Research ArticleGENETICS

Structural variants in genes associated with human Williams-Beuren syndrome underlie stereotypical hypersociability in domestic dogs

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Science Advances  19 Jul 2017:
Vol. 3, no. 7, e1700398
DOI: 10.1126/sciadv.1700398
  • Fig. 1 Association of structural variants with indices of human-directed social behavior.

    Association with ABS (A), HYP (B), and SIS (C). Manhattan plots show statistical significance of each variant as a function of position in target region. Blue line denotes statistical significance to Bonferroni-corrected level (P = 2.38 × 10−3). Genic and intergenic variants are shown as green and red boxes, respectively.

  • Fig. 2 Association of structural variants with human-directed social behavior in multivariate regressions.

    Association in behavioral index model (A) and PC model (B). Manhattan plots show statistical significance of each variant as a function of position in the target region. Blue line denotes significance to Bonferroni-corrected level (P = 2.38 × 10−3); dashed purple line denotes suggestive significance (P = 0.01). Genic and intergenic variants are shown as green and red boxes, respectively.

  • Table 1 Genic loci associated with indices of human-directed social behavior across dogs and wolves.

    NA, not applicable.

    PhenotypeLocus IDSV typePosition
    (Mb)*
    β (SE)% Variation
    explained
    PCandidate
    gene
    ABSCfa6.66Deletion5.750.23 (0.09)4.451.38 × 10−4GTF2I
    Cfa6.3Insertion2.140.11 (0.07)0.568.12 × 10−4WBSCR17
    Cfa6.7Deletion2.540.12 (0.07)0.628.89 × 10−4WBSCR17
    SISCfa6.66Deletion5.75−27.0 (24.80)11.451.95 × 10−4GTF2I
    Top three principal
    components
    (PC model)
    Cfa6.72Deletion5.900.04 (0.052),
    −0.96 (0.57),
    1.11 (0.36)
    NA4.98 × 10−4GTF2IRD1

    *See table S7 for locus details.

    P values from likelihood ratio test (adjusted significance threshold P = 2.38 × 10−3).

    Supplementary Materials

    • Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/3/7/e1700398/DC1

      fig. S1. Differences between dogs and wolves for three behavioral indices used to predict the WBS phenotype.

      fig. S2. Scree plot of principal components of human-directed social behavior.

      fig. S3. Scan for positive selection using a bivariate percentile score (XP-EHH and FST) to identify outliers (dashed line; bivariate score, >2) indicated as sites in the 97.5th percentile.

      fig. S4. Gel electrophoresis banding patterns for three hypersociability-associated SV genotypes.

      fig. S5. A dot plot to represent the total number of insertions per population of species for each outlier locus.

      fig. S6. Plots from the ANOVA of the total number of SV insertions at four outlier loci.

      fig. S7. PCA from 25,510 unlinked genome-wide SNPs from the Affymetrix K9HDSNP array for six wolves and five dogs.

      fig. S8. SV discovery pipeline.

      fig. S9. Overlap in number of SVs identified by SVMerge, SoftSearch, and inGAP-sv.

      table S1. Raw behavioral data.

      table S2. Data for indices of human-directed social behavior.

      table S3. Loadings of first three PCs of human-directed social behavior.

      table S4. Genes in target region on canine chromosome 6.

      table S5. Sample information and the total number of raw reads compared to the number of processed reads after using cutadapt to trim/clip paired-end sequences.

      table S6. Outlier clusters on chromosome 6 (CanFam3.1) showing signals of positive selection from XP-EHH.

      table S7. Summary of de novo annotated structural variants on canine chromosome 6.

      table S8. De novo annotated structural variants on canine chromosome 6 (coordinates based on CanFam3.1 assembly).

      table S9. Structural variant summary statistics per individual.

      table S10. Genic loci associated with indices of human-directed social behavior across dogs and wolves after inclusion of species as a covariate.

      table S11. Association to species membership.

      table S12. Predicted functional consequences of SVs.

      table S13. The significantly enriched (adjusted P < 0.05) gene ontology term from a quantitative association test with each behavioral trait and 544,000 genome-wide SNPs.

      table S14. The significantly enriched (adjusted P < 0.05) gene ontology term from the univariate regression analysis conducted in GEMMA with each behavioral trait and 544,000 genome-wide SNPs.

      table S15. Behavioral data and description relative to WBS.

      table S16. Parameters for in silico annotation of structural variants for the three methods SVMerge, SoftSearch, and InGAP-SV.

      table S17. Structural variant genotype per individual.

      table S18. Primer sequences used for PCR and gel-based validation of structural variants.

      data file S1. Genotypes of the four outlier insertions in wild and domestic canids.

      Reference (99)

    • Supplementary Materials

      This PDF file includes:

      • fig. S1. Differences between dogs and wolves for three behavioral indices used to predict the WBS phenotype.
      • fig. S2. Scree plot of principal components of human-directed social behavior.
      • fig. S3. Scan for positive selection using a bivariate percentile score (XP-EHH and FST) to identify outliers (dashed line; bivariate score, >2) indicated as sites in the 97.5th percentile.
      • fig. S4. Gel electrophoresis banding patterns for three hypersociability-associated SV genotypes.
      • fig. S5. A dot plot to represent the total number of insertions per population of species for each outlier locus.
      • fig. S6. Plots from the ANOVA of the total number of SV insertions at four outlier loci.
      • fig. S7. PCA from 25,510 unlinked genome-wide SNPs from the Affymetrix K9HDSNP array for six wolves and five dogs.
      • fig. S8. SV discovery pipeline.
      • fig. S9. Overlap in number of SVs identified by SVMerge, SoftSearch, and inGAP-sv.
      • table S1. Raw behavioral data.
      • table S2. Data for indices of human-directed social behavior.
      • table S3. Loadings of first three PCs of human-directed social behavior.
      • table S4. Genes in target region on canine chromosome 6.
      • table S5. Sample information and the total number of raw reads compared to the number of processed reads after using cutadapt to trim/clip paired-end sequences.
      • table S6. Outlier clusters on chromosome 6 (CanFam3.1) showing signals of positive selection from XP-EHH.
      • table S7. Summary of de novo annotated structural variants on canine chromosome 6.
      • table S8. De novo annotated structural variants on canine chromosome 6 (coordinates based on CanFam3.1 assembly).
      • table S9. Structural variant summary statistics per individual.
      • table S10. Genic loci associated with indices of human-directed social behavior across dogs and wolves after inclusion of species as a covariate.
      • table S11. Association to species membership.
      • table S12. Predicted functional consequences of SVs.
      • table S13. The significantly enriched (adjusted P < 0.05) gene ontology term from a quantitative association test with each behavioral trait and 544,000 genome-wide SNPs.
      • table S14. The significantly enriched (adjusted P < 0.05) gene ontology term from the univariate regression analysis conducted in GEMMA with each behavioral trait and 544,000 genome-wide SNPs.
      • table S15. Behavioral data and description relative to WBS.
      • table S16. Parameters for in silico annotation of structural variants for the three methods SVMerge, SoftSearch, and InGAP-SV.
      • table S17. Structural variant genotype per individual.
      • table S18. Primer sequences used for PCR and gel-based validation of structural variants.
      • Reference (99)

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      Other Supplementary Material for this manuscript includes the following:

      • data file S1 (Microsoft Excel format). Genotypes of the four outlier insertions in wild and domestic canids.

      Files in this Data Supplement: