Nucleotide sequence diversity of HLA class II genes in Australian Aborigines and populations of Asia-Oceania
Date
1992
Authors
Gao, Xiaojiang
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Abstract
The aim of this thesis was to investigate nucleotide
sequence diversity of HLA class II genes in Australian
Aborigines and indigenous peoples of Asia-Oceania. Nineteen
study populations represented eight major ethnic groups
including Australian Aborigines, Papua New Guinean
highlanders, coastal Melanesians, Polynesians, Micronesians,
Javanese, southern and northern Chinese, and a minority group
from northwestern China. Using PCR-based technologies, the
nucleotide sequence polymorphism in exon 2 DRB1, DRB3, DRB5,
DQA1 and DQB1 genes was examined in all these populations. The
DPB1 exon 2 polymorphism was examined in Australian Aborigines
and a Chinese population.
Six novel HLA class II alleles including four DRB1, one
DRB5 and one DPBl were discovered in this study by the
occurrence of unusual hybridization patterns in the PCR-SSO
typing procedure and were confirmed by DNA Sequencing. These
new alleles, DRB1*0412, 1408, 1409, 1410, DRB5*0203 and
DBP1*2201 have been recognized by the WHO Nomenclature
Committee. The nucleotide sequences and the deduced amino acid
sequences of the novel class II alleles indicated that
multiple molecular mechanisms were involved in generating
these alleles including point mutation and hypermutational
events of segmental transfer and intra-exonic recombination.
In two cases (DRB1*0412 and DRB1*1410), hypermutational events
have created unique peptide binding sites which are
drastically different from all their putative progenitor
molecules. Five of the six novel alleles were found in
Australian Aborigines and four novel DRB1 alleles were
detected in 45% of the Aboriginal individuals tested.
PCR-SSO typing revealed some HLA class II polymorphisms
previously difficult or impossible to detect with more
traditional typing techniques. Remarkable differences in the
V
class II HLA allele frequency distributions, especially in the
subtypes of major DR antigen groups, were observed between the
study populations. Australian Aborigines showed the most
divergent class II HLA profile; most of their DRB1 alleles did
not overlap with other study populations. PNG highlanders and
Javanese were highly homogeneous with quite restricted class
II HLA distributions. Other Oceanic populations of
Polynesians, Micronesians and coastal Melanesians were each
characterized with unique class II HLA distribution but shared
common features which indicated their historical ties.
Distinctive HLA distributions were observed between Chinese
populations from southern and northern China, while the
minority group from northwestern China demonstrated a mixed
ancestry of both Caucasoids and Orientals.
Further information came from the analysis of HLA-DR, -DQ
haplotypes. A total of 80 three-locus or four-locus DR-DQ
combinations including 16 DR2-related, 12 DR4-related, 11 DR5-
related, and 24 DR6-related haplotypes were inferred from the
study populations. Haplotype frequencies were used to
calculate genetic distances between these populations and to
reconstruct population phylogeny, which proved a sensitive
indicator of population affinities. The unusual linkage
relationships detected in the study populations also had
important implications for the understanding of MHC evolution.
Knowledge of the nucleotide sequence polymorphism of HLA
class II genes in general populations has fundamental
importance in HLA-related clinical investigations. The
apparent lack of susceptible alleles in the HLA gene pool of
native Australians and Pacific islanders, or the high
frequency of protective alleles, might partly explain the
extremely low incidence of autoimmune diseases in these
populations.
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John Curtin School of Medical Research, nucleotide sequence diversity, HLA class II geners, Australian Aborigines, indigenous peoples, Asia-Oceania
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Thesis (PhD)
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