Genomic Anatomy of a Premier Major Histocompatibility Complex Paralogous Region on Chromosome 1q21–q22

Abstract

Human chromosomes 1q21-q25, 6p21.3-22.2, 9q33-q34, and 19p13.1-p13.4 carry clusters of paralogous loci, to date best defined by the flagship 6p MHC region. They have presumably been created by two rounds of large-scale genomic duplications around the time of vertebrate emergence. Phylogenetically, the 1q21-25 region seems most closely related to the 6p21.3 MHC region, as it is only the MHC paralogous region that includes bona fide MHC class I genes, the CD1 and MR1 loci. Here, to clarify the genomic structure of this model MHC paralogous region as well as to gain insight into the evolutionary dynamics of the entire quadriplication process, a detailed analysis of a critical 1.7 megabase (Mb) region was performed. To this end, a composite, deep, YAC, BAC, and PAC contig encompassing all five CD1 genes and linking the centromeric +P5 locus to the telomeric KRTC7 locus was constructed. Within this contig a 1.1-Mb BAC and PAC core segment joining CD1D to FCER1A was fully sequenced and thoroughly analyzed. This led to the mapping of a total of 41 genes (12 expressed genes, 12 possibly expressed genes, and 17 pseudogenes), among which 31 were novel. The latter include 20 olfactory receptor (OR) genes, 9 of which are potentially expressed. Importantly, CD1, SPTA1, OR, and FCERIA belong to multigene families, which have paralogues in the other three regions. Furthermore, it is noteworthy that 12 of the 13 expressed genes in the 1q21-q22 region around the CD1 loci are immunologically relevant. In addition to CD1A-E, these include SPTA1, MNDA, AIM2, BL1A, FY and FCERIA. This functional convergence of structurally unrelated genes is reminiscent of the 6p MHC region, and perhaps represents the emergence of yet another antigen presentation gene cluster, in this case dedicated to lipid/glycolipid antigens rather than antigen-derived peptides.

Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution

“…The most marked expansion involves at least 218 non-identical chicken genes that are predicted to be orthologous to one of two olfactory receptor genes (OR5U1 and OR5BF1). In humans, OR5U1 and OR5BF1 genes lie within olfactory receptor gene clusters that each are positioned next to paralogous major histocompatibility complex (MHC) class I gene clusters 80 . These olfactory receptors have been tentatively proposed to be involved in odorant-mediated detection of MHC diversity 81 .…”

Microarrays Reveal Distinct Gene Signatures in the Thymus of Seropositive and Seronegative Myasthenia Gravis Patients and the Role of CC Chemokine Ligand 21 in Thymic Hyperplasia

“…The overrepresentation of this region was particularly due to the expression of MHC class II genes (supplemental table S3-A). Two clusters corresponding to MHC paralogous clusters, 1q21 and 9q34, were also identified (17). The other MHC paralogous cluster, in 19p13, was not significant with the 2 test but was nevertheless strongly represented in each MG subgroup.…”

Evidence of en bloc duplication in vertebrate genomes

“…The positive clones are MPMGc117C0356 for BAT1, DDX39; MPMGc117 (G0971, D1293 and A156) for BRD2, 3,4 Clone sequencing. Cosmids were sequenced according to previously described protocols 8 . The names of the sequenced clones are given in Table 1.…”