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New insights into the role of MHC diversity in devil facial tumour disease.

Lane A, Cheng Y, Wright B, Hamede R, Levan L, Jones M, Ujvari B, Belov K - PLoS ONE (2012)

Bottom Line: Genetic variation between the two sub-groups (healthy and diseased) was also compared using eight MHC-linked microsatellite markers.No significant differences were identified in allele frequency, however differences were noted in the genotype frequencies of two microsatellites located near non-antigen presenting genes within the MHC.We did not find predictable differences in MHC class I copy number variation to account for differences in susceptibility to DFTD.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Veterinary Science, University of Sydney, Sydney, Australia.

ABSTRACT

Background: Devil facial tumour disease (DFTD) is a fatal contagious cancer that has decimated Tasmanian devil populations. The tumour has spread without invoking immune responses, possibly due to low levels of Major Histocompatibility Complex (MHC) diversity in Tasmanian devils. Animals from a region in north-western Tasmania have lower infection rates than those in the east of the state. This area is a genetic transition zone between sub-populations, with individuals from north-western Tasmania displaying greater diversity than eastern devils at MHC genes, primarily through MHC class I gene copy number variation. Here we test the hypothesis that animals that remain healthy and tumour free show predictable differences at MHC loci compared to animals that develop the disease.

Methodology/principal findings: We compared MHC class I sequences in 29 healthy and 22 diseased Tasmanian devils from West Pencil Pine, a population in north-western Tasmania exhibiting reduced disease impacts of DFTD. Amplified alleles were assigned to four loci, Saha-UA, Saha-UB, Saha-UC and Saha-UD based on recently obtained genomic sequence data. Copy number variation (caused by a deletion) at Saha-UA was confirmed using a PCR assay. No association between the frequency of this deletion and disease status was identified. All individuals had alleles at Saha-UD, disproving theories of disease susceptibility relating to copy number variation at this locus. Genetic variation between the two sub-groups (healthy and diseased) was also compared using eight MHC-linked microsatellite markers. No significant differences were identified in allele frequency, however differences were noted in the genotype frequencies of two microsatellites located near non-antigen presenting genes within the MHC.

Conclusions/significance: We did not find predictable differences in MHC class I copy number variation to account for differences in susceptibility to DFTD. Genotypic data was equivocal but indentified genomic areas for further study.

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Genotype frequencies for healthy and DFTD infected devils.(A) At the six microsatellite loci associated with antigen-presenting genes within the MHC (Sh-I01, Sh-I02, Sh-I05, Sh-I06, Sh-I10 and Sh-I11). No deviations from Hardy-Weinberg equilibrium are observed for either healthy or DFTD infected devils. (B) For two microsatellite markers more closely associated with non-antigen presenting genes within the MHC region (Sh-I07 and Sh-I08). The Sh-I07 locus is out of Hardy-Weinberg equilibrium for healthy devils only (p = 0.029) and the Sh-I08 locus does not conform to Hardy-Weinberg equilibrium at the 0.1 significance level (p = 0.076). Three differences in genotype frequencies were significant before Bonferroni correction (Sh-I07∶173/185, p = 0.041 and 185/187, p = 0.024; Sh-I08∶223/225, p = 0.024).
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pone-0036955-g003: Genotype frequencies for healthy and DFTD infected devils.(A) At the six microsatellite loci associated with antigen-presenting genes within the MHC (Sh-I01, Sh-I02, Sh-I05, Sh-I06, Sh-I10 and Sh-I11). No deviations from Hardy-Weinberg equilibrium are observed for either healthy or DFTD infected devils. (B) For two microsatellite markers more closely associated with non-antigen presenting genes within the MHC region (Sh-I07 and Sh-I08). The Sh-I07 locus is out of Hardy-Weinberg equilibrium for healthy devils only (p = 0.029) and the Sh-I08 locus does not conform to Hardy-Weinberg equilibrium at the 0.1 significance level (p = 0.076). Three differences in genotype frequencies were significant before Bonferroni correction (Sh-I07∶173/185, p = 0.041 and 185/187, p = 0.024; Sh-I08∶223/225, p = 0.024).

Mentions: The frequency of genotypes in the population was also assessed. This measure is particularly sensitive to changes over short time scales (allele frequencies take longer to change in a population than genotype frequencies), which is relevant considering the recent arrival of DFTD in the region. Microsatellite markers located closest to antigen presenting MHC class I loci (Sh-I01, Sh-I02, Sh-I05, Sh-I06, Sh-I10, Sh-I11) had low allelic (Fig. 2) and genotype diversity (Fig. 3a), possibly the result of a selective sweep due to a prior disease epidemic [32], [33]. Two markers (Sh-I07 and Sh-I08) are located within the MHC but are closest to non-antigen presenting genes, MTCH1 and FGD2 (Fig. 3). Both loci have considerably higher polymorphism with six alleles each and 10–15 genotypes (mean 12.5), compared to 2–4 alleles (mean 2.83) and 3–7 genotypes (mean 4.67) in the six remaining markers which are located closest to genes involved in antigen presentation.


New insights into the role of MHC diversity in devil facial tumour disease.

Lane A, Cheng Y, Wright B, Hamede R, Levan L, Jones M, Ujvari B, Belov K - PLoS ONE (2012)

Genotype frequencies for healthy and DFTD infected devils.(A) At the six microsatellite loci associated with antigen-presenting genes within the MHC (Sh-I01, Sh-I02, Sh-I05, Sh-I06, Sh-I10 and Sh-I11). No deviations from Hardy-Weinberg equilibrium are observed for either healthy or DFTD infected devils. (B) For two microsatellite markers more closely associated with non-antigen presenting genes within the MHC region (Sh-I07 and Sh-I08). The Sh-I07 locus is out of Hardy-Weinberg equilibrium for healthy devils only (p = 0.029) and the Sh-I08 locus does not conform to Hardy-Weinberg equilibrium at the 0.1 significance level (p = 0.076). Three differences in genotype frequencies were significant before Bonferroni correction (Sh-I07∶173/185, p = 0.041 and 185/187, p = 0.024; Sh-I08∶223/225, p = 0.024).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3368896&req=5

pone-0036955-g003: Genotype frequencies for healthy and DFTD infected devils.(A) At the six microsatellite loci associated with antigen-presenting genes within the MHC (Sh-I01, Sh-I02, Sh-I05, Sh-I06, Sh-I10 and Sh-I11). No deviations from Hardy-Weinberg equilibrium are observed for either healthy or DFTD infected devils. (B) For two microsatellite markers more closely associated with non-antigen presenting genes within the MHC region (Sh-I07 and Sh-I08). The Sh-I07 locus is out of Hardy-Weinberg equilibrium for healthy devils only (p = 0.029) and the Sh-I08 locus does not conform to Hardy-Weinberg equilibrium at the 0.1 significance level (p = 0.076). Three differences in genotype frequencies were significant before Bonferroni correction (Sh-I07∶173/185, p = 0.041 and 185/187, p = 0.024; Sh-I08∶223/225, p = 0.024).
Mentions: The frequency of genotypes in the population was also assessed. This measure is particularly sensitive to changes over short time scales (allele frequencies take longer to change in a population than genotype frequencies), which is relevant considering the recent arrival of DFTD in the region. Microsatellite markers located closest to antigen presenting MHC class I loci (Sh-I01, Sh-I02, Sh-I05, Sh-I06, Sh-I10, Sh-I11) had low allelic (Fig. 2) and genotype diversity (Fig. 3a), possibly the result of a selective sweep due to a prior disease epidemic [32], [33]. Two markers (Sh-I07 and Sh-I08) are located within the MHC but are closest to non-antigen presenting genes, MTCH1 and FGD2 (Fig. 3). Both loci have considerably higher polymorphism with six alleles each and 10–15 genotypes (mean 12.5), compared to 2–4 alleles (mean 2.83) and 3–7 genotypes (mean 4.67) in the six remaining markers which are located closest to genes involved in antigen presentation.

Bottom Line: Genetic variation between the two sub-groups (healthy and diseased) was also compared using eight MHC-linked microsatellite markers.No significant differences were identified in allele frequency, however differences were noted in the genotype frequencies of two microsatellites located near non-antigen presenting genes within the MHC.We did not find predictable differences in MHC class I copy number variation to account for differences in susceptibility to DFTD.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Veterinary Science, University of Sydney, Sydney, Australia.

ABSTRACT

Background: Devil facial tumour disease (DFTD) is a fatal contagious cancer that has decimated Tasmanian devil populations. The tumour has spread without invoking immune responses, possibly due to low levels of Major Histocompatibility Complex (MHC) diversity in Tasmanian devils. Animals from a region in north-western Tasmania have lower infection rates than those in the east of the state. This area is a genetic transition zone between sub-populations, with individuals from north-western Tasmania displaying greater diversity than eastern devils at MHC genes, primarily through MHC class I gene copy number variation. Here we test the hypothesis that animals that remain healthy and tumour free show predictable differences at MHC loci compared to animals that develop the disease.

Methodology/principal findings: We compared MHC class I sequences in 29 healthy and 22 diseased Tasmanian devils from West Pencil Pine, a population in north-western Tasmania exhibiting reduced disease impacts of DFTD. Amplified alleles were assigned to four loci, Saha-UA, Saha-UB, Saha-UC and Saha-UD based on recently obtained genomic sequence data. Copy number variation (caused by a deletion) at Saha-UA was confirmed using a PCR assay. No association between the frequency of this deletion and disease status was identified. All individuals had alleles at Saha-UD, disproving theories of disease susceptibility relating to copy number variation at this locus. Genetic variation between the two sub-groups (healthy and diseased) was also compared using eight MHC-linked microsatellite markers. No significant differences were identified in allele frequency, however differences were noted in the genotype frequencies of two microsatellites located near non-antigen presenting genes within the MHC.

Conclusions/significance: We did not find predictable differences in MHC class I copy number variation to account for differences in susceptibility to DFTD. Genotypic data was equivocal but indentified genomic areas for further study.

Show MeSH
Related in: MedlinePlus