Haplotypic Associations and Differentiation of MHC Class II Polymorphic Alu Insertions at Five Loci With HLA-DRB1 Alleles in 12 Minority Ethnic Populations in China

Abstract

The analysis of polymorphic variations in the human major histocompatibility complex (MHC) class II genomic region on the short-arm of chromosome 6 is a scientific enquiry to better understand the diversity in population structure and the effects of evolutionary processes such as recombination, mutation, genetic drift, demographic history, and natural selection. In order to investigate associations between the polymorphisms of HLA-DRB1 gene and recent Alu insertions (POALINs) in the HLA class II region, we genotyped HLA-DRB1 and five Alu loci (AluDPB2, AluDQA2, AluDQA1, AluDRB1, AluORF10), and determined their allele frequencies and haplotypic associations in 12 minority ethnic populations in China. There were 42 different HLA-DRB1 alleles for ethnic Chinese ranging from 12 alleles in the Jinuo to 28 in the Yugur with only DRB1∗08:03, DRB1∗09:01, DRB1∗12:02, DRB1∗14:01, DRB1∗15:01, and DRB1∗15:02 present in all ethnic groups. The POALINs varied in frequency between 0.279 and 0.514 for AluDPB2, 0 and 0.127 for AluDQA2, 0.777 and 0.995 for AluDQA1, 0.1 and 0.455 for AluDRB1 and 0.084 and 0.368 for AluORF10. By comparing the data of the five-loci POALIN in 13 Chinese ethnic populations (including Han-Yunnan published data) against Japanese and Caucasian published data, marked differences were observed between the populations at the allelic or haplotypic levels. Five POALIN loci were in significant linkage disequilibrium with HLA-DRB1 in different populations and AluDQA1 had the highest percentage association with most of the HLA-DRB1 alleles, whereas the nearby AluDRB1 indel was strongly haplotypic for only DRB1∗01, DRB1∗10, DRB1∗15 and DRB1∗16. There were 30 five-locus POALIN haplotypes inferred in all populations with H5 (no Alu insertions except for AluDQA1) and H21 (only AluDPB2 and AluDQA1 insertions) as the two predominant haplotypes. Neighbor joining trees and principal component analyses of the Alu and HLA-DRB1 polymorphisms showed that genetic diversity of these genomic markers is associated strongly with the population characteristics of language family, migration and sociality. This comparative study of HLA-DRB1 alleles and multilocus, lineage POALIN frequencies of Chinese ethnic populations confirmed that POALINs whether investigated alone or together with the HLA class II alleles are informative genetic and evolutionary markers for the identification of allele and haplotype lineages and genetic variations within the same and/or different populations.

Regulation of expression quantitative trait loci by SVA retrotransposons within the major histocompatibility complex

“…2 The absence and presence of a variety of structurally dimorphic retroelements within the MHC, such as Alu, SVA, long terminal repeats (LTR), and human endogenous viruses (HERVs), have been used as haplotypic markers and for phylogenetic analyses of population ancestral relationships and diversity. [20][21][22][23][24] The investigation of MHC multilocus haplotypes and disease associations is complicated by the regulatory network of cis-acting multilocus expression units known as haplotypespecific expression quantitative trait loci (eQTL). 2,25,26 These eQTL are controlled by an array of retroelements and DNA transposons, 27 both as binding sites for transcription factors 28 and as sources of regulatory noncoding RNAs.…”

Human leukocyte antigen super-locus: nexus of genomic supergenes, SNPs, indels, transcripts, and haplotypes

“…For example, ten young AluY indels that are either present or absent in particular human MHC class I and class II haplotypes are useful evolutionary genetic markers of past recombination events, as well as excellent markers for elucidating population phylogenetics and genetic interrelationships [70][71][72] . In this regard, Cun et al recently showed that five different MHC class II dimorphic Alu elements either alone or linked together as haplotypes with HLA-DRB1 alleles can differentiate 12 Chinese minority ethnic groups according to their geographic locations, and correlate them with their population characteristics of language family, migration and sociality 73 .…”

Allelic and haplotypic data of MHC class II Alu insertions in Ngazidja (Comoros archipelago) and insight on its historical biology

“…For comparative and phylogenetic analyses, we used haplotype frequencies data from previously published works (Cun et al., 2021; Kulski et al., 2010; Shi et al., 2014). Genetic distances (Nei, 1972) were computed by the phylip 3.5 package using haplotypic frequencies as raw data (Felsenstein, 1993).…”

“…Among the polymorphisms existing in the MHC class II region, there are several polymorphic Alu insertions (POALINs) including five human‐specific ones (AluDPB2, AluDQA2, AluDQA1, AluDRB1 and AluORF10) that are informative lineage markers (Kulski et al., 2010; Kulski et al., 2021). Investigations of the MHC II POALINs in Japanese, Caucasians and Chinese have shown that whether investigated alone or together with the HLA class II alleles, they are informative genetic markers for the identification of allele and haplotype lineages as well as variations within the same and/or different populations (Cun et al., 2021; Kulski et al., 2010). Despite their informativeness, studies on MHC II POALINs are scarce and to our knowledge never reported among African populations.…”