HLA-A,B,C: Patterns of Polymorphism in Peptide-Binding Proteins

The fifth exons of major histocompatibility complex (MHC) class I genes encode a transmembrane domain (TM) that is largely responsible for class I antigen cell-surface expression usually through conventional hydrophobic amino acid-membrane interactions or, less often, through phosphatidylinositol linkage. In this report we show that Peromyscus lucopus, a Cricetidae rodent, has MHC class I genes (Pele-A genes) encoding three distinct sizes of TMs. Increases in TM lengths were due to tandem duplications ofsequences similar to human hypervariable minisatellite repeats and the A chi site. We discerned remnants of a similar duplication event in comparable rodent and primate MHC class I genes. Furthermore, several duplications and deletions appear to have occurred independently in H-2, RTI, Pele-A, and ChLA genes in near-identical positions. Accumulated data suggests that sequences in the fifth exon of MHC class I genes may, therefore, constitute a mutational or recoombinational hot spot that is mediated by minisatellite-and chi-like sequences imbedded within the coding region. The MHC class I genes may thus have recruited "selfish" DNA in their evolution to encode cell surface proteins. Expression of Pele-A genes was examined by the polymerase chain reaction (PCR) using oligonucleotide primers specific for exon 4 and 5 sequences. The PCR product sizes indicated that genes encoding each TM domain length are ubiquitously transcribed.

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“…lb). Though observed in another ChLA-B allele (ChLA-B39), this 9-bp repeat does not appear to be found in any HLA-B genes (22). Three …”

Section: Homology Of Exon 5 Tandem Repeats To Thementioning

confidence: 81%

“…To understand the evolution of MHC class I loci, we have initially focused upon the transmembrane domain (TM)-encoding exon (exon 5). This region exhibits relatively low allelic polymorphism and the sequence of the TM is distinctive of various class I subtypes in H-2 and HLA systems (5,6,(18)(19)(20)(21)(22) …”

mentioning

confidence: 99%

Transmembrane domain length variation in the evolution of major histocompatibility complex class I genes.

Crew

Filipowsky

Neshat

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

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“…USA 87 (1990) translated region (25,26) is truly a locus-specific marker in these sequences. Segmental exchange between HLA loci has been proposed from patterns of sequence shared between alleles at different loci (27)(28)(29). However, clear-cut divergence of sequence between loci in HLA suggests that intralocus exchanges play a more important evolutionary role than interlocus exchanges in generating polymorphism in humans and the higher primates (29,30).…”

Section: L L L L a A A L Ap T Q T R A G S H S L R T Pty T A V Smentioning

confidence: 99%

“…Segmental exchange between HLA loci has been proposed from patterns of sequence shared between alleles at different loci (27)(28)(29). However, clear-cut divergence of sequence between loci in HLA suggests that intralocus exchanges play a more important evolutionary role than interlocus exchanges in generating polymorphism in humans and the higher primates (29,30). Extensive recent duplication in the murine MHCs may favor nonhomologous pairing and thus a relative excess of interlocus exchanges in this taxonomic group.…”

Section: L L L L a A A L Ap T Q T R A G S H S L R T Pty T A V Smentioning

confidence: 99%

Concerted evolution of class I genes in the major histocompatibility complex of murine rodents.

Rada

Lorenzi²,

Powis³

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

118

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Full-length cDNA sequences of two class I major histocompatibility complex molecules from the DA strain of Rattus norvegicus are reported. One codes for the classical class I restriction element RTL.Aa, which maps to the locus in the rat major histocompatibility complex homologous to H-2K in the mouse. The other probably codes for a soluble nonclassical class I molecule present in DA rat serum; a short deletion in the fifth exon implies that the translated product will terminate in the membrane-spanning region. These sequences have been compared with mouse classical class I sequences as well as with three published rat class I cDNA partial sequences. The results show, first, that "locus-specific" substitutions from the H-2K, H-2D, and H-2L data set are scrambled in the RTl.A molecule; a majority of these substitutions have H-2D/L-specific features. Second, the data show that the four rat sequences are strikingly similar to one another regardless of locus or haplotype of origin; they share a number of apparently species-specific features that distinguish them all from mouse classical class I sequences, which likewise share distinctive features of their own. The results suggest that segmental sequence exchange plays a major role in determining the evolution of sequence in class I masjor histocompatibility complex molecules.Some multigene families display a degree of species specificity at the level of DNA sequence, as if the whole family were evolving within a species as a unit (1-3). Such concerted evolution has been suspected in mouse major histocompatibility complex (MHC) class I genes because of the lack of clear locus-specific sequence variation distinguishing the widely separated H-2K and H-2D end classical loci (4, 5). Short segmental exchanges of sequence are indeed occurring between widely separated class I MHC loci in laboratory mice (6). Nevertheless it remains controversial whether such processes contribute significantly to the pattern of evolution of class I genes (7), since sequences of class I genes from a closely related murine species such as the rat are not yet available. Rattus norvegicus is in the same subfamily, the Murinae, as the mouse. The rat MHC, RTI, is like H-2 in structure, with a classical class I gene, RTJ.A, at the left end of the MHC in the same location as H-2K and a long array of other class I genes to the right (8). In the middle is a region specifying class II genes that closely resembles the homologous region of H-2 (9). It is most likely that the translocation of class I genes that formed the H-2K end was a unique event occurring shortly before the separation of the rat and mouse lineages (7). Rat class I gene sequences thus provide a stringent test of the concerted evolution hypothesis. With simple divergent evolution alone, the sequence of an RTI.A allele should have greater similarity to H-2K on average than to other rat class I sequences, since RTI.A and H-2K share a more recent common ancestor than either does with genes at the other end of the MHC. If, on the ot...

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“…We have been analyzing a mechanism that generates new alleles from existing diversity within the mouse major histocompatibility complex (MHC) class I multigene family by the exchange of short stretches of sequence between ectopic members of the gene family. The structure of human class I alleles indicates that similar genetic events are occurring in human populations (2). However, new variants occur rarely and have never been observed within human family studies.…”

mentioning

confidence: 99%

A complex major histocompatibility complexDlocus variant generated by an unusual recombination mechanism in mice

Yun

Melvold

Pease

1997

Proc. Natl. Acad. Sci. U.S.A.

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A spontaneous variant of the mouse class I major histocompatibility complex D b gene, designated D bm28 , is characterized. This mutation consists of a cluster of nucleotide substitutions in exon 3 that resembles the product of a classical gene conversion event in that the substituted nucleotides appear to be templated. However, D bm28 is distinctive, because no single donor gene containing the nucleotide sequence of the mutation exists in the genome of the parent strain. The mutation is consistent with the expected result of an interaction of two donor genes at the target locus during a single recombination event. While no known genetic mechanism gives rise to this class of mutation, we have established that 10 percent of spontaneous class I mutations in the mouse major histocompatibility complex have this complex phenotype. This process occurs at the D locus and the K locus. The significance of this kind of genetic interaction may extend beyond the major histocompatibility complex and have importance in shaping other multigene families.

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HLA-A,B,C: Patterns of Polymorphism in Peptide-Binding Proteins

Cited by 43 publications

References 97 publications

Transmembrane domain length variation in the evolution of major histocompatibility complex class I genes.

Transmembrane domain length variation in the evolution of major histocompatibility complex class I genes.

Concerted evolution of class I genes in the major histocompatibility complex of murine rodents.

A complex major histocompatibility complexDlocus variant generated by an unusual recombination mechanism in mice

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