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The assembly and characterisation of two structurally distinct cattle MHC class I haplotypes point to the mechanisms driving diversity.

Schwartz JC, Hammond JA - Immunogenetics (2015)

Bottom Line: This variable region appears to have undergone block gene duplication and likely deletion at regular breakpoints, suggestive of a site-specific mechanism.Phylogenetic analysis using complete gene sequences provided evidence of allelic diversification via gene conversion, with breakpoints between each of the extracellular domains that were associated with high guanine-cytosine (GC) content.Advancing our knowledge of cattle MHC class I evolution will help inform investigations of cattle genetic diversity and disease resistance.

View Article: PubMed Central - PubMed

Affiliation: Livestock Viral Diseases Programme, The Pirbright Institute, Ash Road, Pirbright, Woking, Surrey, GU24 0NF, UK.

ABSTRACT
In cattle, there are six classical MHC class I genes that are variably present between different haplotypes. Almost all known haplotypes contain between one and three genes, with an allele of Gene 2 present on the vast majority. However, very little is known about the sequence and therefore structure and evolutionary history of this genomic region. To address this, we have refined the MHC class I region in the Hereford cattle genome assembly and sequenced a complete A14 haplotype from a homozygous Holstein. Comparison of the two haplotypes revealed extensive variation within the MHC class Ia region, but not within the flanking regions, with each gene contained within a conserved 63- to 68-kb sequence block. This variable region appears to have undergone block gene duplication and likely deletion at regular breakpoints, suggestive of a site-specific mechanism. Phylogenetic analysis using complete gene sequences provided evidence of allelic diversification via gene conversion, with breakpoints between each of the extracellular domains that were associated with high guanine-cytosine (GC) content. Advancing our knowledge of cattle MHC class I evolution will help inform investigations of cattle genetic diversity and disease resistance.

No MeSH data available.


Intron/exon structure and GC content of the known complete MHC class I genes. Exons for each gene are shaded and numbered. Y-axis shows percent GC (from 50 to 100 %) using a sliding window of 100 bp and a 2.5-standard deviation cut-off indicating abnormally high GC content near the intron/exon boundaries of the first three exons. GC content was visualised using Artemis (Rutherford et al. 2000)
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Fig4: Intron/exon structure and GC content of the known complete MHC class I genes. Exons for each gene are shaded and numbered. Y-axis shows percent GC (from 50 to 100 %) using a sliding window of 100 bp and a 2.5-standard deviation cut-off indicating abnormally high GC content near the intron/exon boundaries of the first three exons. GC content was visualised using Artemis (Rutherford et al. 2000)

Mentions: Finally, we compared the intronic and exonic sequences for all MHC class Ia and class Ib genes for which the information is available. This includes those from this manuscript, as well as five additional genes from GenBank; including two alleles of Gene 3 (AF396750 and AF396754), two additional alleles of Gene 2 (AF396752 and AF396753), and another allele of Gene 1 (AF396751). Domain by domain analysis showed that sequences from the current six gene designations clade together at the more conserved 3′ end of the gene, after the α2 domain in intron 3, and confirmed the close relationship of NC1 with the classical genes (Fig. 3). The relationship between the peptide-binding domains is far more complex, with no consistent relationships emerging with either exon or intron sequence at the 5′ end of the molecule, apart from the NC1 sequences which always form a discrete cluster. From this limited number of sequences, it is not possible to disentangle the relative contributions of mutation and recombination to this diversification. However, it seems likely that break points in introns 1, 2, and at the 5′ of intron 3 have led to multiple gene conversion events. Interestingly, these regions all contain unusually high guanine-cytosine (GC) content (Fig. 4), possibly representing a signature of GC-biased gene conversion (Mancera et al. 2008). As well as gene conversion, diversity would be further facilitated by the haplotype block structure that the classical genes have formed.Fig. 3


The assembly and characterisation of two structurally distinct cattle MHC class I haplotypes point to the mechanisms driving diversity.

Schwartz JC, Hammond JA - Immunogenetics (2015)

Intron/exon structure and GC content of the known complete MHC class I genes. Exons for each gene are shaded and numbered. Y-axis shows percent GC (from 50 to 100 %) using a sliding window of 100 bp and a 2.5-standard deviation cut-off indicating abnormally high GC content near the intron/exon boundaries of the first three exons. GC content was visualised using Artemis (Rutherford et al. 2000)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4539362&req=5

Fig4: Intron/exon structure and GC content of the known complete MHC class I genes. Exons for each gene are shaded and numbered. Y-axis shows percent GC (from 50 to 100 %) using a sliding window of 100 bp and a 2.5-standard deviation cut-off indicating abnormally high GC content near the intron/exon boundaries of the first three exons. GC content was visualised using Artemis (Rutherford et al. 2000)
Mentions: Finally, we compared the intronic and exonic sequences for all MHC class Ia and class Ib genes for which the information is available. This includes those from this manuscript, as well as five additional genes from GenBank; including two alleles of Gene 3 (AF396750 and AF396754), two additional alleles of Gene 2 (AF396752 and AF396753), and another allele of Gene 1 (AF396751). Domain by domain analysis showed that sequences from the current six gene designations clade together at the more conserved 3′ end of the gene, after the α2 domain in intron 3, and confirmed the close relationship of NC1 with the classical genes (Fig. 3). The relationship between the peptide-binding domains is far more complex, with no consistent relationships emerging with either exon or intron sequence at the 5′ end of the molecule, apart from the NC1 sequences which always form a discrete cluster. From this limited number of sequences, it is not possible to disentangle the relative contributions of mutation and recombination to this diversification. However, it seems likely that break points in introns 1, 2, and at the 5′ of intron 3 have led to multiple gene conversion events. Interestingly, these regions all contain unusually high guanine-cytosine (GC) content (Fig. 4), possibly representing a signature of GC-biased gene conversion (Mancera et al. 2008). As well as gene conversion, diversity would be further facilitated by the haplotype block structure that the classical genes have formed.Fig. 3

Bottom Line: This variable region appears to have undergone block gene duplication and likely deletion at regular breakpoints, suggestive of a site-specific mechanism.Phylogenetic analysis using complete gene sequences provided evidence of allelic diversification via gene conversion, with breakpoints between each of the extracellular domains that were associated with high guanine-cytosine (GC) content.Advancing our knowledge of cattle MHC class I evolution will help inform investigations of cattle genetic diversity and disease resistance.

View Article: PubMed Central - PubMed

Affiliation: Livestock Viral Diseases Programme, The Pirbright Institute, Ash Road, Pirbright, Woking, Surrey, GU24 0NF, UK.

ABSTRACT
In cattle, there are six classical MHC class I genes that are variably present between different haplotypes. Almost all known haplotypes contain between one and three genes, with an allele of Gene 2 present on the vast majority. However, very little is known about the sequence and therefore structure and evolutionary history of this genomic region. To address this, we have refined the MHC class I region in the Hereford cattle genome assembly and sequenced a complete A14 haplotype from a homozygous Holstein. Comparison of the two haplotypes revealed extensive variation within the MHC class Ia region, but not within the flanking regions, with each gene contained within a conserved 63- to 68-kb sequence block. This variable region appears to have undergone block gene duplication and likely deletion at regular breakpoints, suggestive of a site-specific mechanism. Phylogenetic analysis using complete gene sequences provided evidence of allelic diversification via gene conversion, with breakpoints between each of the extracellular domains that were associated with high guanine-cytosine (GC) content. Advancing our knowledge of cattle MHC class I evolution will help inform investigations of cattle genetic diversity and disease resistance.

No MeSH data available.