The genomic signature of dog domestication reveals adaptation to a starch-rich diet

Abstract

The domestication of dogs was an important episode in the development of human civilization. The precise timing and location of this event is debated1,2,3,4,5 and little is known about the genetic changes that accompanied the transformation of ancient wolves into domestic dogs. Here we conduct whole-genome resequencing of dogs and wolves to identify 3.8 million genetic variants used to identify 36 genomic regions that probably represent targets for selection during dog domestication. Nineteen of these regions contain genes important in brain function, eight of which belong to nervous system development pathways and potentially underlie behavioural changes central to dog domestication6. Ten genes with key roles in starch digestion and fat metabolism also show signals of selection. We identify candidate mutations in key genes and provide functional support for an increased starch digestion in dogs relative to wolves. Our results indicate that novel adaptations allowing the early ancestors of modern dogs to thrive on a diet rich in starch, relative to the carnivorous diet of wolves, constituted a crucial step in the early domestication of dogs.

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Figure 1: Selection analyses identified 36 candidate domestication regions.
Figure 2: Selection for increased amylase activity.
Figure 3: Selection is associated with increased maltase activity.

Accession codes

Primary accessions

Sequence Read Archive

Data deposits

Sequence reads are available under the accession number SRA061854 (NCBI Sequence Read Archive).

References

  1. 1

    Ovodov, N. D. et al. A 33,000-year-old incipient dog from the Altai mountains of Siberia: evidence of the earliest domestication disrupted by the last glacial maximum. PLoS ONE 6, e22821 (2011)

    ADS  CAS  Article  Google Scholar 

  2. 2

    Davis, S. J. M. & Valla, F. R. Evidence for domestication of the dog 12,000 years ago in the Natufian of Israel. Nature 276, 608–610 (1978)

    ADS  Article  Google Scholar 

  3. 3

    Skoglund, P., Gotherstrom, A. & Jakobsson, M. Estimation of population divergence times from non-overlapping genomic sequences: examples from dogs and wolves. Mol. Biol. Evol. 28, 1505–1517 (2011)

    CAS  Article  Google Scholar 

  4. 4

    Pang, J. F. et al. mtDNA data indicate a single origin for dogs south of Yangtze River, less than 16,300 years ago, from numerous wolves. Mol. Biol. Evol. 26, 2849–2864 (2009)

    CAS  Article  Google Scholar 

  5. 5

    vonHoldt, B. M. et al. Genome-wide SNP and haplotype analyses reveal a rich history underlying dog domestication. Nature 464, 898–902 (2010)

    ADS  CAS  Article  Google Scholar 

  6. 6

    Coppinger, R. & Coppinger, L. Dogs: a Startling New Understanding of Canine Origin, Behaviour and Evolution (Scribner, 2001)

    Google Scholar 

  7. 7

    Hare, B., Wobber, V. & Wrangham, R. The self-domestication hypothesis: evolution of bonobo psychology is due to selection against aggression. Anim. Behav. 83, 573–585 (2012)

    Article  Google Scholar 

  8. 8

    Belyaev, D. K. Destabilizing selection as a factor in domestication. J. Hered. 70, 301–308 (1979)

    CAS  Article  Google Scholar 

  9. 9

    Fang, M., Larson, G., Ribeiro, H. S., Li, N. & Andersson, L. Contrasting mode of evolution at a coat color locus in wild and domestic pigs. PLoS Genet. 5, e1000341 (2009)

    Article  Google Scholar 

  10. 10

    Rubin, C. J. et al. Whole-genome resequencing reveals loci under selection during chicken domestication. Nature 464, 587–591 (2010)

    ADS  CAS  Article  Google Scholar 

  11. 11

    Lindblad-Toh, K. et al. Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature 438, 803–819 (2005)

    ADS  CAS  Article  Google Scholar 

  12. 12

    Koike, N. et al. Brorin, a novel secreted bone morphogenetic protein antagonist, promotes neurogenesis in mouse neural precursor cells. J. Biol. Chem. 282, 15843–15850 (2007)

    CAS  Article  Google Scholar 

  13. 13

    Cheng, L. et al. Tlx3 and Tlx1 are post-mitotic selector genes determining glutamatergic over GABAergic cell fates. Nature Neurosci. 7, 510–517 (2004)

    CAS  Article  Google Scholar 

  14. 14

    Napoli, I. et al. The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP. Cell 134, 1042–1054 (2008)

    CAS  Article  Google Scholar 

  15. 15

    Weston, M. C., Nehring, R. B., Wojcik, S. M. & Rosenmund, C. Interplay between VGLUT isoforms and endophilin A1 regulates neurotransmitter release and short-term plasticity. Neuron 69, 1147–1159 (2011)

    CAS  Article  Google Scholar 

  16. 16

    Varga, Z. M. et al. Zebrafish smoothened functions in ventral neural tube specification and axon tract formation. Development 128, 3497–3509 (2001)

    CAS  PubMed  Google Scholar 

  17. 17

    Tokuhiro, K., Ikawa, M., Benham, A. M. & Okabe, M. Protein disulfide isomerase homolog PDILT is required for quality control of sperm membrane protein ADAM3 and male fertility. Proc. Natl Acad. Sci. USA 109, 3850–3855 (2012)

    ADS  CAS  Article  Google Scholar 

  18. 18

    Gardner, A. J. & Evans, J. P. Mammalian membrane block to polyspermy: new insights into how mammalian eggs prevent fertilisation by multiple sperm. Reprod. Fertil. Dev. 18, 53–61 (2006)

    CAS  Article  Google Scholar 

  19. 19

    Boomgaarden, I., Vock, C., Klapper, M. & Doring, F. Comparative analyses of disease risk genes belonging to the acyl-CoA synthetase medium-chain (ACSM) family in human liver and cell lines. Biochem. Genet. 47, 739–748 (2009)

    CAS  Article  Google Scholar 

  20. 20

    Nichols, B. L. et al. The maltase-glucoamylase gene: common ancestry to sucrase-isomaltase with complementary starch digestion activities. Proc. Natl Acad. Sci. USA 100, 1432–1437 (2003)

    ADS  CAS  Article  Google Scholar 

  21. 21

    Wright, E. M., Loo, D. D. F. & Hirayama, B. A. Biology of human sodium glucose transporters. Physiol. Rev. 91, 733–794 (2011)

    CAS  Article  Google Scholar 

  22. 22

    Meisler, M. H. & Ting, C. N. The remarkable evolutionary history of the human amylase genes. Crit. Rev. Oral Biol. Med. 4, 503–509 (1993)

    CAS  Article  Google Scholar 

  23. 23

    Simpson, J. W., Doxey, D. L. & Brown, R. Serum isoamylase values in normal dogs and dogs with exocrine pancreatic insufficiency. Vet. Res. Commun. 8, 303–308 (1984)

    CAS  Article  Google Scholar 

  24. 24

    Worth, C. L., Preissner, R. & Blundell, T. L. SDM-a server for predicting effects of mutations on protein stability and malfunction. Nucleic Acids Res. 39, W215–W222 (2011)

    CAS  Article  Google Scholar 

  25. 25

    Pei, L. et al. NR4A orphan nuclear receptors are transcriptional regulators of hepatic glucose metabolism. Nature Med. 12, 1048–1055 (2006)

    MathSciNet  CAS  Article  Google Scholar 

  26. 26

    Mochizuki, K., Honma, K., Shimada, M. & Goda, T. The regulation of jejunal induction of the maltase-glucoamylase gene by a high-starch/low-fat diet in mice. Mol. Nutr. Food Res. 54, 1445–1451 (2010)

    CAS  Article  Google Scholar 

  27. 27

    Andersson, L. Studying phenotypic evolution in domestic animals: a walk in the footsteps of Charles Darwin. Cold Spring Harb. Symp. Quant. Biol. 74, 319–325 (2009)

    CAS  Article  Google Scholar 

  28. 28

    Diez-Sampedro, A. et al. A glucose sensor hiding in a family of transporters. Proc. Natl Acad. Sci. USA 100, 11753–11758 (2003)

    ADS  CAS  Article  Google Scholar 

  29. 29

    Hediger, M. A., Mendlein, J., Lee, H. S. & Wright, E. M. Biosynthesis of the cloned intestinal Na+ glucose cotransporter. Biochim. Biophys. Acta 1064, 360–364 (1991)

    CAS  Article  Google Scholar 

  30. 30

    Perry, G. H. et al. Diet and the evolution of human amylase gene copy number variation. Nature Genet. 39, 1256–1260 (2007)

    CAS  Article  Google Scholar 

  31. 31

    Li, H. et al. The sequence alignment/map format and SAMtools. Bioinformatics 25, 2078–2079 (2009)

    Article  Google Scholar 

  32. 32

    Weir, B. S. & Cockerham, C. C. Estimating F-statistics for the analysis of population-structure. Evolution 38, 1358–1370 (1984)

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Beissbarth, T. & Speed, T. P. GOstat: find statistically overrepresented Gene Ontologies within a group of genes. Bioinformatics 20, 1464–1465 (2004)

    CAS  Article  Google Scholar 

  34. 34

    Scheet, P. & Stephens, M. A fast and flexible statistical model for large-scale population genotype data: applications to inferring missing genotypes and haplotypic phase. Am. J. Hum. Genet. 78, 629–644 (2006)

    CAS  Article  Google Scholar 

  35. 35

    Dahlqvist, A. Method for assay of intestinal disaccharidases. Anal. Biochem. 7, 18–25 (1964)

    CAS  Article  Google Scholar 

  36. 36

    Xie, C. & Tammi, M. T. CNV-seq, a new method to detect copy number variation using high-throughput sequencing. BMC Bioinformatics 10, 80 (2009)

    Article  Google Scholar 

  37. 37

    Abyzov, A., Urban, A. E., Snyder, M. & Gerstein, M. CNVnator: An approach to discover, genotype, and characterize typical and atypical CNVs from family and population genome sequencing. Genome Res. 21, 974–984 (2011)

    CAS  Article  Google Scholar 

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Acknowledgements

We thank Järvzoo, Nordens ark and the Canine Biobank at Uppsala University and the Swedish University of Agricultural Sciences for providing samples, Uppsala Genomics Platform at SciLifeLab Uppsala for generating the resequencing data, the UPPNEX platform for assisting with computational infrastructure for data analysis and the Broad Institute Genomics Platform for validation genotyping. The project was funded by the SSF, the Swedish Research Council, the Swedish Research Council Formas, Uppsala University and a EURYI to K.L.-T. funded by the ESF supporting also E.A.; K.M. was funded by the Higher Education Commission, Pakistan.

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Contributions

K.L.-T. and Å.H. designed the study. K.L.-T. and E.A. oversaw the study. M.-L.A. coordinated and performed the majority of the sample collecting and O.L. and J.M.A. provided samples of critical importance. E.A. performed the SNP detection and selection analyses; A.R. identified candidate causative mutations and analysed haplotypes in CDRs; K.M. detected CNVs bioinformatically; M.T.W. performed phylogenetic analysis and analysed the Canine HD-array data; A.R. performed the maltase activity assay; M.-L.A. validated CNVs and quantified mRNA expression of candidate genes; M.P. performed validation SNP genotyping; E.A., A.R., M.-L.A. and K.L-T. interpreted the data; E.A. and K.L.-T. wrote the paper with input from the other authors.

Corresponding authors

Correspondence to Erik Axelsson or Kerstin Lindblad-Toh.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Discussions sections 1-9, Supplementary references, Supplementary Figures 1-24 and Supplementary Tables 1-25. (PDF 6581 kb)

Supplementary Data 1

This zipped file lists the position of short indels in the canine genome. (ZIP 3569 kb)

Supplementary Data 2

This zipped file lists the position of CNVs in the canine genome. (ZIP 257 kb)

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Axelsson, E., Ratnakumar, A., Arendt, M. et al. The genomic signature of dog domestication reveals adaptation to a starch-rich diet. Nature 495, 360–364 (2013). https://doi.org/10.1038/nature11837

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