotype reconstruction in outbred mice, Yin–Yang crosses, in silico analysis of sequence variants in multiple inbred strains, gene-expression profiling and quantitative complementation tests.

  • CSSs consist of a set of animals in which one chromosome is derived from one strain and all the rest from another. QTL mapping in a CSS delivers researchers faster to same the point that classical strategies have led them, but no further. The main drawback of the method is that it makes no allowances for the fractionation of a large QTL effect into many loci with smaller effects.

  • The proposed Collaborative Cross will be a panel of 1,000 recombinant lines derived from 8 inbred strains. Its creation would make it possible to map multiple small-effect QTLs onto regions of 4 cM or less, and it would be able to detect many interacting loci. However, the resolution would still be insufficient to identify genes.

  • Recombination inbred segregation tests and Yin–Yang crosses, applied to a large number of recombinant inbreds such as the Collaborative Cross, will increase mapping resolution to the point where individual genes could be identified.

  • Probabilistic ancestral haplotype reconstruction of outbred animals makes it possible to map QTLs to a resolution that is sufficient to guarantee candidature of a single gene. The disadvantages of the method are the complexities of the analysis, and the need for large numbers of animals and high-density genotyping.

  • In silico mapping exploits the shared ancestry of laboratory mouse strains to identify regions of common descent containing QTLs. However, the method is compromised by low power and the complex structure of the genomes of laboratory strains.

  • Gene-expression profiling, combined with genetic mapping data, can help to identify candidate genes. However, differential gene expression is not always a marker of a QTL, expression differences might be restricted to certain tissues or developmental stages, and finding a gene-expression difference within a relevant tissue in a relevant biochemical pathway does not prove the gene's candidacy at the QTL.

  • Quantitative complementation tests for an interaction between the null allele of the candidate gene and the QTL, rather than for a main effect of either. A positive result indicates allelism or epistasis at the QTL. The current drawback of such tests is the lack of appropriate mutants.

  • None of the strategies described in this review provide a comprehensive solution to gene identification after QTL mapping, but together they provide a powerful armamentarium to aid QTL cloning in the twenty-first century.

Abstract

Over the past 15 years, more than 2,000 quantitative trait loci (QTLs) have been identified in crosses between inbred strains of mice and rats, but less than 1% have been characterized at a molecular level. However, new resources, such as chromosome substitution strains and the proposed Collaborative Cross, together with new analytical tools, including probabilistic ancestral haplotype reconstruction in outbred mice, Yin–Yang crosses and in silico analysis of sequence variants in many inbred strains, could make QTL cloning tractable. We review the potential of these strategies to identify genes that underlie QTLs in rodents.

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Figure 1: The distribution of QTL effect sizes.
Figure 2: Effect size in F2 and BC relative to RI.
Figure 3: Haplotype complexity in inbred strains of mice.

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Acknowledgements

The authors are supported by the Wellcome Trust. We would like to thank C. Benoist for comments on the manuscript.

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Glossary

EFFECT SIZE

The percentage of the total phenotypic variation that is attributable to a QTL.

CONGENIC

A strain produced by a breeding strategy that delineates a genomic region containing a trait locus. Recombinants between two inbred strains are backcrossed to produce a strain that carries a single segment from one strain on the genetic background of the other.

INTROGRESSION

Introduction of a chromosomal segment from one strain into another by interbreeding.

HIDDEN MARKOV MODEL

A probabilistic description of a system in which the observed data depends on the hidden internal state of the system. The objective is usually to infer the likelihood that the system is in a particular hidden state, given the observed data.

DYNAMIC PROGRAMMING ALGORITHM

An algorithm that finds the optimum solution to a problem involving N objects in terms of the solutions to a series of smaller problems that involve subsets of the objects.

ANALYSIS OF VARIANCE

A statistical method to test the null hypothesis that the mean values of two or more groups are equal. The variance around the mean in groups is compared with the variance of the group mean. In genetic applications, the variance between families is compared with the variance within families. A significant F-ratio implies that variance between families is larger than within families.

ADMIXTURE MAPPING

Genetic mapping using individuals whose genomes are mosaics of fragments that are descended from genetically distinct populations. This method exploits differences in allele frequencies in the founders to determine ancestry at a locus in order to map traits, in a way that is broadly similar to an advanced intercross.

LINKAGE DISEQUILIBRIUM

The tendency for markers to have correlated genotypes when they are physically close together. Over several generations, recombination will break down linkage between markers and a QTL, so that linkage disequilibrium will only occur between markers that are close to a QTL. This explains why outbred animals can provide high-mapping resolution.

HAPLOTYPE SHARING

Sets of closely linked genetic variants in different individuals that are identical by descent around a locus.

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Flint, J., Valdar, W., Shifman, S. et al. Strategies for mapping and cloning quantitative trait genes in rodents. Nat Rev Genet 6, 271–286 (2005). https://doi.org/10.1038/nrg1576

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