The IGF1 small dog haplotype is derived from Middle Eastern grey wolves

Abstract

Background: A selective sweep containing the insulin-like growth factor 1 (IGF1) gene is associated with size variation in domestic dogs. Intron 2 of IGF1 contains a SINE element and single nucleotide polymorphism (SNP) found in all small dog breeds that is almost entirely absent from large breeds. In this study, we surveyed a large sample of grey wolf populations to better understand the ancestral pattern of variation at IGF1 with a particular focus on the distribution of the small dog haplotype and its relationship to the origin of the dog.

Results: We present DNA sequence data that confirms the absence of the derived small SNP allele in the intron 2 region of IGF1 in a large sample of grey wolves and further establishes the absence of a small dog associated SINE element in all wild canids and most large dog breeds. Grey wolf haplotypes from the Middle East have higher nucleotide diversity suggesting an origin there. Additionally, PCA and phylogenetic analyses suggests a closer kinship of the small domestic dog IGF1 haplotype with those from Middle Eastern grey wolves.

Conclusions: The absence of both the SINE element and SNP allele in grey wolves suggests that the mutation for small body size post-dates the domestication of dogs. However, because all small dogs possess these diagnostic mutations, the mutations likely arose early in the history of domestic dogs. Our results show that the small dog haplotype is closely related to those in Middle Eastern wolves and is consistent with an ancient origin of the small dog haplotype there. Thus, in concordance with past archeological studies, our molecular analysis is consistent with the early evolution of small size in dogs from the Middle East.See associated opinion by Driscoll and Macdonald: http://jbiol.com/content/9/2/10.

Figure 1

Sample map of grey wolf populations sequenced and schematic of insulin-like growth factor 1 (IGF1) molecular markers and exons. (a) The numbers outside the parentheses are sample sizes for the long sequence (6331 bps) and the numbers inside are sample sizes for the short sequence (4881 bps). (b) The chromosomal segment on the bottom shows the location of 94 dog-derived single nucleotide polymorphism (SNP) loci shown as black vertical lines. The chromosomal segments on the top show the locations of SNPs and indels discovered from sequencing.

Figure 2

Insulin-like growth factor 1 (IGF1) microsatellite allele frequency distributions in domestic and wild canids. Allele sizes of the di-nucleotide repeats are given on the X axis and their frequency is on the Y axis.

Figure 3

Principal components analysis of 94 dog-derived single nucleotide polymorphism loci in domestic and wild canids. Principal components one (PC1) is on the X axis and principal components two (PC2) is on the Y axis. The percent variation explained by each axis is also provided.

Figure 4

Insulin-like growth factor 1 (IGF1) Intron 2 neighbour-joining tree based on 6331 bp of phased sequence. Branch support (>50%) is based on 1000 bootstrap replications and shown as a percentage. Dashed lines indicate the location the small dog haplotype 5 was placed in the three constraint trees. Dog breeds are italicized while grey wolf populations are normal font and listed by geographic location.

Figure 5

Insulin-like growth factor 1 (IGF1) Intron 2 neighbour-joining tree from 4811 bp of phased sequence. Branch support (>50%) is based on 1000 bootstrap replications and shown as a percentage. Dashed lines indicate the location the small dog haplotype 3 was placed in the three constraint trees. Dog breeds are italicized while grey wolf populations are normal font and listed by geographic location.