Sequence and Phylogenetic Analysis of the Untranslated Promoter Regions for HLA Class I Genes

Polymorphisms located within the MHC have been linked to many disease outcomes by mechanisms not yet fully understood in most cases. Variants located within untranslated regions of HLA genes are involved in allele-specific expression and may therefore underlie some of these disease associations. We determined sequences extending nearly 2 kb upstream of the transcription start site for 68 alleles from 57 major lineages of classical HLA class I genes. The nucleotide diversity within this promoter segment roughly follows that seen within the coding regions, with HLA-B showing the highest (∼1.9%), followed by HLA-A (∼1.8%), and HLA-C showing the lowest diversity (∼0.9%). Despite its greater diversity, HLA-B mRNA expression levels determined in 178 European Americans do not vary in an allele- or lineage-specific manner, unlike the differential expression levels of HLA-A or HLA-C reported previously. Close proximity of promoter sequences in phylogenetic trees is roughly reflected by similarity of expression pattern for most HLA-A and -C loci. Although promoter sequence divergence might impact promoter activity, we observed no clear link between the phylogenetic structures as represented by pairwise nucleotide differences in the promoter regions with estimated differences in mRNA expression levels for the classical class I loci. Further, no pair of class I loci showed coordinated expression levels, suggesting that distinct mechanisms across loci determine their expression level under nonstimulated conditions. These data serve as a foundation for more in-depth analysis of the functional consequences of promoter region variation within the classical HLA class I loci.

[1]  J. Boudreau,et al.  KIR3DL1 and HLA-B Density and Binding Calibrate NK Education and Response to HIV , 2016, The Journal of Immunology.

[2]  P. Gaffney,et al.  Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity , 2016, eLife.

[3]  B. Korber,et al.  Broadly targeted CD8+ T cell responses restricted by major histocompatibility complex E , 2016, Science.

[4]  Effie W Petersdorf,et al.  High HLA-DP Expression and Graft-versus-Host Disease. , 2015, The New England journal of medicine.

[5]  T. Barington,et al.  Cell Surface Expression Level Variation between Two Common Human Leukocyte Antigen Alleles, HLA-A2 and HLA-B8, Is Dependent on the Structure of the C Terminal Part of the Alpha 2 and the Alpha 3 Domains , 2015, PloS one.

[6]  M. Carrington,et al.  Epigenetic regulation of differential HLA-A allelic expression levels. , 2015, Human molecular genetics.

[7]  Y. Goldgur,et al.  KIR3DS1-Specific D0 Domain Polymorphisms Disrupt KIR3DL1 Surface Expression and HLA Binding , 2015, The Journal of Immunology.

[8]  M. Carrington,et al.  HLA-C expression levels define permissible mismatches in hematopoietic cell transplantation. , 2014, Blood.

[9]  James Robinson,et al.  The IPD and IMGT/HLA database: allele variant databases , 2014, Nucleic Acids Res..

[10]  Peggy Hall,et al.  The NHGRI GWAS Catalog, a curated resource of SNP-trait associations , 2013, Nucleic Acids Res..

[11]  F. Pereyra,et al.  Genetic interplay between HLA-C and MIR148A in HIV control and Crohn disease , 2013, Proceedings of the National Academy of Sciences.

[12]  S. Factor,et al.  Association of Parkinson disease with structural and regulatory variants in the HLA region. , 2013, American journal of human genetics.

[13]  Matthew S. Lewis,et al.  Immune clearance of highly pathogenic SIV infection , 2013, Nature.

[14]  B. Faircloth,et al.  Primer3—new capabilities and interfaces , 2012, Nucleic acids research.

[15]  M. John,et al.  High Frequency of HIV Mutations Associated with HLA-C Suggests Enhanced HLA-C–Restricted CTL Selective Pressure Associated with an AIDS-Protective Polymorphism , 2012, The Journal of Immunology.

[16]  Richard Apps,et al.  A Novel Variant Marking HLA-DP Expression Levels Predicts Recovery from Hepatitis B Virus Infection , 2012, Journal of Virology.

[17]  K. Kidd,et al.  The molecular origin and consequences of escape from miRNA regulation by HLA-C alleles. , 2011, American journal of human genetics.

[18]  C. O'huigin,et al.  Characterization and polymorphic analysis of 4.5 kb genomic full-length HLA-C in the Chinese Han population. , 2011, Tissue antigens.

[19]  F. Pereyra,et al.  Differential microRNA regulation of HLA-C expression and its association with HIV control , 2011, Nature.

[20]  D. Altshuler,et al.  A map of human genome variation from population-scale sequencing , 2010, Nature.

[21]  M. Kassem,et al.  Impaired Cell Surface Expression of HLA-B Antigens on Mesenchymal Stem Cells and Muscle Cell Progenitors , 2010, PloS one.

[22]  James G. R. Gilbert,et al.  Variation analysis and gene annotation of eight MHC haplotypes: The MHC Haplotype Project , 2008, Immunogenetics.

[23]  J. Kaufman,et al.  Peptide motifs of the single dominantly expressed class I molecule explain the striking MHC-determined response to Rous sarcoma virus in chickens , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[24]  Jan Hillert,et al.  MHC2TA is associated with differential MHC molecule expression and susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction , 2005, Nature Genetics.

[25]  D. Singer,et al.  A T Lymphocyte-Specific Transcription Complex Containing RUNX1 Activates MHC Class I Expression , 2005, The Journal of Immunology.

[26]  R. Wassmuth,et al.  Allele-specific quantification of HLA-DQB1 gene expression by real-time reverse transcriptase-polymerase chain reaction , 2004, Genes and Immunity.

[27]  K. Kiura,et al.  High frequency of allele-specific down-regulation of HLA class I expression in lung cancer cell lines. , 2004, Anticancer research.

[28]  H. Kuipers,et al.  Transcriptional regulation of antigen presentation. , 2004, Current opinion in immunology.

[29]  T. Hviid,et al.  HLA-G allelic variants are associated with differences in the HLA-G mRNA isoform profile and HLA-G mRNA levels , 2003, Immunogenetics.

[30]  Davidr . Johnson.  Locus-Specific Constitutive and Cytokine-Induced HLA Class I Gene Expression 1 , 2003, The Journal of Immunology.

[31]  Y. Allory,et al.  Altered pattern of major histocompatibility complex expression in renal carcinoma: tumor-specific expression of the nonclassical human leukocyte antigen-G molecule is restricted to clear cell carcinoma while up-regulation of other major histocompatibility complex antigens is primarily distributed in , 2003, The American journal of pathology.

[32]  A. Woltman,et al.  Transactivation of classical and nonclassical HLA class I genes through the IFN-stimulated response element. , 1999, Journal of immunology.

[33]  P. J. van den Elsen,et al.  The role of enhancer A in the locus-specific transactivation of classical and nonclassical HLA class I genes by nuclear factor kappa B. , 1998, Journal of immunology.

[34]  J. Boss.  Regulation of transcription of MHC class II genes. , 1997, Current opinion in immunology.

[35]  S. Y. Yang,et al.  Allele assignment for HLA-A, -B, and -C genes to the Tenth International Histocompatibility Workshop cell lines. , 1996, Tissue antigens.

[36]  A. Hughes,et al.  The MHC class I genes of the rhesus monkey. Different evolutionary histories of MHC class I and II genes in primates. , 1996, Journal of immunology.

[37]  J. Karbach,et al.  Tumor escape from immune recognition: loss of HLA-A2 melanoma cell surface expression is associated with a complex rearrangement of the short arm of chromosome 6. , 1996, Clinical cancer research : an official journal of the American Association for Cancer Research.

[38]  F. Sigaux,et al.  Transcriptional regulation of the MHC class I HLA-A11 promoter by the zinc finger protein ZFX. , 1996, Nucleic acids research.

[39]  G. Nepom,et al.  Functional effects of a natural polymorphism in the transcriptional regulatory sequence of HLA-DQB1 , 1995, Molecular and cellular biology.

[40]  S. Y. Yang,et al.  The regulatory complex of HLA class I promoters exhibits locus-specific conservation with limited allelic variation. , 1994, Journal of immunology.

[41]  N. Saitou,et al.  The neighbor-joining method: a new method for reconstructing phylogenetic trees. , 1987, Molecular biology and evolution.

[42]  M. Kimura.  A simple method for estimating evolutionary rates of base substitutions through comparative studies of nucleotide sequences , 1980, Journal of Molecular Evolution.

[43]  R Core Team,et al.  R: A language and environment for statistical computing. , 2014 .

[44]  David Heckerman,et al.  Influence of HLA-C Expression Level on HIV Control , 2013, Science.

[45]  A map of human genome variation from population scale sequencing , 2012 .

[46]  D. Ge,et al.  HLA-C cell surface expression and control of HIV / AIDS correlate with a variant upstream of HLA-C , 2009 .

[47]  L. T. Peltenburg,et al.  Transcriptional suppression of HLA-B expression by c-Myc is mediated through the core promoter elements , 2004, Immunogenetics.

[48]  Josan Chung,et al.  Differential expression of HLA-DQB1 alleles in a heterozygous cell line , 2004, Immunogenetics.

[49]  R. Strong,et al.  CORRELATING DIFFERENTIAL EXPRESSION, PEPTIDE AFFINITIES, CRYSTAL STRUCTURES, AND THERMAL STABILITIES* , 2003 .

[50]  Niels Grabe,et al.  AliBaba2: Context specific identification of transcription factor binding sites , 2000, Silico Biol..

[51]  Edinburgh Research Explorer Expression levels of MHC class I molecules are inversely correlated with promiscuity of peptide binding , 2022 .