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Cited by 204Genetic diversity and population structureGenetic and phenotypic traits in livestockGenomics and Phylogenetic Studies

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Genomic legacy of the African cheetah, Acinonyx jubatus

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Dobrynin, Pavel, Liu, Shiping, Tamazian, Gaik, Xiong, Zijun, Yurchenko, Andrey A., Krasheninnikova, Ksenia, Kliver, Sergey, Schmidt-Küntzel, Anne, Koepfli, Klaus-Peter, Johnson, Warren, Kuderna, Lukas F.K., García-Pérez, Raquel, Manuel, Marc de, Godinez, Ricardo, Komissarov, Aleksey, Makunin, Alexey, Brukhin, Vladimir, Qiu, Weilin, Zhou, Long, Li, Fang, Yi, Jian, Driscoll, Carlos, Antunes, Agostinho, Oleksyk, Taras K., Eizirik, Eduardo, Perelman, Polina, Roelke, Melody, Wildt, David, Diekhans, Mark, Marques-Bonet, Tomas, Marker, Laurie, Bhak, Jong, Wang, Jun, Zhang, Guojie, O’Brien, Stephen J.·2015·Genome Biology
DOI 10.1186/s13059-015-0837-4PMC PMC4676127
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Abstract

BACKGROUND: Patterns of genetic and genomic variance are informative in inferring population history for human, model species and endangered populations. RESULTS: Here the genome sequence of wild-born African cheetahs reveals extreme genomic depletion in SNV incidence, SNV density, SNVs of coding genes, MHC class I and II genes, and mitochondrial DNA SNVs. Cheetah genomes are on average 95 % homozygous compared to the genomes of the outbred domestic cat (24.08 % homozygous), Virunga Mountain Gorilla (78.12 %), inbred Abyssinian cat (62.63 %), Tasmanian devil, domestic dog and other mammalian species. Demographic estimators impute two ancestral population bottlenecks: one >100,000 years ago coincident with cheetah migrations out of the Americas and into Eurasia and Africa, and a second 11,084-12,589 years ago in Africa coincident with late Pleistocene large mammal extinctions. MHC class I gene loss and dramatic reduction in functional diversity of MHC genes would explain why cheetahs ablate skin graft rejection among unrelated individuals. Significant excess of non-synonymous mutations in AKAP4 (p<0.02), a gene mediating spermatozoon development, indicates cheetah fixation of five function-damaging amino acid variants distinct from AKAP4 homologues of other Felidae or mammals; AKAP4 dysfunction may cause the cheetah's extremely high (>80 %) pleiomorphic sperm. CONCLUSIONS: The study provides an unprecedented genomic perspective for the rare cheetah, with potential relevance to the species' natural history, physiological adaptations and unique reproductive disposition.

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Fig. 1 Estimates of genome diversity in the cheetah genome relative to other mammal genomes. a SNV rate in mammals. SNV rate for each individual was estimated using all variant positions, with repetitive regions not filtered. b SNV density in cheetahs, four other felids and human based upon estimates in 50-kbp sliding windows. Of these, 38,661 fragments had lengths less than the specified window size and thus were excluded from further analysis; most of those fragments are contigs with length less than 500 bp, and thus 46,787 windows of total length 2.337 Gb were built and analyzed. c Number of SNVs in protein-coding genes in felid genomes. d The cheetah genome is composed of 93 % homozygous stretches. The genome of Boris, an outbred feral domestic cat living in St. Petersburg (top) is compared to Cinnamon, a highly inbred Abyssinian cat (Fca-6.2 reference for domestic cat genome sequence [19, 20], middle) and a cheetah (Chewbacca, bottom) as described here. Approximately 15,000 regions of 100 Mb across the genome for each species were assessed for SNVs. Regions of high variability (>40 SNVs/100 kbp) are colored red; highly homozygous regions (≤40 SNVs/100 kbp) are colored green. The first seven chromosome homologues of the genomes of Boris, Cinnamon and Chewbacca are displayed for direct comparison. The median lengths of homozygosity stretches in cheetahs (seven individuals), African lions (five individuals), Siberian and Bengal tigers, and the domestic cat are presented in Additional file 1: Figure S7
Fig. 1 Estimates of genome diversity in the cheetah genome relative to other mammal genomes. a SNV rate in mammals. SNV rate for each individual was estimated using all variant positions, with repetitive regions not filtered. b SNV density in cheetahs, four other felids and human based upon estimates in 50-kbp sliding windows. Of these, 38,661 fragments had lengths less than the specified window size and thus were excluded from further analysis; most of those fragments are contigs with length less than 500 bp, and thus 46,787 windows of total length 2.337 Gb were built and analyzed. c Number of SNVs in protein-coding genes in felid genomes. d The cheetah genome is composed of 93 % homozygous stretches. The genome of Boris, an outbred feral domestic cat living in St. Petersburg (top) is compared to Cinnamon, a highly inbred Abyssinian cat (Fca-6.2 reference for domestic cat genome sequence [19, 20], middle) and a cheetah (Chewbacca, bottom) as described here. Approximately 15,000 regions of 100 Mb across the genome for each species were assessed for SNVs. Regions of high variability (>40 SNVs/100 kbp) are colored red; highly homozygous regions (≤40 SNVs/100 kbp) are colored green. The first seven chromosome homologues of the genomes of Boris, Cinnamon and Chewbacca are displayed for direct comparison. The median lengths of homozygosity stretches in cheetahs (seven individuals), African lions (five individuals), Siberian and Bengal tigers, and the domestic cat are presented in Additional file 1: Figure S7CC BY · PubMed Central
Fig. 2 Comparison of MHC region structure between cheetah and domestic cats. Left side: Two chromosome B2 segments containing domestic cat MHC genes ordered on BAC libraries [29, 30]. Right side: Cheetah scaffolds related to MHC region. Order of scaffolds is based on the results of synteny analysis (light blue fill). Individual genes are denoted by dots and colored according to their MHC class: light blue for extended class II, blue for class II, green for class III, orange for class I, red for olfactory receptors and purple for histones. Genetic diversity in the MHC region was estimated by calculating SNV counts in non-overlapping 50-kbp windows. These counts are visualized by colored lines in the plot; for cats: green for wildcat, red for Boris and purple for Cinnamon; for cheetahs: red for Tanzania and orange for Namibia
Fig. 2 Comparison of MHC region structure between cheetah and domestic cats. Left side: Two chromosome B2 segments containing domestic cat MHC genes ordered on BAC libraries [29, 30]. Right side: Cheetah scaffolds related to MHC region. Order of scaffolds is based on the results of synteny analysis (light blue fill). Individual genes are denoted by dots and colored according to their MHC class: light blue for extended class II, blue for class II, green for class III, orange for class I, red for olfactory receptors and purple for histones. Genetic diversity in the MHC region was estimated by calculating SNV counts in non-overlapping 50-kbp windows. These counts are visualized by colored lines in the plot; for cats: green for wildcat, red for Boris and purple for Cinnamon; for cheetahs: red for Tanzania and orange for NamibiaCC BY · PubMed Central
Fig. 3 Demographic history analysis of African cheetah. a Demographic history of two cheetah populations (southern in Namibia and eastern in Tanzania) based on DaDi analyses. Four distinctive but plausible model scenarios were simulated by the DaDi analysis with the AFS data. Model 4 fits the data best; see “Materials and methods” for our decision algorithm pathway that identified model 4 as best. b First and second graphs represent marginal spectra for a pair of populations. The third graph shows residuals between the model and the observed data. Red or blue residuals indicate that the model predicts too many or too few alleles in a given cell, respectively. The fourth graph shows goodness-of-fit tests based on the likelihood and Pearson’s statistic, with both indicating that our model is a reasonable, though incomplete, description of the data
Fig. 3 Demographic history analysis of African cheetah. a Demographic history of two cheetah populations (southern in Namibia and eastern in Tanzania) based on DaDi analyses. Four distinctive but plausible model scenarios were simulated by the DaDi analysis with the AFS data. Model 4 fits the data best; see “Materials and methods” for our decision algorithm pathway that identified model 4 as best. b First and second graphs represent marginal spectra for a pair of populations. The third graph shows residuals between the model and the observed data. Red or blue residuals indicate that the model predicts too many or too few alleles in a given cell, respectively. The fourth graph shows goodness-of-fit tests based on the likelihood and Pearson’s statistic, with both indicating that our model is a reasonable, though incomplete, description of the dataCC BY · PubMed Central
Fig. 4 Comparison of Dn/Ds distributions for reproduction-related and all cheetah genes. a Distributions of branch-specific values of Dn/Ds for reproductive system genes. Dn/Ds ratios were calculated for five species (dog, human, cat, tiger and cheetah) based on 500 bootstrap replications and the free-ratio model in PAML [37]. b Distributions of branch-specific Dn/Ds values for four species (dog, cat, tiger and cheetah) and ancestral reconstructed Felidae branch. Dn/Ds ratios for branches based on 200 bootstrap replications of 10 Mb protein-coding sequences
Fig. 4 Comparison of Dn/Ds distributions for reproduction-related and all cheetah genes. a Distributions of branch-specific values of Dn/Ds for reproductive system genes. Dn/Ds ratios were calculated for five species (dog, human, cat, tiger and cheetah) based on 500 bootstrap replications and the free-ratio model in PAML [37]. b Distributions of branch-specific Dn/Ds values for four species (dog, cat, tiger and cheetah) and ancestral reconstructed Felidae branch. Dn/Ds ratios for branches based on 200 bootstrap replications of 10 Mb protein-coding sequencesCC BY · PubMed Central
Fig. 5 Analysis of orthologous gene families. a Unique and shared gene families in the cheetah genome. b Dynamic evolution of ortholog gene clusters. The estimated numbers of ortholog groups in the common ancestral species are shown on the internal nodes. The numbers of orthologous groups that expanded or contracted in each lineage after speciation are shown on the corresponding branch, with + referring to expansion and − referring to contraction. The cheetah genome contained 17,863 orthologous gene families. Among these, 10,983 orthologous gene families were shared by all eight genomes and 12,114 by felids while 11 orthologous gene families were exclusively shared among Felidae species (cat, lion, tiger and cheetah) and another 112 were exclusively shared by the cheetah and cat (Additional file 3: Datasheet S2). There were 1335 predicted genes containing 2293 InterPro domains unique to cheetahs (Additional file 3: Datasheet S1). Both figures are based on the comparison of orthologous gene families among eight mammalian species
Fig. 5 Analysis of orthologous gene families. a Unique and shared gene families in the cheetah genome. b Dynamic evolution of ortholog gene clusters. The estimated numbers of ortholog groups in the common ancestral species are shown on the internal nodes. The numbers of orthologous groups that expanded or contracted in each lineage after speciation are shown on the corresponding branch, with + referring to expansion and − referring to contraction. The cheetah genome contained 17,863 orthologous gene families. Among these, 10,983 orthologous gene families were shared by all eight genomes and 12,114 by felids while 11 orthologous gene families were exclusively shared among Felidae species (cat, lion, tiger and cheetah) and another 112 were exclusively shared by the cheetah and cat (Additional file 3: Datasheet S2). There were 1335 predicted genes containing 2293 InterPro domains unique to cheetahs (Additional file 3: Datasheet S1). Both figures are based on the comparison of orthologous gene families among eight mammalian speciesCC BY · PubMed Central

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Authors
Dobrynin, P., Liu, S., Tamazian, G., Xiong, Z., Yurchenko, A. A., Krasheninnikova, K., Kliver, S., Schmidt-Küntzel, A., Koepfli, K.-P., Johnson, W., Kuderna, L. F. K., García-Pérez, R., Manuel, M. D., Godinez, R., Komissarov, A., Makunin, A., Brukhin, V., Qiu, W., Zhou, L., Li, F., Yi, J., Driscoll, C., Antunes, A., Oleksyk, T. K., Eizirik, E., Perelman, P., Roelke, M., Wildt, D., Diekhans, M., Marques-Bonet, T., Marker, L., Bhak, J., Wang, J., Zhang, G., & O’Brien, S. J.
Affiliations
  • St Petersburg University (RU)
  • Sun Yat-sen University (CN)
  • China National GeneBank (CN)
  • Smithsonian Conservation Biology Institute (US)
  • Consejo Superior de Investigaciones Científicas (ES)
  • Harvard University (US)
  • National Institutes of Health (US)
  • Universidade do Porto (PT)
  • Russian Academy of Sciences (RU)
  • Leidos Biomedical Research Inc. (United States) (US)
  • University of California, Santa Cruz (US)
  • Cheetah Conservation Fund (NA)
  • Ulsan National Institute of Science and Technology (KR)
  • BGI Group (China) (CN)
  • University of Copenhagen (DK)
Corresponding author
O’Brien, Stephen J.
ORCID
Venue
Genome Biology
Publisher
Springer Science and Business Media LLC
Published
2015-12
Volume
16
Issue
1
Pages
277-277
ISSN
  • 1465-6906 (ISSN-L)
  • 1474-760X
DOI
10.1186/s13059-015-0837-4
PMC
PMC4676127
OpenAlex
W2196011667
Cited by
204
References
95
Citations by year
2026: 8 · 2025: 16 · 2024: 10 · 2023: 16 · 2022: 23 · 2021: 18 · 2020: 20 · 2019: 18 · 2018: 51 · 2017: 9 · 2016: 13
FWCI
16.63
Type
journal article
Language
en
Open access
Licence
Locations
  • Genome biology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion, other-oa)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
  • RECERCAT (Consorci de Serveis Universitaris de Catalunya) (publishedVersion, other-oa)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • NSUWorks (Nova Southeastern University) (submittedVersion, cc-by)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
  • Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion, cc-by)
  • Scholarworks@UNIST (Ulsan National Institute of Science and Technology) (submittedVersion)
  • Figshare (cc-by)
Funders
  • Ministry of Environment
  • Institució Catalana de Recerca i Estudis Avançats
  • Saint Petersburg State University (1.50.1623.2013)
  • Ministerio de Ciencia e Innovación (BFU2014-55090-P)
  • Megagrants
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic diversity and population structure
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
Keywords
cheetah, inbreeding depression, homozygosity, population bottleneck, non-synonymous mutations, AKAP4, sperm abnormalities, skin graft rejection, Late Pleistocene extinction, demographic history
MeSH terms
Animals, Cats, Acinonyx, Dogs, Multigene Family, Male, Genetic Variation, Genome, Genomics

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