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North African fox genomes show signatures of repeated introgression and adaptation to life in deserts

Nature Ecology & Evolution volume 7, pages 1267–1286 (2023)Cite this article

Subjects

Abstract

Elucidating the evolutionary process of animal adaptation to deserts is key to understanding adaptive responses to climate change. Here we generated 82 individual whole genomes of four fox species (genus Vulpes) inhabiting the Sahara Desert at different evolutionary times. We show that adaptation of new colonizing species to a hot arid environment has probably been facilitated by introgression and trans-species polymorphisms shared with older desert resident species, including a putatively adaptive 25 Mb genomic region. Scans for signatures of selection implicated genes affecting temperature perception, non-renal water loss and heat production in the recent adaptation of North African red foxes (Vulpes vulpes), after divergence from Eurasian populations approximately 78 thousand years ago. In the extreme desert specialists, Rueppell’s fox (V. rueppellii) and fennec (V. zerda), we identified repeated signatures of selection in genes affecting renal water homeostasis supported by gene expression and physiological differences. Our study provides insights into the mechanisms and genetic underpinnings of a natural experiment of repeated adaptation to extreme conditions.

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Fig. 1: Species relationships and geographic distribution of North African foxes.
Fig. 2: Genetic structure, diversity and joint evolutionary history of North African red fox and Rueppell’s fox.
Fig. 3: Introgression in North African foxes.
Fig. 4: Demographic and selection history of North African red fox.
Fig. 5: Genome-wide selection scans for Rueppell’s fox and fennec using Ohana based on the structure and tree results from K = 4 highlight unique adaptations supported by expression and physiological differences.

Data availability

The sequencing data (genomic and transcriptomic raw reads) generated in this study are available through NCBI repositories linked to BioProject accession number PRJNA951250. Physiological and morphological data per individual are available from GitHub (https://doi.org/10.5281/zenodo.7826260)132.

Code availability

All code written for this project is available on GitHub (https://doi.org/10.5281/zenodo.7826260)132 archived from repository https://github.com/joanocha/HOTFOXES.

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Acknowledgements

We thank M. Samlali, B. Habib and M. Milanese for their assistance in sampling collection in North Africa. We thank J. V. López Bao, H. R. Maior and F. Alvares for support and assistance in sampling collection in Iberia and J. F. Layna (Spain), V. Soeiro (Parque Biológico de Gaia, Portugal), Temara Zoo and Dream Village (Morocco) for access to foxes in captivity. We thank L. Smith (UC Berkeley), P. Ribeiro, S. Mourão and S. Lopes (CIBIO, UP) for support during laboratory work and generation of data. We thank A. Múrias, C. Pacheco, D. Lobo, M. S. Ferreira, D. Brandt, D. Aguillar-Gomez, L. Pipes, H. Wang and T. Linderoth for helpful discussions during data analysis and interpretation of results. We thank L. Dalén and A. Gaur for kindly sharing the arctic fox reference genome and Bengal fox mitogenome, respectively. We acknowledge M. Laranjeira Rocha for the illustrations featured in this work. This project was supported by the Portuguese Foundation for Science and Technology, FCT (PTDC/BIA-EVF/31902/2017 granted to R.G.) and the National Institutes of Health (R01GM138634 granted to R.N.). J.L.R., N.S., M.N., J.C.B. and R.G. worked under scholarships or research contracts from FCT (SFRH/BD/116397/2016, SFRH/BPD/116596/2016, SFRH/BD/144087/2019, CEECINST/00014/2018/CP1512/CT0001 and 2021/00647/CEECIND, respectively).

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Author notes

  1. These authors jointly supervised this work: Rasmus Nielsen, Raquel Godinho.

  2. These authors contributed equally: Rasmus Nielsen, Raquel Godinho.

Authors and Affiliations

  1. CIBIO, Centro de Investigação em Biodiversidade e Recursos Genéticos, InBIO Laboratório Associado, Campus de Vairão, Universidade do Porto, Vairão, Portugal

    Joana L. Rocha, Pedro Silva, Nuno Santos, Mónia Nakamura, Sandra Afonso, Zbyszek Boratynski, José C. Brito & Raquel Godinho

  2. Departamento de Biologia, Faculdade de Ciências, Universidade do Porto, Porto, Portugal

    Joana L. Rocha, Pedro Silva, Mónia Nakamura, José C. Brito & Raquel Godinho

  3. BIOPOLIS Program in Genomics, Biodiversity and Land Planning, CIBIO, Campus de Vairão, Vairão, Portugal

    Joana L. Rocha, Pedro Silva, Nuno Santos, Mónia Nakamura, Sandra Afonso, Zbyszek Boratynski, José C. Brito & Raquel Godinho

  4. Department of Integrative Biology and Department of Statistics, University of California Berkeley, Berkeley, CA, USA

    Joana L. Rocha, Peter H. Sudmant & Rasmus Nielsen

  5. Laboratory of Geophysics and Natural Hazards, Geophysics, Natural Patrimony and Green Chemistry Research Center (GEOPAC), Institut Scientifique, Mohammed V University of Rabat, Rabat, Morocco

    Abdeljebbar Qninba

  6. Center for Computational Biology, University of California, Berkeley, CA, USA

    Peter H. Sudmant & Rasmus Nielsen

  7. Globe Institute, University of Copenhagen, Copenhagen, Denmark

    Rasmus Nielsen

  8. Department of Zoology, University of Johannesburg, Auckland Park, South Africa

    Raquel Godinho

Authors
  1. Joana L. Rocha
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  2. Pedro Silva
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  3. Nuno Santos
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  4. Mónia Nakamura
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  5. Sandra Afonso
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  6. Abdeljebbar Qninba
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  7. Zbyszek Boratynski
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  8. Peter H. Sudmant
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  9. José C. Brito
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  10. Rasmus Nielsen
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Contributions

R.G. and J.L.R. conceived and designed the study with R.N. R.G. and J.L.R. initiated the project. J.L.R., N.S., M.N., R.G., Z.B., J.C.B. and A.Q. collected the samples. J.C.B. and A.Q. provided logistical support in North Africa. J.L.R. performed DNA laboratory work and processed the sequencing data. S.A. performed RNA laboratory work. J.L.R. and N.S. processed samples for physiological analysis. R.N. oversaw all statistical and computational analyses, which were performed by J.L.R. (phenotypic and whole-genome data analyses) and P.S. (transcriptomics). P.H.S., R.G. and R.N. helped with editing and reviewing the paper for submission. J.L.R., R.G. and R.N. wrote the paper with input from all authors.

Corresponding authors

Correspondence to Joana L. Rocha, Rasmus Nielsen or Raquel Godinho.

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Extended data

Extended Data Fig. 1 Mitogenomics of Vulpes using the raccoon dog as an outgroup (related to Fig. 1).

(a) Maximum-likelihood tree followed by species distribution range downloaded from IUCN (2021). Fox illustrations by Margarida Laranjeira Rocha. (b) Bayesian phylogenetic tree and time to the most recent common ancestor estimates; timescale in Ma represented bellow (see Supplementary Table 5 for the median time estimates and 95% HPD for each node). Accession numbers of published sequences are available in Supplementary Table 2. North African red foxes are coloured in orange, Eurasian red foxes green and Rueppell’s fox in red. Rueppell’s foxes are outgrouped by a non-coloured clade of 6 red foxes (n = 1 North Africa, n = 6 Middle East), revealing a paraphyletic pattern in red foxes.

Extended Data Fig. 2 ABBA-BABA on windows using the arctic fox (A-D) and the domestic dog (E-H) as reference genomes (related to Fig. 3).

D statistics between Rueppell’s fox (Vulpes rueppellii) and North African red fox (V. vulpes) (a–b, e–f) and between Rueppell’s fox and fennec fox (V. zerda) (c–d, g–h). (a, c, e, g) The pattern of ABBA/BABA in A and E is as follows: red fox Eurasia (H1) and North African red foxes (H2) have a recent common ancestor that diverged from the ancestral of the Rueppell’s fox (H3), using the arctic fox as outgroup (O) in A and the dog as outgroup (O) in E. The pattern of ABBA/BABA in C and G: all red foxes (H1) Rueppell’s foxes (H2) have a recent common ancestor that diverged from the ancestral of the fennec fox (H3), using the pale fox as outgroup (O) in C and the dog as outgroup (O) in E. Illustrations by Margarida Laranjeira Rocha. (b, d, f, h) Manhattan plot of the Z-transformed D statistic for non-overlapping windows of 200 kb across all chromosomes, according to pattern described in A, C, E, G respectively. Each dot represents a window and windows from the same chromosome have the same colour. Line threshold represents regions with Z score values above the 99th percentiles of the empirical distribution.

Extended Data Fig. 3 CRADD gene – top outlier above the 99th percentile of the empirical distribution for ƒd and Z(D) in ABBA-BABA on windows (related to Fig. 3).

a) Maximum-likelihood tree estimated with IQtree for a sequence alignment of pseudohaploids comprising the CRADD gene ( ~ 180 kb) based on sampling of a random base (samples from our dataset are highlighted in the legend of the figure, see Supplementary Table 2 for additional genomes with legend in the tree). (b) PCA with 48 red foxes and 24 Rueppell’s using 23,016 SNPs called from a 1.3 Mbp region containing CRADD; (c) Read depth-based estimate for CRADD per individual (depth for CRADD divided by the genome-wide coverage per individual). There is no evidence for CRADD copy number variation.

Extended Data Fig. 4 Principal component analysis for SLC6A16 (ranked 2nd) and two other genes (MGAM, HPS5) above the 99th percentile of ƒd empirical distribution (related to Fig. 3).

PCA based on sampling of a single read at each site. North African red foxes individuals (n = 30) unambiguously cluster closer to Rueppell’s (n = 24) than other red foxes (n = 18). Arrow highlights hidden North African red fox individuals clustering within Rueppell’s fox (MGAM). See also Figure S9 for gene tree topologies.

Extended Data Fig. 5 Tree topologies and Principal Component Analysis on the ~ 25 Mb outlier region above the 99th percentile of the empirical distribution for ƒd in ABBA-BABA on windows (related to Fig. 3).

Maximum-likelihood tree estimated with IQtree for the affected chromosomal region called with ANGSD (-doHaplo 1) using both (a) the dog genome (NC_006595.3, 38236300–63241923), and (b) the arctic fox as references (scaffolds 47, 126, 155, 200); (c) PCA of the 25 Mb region in 48 red foxes, 24 Rueppell’s foxes and 5 fennecs, based on sampling of a single read at each site. PC1 first separates Rueppell’s and fennec and PC2 separates Rueppell’s and red foxes.

Extended Data Fig. 6 Genetic Divergence for the 25 Mb region above the 99th percentile of the empirical distribution for ƒd on windows (related to Fig. 3).

Estimated genetic divergences (dXY) between different pairs of Vulpes species on sliding windows of 50 kb overlapped every 10 kb for the affected chromosomal region and for all the autosomes (excluding the CRADD gene). Boxes indicate upper and lower quartiles; centre line represents median; whiskers extend to minimum and maximum values within 1.5x interquartile range; points show outliers beyond whiskers. Sample sizes for pairs of species are as follows: n = 24 Rueppell’s fox, n = 48 Red fox.

Extended Data Fig. 7 Evidence for potential introgression of the 25 Mb region supported by KIT (related to Fig. 3).

(a) Tree topology for one of the four scaffolds comprising the 25 Mb region above the 99th percentile of the empirical distribution for ƒd in ABBA-BABA on windows; fennec and Rueppell’s are sister species. (b) Tree topology for KIT; Rueppell’s (n = 24) and red foxes (n = 48) become sister species, as in the average genome-wide tree. (c) Nucleotide diversity for the 25 Mb outlier region in 4 Vulpes species; KIT stands as being highly polymorphic in Rueppell’s fox, suggesting the simultaneous mapping of divergent alleles likely introduced via introgression and alleles located in the B chromosomes which are closer to red foxes. Dotted lines show the 99.95th percentile of the empirical distribution of nucleotide diversity for the region. The fact that KIT is not highly polymorphic in red foxes, which also have autosomal and B alleles mapped to the same region further confirms our hypothesis of shared structural variation between Rueppell’s fox and the fennec.

Extended Data Fig. 8 Gene expression differences between North African and Eurasian red foxes and Rueppell’s foxes (related to Fig. 4).

The plots represent top candidate genes putatively under selection in North African red foxes (CD163, SLC12A2) for which differential expression was significant between North African and Eurasian foxes (p-adjusted CD163 = 9.3e-08, p-adjusted SLC12A2 = 0.001), and/or North African red fox and Eurasian red foxes (p-adjusted CD163 = 2.5e-06; p-adjusted SLC12A2 = 0.079). The arctic fox transcriptome was used as reference.

Extended Data Fig. 9 Selection specific to Eurasian red foxes (related to Fig. 4).

Genome-wide selection scans on windows of 50 kb with a 10 kb slide across autosomal chromosomes, displayed as in the dog genome (x axis): population branch statistics (PBS) and alpha (negative logarithm of alpha) were estimated using Eurasian red foxes as focal group, North African red foxes as closest ingroup and Rueppell’s fox as outgroup; genes in grey are genes that stand out above the 99th percentile of the empirical distribution of f statistics in ABBA-BABA on windows for introgression between Rueppell’s and North African red foxes. The CRADD region and the 25 Mb region identified in Fig. 3 in main text were removed from the analysis. Lines show the 99.95th percentile of the empirical distribution. Names of genes within the highest peaks are shown (non-label peaks represent no overlap with genes). The arctic fox (V. lagopus) was used as reference genome. We note that other genes not displayed in the figure can overlap the outlier regions; a full list can be found in Supplementary Tables S16–S17.

Extended Data Fig. 10 Physiological differences between three species of Vulpes (related to Supplementary Tables 22–23 and Fig. 5).

Boxplots of 12 physiological parameters measured from the serum/plasma of red fox (V. vulpes; n = 10), desert-dwelling Rueppell’s fox (V. rueppellii; n = 13), and fennec fox (V. zerda; n = 10): (a) Copeptin (used as biomarker for vasopressin; pmol/L), (b) Aldosterone (pg/mL), (c) Total T4 (ug/dL), (d) Urea (mg/dL), (e) Uric acid (mg/dL), (f) Creatinine (mg/dL); (g) Albumin (g/dL), (h) Cholesterol (mg/dL), (i) Osmolality (mOSm/Kg), (j) Sodium (mEq/L), (k) Potassium (mEq/L), (l) Chloride (mEq/L); Juveniles were excluded. Boxes indicate upper and lower quartiles; centre line represents median; whiskers extend to minimum and maximum values within 1.5× interquartile range; points show outliers beyond whiskers. Additional pairwise t-tests comparing the three different fox species were performed with Bonferroni correction for multiple comparisons on each parameter, as well as Welch’s two-sample t-test comparing males versus females, North African versus European red foxes, and captive versus free-ranging individuals. All tests are two-sided. No significant differences between species were found except for A-C (pCopeptin = 0.00037; pAldosterone = 0.0034; pT4 = 8.8e-05) and between red fox and fennec (pCopeptin=0.02273; pAldosterone = 0.0027; pT4 = 1.0e-06). No significant differences were found between Rueppell’s and fennec for copeptin (AVP) and Aldosterone (PCopeptin= 0.55044; PAldosterone = 1.00; PT4 = 0.16), nor between captive and wild-caught individuals (PCopeptin=0.9811; PAldosterone = 0.3522; PT4 = 0.3867). After correcting for the potentially confounding factors caused by sex, weight, body mass index and whether the individuals were caught free-ranging or captive as covariates, we still found the same pattern of significance (Supplementary Table 23). This seems to suggest that, at least for these three hormones (A-C), there is no evidence of significant intraspecific differences in red foxes (n = 4 North Africa and n = 6 Iberia), and that the differences observed are not due to individuals being free-ranging or held in captivity, though this should be taken with caution given the small sample size (Supplementary Table 23).

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Supplementary Text, Figs. 1–18 and Tables 1–23.

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Supplementary Data

Metadata spreadsheet-based table with three tabs, each containing additional information to Supplementary Tables 1 and 3, including geolocation and morphological and physiological data.

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L. Rocha, J., Silva, P., Santos, N. et al. North African fox genomes show signatures of repeated introgression and adaptation to life in deserts. Nat Ecol Evol 7, 1267–1286 (2023). https://doi.org/10.1038/s41559-023-02094-w

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