Nucleotide substitution at major histocompatibility complex class II loci: evidence for overdominant selection.

Hughes, Austin L.; Nei, Masatoshi

doi:10.1073/pnas.86.3.958

Cited by 806 publications

(437 citation statements)

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“…61 Analysis of DRB loci in this region has defined five major haplogroups in which variable numbers of functional genes and pseudogenes are present ( Figure 3). 62,63 The high level of nucleotide diversity in the class II region is likely to reflect balancing selection acting not only on the epitope-binding sites 64 but also on the promoter regions. 65,66 Selection involving such non-coding DNA sequences important to gene regulation is supported by the evidence of haplotype-specific variation in MHC class II gene expression.…”

Section: Mhc Haplotypes Sequence Variation and Class II Regulationmentioning

confidence: 99%

Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

et al. 2009

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Major histocompatibility complex (MHC) class II molecules are central to adaptive immune responses and maintenance of selftolerance. Since the early 1970s, the MHC class II region at chromosome 6p21 has been shown to be associated with a remarkable number of autoimmune, inflammatory and infectious diseases. Given that a full explanation for most MHC class II disease associations has not been reached through analysis of structural variation alone, in this review we examine the role of genetic variation in modulating gene expression. We describe the intricate architecture of the MHC class II regulatory system, indicating how its unique characteristics may relate to observed associations with disease. There is evidence that haplotypespecific variation involving proximal promoter sequences can alter the level of gene expression, potentially modifying the emergence and expression of key phenotypic traits. Although much emphasis has been placed on cis-regulatory elements, we also examine the role of more distant enhancer elements together with the evidence of dynamic inter-and intra-chromosomal interactions and epigenetic processes. The role of genetic variation in such mechanisms may hold profound implications for susceptibility to common disease.

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Section: Mhc Haplotypes Sequence Variation and Class II Regulationmentioning

confidence: 99%

Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

et al. 2009

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“…Further, patterns of mutational substitutions within the PBR have affirmed the strong role of historic selection pressures in preserving functional variation, likely with peptide binding consequences, for this region. 8,[11][12][13] To date there are some 108 HLA-A, 223 HLA-B and 67 HLA-C alleles which have been classified into groups or families on the basis of serological reactivity. 14 For example, HLA-A alleles separate into six serological families; A1/3/11, A9, A2/28, A10, A19 15 and A80.…”

Section: Correspondence: Stephen J O'brien Phd Laboratory Of Genomimentioning

confidence: 99%

Taxonomic hierarchy of HLA class I allele sequences

et al. 1999

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The markedly high levels of polymorphism present in classical class I loci of the human major histocompatibility complex have been implicated in infectious and immune disease recognition. The large numbers of alleles present at these loci have, however, limited efforts to verify associations between individual alleles and specific diseases. As an approach to reduce allele diversity to hierarchical evolutionarily related groups, we performed phylogenetic analyses of available HLA-A, B and C allele complete sequences (n = 216 alleles) using different approaches (maximum parsimony, distance-based minimum evolution and maximum likelihood). Full nucleotide and amino acid sequences were considered as well as abridged sequences from the hypervariable peptide binding region, known to interact in vivo, with HLA presented foreign peptide. The consensus analyses revealed robust clusters of 36 HLA-C alleles concordant for full and PBR sequence analyses. HLA-A alleles (n = 60) assorted into 12 groups based on full nucleotide and amino acid sequence which with few exceptions recapitulated serological groupings, however the patterns were largely discordant with clusters prescribed by PBR sequences. HLA-B which has the most alleles (n = 120) and which unlike HLA-A and -C is thought to be subject to frequent recombinational exchange, showed limited phylogenetic structure consistent with recent selection driven retention of maximum heterozygosity and population diversity. Those allele categories recognized offer an explicit phylogenetic criterion for grouping alleles potentially relevant for epidemiologic associations, for inferring the origin of MHC genome organization, and for comparing functional constraints in peptide presentation of HLA alleles.

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“…15,16 The ratio between non-synonymous (pa) to synonymous nucleotide polymorphisms (ps) can then be calculated (pa/ps) and plotted in a sliding window against nucleotide position. 17,18 In this paper, we examine natural selection that acts on successful examples of PKSs with the aim of identifying critical amino acid residues to gain a better overview of the evolutionary constraints that govern functionality, which might, in the future, be exploited for more efficient synthesis of new compounds from hybrid PKSs.…”

Section: Introductionmentioning

confidence: 99%

Evolutionary dynamics of modular polyketide synthases, with implications for protein design and engineering

et al. 2010

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Attempts at generating novel chemistries by genetically manipulating polyketide synthases (PKSs) usually result in no detectable or poor product yield. Understanding processes that drive the evolution of PKSs might provide a solution to this problem. The synonymous-to-non-synonymous nucleotide substitution ratios across alignments of well-characterized PKS modules were examined using a sliding windows approach. Not surprisingly, the overall substitution ratios showed that PKS modules are generally under strong purifying selection, confirming experimental observations that changes to the primary amino acid sequence, regardless of whether these changes are conservative or not, will most likely result in some loss in function. Despite the masking effect of negative selection, by judicious choice of window size, it was possible to recognize amino acid residues that appear to be under strong positive selection. The importance of these amino acids has not been recognized by other analysis methods before and we suggest that they may function to 'fine tune' modular PKSs. Future efforts will concentrate on understanding if this 'fine tuning' is at the level of protein expression, for example, transcription or translation, or at the level of protein function, for example, efficient selection and channeling of acyl intermediates between domains.

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Nucleotide substitution at major histocompatibility complex class II loci: evidence for overdominant selection.

Cited by 806 publications

References 50 publications

Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

Taxonomic hierarchy of HLA class I allele sequences

Evolutionary dynamics of modular polyketide synthases, with implications for protein design and engineering

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