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Rabbit genome analysis reveals a polygenic basis for phenotypic change during domestication

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Science  29 Aug 2014:
Vol. 345, Issue 6200, pp. 1074-1079
DOI: 10.1126/science.1253714
  • Fig. 1 Experimental design and population data.

    (A) Images of the six rabbit breeds included in the study (sized to reflect differences in body weight) and of a wild rabbit. (B) Map of the Iberian Peninsula and southern France with sample locations marked (orange dots). Demographic history of this species is indicated, and a logarithmic time scale is shown at right. The hybrid zone between the two subspecies is marked with dashes. (C) Nucleotide diversities in domestic and wild populations. The French (FRW1 to FRW3) and Iberian (IW1 to IW11) wild rabbit populations are ordered according to a northeast-to-southwest transection. Sample locations are provided in table S4.

  • Fig. 2 Selective sweep and Δ allele frequency analyses.

    (A) Plot of FST values between wild and domestic rabbits. Sweeps detected with the FST-H outlier approach, SweepFinder, and their overlaps are marked on top. Unassigned scaffolds were not included in the analysis. (B and C) Selective sweeps at GRIK2 (B) and SOX2 (C). Heterozygosity plots for wild (red) and domestic (black) rabbits together with plots of FST values and SNPs with ΔAF > 0.75 (HΔAF). The bottom panels show putative sweep regions, detected with the FST-H outlier approach and SweepFinder, marked with horizontal bars. Gene annotations in sweep regions are indicated: * represents ENSOCUT000000; **SOX2-OT represents the manually annotated SOX2 overlapping transcript (4). (D) The majority of SNPs showed low ΔAF between wild and domestic rabbits. The black line indicates the number of SNPs in nonoverlapping ΔAF bins (left y axis). Colored lines denote M values (log2-fold changes) of the relative frequencies of SNPs at noncoding evolutionary conserved sites (blue), in UTRs (red), exons (yellow), and introns (green), according to ΔAF bins (right y axis). M values were calculated by comparing the frequency of SNPs in a given annotation category in a specific bin with the corresponding frequency across all bins. (E) Location of SNPs at conserved noncoding sites with ΔAF ≥ 0.8 SNPs (n = 1635) and ΔAF < 0.8 SNPs (n = 502,343) in relation to the TSS of the most closely linked gene. **P < 0.01.

  • Fig. 3 Bioinformatic and functional analysis of candidate causal mutations.

    Three examples of SNPs near SOX2 and PAX2 where the domestic allele differs from other mammals. The locations of these three SNPs assessed with EMSA are indicated by red crosses on top. EMSA with nuclear extracts from embryonic stem cell–derived neural stem cells or from mouse P19 embryonic carcinoma cells before (un-diff) or after neuronal differentiation (diff) are shown for three SNPs. Exact nucleotide positions of polymorphic sites are indicated. Allele-specific gel shifts are indicated by arrows. WT, wild-type allele; Dom, domestic, the most common allele in domestic rabbits. Cold probes at 100-fold excess were used to verify specific DNA-protein interactions.

  • Table 1 Summary of results from enrichment analysis of ΔAF > 0.8 SNPs located in conserved noncoding elements.

    One significantly enriched term was chosen from each group of significantly enriched intercorrelated terms. Full lists of enriched terms and intercorrelations are presented in database S3, and the most enriched intercorrelated terms are presented in fig. S5. P values are Bonferroni-corrected. O/R, number of distinct nonoverlapping 1-Mb windows observed (O) and the average number of 1-Mb windows observed in 1000 random (R) samplings of the same number of genes (rounded to the nearest integer). TS, Thieler stage.

    Database entryEnriched termNumber of genesPEnrichmentDistinct loci (O/R)
    Gene Ontology biological process
    GO:0007399Nervous system
    development
    1913.7 × 10–101.7154/155
    GO:0045595Regulation of
    cell differentiation
    1074.5 × 10–61.894/91
    GO:0045935Positive regulation of
    nucleobase-containing
    compound metabolic
    process
    1222.0 × 10–51.7101/100
    GO:0045165Cell fate commitment365.5 × 10–52.931/32
    GO:0007389Pattern specification
    process
    571.4 × 10–42.243/44
    GO:0009887Organ morphogenesis852.0 × 10–31.872/73
    GO:0048646Anatomical structure
    formation involved
    in morphogenesis
    752.8 × 10–31.865/64
    GO:0045892Negative regulation
    of transcription,
    DNA-dependent
    821.4 × 10–21.762/62
    GO:0034332Adherens junction
    organization
    131.5 × 10–24.711/11
    Mouse Genome Informatics gene expression
    11853TS23 diencephalon,
    lateral wall,
    mantle layer
    1093.9 × 10–253.386/85
    12449TS23 medulla
    oblongata, lateral
    wall, basal plate,
    mantle layer
    1152.6 × 10–132.390/89
    2257TS17 sensory organ1133.4 × 10–132.398/99
    1324TS15 future brain728.5 × 10–92.461/61
    Mouse Genome Informatics phenotype
    MP:0010832Lethality during
    fetal growth
    through weaning
    2407.5 × 10–171.8197/189
    MP:0003632Abnormal nervous
    system morphology
    2371.2 × 10–131.7191/193
    MP:0005388Respiratory system
    phenotype
    1271.7 × 10–71.8101/102
    MP:0000428Abnormal craniofacial
    morphology
    1091.4 × 10–61.993/92
    MP:0002925Abnormal
    cardiovascular
    development
    883.3 × 10–51.973/73
    MP:0005377Hearing/vestibular/ear
    phenotype
    731.8 × 10–42.061/62

Supplementary Materials

  • Rabbit genome analysis reveals a polygenic basis for phenotypic change during domestication

    Miguel Carneiro, Carl-Johan Rubin, Federica Di Palma, Frank W. Albert, Jessica Alföldi, Alvaro Martinez Barrio, Gerli Pielberg, Nima Rafati, Shumaila Sayyab, Jason Turner-Maier, Shady Younis, Sandra Afonso, Bronwen Aken, Joel M. Alves, Daniel Barrell, Gerard Bolet, Samuel Boucher, Hernán A. Burbano, Rita Campos, Jean L. Chang, Veronique Duranthon, Luca Fontanesi, Hervé Garreau, David Heiman, Jeremy Johnson, Rose G. Mage, Ze Peng, Guillaume Queney, Claire Rogel-Gaillard, Magali Ruffier, Steve Searle, Rafael Villafuerte, Anqi Xiong, Sarah Young, Karin Forsberg-Nilsson, Jeffrey M. Good, Eric S. Lander, Nuno Ferrand, Kerstin Lindblad-Toh, Leif Andersson

    Materials/Methods, Supplementary Text, Tables, Figures, and/or References

    Download Supplement
    • Materials and Methods
    • Figs. S1 to S7
    • Tables S1 to S7
    • Legends for Databases S1 to S5
    • Full Reference List
    Database S1
    Regions inferred to have been targeted by directional selection using: 1) a FST-H outlier approach contrasting genetic diversity between wild and domestic rabbits, 2) allele frequency spectra (SweepFinder), and 3) an explicit demographic model contrasting genetic diversity between wild and domestic rabbits (capture arrays data).
    Database S2
    P-values obtained using coalescent simulations of the demographic scenario inferred in this study for the SweepFinder and targeted capture analyses. The obtained value for the magnitude of the domestication bottleneck in this study (kdom = 1.3) was lower than a previous estimate (kdom = 2.8). Under the model used to infer directional selection in the domesticated lineage using the targeted capture dataset, the estimation from this study describes a stronger bottleneck and thus renders our selection tests conservative. However, this is not the case for the SweepFinder analysis and P-values using both bottlenecks estimates are provided.
    Database S3
    Full results of overrepresentation analysis using SNPs at conserved non-coding sited with ΔAF>0.80 performed using the GREAT tool.
    Database S4
    Missense SNPs showing a delta allele frequency difference of 0.90 or higher between wild and domestic rabbits.
    Database S5
    Duplications and deletions showing allele frequency differences between wild and domestic rabbits according to an ANOVA analysis.

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