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  • Review Article
  • Published:

Leader of the pack: gene mapping in dogs and other model organisms

Nature Reviews Genetics volume 9, pages 713–725 (2008)Cite this article

Key Points

  • The domestic dog offers a unique opportunity to explore the genetic basis of disease, morphology and behaviour by using over 400 distinct dog breeds created by artificial selection. Dogs and humans have roughly the same genes, share many aspects of their environment and suffer similar diseases, including cancer, diabetes and epilepsy.

  • The canine genome project provided a complete genome sequence, a SNP map and an understanding of the haplotype structure, and now genome-wide SNP genotyping arrays make it possible to carry out whole-genome trait mapping.

  • Trait-mapping strategies that are possible in dogs include genome-wide association mapping, quantitative trait loci mapping, across-breed mapping and selection mapping. Although traits that segregate within breeds are amenable to whole-genome association, fixed phenotypes might require cross-breed mapping strategies.

  • The dog-breed populations are ideally suited to a two-stage genome-wide association mapping strategy. First, genome-wide association in hundreds of cases and controls identifies one or more ∼1 Mb regions of association. Second, fine-mapping in multiple breeds with the same phenotype refines the association to 10–100 kb regions that contain the mutations.

  • Many of the mutations that have been linked to dog phenotypes so far are regulatory and involve diverse mutational mechanisms, including copy number polymorphisms, short interspersed nuclear element insertions and repeat length polymorphisms. This suggests that mutations in dogs are likely to be similar in nature to those that underlie human complex traits.

  • Many other model organisms have significant trait-mapping potential, and, as with the dog, the unique population history and biology of each should be considered when developing the necessary tools. This work is underway in numerous domestic animals, including the chicken, cattle, the cat and the horse, and is proposed for several fish, including sticklebacks and tilapia.

Abstract

The domestic dog offers a unique opportunity to explore the genetic basis of disease, morphology and behaviour. We share many diseases with our canine companions, including cancer, diabetes and epilepsy, making the dog an ideal model organism for comparative disease genetics. Using newly developed resources, whole-genome association in dog breeds is proving to be exceptionally powerful. Here, we review the different trait-mapping strategies, some key biological findings emerging from recent studies and the implications for human health. We also discuss the development of similar resources for other vertebrate organisms.

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Figure 1: Haplotype structure of the dog.
Figure 2: Two-stage mapping strategy.

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Acknowledgements

We thank L. Andersson for helpful comments on the manuscript and our colleagues in the canine genetics community.

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Authors and Affiliations

  1. Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, 02142, Massachusetts, USA

    Elinor K. Karlsson & Kerstin Lindblad-Toh

  2. FAS Center for Systems Biology, Harvard University, 7 Divinity Avenue, Cambridge, 02138, Massachusetts, USA

    Elinor K. Karlsson

  3. Department of Medical Biochemistry and Microbiology, Uppsala University, BOX 597, Uppsala, 751 24, Sweden

    Kerstin Lindblad-Toh

Authors
  1. Elinor K. Karlsson
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Correspondence to Kerstin Lindblad-Toh.

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Glossary

Population bottleneck

A marked reduction in population size followed by the survival and expansion of a small random sample of the original population.

Linkage disequilibrium

(LD). Non-random association of alleles at two or more loci.

Haplotype block

A haplotype is the combination of alleles observed for one or more consecutive markers on a chromosome. A haplotype block is the region of a chromosome that contains no recombination.

Genome-wide association

(GWA). An approach that tests the whole genome for a statistical association between a marker and a trait in unrelated cases and controls.

Simple sequence length polymorphism

Short tandem repeats of DNA that vary in length.

Linkage mapping

A mapping method which uses pedigrees to find broad genomic regions (10–20 centimorgans) that adhere to an inheritance model proposed for the trait of interest.

1:1 orthologues

Pairs of single genes in two different species that are descended from the same ancestral gene.

Selection mapping

A mapping design that finds trait loci by searching for selective sweeps. A selective sweep describes the reduction or elimination of genetic variation in a region owing to strong selection.

Genome coverage

The number of times, on average, that each base is sequenced.

Genome assembly

The consensus sequence of many short reads put together (a read is a fragment of sequenced DNA).

N50 contig size

A contig is a segment of the genome assembly that contains no gaps. An N50 contig size means that half of all bases reside in contigs of this size or longer.

Supercontig

Consecutive contigs that are separated by gaps of known size and connected by paired end-reads.

Validation rate

The rate at which genotypes are confirmed using a different technology.

Coalescence modelling

Retrospective modelling of population history, used to generate expectations on genomic variation.

Penetrance

The proportion of individuals carrying a genetic variant who express the trait connected with that variant.

Phenocopy

Describes an individual without the trait mutation who nonetheless exhibit the trait owing to environmental or other causes.

Multiplicative risk

An inheritance model whereby disease risk increases by λ in heterozygotes and λ2 in homozygotes.

Corrects for multiple tests

The adjusting of p-values for statistical tests that include many markers, when the probability that significant values will occur by random chance is increased.

Assay conversion rate

The fraction of assays that work on a certain genotyping platform.

Call rate

The fraction of individuals that give genotyping calls for a particular SNP.

Copy number variant

(CNV). A genomic region that is longer than 1 kb and occurs a variable number of times.

Semi-dominant

A Mendelian inheritance pattern in which heterozygous individuals exhibit a phenotype that is intermediate to the two homozygous phenotypes.

Population stratification

The presence of multiple population subgroups that show limited interbreeding. When such subgroups differ both in allele frequency and in disease prevalence, this can lead to erroneous results in association studies.

Quantitative trait locus

(QTL). A stretch of DNA that is closely linked to a continuously variable phenotype.

Inbreeding coefficient

The probability that two alleles are identical by descent.

Short interspersed nuclear element

(SINE). Retrotransposons ∼200 bases long that are derived from a tRNA–Lysine and occur frequently throughout the canine genome.

Adaptive radiation

The evolution, through adaptation to different ecological niches, of phenotypic differences between individuals derived from a single species.

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Karlsson, E., Lindblad-Toh, K. Leader of the pack: gene mapping in dogs and other model organisms. Nat Rev Genet 9, 713–725 (2008). https://doi.org/10.1038/nrg2382

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