Sequence and Phylogenetic Analysis of the Untranslated Promoter Regions forHLAClass I Genes.
Polymorphisms located within theMHChave been linked to many disease outcomes by mechanisms not yet fully understood in most cases. Variants located within untranslated regions ofHLAgenes 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 classicalHLAclass I genes. The nucleotide diversity within this promoter segment roughly follows that seen within the coding regions, withHLA-Bshowing the highest (∼1.9%), followed byHLA-A(∼1.8%), andHLA-Cshowing the lowest diversity (∼0.9%). Despite its greater diversity,HLA-BmRNA expression levels determined in 178 European Americans do not vary in an allele- or lineage-specific manner, unlike the differential expression levels ofHLA-AorHLA-Creported previously. Close proximity of promoter sequences in phylogenetic trees is roughly reflected by similarity of expression pattern for mostHLA-Aand-Cloci. 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 classicalHLAclass I loci.
Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702.|Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139.
Veron
V
Ramsuran
Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702.|Laboratorio de Genómica Viral y Humana, Facultad de Medicina de la Universidad Autónoma de San Luis Potosi, 78210 San Luis Potosi, Mexico.
Pedro G
0000-0001-6094-2575
PG
Hernández-Sanchez
Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702.
Colm
C
O'hUigin
Department of Transplant Immunology and Immunogenetics, All India Institute of Medical Sciences, New Delhi 110029, India.|Laboratory Oncology, Dr. B.R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110029, India; and.
Gaurav
0000-0003-2237-0902
G
Sharma
Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702.|Laboratory Oncology, Dr. B.R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110029, India; and.
Niamh
0000-0002-5191-3614
N
Spence
Laboratório de Genética Molecular Humana, Departamento de Genética, Universidade Federal do Paraná, Curitiba, CEP 81531-980, Brazil.
Danillo G
DG
Augusto
Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702.
Xiaojiang
X
Gao
Laboratorio de Genómica Viral y Humana, Facultad de Medicina de la Universidad Autónoma de San Luis Potosi, 78210 San Luis Potosi, Mexico.
Christian A
0000-0002-1169-7857
CA
García-Sepúlveda
Department of Transplant Immunology and Immunogenetics, All India Institute of Medical Sciences, New Delhi 110029, India.
Gurvinder
0000-0002-1319-7012
G
Kaur
Department of Transplant Immunology and Immunogenetics, All India Institute of Medical Sciences, New Delhi 110029, India.
Narinder K
0000-0003-2682-7471
NK
Mehra
Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702; carringm@mail.nih.gov.|Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139.
Mary
0000-0002-2692-2180
M
Carrington
D000483:Alleles; D001483:Base Sequence; D002460:Cell Line; D005838:Genotype; D015234:HLA-A Antigens / Q000235:genetics*; D015235:HLA-B Antigens / Q000235:genetics*; D015236:HLA-C Antigens / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D010802:Phylogeny; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics*; D017422:Sequence Analysis, DNA
D015234:HLA-A Antigens; D015235:HLA-B Antigens; D015236:HLA-C Antigens