The Association Between HLA-A Alleles and an Alu Dimorphism Near HLA-G

Abstract

The AluYb8 sequences are a subfamily of short interspersed Alu retroelements that have been amplified within the human genome during recent evolutionary time and are useful polymorphic markers for studies on the origin of human populations. We have identified a new member of the Yb8 subfamily, AluyHG, located between the HLA-H and -G genes and 88-kb telomeric of the highly polymorphic HLA-A gene within the alpha block of the major histocompatibility complex (MHC). The AluyHG element was characterised with a view to examining the association between AluyHG and HLA-A polymorphism and reconstructing the history of the MHC alpha block. A specific primer pair was designed for a simple PCR assay to detect the absence or presence (dimorphism) of the AluyHG element within the DNA samples prepared from a panel of 46 homozygous cell-lines containing complete or recombinant ancestral haplotypes (AH) of diverse ethnic origin and 92 Caucasoid and Asian subjects on which HLA-A typing was available. The AluyHG insertion was most strongly associated with HLA-A2 and, to a lesser degree with HLA-A1, -A3, -A11, and A-19. The gene frequency of the AluyHG insertion for 146 Caucasians and 94 Chinese-Han was 0.30 and 0.32 and there was no significant difference between the observed and expected frequencies. The results of the association studies and the phylogenetic analysis of HLA-A alleles suggest that the AluyHG sequence was integrated within the progenitor of HLA-A2, but has been transferred by recombination to other human ancestral populations. In this regard, the dimorphic AluyHG element is an important diagnostic marker for HLA association studies and could help in elucidating the evolution and functions of the MHC alpha block and polymorphism within and between ancestral haplotypes.

Human Endogenous Retrovirus (HERVK9) Structural Polymorphism With Haplotypic HLA-A Allelic Associations

“…Some HLA-A30 alleles were linked to a HERVK9 insertion as in the LBF cell line (HLA-A3001-Cw6-B13-DR7-DQ2) and others to a HERVK9 deletion as in the cell line EJ32B (HLA-A3002-Cw5-B18-DR3-DQ2). In this regard, the different associations and/or linkages between HLA-A30 and HERVK9.HG support previous reports that the HLA-A30 allelic group has evolved into at least two major subgroups of two different ancestral haplotypes (Bodmer et al 1997;Tanaka et al 1997;Kulski et al 2001).…”

“…In contrast, HLA-A11 was associated only with the HERVK9 insertion in the Australian Caucasians. A similar variability between the HLA-A11 allele and a polymorphic retroelement was found previously between the HLA-A11 alleles and the AluyHG polymorphic marker in the Japanese (Kulski et al 2001). The associations between HLA-A11 and HERVK9.HG might vary in the Japanese and not in the Australian Caucasians because (1) the original HERVK9.HG insertion that was previously linked to HLA-A11 was deleted from one or more founder individuals, (2) the original linkage between the HLA-A11 and HERVK9.HG deletion or insertion was lost due to recombinational crossing over in one or more founder individuals, or (3) HLA-A11 was originally linked with the HERVK9.HG deletion, but then a new HERVK9 insertion occurred at exactly the same location by recombination or a new retrotransposition event.…”

Dimorphic Alu element located between the TFIIH and CDSN genes within the major histocompatibility complex

“…Forty-eight DNA samples were obtained from the 10IHW panel [7,8]. These cells were previously typed for AluyHG [7], AluyMICB [8], AluyHJ, and AluyHF [20].…”

“…The dimorphic Alu elements have also been used to differentiate between ethnic groups and to trace the migration patterns of modern humans [25,26]. Recently, the evolutionary relationships have been described between MHC haplotypes and four dimorphic AluYb8/AluYa5 subfamily members with AluyHG located near HLA-G [7], AluyMICB within intron 1 of the MICB gene [8], AluyHJ near HLA-J, and AluyHF near HLA-F [20].…”

“…Genomic polymorphisms in this region are characterized predominantly by nucleotide substitutions [1][2][3] and insertions/deletions (indels) represented by the polynucleotide repeats (microsatellites) [4] and retroelements such as the Alu repeat elements [6][7][8]). …”