Abstract
When compared to the approximately 22 other macaque species, Macaca arctoides has many unique phenotypes. These traits fall into various phenotypic categories, including genitalia, coloration, mating, and olfactory traits. Here we used a previously identified whole genome set of 690 outlier genes to look for possible genetic explanations of these unique traits. Of these, 279 genes were annotated miRNAs, which are non-coding. Patterns within the remaining outliers in coding genes were investigated using GO (n = 370) and String (n = 383) analysis, which showed many interconnected immune-related genes. Further, we compared the outliers to candidate pathways associated with M. arcotides’ unique phenotypes, revealing 10/690 outlier genes that overlapped these four pathways: hedgehog signaling, WNT signaling, olfactory, and melanogenesis. Of these, genes in all pathways except olfactory had higher FST values than the rest of the genes in the genome based on permutation tests. Overall, our results point to many genes each having a small impact on phenotype, working in tandem to cause large systemic changes. Additionally, these results may indicate pleiotropy. This seems to be especially true with the development and coloration of M. arctoides. Our results highlight that development, melanogenesis, immune function, and miRNAs may be heavily involved in M. arctoides’ evolutionary history.
Similar content being viewed by others
Data availability
The data used in this article are from a previously published study that is cited within the text and any additional information is provided as supplementary material.
References
Association between NME8 Locus Polymorphism and Cognitive Decline, Cerebrospinal Fluid and Neuroimaging Biomarkers in Alzheimer’s Disease - PMC. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4259473/. Accessed 22 Jun 2022c
Bailey NP, Stevison LS (2021) Mitonuclear conflict in a macaque species exhibiting phylogenomic discordance. J Evol Biol 34:1568–1579. https://doi.org/10.1111/jeb.13914
Baxter LL, Pavan WJ (2013) The etiology and molecular genetics of human pigmentation disorders. Wiley Interdiscip Rev Dev Biol 2:379–392. https://doi.org/10.1002/wdev.72
Bellei B, Flori E, Izzo E et al (2008) GSK3beta inhibition promotes melanogenesis in mouse B16 melanoma cells and normal human melanocytes. Cell Signal 20:1750–1761. https://doi.org/10.1016/j.cellsig.2008.06.001
Bennett A, Hayssen V (2010) Measuring cortisol in hair and saliva from dogs: coat color and pigment differences. Domest Anim Endocrinol 39:171–180. https://doi.org/10.1016/j.domaniend.2010.04.003
Bhateja P, Cherian M, Majumder S, Ramaswamy B (2019) The Hedgehog signaling pathway: a viable target in breast cancer? Cancers 11:1126. https://doi.org/10.3390/cancers11081126
Chen C-C, Zimmer A, Sun W-H et al (2002) A role for ASIC3 in the modulation of high-intensity pain stimuli. Proc Natl Acad Sci U S A 99:8992–8997. https://doi.org/10.1073/pnas.122245999
Cheng JPX, Betin VMS, Weir H et al (2010) Caspase cleavage of the Golgi stacking factor GRASP65 is required for Fas/CD95-mediated apoptosis. Cell Death Dis 1:e82. https://doi.org/10.1038/cddis.2010.59
Chourabi M, Liew MS, Lim S et al (2018) ENPP1 mutation causes recessive Cole disease by altering melanogenesis. J Investig Dermatol 138:291–300. https://doi.org/10.1016/j.jid.2017.08.045
Cole JB, Florez JC, Hirschhorn JN (2020) Comprehensive genomic analysis of dietary habits in UK Biobank identifies hundreds of genetic associations. Nat Commun 11:1467. https://doi.org/10.1038/s41467-020-15193-0
Conway J, Gehlenborg N (2019) UpSetR: A More Scalable Alternative to Venn and Euler Diagrams for Visualizing Intersecting Sets
Cook RD, Weisberg S (1982) Residuals and influence in regression. Chapman and Hall, New York
Cunningham F, Allen JE, Allen J et al (2022) Ensembl 2022. Nucleic Acids Res 50:D988–D995. https://doi.org/10.1093/nar/gkab1049
De Jaime-Soguero A, Abreu de Oliveira WA, Lluis F (2018) The pleiotropic effects of the canonical Wnt pathway in early development and pluripotency. Genes 9:93. https://doi.org/10.3390/genes9020093
Dhillon AS, Meikle S, Yazici Z et al (2002) Regulation of Raf-1 activation and signalling by dephosphorylation. EMBO J 21:64–71. https://doi.org/10.1093/emboj/21.1.64
Disotell TR, Tosi AJ (2007) The monkey’s perspective. Genome Biol 8:226. https://doi.org/10.1186/gb-2007-8-9-226
Echevarría-Andino ML, Allen BL (2020) The hedgehog co-receptor BOC differentially regulates SHH signaling during craniofacial development. Development 147:dev189076. https://doi.org/10.1242/dev.189076
Fabbri C, Tansey KE, Perlis RH et al (2018) New insights into the pharmacogenomics of antidepressant response from the GENDEP and STAR*D studies: rare variant analysis and high-density imputation. Pharmacogenomics J 18:413–421. https://doi.org/10.1038/tpj.2017.44
Fooden J (1990) The bear macaque, Macaca arctoides: a systematic review. J Hum Evol 19:607–686. https://doi.org/10.1016/0047-2484(90)90002-S
Girotto G, Abdulhadi K, Buniello A et al (2013) Linkage study and exome sequencing identify a BDP1 mutation associated with hereditary hearing loss. PLoS One 8:e80323. https://doi.org/10.1371/journal.pone.0080323
Ha M, Kim VN (2014) Regulation of microRNA biogenesis. Nat Rev Mol Cell Biol 15:509–524. https://doi.org/10.1038/nrm3838
Haase B, Brooks SA, Tozaki T et al (2009) Seven novel KIT mutations in horses with white coat colour phenotypes. Anim Genet 40:623–629. https://doi.org/10.1111/j.1365-2052.2009.01893.x
Harris SE, Fox H, Wright AF et al (2007) A genetic association analysis of cognitive ability and cognitive ageing using 325 markers for 109 genes associated with oxidative stress or cognition. BMC Genet 8:43. https://doi.org/10.1186/1471-2156-8-43
Hattori M, Fujiyama A, Taylor TD et al (2000) The DNA sequence of human chromosome 21. Nature 405:311–319. https://doi.org/10.1038/35012518
Hjeij R, Lindstrand A, Francis R et al (2013) ARMC4 mutations cause primary ciliary dyskinesia with randomization of left/right body asymmetry. Am J Hum Genet 93:357–367. https://doi.org/10.1016/j.ajhg.2013.06.009
Hu P, Samudre K, Wu S et al (2004) CK2 phosphorylation of Bdp1 executes cell cycle-specific RNA polymerase III transcription repression. Mol Cell 16:81–92. https://doi.org/10.1016/j.molcel.2004.09.008
Huelsken J, Birchmeier W (2001) New aspects of Wnt signaling pathways in higher vertebrates. Curr Opin Genet Dev 11:547–553. https://doi.org/10.1016/S0959-437X(00)00231-8
Jahromi MM (2012) Haplotype specific alteration of diabetes MHC risk by olfactory receptor gene polymorphism. Autoimmun Rev 12:270–274. https://doi.org/10.1016/j.autrev.2012.05.001
Jensen LJ, Kuhn M, Stark M et al (2009) STRING 8–a global view on proteins and their functional interactions in 630 organisms. Nucleic Acids Res 37:D412-416. https://doi.org/10.1093/nar/gkn760
Karim S, Jamal HS, Rouzi A et al (2017) Genomic answers for recurrent spontaneous abortion in Saudi Arabia: an array comparative genomic hybridization approach. Reprod Biol 17:133–143. https://doi.org/10.1016/j.repbio.2017.03.003
Ko Y-L, Hsu L-A, Wu S et al (2008) Genetic variation in the ASIC3 gene influences blood pressure levels in Taiwanese. J Hypertens 26:2154–2160. https://doi.org/10.1097/HJH.0b013e32830e251b
Li J, Han K, Xing J et al (2009) Phylogeny of the macaques (Cercopithecidae: Macaca) based on Alu elements. Gene 448:242–249. https://doi.org/10.1016/j.gene.2009.05.013
Li J, Liu L, Zhang J et al (2021) The expression of miR-129-5p and its target genes in the skin of goats. Anim Biotechnol 32:573–579. https://doi.org/10.1080/10495398.2020.1730392
Liang H, Li W-H (2009) Lowly expressed human MicroRNA genes evolve rapidly. Mol Biol Evol 26:1195–1198. https://doi.org/10.1093/molbev/msp053
Liu S-L, Wang X-C, Tan M-S et al (2016) NME8 rs2718058 Polymorphism with Alzheimer’s disease risk a replication and meta-analysis. Oncotarget 7:36014–36020. https://doi.org/10.18632/oncotarget.9086
Loughlin J, Meulenbelt I, Min J et al (2007) Genetic association analysis of RHOB and TXNDC3 in osteoarthritis. Am J Hum Genet 80:383–386
Mahr S, Burmester G-R, Hilke D et al (2006) Cis- and trans-acting gene regulation is associated with osteoarthritis. Am J Hum Genet 78:793–803
Mao Y, Zhu X, Xing S et al (2015) Polymorphisms in the promoter region of the bovine lactoferrin gene influence milk somatic cell score and milk production traits in Chinese Holstein cows. Res Vet Sci 103:107–112. https://doi.org/10.1016/j.rvsc.2015.09.021
Marklund S, Moller M, Sandberg K, Andersson L (1999) Close association between sequence polymorphism in the KIT gene and the roan coat color in horses. Mamm Genome 10:283–288. https://doi.org/10.1007/s003359900987
Matsumura S (2007) The evolution of “egalitarian” and “despotic” social systems among macaques. In: undefined. /paper/The-evolution-of-%E2%80%9Cegalitarian%E2%80%9D-and-%E2%80%9Cdespotic%E2%80%9D-among-Matsumura/245b8848cb61cecec683de4e2b50ef44289fac70/figure/2. Accessed 30 Mar 2020
May-Wilson S, Matoba N, Wade K, et al (2021) Large-scale genome-wide association study of food liking reveals genetic determinants and genetic correlations with distinct neurophysiological traits. 2021.07.28.454120
McCreight JC, Schneider SE, Wilburn DB, Swanson WJ (2017) Evolution of microRNA in primates. PLOS ONE 12:e0176596. https://doi.org/10.1371/journal.pone.0176596
Metzger J, Philipp U, Lopes MS et al (2013) Analysis of copy number variants by three detection algorithms and their association with body size in horses. BMC Genomics 14:487. https://doi.org/10.1186/1471-2164-14-487
Meyer WK, Venkat A, Kermany AR et al (2015) Evolutionary history inferred from the de novo assembly of a nonmodel organism, the blue-eyed black lemur. Mol Ecol 24:4392–4405. https://doi.org/10.1111/mec.13327
Mi H, Ebert D, Muruganujan A et al (2021) PANTHER version 16: a revised family classification, tree-based classification tool, enhancer regions and extensive API. Nucleic Acids Res 49:D394–D403. https://doi.org/10.1093/nar/gkaa1106
Miao Y, Ha A, de Lau W et al (2020) Next-generation surrogate Wnts support organoid growth and deconvolute frizzled pleiotropy in vivo. Cell Stem Cell 27:840-851.e6. https://doi.org/10.1016/j.stem.2020.07.020
Muhaghegh M, Habibizad J (2014) Sequence characterization of promoter region at the Melanocortin-1 receptor MC1R gene in Karakul sheep breed. J Agric Sci Technol 16:551–560
Mulieri PJ, Kang J-S, Sassoon DA, Krauss RS (2002) Expression of the boc gene during murine embryogenesis. Dev Dyn 223:379–388. https://doi.org/10.1002/dvdy.10063
Mundy NI, Kelly J (2003) Evolution of a pigmentation gene, the melanocortin-1 receptor, in primates. Am J Phys Anthropol 121:67–80. https://doi.org/10.1002/ajpa.10169
Mundy NI, Kelly J (2006) Investigation of the role of the agouti signaling protein gene (ASIP) in coat color evolution in primates. Mamm Genome 17:1205–1213. https://doi.org/10.1007/s00335-006-0056-0
Naumova OY, Rychkov SY, Kornilov SA et al (2019) Effects of early social deprivation on epigenetic statuses and adaptive behavior of young children: a study based on a cohort of institutionalized infants and toddlers. PLOS ONE 14:e0214285. https://doi.org/10.1371/journal.pone.0214285
Niwa R, Slack FJ (2007) The evolution of animal microRNA function. Curr Opin Genet Dev 17:145–150. https://doi.org/10.1016/j.gde.2007.02.004
Omariba G, Xu F, Wang M et al (2020) Genome-wide analysis of MicroRNA-related Single Nucleotide Polymorphisms (SNPs) in mouse genome. Sci Rep 10:5789. https://doi.org/10.1038/s41598-020-62588-6
Onoufriadis A, Shoemark A, Munye MM et al (2014) Combined exome and whole-genome sequencing identifies mutations in ARMC4 as a cause of primary ciliary dyskinesia with defects in the outer dynein arm. J Med Genet 51:61–67. https://doi.org/10.1136/jmedgenet-2013-101938
Pavlicev M, Wagner GP (2012) A model of developmental evolution: selection, pleiotropy and compensation. Trends Ecol Evol 27:316–322. https://doi.org/10.1016/j.tree.2012.01.016
Qu L, Li J, Zhao Z et al (2017) Differential expression of miR-202 and validation of predicted target genes in the skin tissue of C57BL/6 black mice and BALB/c white mice. DNA Cell Biol 36:443–450. https://doi.org/10.1089/dna.2016.3613
Raidt J, Wallmeier J, Hjeij R et al (2014) Ciliary beat pattern and frequency in genetic variants of primary ciliary dyskinesia. Eur Respir J 44:1579–1588. https://doi.org/10.1183/09031936.00052014
Rao TP, Kühl M (2010) An updated overview on Wnt signaling pathways. Circ Res 106:1798–1806. https://doi.org/10.1161/CIRCRESAHA.110.219840
Rathkey JK, Xiao TS, Abbott DW (2020) Human polymorphisms in GSDMD alter the inflammatory response. J Biol Chem 295:3228–3238. https://doi.org/10.1074/jbc.RA119.010604
Samuelov L, Sprecher E, Sugawara K et al (2013) Topobiology of human pigmentation: P-Cadherin selectively stimulates hair follicle melanogenesis. J Investig Dermatol 133:1591–1600. https://doi.org/10.1038/jid.2013.18
San L-Z, Liu B-S, Liu B et al (2021) Genome-wide association study reveals multiple novel SNPs and putative candidate genes associated with low oxygen tolerance in golden pompano Trachinotus ovatus (Linnaeus 1758). Aquaculture 544:737098. https://doi.org/10.1016/j.aquaculture.2021.737098
Schmeisser K, Parker JA (2019) Pleiotropic effects of mTOR and autophagy during development and aging. Front Cell Dev Biol 7:192
Shi D, Nakamura T, Nakajima M et al (2008) Association of single-nucleotide polymorphisms in RHOB and TXNDC3 with knee osteoarthritis susceptibility: two case–control studies in East Asian populations and a meta-analysis. Arthritis Res Ther 10:R54. https://doi.org/10.1186/ar2423
Shi J, Zhao Y, Wang K et al (2015) Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526:660–665. https://doi.org/10.1038/nature15514
Stevison LS, McGaugh SE (2020) It’s time to stop sweeping recombination rate under the genome scan rug. Mol Ecol 29:4249–4253. https://doi.org/10.1111/mec.15690
Stevison L, Szpiech Z, Bailey N et al (2021) VCF files associated with Macaca arctoides hybridization analysis. https://doi.org/10.35099/aurora-67
Stevison L, Bailey NP, Szpiech ZA et al (2022) Evolution of genes involved in the unusual genitals of the bear macaque Macaca arctoides. Ecol Evol 12(5):e8897
Szpiech ZA, Novak TE, Bailey NP, Stevison LS (2021) Application of a novel haplotype-based scan for local adaptation to study high-altitude adaptation in rhesus macaques. Evol Lett 5:408–421. https://doi.org/10.1002/evl3.232
Taciak B, Pruszynska I, Kiraga L et al (2018) Wnt signaling pathway in development and cancer. J Physiol Pharmacol: Off J Pol Physiol Soc. https://doi.org/10.26402/jpp.2018.2.07
Tanha HM, Nyholt DR (2022) Genetic analyses identify pleiotropy and causality for blood proteins and highlight Wnt/β-catenin signalling in migraine. Nat Commun 13:2593. https://doi.org/10.1038/s41467-022-30184-z
Thompson EE, Haller G, Pinto JM et al (2010) Sequence variations at the human leukocyte antigen-linked olfactory receptor cluster do not influence female preferences for male odors. Hum Immunol 71:100–103. https://doi.org/10.1016/j.humimm.2009.10.004
Trimmer C, Keller A, Murphy NR et al (2019) Genetic variation across the human olfactory receptor repertoire alters odor perception. Proc Natl Acad Sci 116:9475–9480. https://doi.org/10.1073/pnas.1804106115
UpSet: Visualization of Intersecting Sets | IEEE Journals & Magazine | IEEE Xplore. https://ieeexplore.ieee.org/abstract/document/6876017. Accessed 30 Jan 2023b
Vitorino Carvalho A, Soler L, Thélie A et al (2021) Proteomic changes associated with sperm fertilizing ability in meat-type roosters. Front Cell Dev Biol. https://doi.org/10.3389/fcell.2021.655866
Waal FBMD, Luttrell LM (1989) Toward a comparative socioecology of the genus Macaca: different dominance styles in rhesus and stumptail monkeys. Am J Primatol 19:83–109. https://doi.org/10.1002/ajp.1350190203
Wang Y, Li Y-P, Paulson C et al (2014) Wnt and the Wnt signaling pathway in bone development and disease. Front Biosci (Landmark Ed) 19:379–407
Wilson D, Heinsohn R, Endler J (2007) The adaptive significance of ontogenetic colour change in a tropical python. Biol Let 3:40–43. https://doi.org/10.1098/rsbl.2006.0574
Wolf JBW, Ellegren H (2017) Making sense of genomic islands of differentiation in light of speciation. Nat Rev Genet 18:87–100. https://doi.org/10.1038/nrg.2016.133
Wu S, Hsu L-A, Chou H-H et al (2010) Association between an ASIC3 gene variant and insulin resistance in Taiwanese. Clin Chim Acta 411:1132–1136. https://doi.org/10.1016/j.cca.2010.04.016
Wu S, Li J, Ma T et al (2021) MiR-27a regulates WNT3A and KITLG expression in Cashmere goats with different coat colors. Anim Biotechnol 32:205–212. https://doi.org/10.1080/10495398.2019.1675683
Xavier GM, Seppala M, Papageorgiou SN et al (2016) Genetic interactions between the hedgehog co-receptors Gas1 and Boc regulate cell proliferation during murine palatogenesis. Oncotarget 7:79233–79246. https://doi.org/10.18632/oncotarget.13011
Xiang B, Li Y, Li J et al (2021) MiR-19 3b regulated the formation of coat colors by targeting WNT10A and GNAI2 in Cashmere goats. Animal Biotechnol. https://doi.org/10.1080/10495398.2021.1998089
Xu J, He T, Wang L et al (2004) Molecular cloning and characterization of a novel human BTBD8 gene containing double BTB/POZ domains. Int J Mol Med 13:193–197. https://doi.org/10.3892/ijmm.13.1.193
Xu X, Dong G-X, Hu X-S et al (2013) The genetic basis of white tigers. Curr Biol 23:1031–1035. https://doi.org/10.1016/j.cub.2013.04.054
Yavropoulou M, Yovos J (2007) The role of the Wnt signaling pathway in osteoblast commitment and differentiation. Hormones 6:279–294. https://doi.org/10.14310/horm.2002.1111024
Zuk M, Bastiaans E, Langkilde T, Swanger E (2014) The role of behaviour in the establishment of novel traits. Anim Behav 92:333–344. https://doi.org/10.1016/j.anbehav.2014.02.032
Acknowledgements
We would like to thank Ben Evans for thoughtful discussion of this research. We also thank Dasia Simpson for help with String analysis. We would like to thank members of the Stevison Lab for helpful feedback throughout this project. TEN was supported on an intramural research grant (No. 180262) from Auburn University awarded to LSS.
Funding
Auburn University, 180262, Laurie S Stevison.
Author information
Authors and Affiliations
Corresponding authors
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
About this article
Cite this article
Novak, T.E., Bailey, N.P. & Stevison, L.S. Genetic characterization of Macaca arctoides: A highlight of key genes and pathways. Primates 64, 451–462 (2023). https://doi.org/10.1007/s10329-023-01064-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10329-023-01064-x