A genomic perspective on HLA evolution

Meyer, Diogo; Aguiar, Vitor R. C.; Bitarello, Bárbara Domingues; Brandt, Débora Y. C.; Nunes, Kelly

doi:10.1007/s00251-017-1017-3

Cited by 158 publications

(154 citation statements)

References 181 publications

(203 reference statements)

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“…Variability at HLA‐A , HLA‐B , and HLA‐C is particularly high at the DNA segment encoding the peptide groove (exons 2 and 3) . Variability can also be maintained by natural selection, which is variable over space and/or time, as well as by selection that is frequency‐dependent . Most of known HLA‐A alleles differ in exons 2 and 3 .…”

Section: Introductionmentioning

confidence: 99%

HLA‐A promoter, coding, and 3′UTR sequences in a Brazilian cohort, and their evolutionary aspects

Souza

Porto

Paz

et al. 2019

HLA

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HLA‐A is the second most polymorphic locus of the human leucocyte antigen (HLA) complex encoding a key molecule for antigen presentation and NK cell modulation. Many studies have evaluated HLA‐A variability in worldwide populations, focusing mainly on exons, but the regulatory segments have been poorly characterized. HLA‐A variability is particularly high in the segment encoding the peptide‐binding groove (exons 2 and 3), which is related to the antigen presentation function and the balancing selection in these segments. Here we evaluate the genetic diversity of the HLA‐A gene considering a continuous segment encompassing the extended promoter (1.5 kb upstream of the first translated ATG), all exons and introns, and the entire 3′ untranslated region, by using massively parallel sequencing. To achieve this goal, we used a freely available bioinformatics workflow that optimizes read mapping for HLA genes and defines complete sequences using either the phase among variable sites directly observed in sequencing data and probabilistic models. The HLA‐A variability detected in a highly admixed population sample from Brazil shows that the HLA‐A regulatory segments present few, but divergent sequences. The regulatory segments are in close association with the coding alleles. Both exons and introns are highly variable. Moreover, patterns of molecular diversity suggest that the promoter, in addition to the coding region, might be under the same selective pressure, but a different scenario arises when it comes to exon 4 and the 3′UTR segment.

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Section: Introductionmentioning

confidence: 99%

HLA‐A promoter, coding, and 3′UTR sequences in a Brazilian cohort, and their evolutionary aspects

Souza

Porto

Paz

et al. 2019

HLA

Self Cite

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“…Besides its potential benefits for histocompatibility, DNA sequencing of the HLA region also opens new perspectives in the area of human population genetics by permitting direct analyses of nucleotide variation within a molecular evolutionary genetics framework. [10][11][12] Although stimulating results on human populations' molecular diversity were obtained previously by inferring sequence genotypes to large sets of population samples thanks to the molecular information stored in the IMGT-HLA database, 13 such approaches could only use data defined at the second field level of resolution, thus ignoring the information provided by synonymous substitutions and by regions located outside exons 2 and 3. As NGS established itself very recently as the next HLA typing standard, 14 we thus decided to use NGS techniques to decipher the fine nucleotide diversity of 8 HLA genes in a welldocumented human population.…”

Section: Introductionmentioning

confidence: 99%

Deciphering the fine nucleotide diversity of full HLA class I and class II genes in a well‐documented population from sub‐Saharan Africa

Goeury

Creary

Brunet

et al. 2017

HLA

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With the aim to understand how next‐generation sequencing (NGS) improves both our assessment of genetic variation within populations and our knowledge on HLA molecular evolution, we sequenced and analysed 8 HLA loci in a well‐documented population from sub‐Saharan Africa (Mandenka). The results of full‐gene NGS‐MiSeq sequencing compared with those obtained by traditional typing techniques or limited sequencing strategies showed that segregating sites located outside exon 2 are crucial to describe not only class I but also class II population diversity. A comprehensive analysis of exons 2, 3, 4 and 5 nucleotide diversity at the 8 HLA loci revealed remarkable differences among these gene regions, notably a greater variation concentrated in the antigen recognition sites of class I exons 3 and some class II exons 2, likely associated with their peptide‐presentation function, a lower diversity of HLA‐C exon 3, possibly related to its role as a KIR ligand, and a peculiar molecular diversity of HLA‐A exon 2, revealing demographic signals. Based on full‐length HLA sequences, we also propose that the most frequent DRB1 allele in the studied population, DRB1*13:04, emerged from an allelic conversion involving 3 potential alleles as donors and DRB1*11:02:01 as recipient. Finally, our analysis revealed a high occurrence of the DRB1*13:04‐DQA1*05:05:01‐DQB1*03:19 haplotype, possibly resulting from a selective sweep due to protection to Onchorcerca volvulus, a prevalent pathogen in West Africa. This study unveils highly relevant information on the molecular evolution of HLA genes in relation to their immune function, calling for similar analyses in other populations living in contrasting environments.

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“…The region can be subdivided into class I, II, and III. Class I encompasses HLA-A, -B, and -C that function as presenters of peptides to cytotoxic T cells; class II consists of HLA-DR and HLA-DQ molecules that present epitopes to CD4 + T cells; and class III includes genes of several components in the complement system, such as C4, factor B and C2 [68, 69]. …”

Section: Genetic Studies Of Pmnmentioning

confidence: 99%

The Genetic and Environmental Factors of Primary Membranous Nephropathy: An Overview from China

2018

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Background: Primary membranous nephropathy (pMN) is the most common cause of nephrotic syndrome in adults. The discovery of the 2 autoantigens, M-type phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A), has defined pMN as an autoimmune disease. A remarkable increase in the frequency of pMN in primary glomerular disease was witnessed in China. The genetic and environmental contributors to disease susceptibility have been investigated in these patients. Summary: We reviewed recent publications in genetic and environmental studies of pMN, focusing mainly on those undertaken in China. Following a genome-wide association study, the gene-gene interaction between the 2 most significant risk factors, PLA2R1 and DQA1, was validated in Chinese patients with MN. Fine mapping on human leukocyte antigen (HLA) locus found that DRB1*1501 and DRB1*0301 were risk alleles. Three amino acid residues on positions 13 and 71 of HLA-DRβ1 chain may confer the susceptibility to pMN by presenting T-cell epitopes on PLA2R. Another study found that DRB3*0202 was the most likely culprit allele for the signal at DRB1*0301. One environmental risk factor for pMN has been identified as the long-term exposure to high levels of PM_2.5 in Chinese patients with MN. Each 10 μg/m³ increase in PM_2.5 concentration was associated with 14% higher odds for pMN in the regions with PM_2.5 above 70 μg/m³. Key Message: A gene-environment interaction is suspected as an underlying mechanism for the increasing trend of pMN in China.

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A genomic perspective on HLA evolution

Cited by 158 publications

References 181 publications

HLA‐A promoter, coding, and 3′UTR sequences in a Brazilian cohort, and their evolutionary aspects

HLA‐A promoter, coding, and 3′UTR sequences in a Brazilian cohort, and their evolutionary aspects

Deciphering the fine nucleotide diversity of full HLA class I and class II genes in a well‐documented population from sub‐Saharan Africa

The Genetic and Environmental Factors of Primary Membranous Nephropathy: An Overview from China

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