Journal of Heredity Advance Access published online on November 6, 2007
Journal of Heredity, doi:10.1093/jhered/esm087
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MHC DQB-1 Polymorphism in the Gulf of California Fin Whale (Balaenoptera physalus) Population
From the Laboratorio de Ecología Molecular, Departamento de Biología Marina, Universidad Autónoma de Baja California Sur, Carretera al Sur Km. 5.5, La Paz, B.C.S., México 23080 (Nigenda-Morales and Flores-Ramírez); the Programa de Investigación de Mamíferos Marinos, Departamento de Biología Marina, Universidad Autónoma de Baja California Sur, Carretera al Sur Km. 5.5, La Paz, B.C.S., México 23080 (Urbán-R.); and the Centro de Investigaciones Biológicas del Noroeste, SC Mar Bermejo 195, Playa Palo de Santa Rita, La Paz, B.C.S., México 23090 (Vázquez-Juárez)
Address correspondence to S. Flores-Ramírez at the address above, or e-mail: fflores{at}uabcs.mx.
One of the most isolated populations of fin whales occurs in the Gulf of California (GOC) with 400–800 individuals. This population shows reduced neutral genetic variation in comparison to the North Pacific population and thus might also display limited adaptive polymorphism. We sampled 36 fin whales from the GOC and assessed genetic variation at exon 2 of the major histocompatibility complex class II DQB-1 genes responsible for eliciting immune responses. Three divergent alleles were found with higher nonsynonymous than synonymous substitution rates within the peptide-binding region positions as well as the likely retention of ancient alleles, indicating that positive selection has shaped diversity in this species. Limited levels of nonneutral polymorphism, in addition to previously described low levels of neutral polymorphism, are consistent with the results of previous studies on vertebrate populations that have remained small and demographically stable for a very long time. Such low genetic variation in the GOC fin whales could be explained by 2 demographic scenarios: an ancient isolated population with limited gene flow or a more recent founder event after the last glacial maximum with very restricted gene flow.
Many genetic studies of wild vertebrates use neutral markers to assess genetic diversity in both individuals and populations (Avise 2000). However, such studies provide limited information on selective processes like the interaction of individuals with their environment or adaptive potential to future environmental change (Meyers and Bull 2002; Van Tienderen et al. 2002). In such cases, differences between populations can be detected by analyzing genes under selection (Cohen 2002), like those of the major histocompatibility complex (MHC). In vertebrates, MHC genes play an important role in eliciting immune responses against infectious disease. The MHC class II loci encode highly polymorphic glycoproteins on antigen-presenting cells responsible for binding and presenting foreign peptides to CD4 T cells, which initiate the immune response (Doherty and Zinkernagel 1975; Brown et al. 1993). In MHC molecules, the most important region in terms of functional variation appears to be concentrated in the peptide-binding region (PBR). This functional variation, as evidenced by high nonsynonymous substitution rates, is maintained mainly by parasite-mediated balancing selection through overdominance or frequency-dependent selection and a transspecies mode of evolution (Hughes and Nei 1989; Garrigan and Hedrick 2003).
Previous studies on polymorphism and evolution of MHC class II genes in cetacean populations have focused on the often most diverse DQB and DRB loci and are limited to 5 species: the beluga (Delphinapterus leucas), the narwhal (Monodon monoceros; Murray et al. 1995; Murray and White 1998), the Chinese river dolphin (Lipotes vexillifer; Yang et al. 2005), the finless porpoise (Neophocaena phocaenoides; Hayashi et al. 2006), and the humpback whale (Megaptera novaeangliae; Baker et al. 2006). Evidence of the functionality of these loci (expression) was recently found in the Hector's dolphin (Cephalorhynchus hectori; D. Heimeier, C. S. Baker, P. J. Duignan, K. Russell, A. Hutt, G. S. Stone, unpublished data) and the finless porpoise (Sone E, personal communication). In odontocetes like belugas and narwhals, it appears that DRB is more polymorphic than the DQB locus (Murray et al. 1999), whereas the opposite has been observed in mysticetes, and the duplication of these loci has also been documented in some species of mysticetes (Baker et al. 2006).
High MHC allelic diversity has been found in most outbred terrestrial species (Hedrick 1994) and also in marine mammals (Hoelzel et al. 1999; Baker et al. 2006; Hayashi et al. 2006). However, in populations that have experienced demographic reductions or isolation, MHC diversity can become greatly reduced (Seddon and Baverstock 1999; Weber et al. 2004) and could contribute to a higher infectious disease susceptibility (Evermann et al. 1988) and risk of extinction (Yuhki and O'Brien 1990).
Fin whales (Balaenoptera physalus) are widely distributed in the world's oceans and display high migratory potential. Nevertheless, several ecological and acoustic studies have indicated that fin whales in the Gulf of California (GOC) comprise a resident population (Gilmore 1957; Thompson et al. 1992; Tershy et al. 1993; Urbán-Ramírez et al. 2005). In addition, the reduced mitochondrial control region variation and microsatellite heterozygosity found in the GOC fin whales in comparison to the North Pacific (NP) population, and the high degree of differentiation between both GOC and NP populations (FST 
0.22 for both neutral markers), suggest that the GOC fin whales represent a distinctly isolated population (Bérubé et al. 2002). Limited genetic diversity observed in GOC fin whales is consistent with their reduced population size, estimated at 400–800 individuals (Gerrodette and Palacios 1996; Urbán-Ramírez et al. 2005). Such characteristics define this fin whale population as an outstanding model in which to characterize polymorphism at the DQB locus and to assess how selection and other evolutionary forces like past demographic dynamics have shaped adaptive molecular evolution in this reduced and restricted population of large whales in the GOC.
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Materials and Methods |
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Skin biopsies were obtained from 36 free-ranging fin whales at 5 localities in the GOC from 1995 to 2004 (Bahía de La Paz: n = 12, Loreto: n = 6, Bahía de los Angeles: n = 6, Bahía Kino: n = 7, and Puerto Libertad: n = 5) using a small stainless steel biopsy dart deployed from a crossbow (Lambertsen 1987).
Total genomic DNA was extracted from each sample following standard methods (Sambrook et al. 1989) and used to amplify a 172-bp fragment from the variable exon 2 of the DQB gene with polymerase chain reaction (PCR), using primers DQBF (5'-CTGGTAGTTGTGTCTGCACAC) and DQBR (5'-CATGTGCTACTTCACCAACGG) described by Murray et al. (1995). The PCR reaction conditions were 20 mM Tris–HCl pH 8.3, 100 mM KCl, 3.5 mM MgCl2, 0.4 mM (deoxynucleoside triphosphates), 1 µM of each primer, 1 unit of AmpliTaq Gold, and 50–100 ng of template DNA in a final volume of 25 µl. Thermal cycling conditions comprised an initial denaturation at 94 °C for 12 min, followed by 30 cycles of 94 °C for 1 min, 50 °C for 1 min, 72 °C for 2 min, and a final extension at 72 °C for 7 min. PCR products from the first assayed individual were cloned and sequenced on both strands (as described below) in order to confirm their identity as MHC loci thorough a BLAST search (Altschul et al. 1990). The remaining individuals were assayed for their DQB polymorphism by applying previously described PCR protocol and single-strand conformational polymorphism (SSCP) methods (Orita et al. 1989): PCR products (6 µl) from each individual were added to 20 µl of loading dye (0.05% bromophenol blue, 0.05% xylene cyanol, 95% N,N-dimethylformamide, and 20 mM ethylenediaminetetraacetic acid), denatured by heating (95 °C for 5 min), immediately chilled on ice for 5 min, and loaded onto a nondenaturing gel (12% 39:1 acrylamide:bis-acrylamide, 10% glycerol, and 0.5x tris-borate-ethylenediaminetetraacetic acid (TBE) buffer) electrophoresed at 450 V for 16 h at 4 °C. After electrophoresis, the SSCP gel was incubated for 30 min in darkness with SYBR gold 0.5x (Molecular Probes, Invitrogen, Carlsbad, CA) and visualized by UV illumination for SSCP scoring. All PCR products displaying unique SSCP patterns were cloned using a TOPO TA cloning kit (Invitrogen), and 5 clones per sample were sequenced on both strands using the BigDye Terminator Cycle Sequencing Ready Reaction Kit and an ABI 373 automated sequencer (Macrogen Inc., Seoul, Korea).
Unique B. physalus DQB sequences were aligned with homologous sequences of other mysticete taxa using ClustalX 1.8 (Thompson et al. 1997) and translated using GenDoc (Nicholas et al. 1997). The allelic numbers for fin whale sequences were assigned according to the 4-letter abbreviation for species origins (Klein et al. 1990) followed by the geographic location where the tissue sample was collected (GC for GOC), as suggested by Baker et al. (2006). In order to test if positive selection has acted on DQB evolution in this fin whale population, nonsynonymous (dn) and synonymous (ds) substitution rates were calculated for the PBR and non-PBR amino acid positions following the method of Nei and Gojobori (1986) under the Jukes and Cantor (1969) correction, and the significance levels were determined by a Z-test using the MEGA 3.1 software (Kumar et al. 2004). Also, nucleotide diversity and amino acid sequences divergence were calculated in MEGA 3.1. The evolutionary relationships of B. physalus and other cetacean DQB sequences (including cow [Bos taurus] and pig [Sus scrofa] sequences as out-group) were reconstructed using maximum likelihood (ML) and maximum parsimony (MP) optimization criteria, both with a neighbor-joining (NJ) exploratory approach, using the PAUP* 4.0b10 software (Swofford 2002), based on the F81 + G + I nucleotide substitution model (gamma distribution: 0.3868; invariable sites: 0.3360; base composition: A = 0.2350, C = 0.3067, G = 0.3140, and T = 0.1443), selected by the hierarchical likelihood ratio tests in the program MODELTEST 3.6 (Posada and Crandall 1998). The robustness of each phylogenetic reconstruction was assessed by bootstrap analysis (1000 replicates).
Expected heterozygosity was calculated assuming random mating. Finally, we assessed differences in allele frequencies between the 5 sampling sites (using Fisher's exact test) and deviation from Hardy–Weinberg equilibrium due to heterozygote excess (indicative of selection acting on MHC; Garrigan and Hedrick 2003) using a Markov chain method in the program GENEPOP 3.4 (Raymond and Rousset 1995).
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Results |
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Total genomic DNA was extracted from the 36 skin samples of fin whales and used to successfully amplify DQB exon 2 sequences (172 bp) from all individuals. PCR products from the first assayed individual were sequenced, indicating that this individual was homozygous for a fin whale DQB sequence already described (Baph-a, AB164199) by Hayashi et al. (2003). DQB polymorphism in the remaining 35 individuals was assessed applying SSCP, molecular cloning, and automated sequencing analyses, and no more than 2 alleles were detected in any individual, suggesting that only one locus was amplified.
Three unique fin whale DQB allelic sequences were identified: BaphGC-DQB*01, which showed to be identical to the previously described allele Baph-a (Hayashi et al. 2003); BaphGC-DQB*02, which turned to be identical to allele BaphM09-DQB*1 (DQ354626), isolated by Baker et al. (2006) from a fin whale from the Mediterranean Sea (North Atlantic), and a previously undescribed allele BaphGC-DQB*03 (Figure 1), which showed to be 94% similar to allele BaphGC-DQB*02. A Blast search of GenBank showed great similarity of these sequences to previously published DQB-1 exon 2 sequences of other cetacean species (Hayashi et al. 2003; Yang et al. 2005). These DQB-1 fin whale sequences were deposited in GenBank (accession numbers: BaphGC-DQB*01: DQ300261, BaphGC-DQB*02: DQ300262, and BaphGC-DQB*03: DQ300263). All 3 referred BaphGC-DQB sequences comprised continuous open reading frames and translated into amino acid sequences, each comprising 57 peptides (Figure 1). Nucleotide diversity found among these alleles were 3.6% (BaphGC-DQB*01/02), 5.4% (BaphGC-DQB*02/03), and 9.3% (BaphGC-DQB*01/03), average = 6.1%, standard error (SE) = 1.5%. Differences for amino acid sequences were 11.1%, 13.3%, and 26.4%, respectively, average = 16.9%, SE = 4.8%.
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Pairwise sequence comparisons of the 3 alleles revealed 13 nonsynonymous (dn) (Figure 1) and only 2 synonymous (ds) substitutions, resulting in a significantly higher value for dn compared with ds over all sites (Table 1). Amino acid positions at the PBR showed an infinite dn/ds ratio due to the absence of synonymous substitutions, whereas at non-PBR positions the ratio was higher than unity, although not significant (Table 1). Nine of the 13 amino acid changes were in positions that perform peptide recognition (PBR) in human MHC class II molecules (Brown et al. 1993) and 3 at positions 59, 60, and 75 adjacent to such recognition sites (Figure 1), causing physiochemical changes in the residue.
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Overall, ML phylogenetic reconstruction of these fin whale and other cetacean DQB sequences reveals that, with few exceptions, most odontocete and mysticete sequences segregate in distinct lineages and also showed an apparent transspecific sharing of similar alleles (Figure 2) as previously observed by Baker et al. (2006). In this analysis, fin whale DQB alleles segregated independently from each other and clustered with sequences from distinct mysticetes lineages concordant with species relationships. Thus, allele BaphM10DQB*2 (DQ354627, previously described by Baker et al. 2006) appeared to be more closely related to a humpback whale sequence, allele BaphGC-DQB*01 to a minke whale (Balaenoptera acutorostrata) sequence, and alleles BaphGC-DQB*02 and BaphGC-DQB*03 clustered together showing closer relation with Antarctic minke whale (Balaenoptera bonaerensis) sequences (Figure 2). However, none of these relationships were supported by bootstrap values. Phylogenetic reconstructions using MP and NJ as optimization criteria (data not shown) were consistent with such pattern, giving essentially the same results.
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50% from 1000 replicates are indicated adjacent to internal nodes. The tree is constructed based on a F81 + G + I nucleotide substitution model selected by a hierarchical likelihood ratio tests (The observed heterozygosity (Ho = 0.55) was not significantly different from the expected (He = 0.58), and there were no significant departures from the frequencies of expected genotypes (Table 2). Finally, BaphGC-DQB allelic frequencies were not significantly different between 5 sampling localities at the GOC (P = 0.145). In the total sample, allelic frequencies were 0.57, 0.18, and 0.25 for BaphGC-DQB*01, 02, and 03, respectively (Table 2).
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Discussion |
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We characterized and assessed the DQB polymorphism in 36 fin whales from the GOC population. From the 3 unique fin whale sequences that we identified, none included stop codons (Figure 1) indicating the probable functionality of the locus. These alleles shared greatest homology with previously published cetacean DQB-1 exon 2 sequences (Murray et al. 1995; Hayashi et al. 2003; Yang et al. 2005) and were therefore identified as belonging to the DQB-1 locus. The identification of only 3 alleles suggests limited DQB-1 polymorphism in this fin whale population because DQB variation assessments in other cetacean species like Antarctic minke whale (n = 11; Hayashi et al. 2003), a finless porpoise population (n = 26; Hayashi et al. 2006), and in a NP humpback whale population (n = 10; Baker et al. 2006) found 6, 8, and 9 alleles, respectively.
Although reduced, DQB-1 variation in the GOC fin whale population showed evidence of positive selection along the deep evolutionary history of this species (Hughes and Nei 1989; Garrigan and Hedrick 2003). Significant higher divergence nonsynonymous sites (Table 1) shifting the physiochemical properties at peptide-binding sites (Figure 1) indicated selective changes for peptide recognition and provided support for the hypothesis that peptide binding affinities of each one of these fin whale MHC proteins are different adaptive variants.
Though in general, phylogenies exhibited an apparent transspecific sharing of similar alleles and BaphGC-DQB alleles showed closer evolutionary relationships with minke whale and Antarctic minke whale sequences, these relationships were not strongly supported (Figure 2) and cannot be considered as strong evidence of transspecific evolution (Figueroa et al. 1988). Alternatively, DQB-1 alleles might have formed independently in each species and converged (Kriener et al. 2000) due to exposure to similar pathogens. Previous analyses on primates and other mammalian taxa indicated that, because overdominant selection drives the diversification of exon 2 sequences, these genes often do not provide enough phylogenetic information to reconstruct MHC sequences evolution. When these analyses included additional exonic sequences encoding proximal or transmembrane domains, phylogenies of MHC class I and II genes were more robust (Trtkova et al. 1995; Wettstein et al. 1996). Thus, although DQB-1 exon 2 sequences can be informative to understand selective forces driving the diversification of specific peptide-binding function, more complete cetacean DQB sequences are needed to evaluate the true phylogenetic relationships of these genes.
The high nucleotide diversity found among GOC fin whale DQB-1 sequences and the fact that some of these alleles are shared by fin whales from distinct ocean basins (BaphGC-DQB*02, GOC and Ligurian Sea; Baker CS, personal communication; BaphGC-DQB*01 likely recorded in the Western NP by Hayashi et al. 2003) provided evidence of divergence and retention of ancient alleles due to selection within the history of the species (Parham and Ohta 1996). This is evident when considering that the NP and North Atlantic fin whale populations likely diverged 3 mya, when the Panama isthmus arose. In contrast, BaphGC-DQB*03 allele was found only in GOC fin whales, but larger surveys in other populations are needed to determine if this allele is exclusive of the GOC. Thus, DQB-1 allelic features for GOC fin whales imply that this locus has played an important role for antigen diversity recognition in this population.
There are several possible explanations for the low DQB-1 polymorphism in the GOC fin whale population. First, initial studies suggested that reduced pathogenic pressure in marine as compared with terrestrial environments might explain limited MHC variation in marine mammals (Trowsdale et al. 1989; Slade 1992). However, recent assessments showed that cetacean MHC class II genes have undergone positive selection and their levels of diversity are variable among species as in wild terrestrial mammals (Murray et al. 1999; Hayashi et al. 2003; Baker et al. 2006). The latter and documented diseases and epizootics in cetaceans (Van Bressem et al. 1999) argue against reduced pathogenic pressure acting on marine mammal MHC genes.
Second, independent of their synonymous or nonsynonymous nature, MHC nucleotide substitution rates may be reduced in large cetaceans due to their long generation time, large body size, and low metabolic rate (Martin and Palumbi 1993; Gillooly et al. 2005). If true, mutation rates giving rise to new MHC alleles will be very slow in one of the largest mammals in the world. However, the recent isolation of 23 DQB alleles in 30 humpback whales (Baker et al. 2006) provides a counter example to the expectations of a slow mutation rate.
Third, low MHC diversity has been related to demographic reductions due to recent human impacts on wild populations. For instance, southern elephant seals (Mirounga leonina) show higher DQB variation than northern elephant seals (Mirounga angustirostris), which were hunted to the brink of extinction (Hoelzel et al. 1999; Weber et al. 2004). However, it is unlikely that observed MHC variation resulted from the population depletion due to human impacts (Mizroch S, unpublished data) because fin whales were never hunted in the GOC.
Alternatively, concordant levels of variation at both neutral and nonneutral (MHC) loci are reported when populations have remained historically stable (Boyce et al. 1997; Hedrick, Gutierrez-Espeleta, et al. 2001) or where stochastic events have been important in shaping the distribution of genetic variation (Gutierrez-Espeleta et al. 2001; Hedrick, Parker, et al. 2001; Landry and Bernatchez 2001). GOC fin whales show highly reduced neutral diversity for both mtDNA control region and microsatellite loci (Bérubé et al. 2002), consistent with low diversity in DQB sequences (this study; Table 3). In contrast, higher neutral variation found in NP fin whales (Bérubé et al. 2002; Table 3) might suggest a concomitant higher DQB polymorphism in such population, but this remains to be proved. In addition, GOC fin whales show very high genetic divergence (mtDNA control region: FST = 0.24, microsatellite loci: FST = 0.22) from the adjacent NP fin whale population, implying a reproductive isolation (Bérubé et al. 2002). Although mtDNA and microsatellite data come from distinct sample sets (Bérubé et al. 2002), the population samples were similar in number to the DQB and large enough to represent extant genetic diversity. Thus, concordant reduced neutral and nonneutral MHC variation patterns observed in these fin whales (Table 3) suggest that, although evidence of ancient selection on MHC genes was found, probably nonselective factors associated to historical demographic events (i.e., genetic drift) have been shaping DQB-1 polymorphism in this isolated fin whale population (Garrigan and Hedrick 2003). In this context, the genetic and demographic features of GOC fin whales might be explained by 2 hypothetical scenarios: 1) an ancient isolated population with limited gene flow, consistent with evidence indicating that the Baja California Peninsula was completely formed by 1–2 mya (Riddle et al. 2000) or 2) a more recent founder event by the end of the last glacial maximum, after which the population remained small, demographically stable, and exposed to very restricted gene flow, a concordant scenario with oceanographic data which indicate that actual biogeographic conditions have prevailed in the GOC for the last 12 000 years (Maluf 1983). Further analyses are required to evaluate these hypotheses by simultaneously assessing neutral (i.e., control region, microsatellite, and introns) and nonneutral (MHC) variation in both NP and GOC fin whale populations, in the context of estimated migration rates, divergence times, effective population sizes, and distinct selective pressures.
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) for neutral and nonneutral loci in the GOC and NP fin whale populationsAlthough the amount of genetic variation at one part of a single MHC locus is not a measure of the entire MHC, patterns of genetic diversity at the PBR of the DQB locus in GOC fin whales indicated that this locus has experienced strong positive selection. However, relatively low MHC polymorphism at the population level suggests that GOC fin whales might be susceptible to infections caused by novel pathogens. Together with similarly low levels of diversity at neutral loci, these data support the hypothesis that the GOC fin whale population has been small throughout its evolutionary history. To test this hypothesis, analyses on additional MHC loci such as the more variable DRB, as well as neutral nuclear loci for comparative purposes, are needed.
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Funding |
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Mexico's Consejo Nacional de Ciencia y Tecnología (34457 to S.F.-R.); UCMEXUS- CONACYT 2006 Collaborative Grant to S.F.-R; Secretaria de Medio Ambiente y Recursos Naturales-Consejo Nacional de Ciencia y Tecnología (SGPA/DGVS/00668 to J.U.R.); WWF-Mexico.
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Acknowledgments |
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The authors greatly appreciate the collaboration of A. Munguía-Vega for technical assistance and his comments on the research. We specially thank S. E. Alter, C. S. Baker, and 2 anonymous reviewers for insightful suggestions on the manuscript.
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Footnotes |
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Corresponding Editor: C. Scott Baker
Received September 6, 2006
Accepted September 20, 2007
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