Abstract
The role the major histocompatibility complex (MHC) plays in response to exposure to environmental toxins is relatively poorly understood, particularly in comparison to its well-described role in pathogen immunity. We investigated associations between MHC diversity and resistance to brevetoxins in common bottlenose dolphins (Tursiops truncatus). A previous genome-wide association study investigating an apparent difference in harmful algal bloom (HAB) resistance among dolphin populations in the Gulf of Mexico identified genetic variation associated with survival in close genomic proximity to multiple MHC class II loci. Here, we characterized genetic variation at DQA, DQB, DRA, and DRB loci in dolphins from central-west Florida and the Florida Panhandle, including dolphins that died during HABs and dolphins presumed to have survived HAB exposure. We found that DRB and DQB exhibited patterns of genetic differentiation among geographic regions that differed from neutral microsatellite loci. In addition, genetic differentiation at DRB across multiple pairwise comparisons of live and dead dolphins was greater than differentiation observed at neutral loci. Our findings at these MHC loci did not approach the strength of association with survival previously described for a nearby genetic variant. However, the results provide evidence that selective pressures at the MHC vary among dolphin populations that differ in the frequency of HAB exposure and that the overall composition of DRB variants differs between dolphin survivors and non-survivors of HABs. These results may suggest a potential role of MHC diversity in variable survival of bottlenose dolphins exposed to HABs.
References
Alho J, Välimäki K (2012) Rhh: calculating multilocus heterozygosity and heterozygosity-heterozygosity correlation. R package version 1.0.2
Amos W, Wilmer JW, Fullard K, Burg TM, Croxall JP, Bloch D, Coulson T (2001) The influence of parental relatedness on reproductive success. Proc Biol Sci 268:2021–2027. doi:10.1098/rspb.2001.1751
Antao T, Lopes A, Lopes RJ, Beja-Pereira A, Luikart G (2008) LOSITAN: a workbench to detect molecular adaptation based on a Fst-outlier method. BMC Bioinforma 9:323. doi:10.1186/1471-2105-9-323
Arbanasić H, Čurković S, Gomerčić T, Gomerčić M, Galov A (2012) Diversity of MHC class II DRA gene in the Adriatic bottlenose dolphins (Tursiops truncatus). In: Jelaska SD, Klobučar GIV, Šerić Jelaska L, Leljak Levanić D, Lukša Ž (eds) 11th Croatian biological congress. Croatian Biological Society, Zagreb, pp 151–152
Baden DG, Mende TJ, Walling J, Schultz DR (1984) Specific antibodies directed against toxins of Ptychodiscus brevis (Florida’s red tide dinoflagellate). Toxicon 22:783–789. doi:10.1016/0041-0101(84)90161-2
Brown JH, Jardetzky TS, Gorga JC, Stern LJ, Urban RG, Strominger JL, Wiley DC (1993) Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1. Nature 364:33–39. doi:10.1038/364033a0
Caballero S, Heimeier D, Trujillo F et al (2010) Initial description of major histocompatibility complex variation at two class II loci (DQA-DQB) in Sotalia fluviatilis and Sotalia guianensis. LAJAM 8:81–95. doi:10.5597/lajam00156
Cohen S (2002) Strong positive selection and habitat-specific amino acid substitution patterns in Mhc from an estuarine fish under intense pollution stress. Mol Biol Evol 19:1870–1880. doi:10.1093/oxfordjournals.molbev.a004011
Coltman DW, Pilkington JG, Smith JA, Pemberton JM (1999) Parasite-mediated selection against inbred Soay sheep in a free-living, island population. Evolution 53:1259–1267. doi:10.2307/2640828
Doherty PC, Zinkernagel RM (1975) Enhanced immunological surveillance in mice heterozygous at the H-2 gene complex. Nature 256:50–52. doi:10.1038/256050a0
Fire SE, Flewelling LJ, Wang ZH, Naar J, Henry MS, Pierce RH, Wells RS (2008) Florida red tide and brevetoxins: association and exposure in live resident bottlenose dolphins (Tursiops truncatus) in the eastern Gulf of Mexico, U.S.A. Mar Mamm Sci 24:831–844
Florida Fish and Wildlife Research Institute (2008) 164 years of suspected and documented red tides off Florida’s west coast. Florida Fish and Wildlife Conservation Commission. http://myfwc.com/research/redtide/monitoring/database/timeline-red-tides-fl-w-coast. Accessed 9 October 2010.
Germain RN, Castellino F, Han R, Sousa CRE, Romagnoli P, Sadegh-Nasseri S, Zhong G (1996) Processing and presentation of endocytically acquired protein antigens by MHC class II and class I molecules. Immunol Rev 151:5–30. doi:10.1111/j.1600-065X.1996.tb00701.x
Goulder PJR, Walker BD (2012) HIV and HLA class I: an evolving relationship. Immunity 37:426–440. doi:10.1016/j.immuni.2012.09.005
Hedrick PW (2005) A standardized genetic differentiation measure. Evolution 59:1633–1638. doi:10.1111/j.0014-3820.2005.tb01814.x
Hilderbrand SC, Murrell RN, Gibson JE, Brown JM (2010) Marine brevetoxin induces IgE-independent mast cell activation. Arch Toxicol 84:135–141. doi:10.1007/s00204-010-0564-2
Hoelzel AR, Potter CW, Best PB (1998) Genetic differentiation between parapatric ‘nearshore’ and ‘offshore’ populations of the bottlenose dolphin. Proc R Soc Lond B Biol Sci 265:1177. doi:10.1098/rspb.1998.0416
Hohn AA, Scott MD, Wells RS, Sweeney JC, Irvine AB (1989) Growth layers in teeth from known-age, free-ranging bottlenose dolphins. Mar Mamm Sci 5:315–342. doi:10.1111/j.1748-7692.1989.tb00346.x
Ingale AG (2010) Antigenic epitopes prediction and MHC binder of a paralytic insecticidal toxin (ITX-1) of Tegenaria agrestis (hobo spider). Open Access Bioinforma 2:97–103. doi:10.2147/OAB.S11886
Keenan K, McGinnity P, Cross TF, Crozier WW, Prodohl PA (2013) diveRsity: an R package for the estimation and exploration of population genetics parameters and their associated errors. Methods Ecol Evol 4:782–788. doi:10.1111/2041-210X.12067
Kita YF, Inoko H, Shiina T, Tanaka S (2010) Development of newly paternity test method for dolphins using microsatellite and MHC-DQB markers. Bull Inst Ocean Res Dev Tokai Univ 31:1–8
Klein J (1987) Origin of major histocompatibility complex polymorphism—the transspecies hypothesis. Hum Immunol 19:155–162. doi:10.1016/0198-8859(87)90066-8
Klein J, Bontrop RE, Dawkins RL et al (1990) Nomenclature for the major histocompatibility complexes of different species: a proposal. Immunogenetics 31:217–219. doi:10.1007/BF00204890
Krützen M, Valsecchi E, Connor RC, Sherwin WB (2001) Characterization of microsatellite loci in Tursiops aduncus. Mol Ecol Notes 1:170–172. doi:10.1046/j.1471-8278.2001.00065.x
Lefebvre KA, Frame ER, Gulland F et al (2012) A novel antibody-based biomarker for chronic algal toxin exposure and sub-acute neurotoxicity. PLoS One 7:e36213. doi:10.1371/journal.pone.0036213
Mancia A, Warr GW, Almeida JS, Veloso A, Wells RS, Chapman RW (2010) Transcriptome profiles: diagnostic signature of dolphin populations. Estuar Coasts 33:919–929. doi:10.1007/s12237-010-9287-0
Marsh SG, Albert ED, Bodmer WF et al (2005) Nomenclature for factors of the HLA system, 2004. Hum Immunol 66:571–636. doi:10.1016/j.humimm.2005.02.002
Mase B, Jones W, Ewing R et al. (2000) Epizootic in bottlenose dolphins in the Florida Panhandle: 1999–2000. In: American Association of Zoo Veterinarians and International Association of Aquatic Animal Medicine Joint Conference, New Orleans, LA, pp 522–525
McCarthy MI, Hirschhorn JN (2008) Genome-wide association studies: potential next steps on a genetic journey. Hum Mol Genet 17:R156–R165. doi:10.1093/hmg/ddn289
Murrell RN, Gibson JE (2009) Brevetoxins 2, 3, 6, and 9 show variability in potency and cause significant induction of DNA damage and apoptosis in Jurkat E6-1 cells. Arch Toxicol 83:1009–1019. doi:10.1007/s00204-009-0443-x
National Marine Fisheries Service (2004) Interim Report on the Bottlenose Dolphin (Tursiops truncatus) Unusual Mortality Event along the Panhandle of Florida, March-April 2004, 36 pp. Available at: http://www.nmfs.noaa.gov/pr/pdfs/health/ume_bottlenose_2004.pdf
Nei M, Chesser R (1983) Estimation of fixation indices and gene diversities. Ann Hum Genet 47:253–259. doi:10.1111/j.1469-1809.1983.tb00993.x
Nei M, Gojobori T (1986) Simple methods for estimating the numbers of synonymous and nonsynonymous nucleotide substitutions. Mol Biol Evol 3:418–426
Pääbo S, Irwin DM, Wilson AC (1990) DNA damage promotes jumping between templates during enzymatic amplification. J Biol Chem 265:4718–4721
Pierce R, Henry M, Blum P (2008) Brevetoxin abundance and composition during ECOHAB-Florida field monitoring cruises in the Gulf of Mexico. Cont Shelf Res 28:45–58. doi:10.1016/j.csr.2007.04.012
Poli MA, Mende TJ, Baden DG (1986) Brevetoxins, unique activators of voltage-sensitive sodium channels, bind to specific sites in rat brain synaptosomes. Mol Pharmacol 30:129–135
R Core Team (2013) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna
Raymond M, Rousset F (1995) GENEPOP (version 1.2): population genetics software for exact tests and ecumenicism. J Hered 96:248–250
Read AJ, Wells RS, Hohn AA, Scott MD (1993) Patterns of growth in wild bottlenose dolphins, Tursiops truncatus. J Zool (Lond) 231:107–123. doi:10.1111/j.1469-7998.1993.tb05356.x
Rice WR (1989) Analyzing tables of statistical tests. Evolution 43:223–225. doi:10.2307/2409177
Rooney AP, Merritt DB, Derr JN (1999) Microsatellite diversity in captive bottlenose dolphins (Tursiops truncatus). J Hered 90:228–231. doi:10.1093/jhered/90.1.228
Rosel PE, Hansen L, Hohn AA (2009) Restricted dispersal in a continuously distributed marine species: common bottlenose dolphins Tursiops truncatus in coastal waters of the western North Atlantic. Mol Ecol 18:5030–5045. doi:10.1111/j.1365-294X.2009.04413.x
Rosel PE, Block BA (1996) Mitochondrial control region variability and global population structure in the swordfish, Xiphias gladius. Mar Biol 125:11–22. doi:10.1007/BF00350756
Rosel PE, Forgetta V, Dewar K (2005) Isolation and characterization of twelve polymorphic microsatellite markers in bottlenose dolphins (Tursiops truncatus). Mol Ecol Notes 5:830–833. doi:10.1111/j.1471-8286.2005.01078.x
Rosel PE, France S, Wang J, Kocher T (1999) Genetic structure of harbour porpoise Phocoena phocoena populations in the northwest Atlantic based on mitochondrial and nuclear markers. Mol Ecol 8:S41–S54. doi:10.1046/j.1365-294X.1999.00758.x
SAS Institute Inc (2014) JMP® 11 fitting linear models. SAS Institute Inc., Cary
Satta Y, O’Huigin C, Takahata N, Klein J (1994) Intensity of natural selection at the major histocompatibility complex loci. Proc Natl Acad Sci 91:7184–7188. doi:10.1073/pnas.91.15.7184
Schwacke LH, Twiner MJ, De Guise S et al (2010) Eosinophilia and biotoxin exposure in bottlenose dolphins (Tursiops truncatus) from a coastal area impacted by repeated mortality events. Environ Res 110:548–555. doi:10.1016/j.envres.2010.05.003
Scott MD, Wells RS, Irvine AB (1990) A long-term study of bottlenose dolphins on the west coast of Florida. In: Leatherwood S, Reeves RR (eds) The bottlenose dolphin. Academic, San Diego, pp 235–244
Seddon JM, Ellegren H (2002) MHC class II genes in European wolves: a comparison with dogs. Immunogenetics 54:490–500. doi:10.1007/s00251-002-0489-x
Sellas AB, Wells RS, Rosel PE (2005) Mitochondrial and nuclear DNA analyses reveal fine scale geographic structure in bottlenose dolphins (Tursiops truncatus) in the Gulf of Mexico. Cons Gen 6:715–728. doi:10.1007/s10592-005-9031-7
Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM, Sirotkin K (2001) dbSNP: the NCBI database of genetic variation. Nucleic Acids Res 29:308–311. doi:10.1093/nar/29.1.308
Sollid LM, Pos W, Wucherpfennig KW (2014) Molecular mechanisms for contribution of MHC molecules to autoimmune diseases. Curr Opin Immunol 31:24–30. doi:10.1016/j.coi.2014.08.005
Sommer S (2005) The importance of immune gene variability (MHC) in evolutionary ecology and conservation. Front Zool 2:1742–9994. doi:10.1186/1742-9994-2-16
Steidinger KA, Vargo GA, Tester PA, Tomas CR (1998) Bloom dynamics and physiology of Gymnodinium breve with emphasis on the Gulf of Mexico. In: Anderson DM, Cembella AD, Hallegraeff GM (eds) Physiological ecology of harmful algal blooms: NATO ASI series. Series G, Ecological sciences, vol. 41, pp 133–153
Takahata N, Nei M (1990) Allelic genealogy under overdominant and frequency-dependent selection and polymorphism of major histocompatibility complex. Genetics 124:967–978
Tamura K, Peterson D, Peterson N, Stecher G, Nei M, Kumar S (2011) MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol Biol Evol 28:2731–2739. doi:10.1093/molbev/msr121
Trowsdale J (2011) The MHC, disease and selection. Immunol Lett 137:1–8. doi:10.1016/j.imlet.2011.01.002
Twiner MJ, Fire S, Schwacke L, Davidson L, Wang Z, Morton S, Roth S, Balmer B, Rowles TK, Wells RS (2011) Concurrent exposure of bottlenose dolphins (Tursiops truncatus) to multiple algal toxins in Sarasota Bay, Florida, USA. PLoS One 6:e17394. doi:10.1371/journal.pone.0017394
Twiner MJ, Flewelling LJ, Fire SE et al (2012) Comparative analysis of three brevetoxin-associated bottlenose dolphin (Tursiops truncatus) mortality events in the Florida Panhandle region (USA). PLoS One 7:e42974. doi:10.1371/journal.pone.0042974
Valsecchi E, Amos W (1996) Microsatellite markers for the study of cetacean populations. Mol Ecol 5:151–156. doi:10.1111/j.1365-294X.1996.tb00301.x
Vollmer NL (2011) Population structure of common bottlenose dolphins in coastal and offshore waters of the Gulf of Mexico revealed by genetic and environmental analyses. Dissertation, University of Louisiana at Lafayette
Villanueva-Noriega MJ, Baker CS, Medrano-Gonzalez L (2013) Evolution of the MHC-DQB exon 2 in marine and terrestrial mammals. Immunogenetics 65:47–61. doi:10.1007/s00251-012-0647-8
Walsh CJ, Leggett SR, Carter BJ, Colle C (2010) Effects of brevetoxin exposure on the immune system of loggerhead sea turtles. Aquat Toxicol 97:293–303. doi:10.1016/j.aquatox.2009.12.014
Xu SX, Ren WH, Li SZ, Wei FW, Zhou KY, Yang G (2009) Sequence polymorphism and evolution of three cetacean MHC genes. J Mol Evol 69:260–275. doi:10.1007/s00239-009-9272-z
Xu S, Ju J, Zhou X, Wang L, Zhou K, Yang G (2012) Considerable MHC diversity suggests that the functional extinction of baiji is not related to population genetic collapse. PLoS One 7:e30423. doi:10.1371/journal.pone.0030423
Yang WC, Hu JM, Chou LS (2008) Sequence variation of MHC class II DQB gene in bottlenose dolphins (Tursiops truncatus) from Taiwanese waters. Taiwania 53:42–50
Acknowledgments
The authors thank the following for providing samples: the Chicago Zoological Society’s Sarasota Dolphin Research Program, the Mote Marine Laboratory Stranding Investigations Program, and the NOAA SEFSC Marine Mammal Tissue and DNA Archive which provided samples donated by A. Costidis and D. Boyd (Florida Fish and Wildlife Conservation Commission), B. Balmer and L. Schwacke (NOAA/NCCOS Hollings Marine Lab), and J. Litz (NOAA/NMFS Southeast Fisheries Science Center). The authors also thank B. Balmer for the information categorizing live dolphins from the Florida Panhandle as coastal or estuarine and I. T. Rodriguez and N. Phillips for the assistance with MHC and microsatellite genotyping. Funding for this work was provided by the PADI Foundation, the American Fisheries Society, the Duke University Marine Lab Kaupe fund, Dolphin Quest, and the Oak Foundation. This manuscript was improved by the thoughtful comments of one anonymous reviewer.
Ethical standards
Samples from live dolphins were collected using protocols approved by the Mote Marine Laboratory Institutional Animal Care and Use Committee (IACUC) and a NOAA/NMFS ad hoc IACUC. Samples were collected under the following scientific research permits issued by NMFS: 522–1527, 522–1569, 522–1785, and 15543 issued to RSW and 932–1489 (as amended) issued to the NOAA Marine Mammal Health and Stranding Response Program.
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Cammen, K.M., Wilcox, L.A., Rosel, P.E. et al. From genome-wide to candidate gene: an investigation of variation at the major histocompatibility complex in common bottlenose dolphins exposed to harmful algal blooms. Immunogenetics 67, 125–133 (2015). https://doi.org/10.1007/s00251-014-0818-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00251-014-0818-x