A Single IGF1 Allele Is a Major Determinant of Small Size in Dogs

National Human Genome Research Institute, Building 50, Room 5349, 50 South Drive MSC 8000, Bethesda, MD 20892-8000, USA.
Science (Impact Factor: 33.61). 05/2007; 316(5821):112-5. DOI: 10.1126/science.1137045
Source: PubMed


The domestic dog exhibits greater diversity in body size than any other terrestrial vertebrate. We used a strategy that exploits
the breed structure of dogs to investigate the genetic basis of size. First, through a genome-wide scan, we identified a major
quantitative trait locus (QTL) on chromosome 15 influencing size variation within a single breed. Second, we examined genetic
variation in the 15-megabase interval surrounding the QTL in small and giant breeds and found marked evidence for a selective
sweep spanning a single gene (IGF1), encoding insulin-like growth factor 1. A single IGF1 single-nucleotide polymorphism haplotype is common to all small breeds and nearly absent from giant breeds, suggesting that
the same causal sequence variant is a major contributor to body size in all small dogs.

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Available from: Badri Padhukasahasram,
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    • "Analysis of the dog genome revealed SINE insertion polymorphisms resulting in anti-sense transcription that provide alternate splice site junctions [30]. For example, alterations of fur color [31], muscular disorders [32,33] and body size diversity [34,35] in Canidae are correlated with SINE insertions associated respectively with SILV, PTPLA and IGF1. In addition, SINE insertion into an exon of STK38L causes retinal degeneration [36] and an ancient SINE locus serves as an enhancer for fibroblast growth factor 8 (Fgf8) during mammalian brain formation [37]. "
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    ABSTRACT: Background Repetitive short interspersed elements (SINEs) are retrotransposons ubiquitous in mammalian genomes and are highly informative markers to identify species and phylogenetic associations. Of these, SINEs unique to the order Carnivora (CanSINEs) yield novel insights on genome evolution in domestic dogs and cats, but less is known about their role in related carnivores. In particular, genome-wide assessment of CanSINE evolution has yet to be completed across the Feliformia (cat-like) suborder of Carnivora. Within Feliformia, the cat family Felidae is composed of 37 species and numerous subspecies organized into eight monophyletic lineages that likely arose 10 million years ago. Using the Felidae family as a reference phylogeny, along with representative taxa from other families of Feliformia, the origin, proliferation and evolution of CanSINEs within the suborder were assessed. Results We identified 93 novel intergenic CanSINE loci in Feliformia. Sequence analyses separated Feliform CanSINEs into two subfamilies, each characterized by distinct RNA polymerase binding motifs and phylogenetic associations. Subfamily I CanSINEs arose early within Feliformia but are no longer under active proliferation. Subfamily II loci are more recent, exclusive to Felidae and show evidence for adaptation to extant RNA polymerase activity. Further, presence/absence distributions of CanSINE loci are largely congruent with taxonomic expectations within Feliformia and the less resolved nodes in the Felidae reference phylogeny present equally ambiguous CanSINE data. SINEs are thought to be nearly impervious to excision from the genome. However, we observed a nearly complete excision of a CanSINEs locus in puma (Puma concolor). In addition, we found that CanSINE proliferation in Felidae frequently targeted existing CanSINE loci for insertion sites, resulting in tandem arrays. Conclusions We demonstrate the existence of at least two SINE families within the Feliformia suborder, one of which is actively involved in insertional mutagenesis. We find SINEs are powerful markers of speciation and conclude that the few inconsistencies with expected patterns of speciation likely represent incomplete lineage sorting, species hybridization and SINE-mediated genome rearrangement.
    BMC Evolutionary Biology 06/2014; 14(1):137. DOI:10.1186/1471-2148-14-137 · 3.37 Impact Factor
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    • "Although growth rate returned to normal after 2 weeks, the weight of the adult mice remained lower than normal due to a decrease in muscle and bone mass and internal organ weight (with the exception of cortex and cerebellum) associated with a decrease in circulating insulin-like growth factor I (IGF1) levels. The IGF1 gene is a strong genetic determinant of body size across mammals and a single IGF1 allele is a major determinant of small size in dogs [1]. Consequently, CNVs near these genes may affect gene expression of this body size associated gene, or act as tag for sequence changes in the gene or its promoter that affect expression. "
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    ABSTRACT: Background Although a variety of genetic changes have been implicated in causing phenotypic differences among dogs, the role of copy number variants (CNVs) and their impact on phenotypic variation is still poorly understood. Further, very limited knowledge exists on structural variation in the gray wolf, the ancestor of the dog, or other closely related wild canids. Documenting CNVs variation in wild canids is essential to identify ancestral states and variation that may have appeared after domestication. Results In this work, we genotyped 1,611 dog CNVs in 23 wolf-like canids (4 purebred dogs, one dingo, 15 gray wolves, one red wolf, one coyote and one golden jackal) to identify CNVs that may have arisen after domestication. We have found an increase in GC-rich regions close to the breakpoints and around 1 kb away from them suggesting that some common motifs might be associated with the formation of CNVs. Among the CNV regions that showed the largest differentiation between dogs and wild canids we found 12 genes, nine of which are related to two known functions associated with dog domestication; growth (PDE4D, CRTC3 and NEB) and neurological function (PDE4D, EML5, ZNF500, SLC6A11, ELAVL2, RGS7 and CTSB). Conclusions Our results provide insight into the evolution of structural variation in canines, where recombination is not regulated by PRDM9 due to the inactivation of this gene. We also identified genes within the most differentiated CNV regions between dogs and wolves, which could reflect selection during the domestication process. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-465) contains supplementary material, which is available to authorized users.
    BMC Genomics 06/2014; 15(1):465. DOI:10.1186/1471-2164-15-465 · 3.99 Impact Factor
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    • "One striking conclusion from these studies is that convergent evolution often occurs via parallel genetic mechanisms, with the same genomic regions, genes, and sometimes even alleles used for evolutionary change. This genetic parallelism of convergent evolution has been observed in naturally [18-23] and artificially [24-26] selected populations of animals, as well as in plants [27-30], and experimentally evolved microbes [31-33]. These common phenomena of convergent and parallel evolution suggest that some evolutionary trajectories are constrained and perhaps even predictable. "
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    ABSTRACT: Background Convergent evolution, the repeated evolution of similar phenotypes in independent lineages, provides natural replicates to study mechanisms of evolution. Cases of convergent evolution might have the same underlying developmental and genetic bases, implying that some evolutionary trajectories might be predictable. In a classic example of convergent evolution, most freshwater populations of threespine stickleback fish have independently evolved a reduction of gill raker number to adapt to novel diets. Gill rakers are a segmentally reiterated set of dermal bones important for fish feeding. A previous large quantitative trait locus (QTL) mapping study using a marine × freshwater F2 cross identified QTL on chromosomes 4 and 20 with large effects on evolved gill raker reduction. Results By examining skeletal morphology in adult and developing sticklebacks, we find heritable marine/freshwater differences in gill raker number and spacing that are specified early in development. Using the expression of the Ectodysplasin receptor (Edar) gene as a marker of raker primordia, we find that the differences are present before the budding of gill rakers occurs, suggesting an early change to a lateral inhibition process controlling raker primordia spacing. Through linkage mapping in F2 fish from crosses with three independently derived freshwater populations, we find in all three crosses QTL overlapping both previously identified QTL on chromosomes 4 and 20 that control raker number. These two QTL affect the early spacing of gill raker buds. Conclusions Collectively, these data demonstrate that parallel developmental genetic features underlie the convergent evolution of gill raker reduction in freshwater sticklebacks, suggesting that even highly polygenic adaptive traits can have a predictable developmental genetic basis.
    EvoDevo 05/2014; 5(1):19. DOI:10.1186/2041-9139-5-19 · 3.03 Impact Factor
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