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, 9 (1), 8329

Comparative Genomics Provides New Insights Into the Remarkable Adaptations of the African Wild Dog (Lycaon Pictus)

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Comparative Genomics Provides New Insights Into the Remarkable Adaptations of the African Wild Dog (Lycaon Pictus)

Daniel E Chavez et al. Sci Rep.

Abstract

Within the Canidae, the African wild dog (Lycaon pictus) is the most specialized with regards to cursorial adaptations (specialized for running), having only four digits on their forefeet. In addition, this species is one of the few canids considered to be an obligate meat-eater, possessing a robust dentition for taking down large prey, and displays one of the most variable coat colorations amongst mammals. Here, we used comparative genomic analysis to investigate the evolutionary history and genetic basis for adaptations associated with cursoriality, hypercanivory, and coat color variation in African wild dogs. Genome-wide scans revealed unique amino acid deletions that suggest a mode of evolutionary digit loss through expanded apoptosis in the developing first digit. African wild dog-specific signals of positive selection also uncovered a putative mechanism of molar cusp modification through changes in genes associated with the sonic hedgehog (SHH) signaling pathway, required for spatial patterning of teeth, and three genes associated with pigmentation. Divergence time analyses suggest the suite of genomic changes we identified evolved ~1.7 Mya, coinciding with the diversification of large-bodied ungulates. Our results show that comparative genomics is a powerful tool for identifying the genetic basis of evolutionary changes in Canidae.

Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Evolutionary history and adaptation in the African wild dog (AWD) and nine other species of canids. (a) A species tree was inferred by applying ASTRAL-III to 8,117 25 kb-windows (light gray, in background), with internal nodes placed according to average genomic divergence estimated via MCMCTree and calibrated using two fossil priors (see Methods and Fig. S1 for details). A demographic model was inferred for the same species (excluding gray fox) by applying G-PhoCS to 11,112 putative neutral 1 kb windows (dark gray, in foreground). The same phylogenetic tree topology was assumed, augmented with 44 directed migration bands (see Methods and Table S2 for details). Block arrows depict the eight migration bands inferred with total rates higher than 0.05, with arrow widths scaled proportionally to the estimated total rate. The widths of branches in the demographic model are scaled proportionally to inferred effective population sizes (see scale bar at top-left), and their lengths are scaled proportionally to inferred species divergence times. Both scales assume an average per-generation mutation rate of μ = 4.0 × 10−9 and an average generation time of three years. Species divergence times are much smaller than the average genomic divergence times. Divergence times associated with AWD are indicated at the bottom with 95% Bayesian credible intervals (note the change in time scale between 2.5–5 Mya). Genes with signals of positive selection are specified on the branches leading to the AWD and the dhole. Different phenotypic categories are indicated by color; genes marked with an asterisk had in-frame deletions and genes marked with a cross were pseudogenized. Note that CREBBP has undergone parallel adaptation in both lineages. (b) Venn diagrams showing shared positively-selected genes (left) and pathways (right) obtained from different analytical approaches. Among the seven genes that resulted in significant scores from both the HKA-like and branch-site tests, only HPS6 was associated with AWD adaptations. Primary cilium was the only pathway that was identified by both G-profiler and polysel.
Figure 2
Figure 2
Apoptosis of the first digit in the African wild dog. (a) Primitive condition of five digits in the Canidae; note the small first digit in gray wolf called the “dewclaw”. The absence of the first digit is shown in the African wild dog (AWD). (b) Schematic representation of digit reduction and separation of digits. In the normal five-digit pattern scenario shown at the top, apoptosis (blue circles) is restricted to interdigital regions. The first digit, enclosed by a rectangle, is protected from apoptosis by FANCC and FANCM that form a complex with CtBP1 and repress DKK1. The stability of this complex is regulated by the FANCD2-FANCI association. In the scenario shown below, amino acid deletions (red stars) observed in FA genes may reduce both the affinity of FA genes to CtBP1 and the stability of the protein complex. Consequently, the FANCC-FNACM-CtBP1 complex is not formed and DKK1 is not suppressed (indicated by empty arrow). Deficiency of the FA complex activity increases DKK1 expression. As a result, apoptosis expands to the first digit; note blue circles (apoptosis) on the region of the thumb. (c) Effect of the mutations in the FA and DKK1 genes in humans (Reprinted from ref.© 2009 with permission from Elsevier) and mice (Reprinted from ref. © 2004 with permission from Elsevier). (d) Multiple sequence alignments of mammalian FANCD2, FANCM, and FANCC amino acid sequences showing deletions specific to AWDs. Five AWDs are shown; “RWK481” and “SAMN04312208” are individuals from Kruger National Park, South Africa; “CN3669” and “SAMN04312209” are individuals from Kenya and “Dnv Lycaon pictus” is the consensus sequence of three de novo reference AWD genomes. The top panel also shows a 3D protein-model of FANCD2 with the location of the observed amino acid deletion, which is important for the association with FANCI.
Figure 3
Figure 3
Possible mode of evolutionary molar cusp modification in the African wild dog through SHH signaling. (a) The figure at the top right shows genes found to be enriched in primary cilium with polysel; genes above dashed line are those found to be enriched with G-profiler as well (see Methods for details). Only gene names with known function in tooth development are shown. The figure at the top left shows a schematic of the primary cilium and the role of candidate genes in SHH transduction. SHH, represented by red circles, reaches the ciliary membrane. Then, transport of transcriptional factors GLIs such as GLI1, through the axoneme, is promoted by WDR35/IFT121 as well as the efficient docking of the axoneme in the plasma membrane, which is conducted by CC2d2a and TMEM67. Together, these components of primary cilium cause rapid accumulation of GLI into the basal body. Ultimately, GLIs will enter the nucleus and promote the expression of SHH-dependent genes. In the case of CREBBP, the observed amino acid deletion (red star) may increase the affinity of this cofactor with smad genes and increase the expression of TGF-β and BMP dependent genes involved in molar cusp development. (b) Left-bottom figure showing the single cuspid talonid of the lower first molar (carnassial) in the AWD as opposed to a bi-cusped talonid carnassial in the gray wolf. Right-bottom figures show the effect that mutations in CREBBP have on humans (reprinted by permission from Wiley-Liss, Inc.; American Journal of Medical Genetics © 2007); talon cusp condition is observed; cusps that protrude from the anterior region of incisors on the left and extra cusps on molars on the right. (c) Amino acid alignment of the glutamine-rich region of CREBBP for 51 species of mammals showing the deletions specific to AWDs and the dhole. Five AWDs are shown; “RWK481” and “SAMN04312208” are individuals from South Africa; “CN3669” and “SAMN04312209” are individuals from East Africa; “Dnv Lycaon pictus” is the consensus sequence of three de novo reference AWD genomes. The ancestral condition in canids is inferred as 15 glutamine residues.
Figure 4
Figure 4
Candidate genes and possible mechanisms associated with coat pigmentation and patterning in African wild dogs. (a) Plot showing Q-values depicted from the branch-site test after a multiple hypothesis correction of 151 different coat color genes with the AWD as the foreground branch (see methods). Significant genes (Q-value < 0.20) are shown above the horizontal blue line; for illustration purposes, Q-values shown on the Y-axis were transformed to -log10. Only names of genes with relevant functions are shown. Illustration at the bottom showing coat color in the AWD; genes are shown in red circles and are placed on the type of color they regulate (e.g., PAH regulates brown and yellow colors). (b) Amino acid alignment of coat color candidate genes for an average of 49 species of mammals showing changes specific to AWDs. Five AWDs are shown: “RWK481” and “SAMN04312208” are individuals from Kruger National Park, South Africa; “CN3669” and “SAMN04312209” are individuals from Kenya and “Dnv Lycaon pictus” is the consensus sequence of three de novo reference AWD genomes. (c) A schematic showing the role of candidate genes in color pattern. (I) shows that black coat color will need both proper cargo of melanin by HPS6 to melanosomes and its transport by MYO5A to the bulk of the hair. (II) In the case of white blotches or spots, they could be the result of either proper transport of melanosomes but containing no melanin or melanosomes containing melanin that fail to reach the bulk of the hair. The figure on the bottom-right shows the effect of MYO5A mutations on the pelage of a domestic mouse. (d) 3D model of the PAH protein depicted with SWISS-model (see methods) that shows a mutation on the cofactor of the enzyme (BH4). The scheme at the bottom illustrates the role of PAH and its cofactor. The right figure shows a gradual recovery of the black color of yellow mice (PKU) with deficiency of PAH (Reprinted by permission from Springer Nature: Springer Nature, Gene Therapy ref. © 2006).

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