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Published on: March 10, 2023
Sequence features of HLA-DRB1 locus define putative basis for gene conversion and point mutations
Jenny von Salomé1, Jyrki P Kukkonen
1University of Helsinki, Department of Basic Veterinary Sciences, Helsinki, Finland. jenny.vonsalome@karolinska.se
Background:
HLA/MHC class II molecules show high degree of polymorphism in the human population. The individual polymorphic motifs have been suggested to be propagated and mixed by transfer of genetic material (recombination, gene conversion) between alleles, but no clear molecular basis for this has been identified as yet. A large number of MHC class II allele sequences is publicly available and could be used to analyze the sequence features behind the recombination, revealing possible basis for such recombination processes both in HLA class II genes and other genes, which recombination acts upon.
Results:
In this study we analyzed the vast dataset of human allelic variants (49 full coding sequences, 374 full exon 2 sequences) of the most polymorphic MHC class II locus, HLA-DRB1, and identified many previously unknown sequence features possibly contributing to the recombination. The CpG-dinucleotide content of exon 2 (containing the antigen-binding sites and subsequently a high degree of polymorphism) was much elevated as compared to the other exons despite similar overall G+C content. Furthermore, the CpG pattern was highly conserved. We also identified more complex, highly conserved sequence motifs in exon 2. Some of these can be identified as putative recombination motifs previously found in other genes, but most are previously unidentified.
Conclusion:
The identified sequence features could putatively act in recombination allowing either less (CpG dinucleotides) or more specific DNA cleavage (complex sequences) or homologous recombination (complex sequences).
Insights
Human leukocyte antigen (HLA) class II genes exhibit high polymorphism, potentially driven by recombination. This study identified novel sequence features in HLA-DRB1 exon 2, including elevated CpG dinucleotides and conserved motifs, suggesting mechanisms for genetic recombination.
Area of Science:
- Immunogenetics
- Molecular Evolution
- Human Population Genetics
Background:
- Human leukocyte antigen (HLA)/MHC class II molecules display significant population polymorphism.
- Recombination and gene conversion are proposed mechanisms for this diversity, but molecular underpinnings remain unclear.
Purpose of the Study:
- To investigate sequence features within HLA class II alleles that may facilitate recombination.
- To identify potential molecular bases for recombination in HLA genes.
Main Methods:
- Analysis of a large dataset of human HLA-DRB1 allelic variants (49 full coding sequences, 374 full exon 2 sequences).
- Comparative sequence analysis focusing on exon 2, known for antigen-binding sites and high polymorphism.
Main Results:
- Exon 2 of HLA-DRB1 shows significantly elevated CpG-dinucleotide content compared to other exons, with a conserved pattern.
- Previously unidentified, complex, and highly conserved sequence motifs were discovered in exon 2.
- Some identified motifs resemble known recombination motifs from other genes.
Conclusions:
- Identified sequence features, including CpG dinucleotides and complex motifs, may play roles in DNA cleavage and homologous recombination.
- These features provide a potential molecular basis for recombination driving HLA class II polymorphism.
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