Human Molecular Genetics, 2000, Vol. 9, No. 10 1481-1486
© 2000 Oxford University Press
Restricted polymorphism of the mannose-binding lectin gene of indigenous Australians
Immunobiology Unit, Institute of Child Health, University College London, London WC1N 1EH, UK, 1Department of Paediatrics, University of Adelaide, South Australia 5006, Australia, 2Australian Red Cross Blood Transfusion Service, South Australia 5000, Australia, 3School of Biological Sciences, University of Newcastle, Newcastle, New South Wales, Australia, 4Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3052, and Victorian Transplantation and Immunogenetics Service, Australian Red Cross Blood Service, PO Box 354, South Melbourne, Victoria 3250, Australia
Received 3 February 2000; Revised and Accepted 10 April 2000.
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ABSTRACT |
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Mannose-binding lectin (MBL) is an important complement-activating protein of the human innate immune system. Deficiency of MBL is associated with an increased risk of various infections and arises from three structural gene mutations in exon 1 (variants B, C and D) and/or the presence of a low efficiency promoter. The C allele is found in sub-Saharan Africa whereas the B allele is found elsewhere, suggesting that these mutations occurred after the suggested hominid migration out of Africa [100–150 000 years before present (BP)]. Paradoxically, these alleles may have a selective advantage in protection against intracellular pathogens and occur at particularly high frequencies in sub-Saharan Africa (C variant) and South America (B variant). Since hominids reached Australia at least 50 000 years ago, a study of MBL polymorphisms in the indigenous population was of interest. Using heteroduplex technology we found a paucity of MBL structural gene mutations in two population groups from geographically distinct regions. Of 293 individuals tested, 289 were wild-type and four were heterozygous for either the B or D allele. In each individual with an MBL mutation the HLA haplotype profile suggested some Caucasian admixture. We also found a restricted range of MBL promoter haplotypes and the serum MBL levels were higher than those of any other ethnic group studied to date (median 3.07 µg/ml). Our data suggest that the B mutation probably arose between 50 000 and 20 000 BP. Its absence from the founder gene pool of indigenous Australians may also partly explain their vulnerability to intracellular infections such as tuberculosis.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Mannose-binding lectin (MBL, also known as mannan-binding lectin) is a member of the collectin family of proteins found in mammals and birds (1–3). Studies on the human and rodent forms of the protein have revealed it to be a potent activator of the complement system and suggest that it is one of the most important constituents of the innate immune system (4–7). A deficiency of the protein was originally recognized in association with a common opsonic defect and frequent unexplained infections in childhood (8). The major cause of such deficiency is the presence of a structural gene mutation in exon 1 of the MBL gene. Three such single point mutations have been described in codons 52, 54 and 57 (also known as variants D, B and C) and each is believed to interfere with oligomerization of the protein (9–11). A number of studies have now shown an association between low serum MBL levels or the presence of MBL structural gene mutations and an increased risk of infection (8,12–14). There is also a substantial emerging literature which indicates that deficiency of the protein predisposes to the autoimmune disease systemic lupus erythematosus (15–18), and is a significant modulator of disease progression in AIDS (19), rheumatoid arthritis (20,21) and cystic fibrosis (22).
In addition to the exon 1 structural gene mutations, polymorphisms have been described in the 5'-untranslated and promoter regions of the MBL gene and these influence serum levels of the protein (23,24). Three polymorphic sites (H/L, X/Y and P/Q at positions –550, –221 and +4, respectively) are in linkage disequilibrium with the structural gene mutations and are expressed as the haplotypes LYPB, HYPD and LYQC together with four wild-type (A variant) haplotypes LYPA, HYPA, LYQA and LXPA. The LXPA haplotype is associated with significantly lower serum MBL levels than the other three wild-type A variant haplotypes.
There is evidence that the B and C variant alleles arose independently in distinct populations (10). The B allele has reached high frequencies in several Eurasian and (native) American populations whereas the C allele is frequent in most sub-Saharan populations (10,24–26). The distribution of the B allele suggests that it arose after the putative migration of hominids out of Africa and subsequently spread to most of the non-African world (10).
There is good evidence of human settlement in Australia for at least 50 000 years and for much of this time there has been minimal contact with other populations. Therefore, it was of interest to investigate both MBL structural gene mutations and promoter polymorphisms in the indigenous population. Two such cohorts that were available for study (n = 293) were known to have a minimal admixture of Caucasian genes based on their HLA class I and II profiles. Using heteroduplexing procedures we found a very low frequency of MBL structural gene mutations and in each of the four individuals with such a mutation there was evidence of Caucasoid admixture. The MBL promoter polymorphisms of these populations were also extremely restricted and serum levels of the protein were the highest yet reported for any population. These findings are discussed in relation to the possible evolution of the MBL gene, the first colonization of Australia and the disease susceptibility of indigenous Australians.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Two distinct populations of indigenous Australians were studied (Fig. 1). Both the Warlpiri cohort (n = 190) and the Central Desert population (n = 103) have been described previously (27) and for each group any known first degree relatives were excluded. Initially, evidence of the MBL structural gene variants B, C and D was sought in DNA samples from the two population groups using a previously published heteroduplex procedure (28) (Fig. 2a and b). Of 293 individuals tested, 289 lacked structural gene mutations and were homozygous for the wild-type or A variant of MBL, two were heterozygous for the D variant and two were heterozygous for the B variant. The HLA haplotypes of the individuals having MBL mutations (Table 1) indicated the presence of admixture, typically Caucasoid, in all four cases.
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The DNA from all 293 individuals was readily typed using a recently developed Promoter Region heteroduplexing procedure (Fig. 2b, bottom). This information was then combined with the exon 1 data for the A, B, C and D alleles to give complete haplotypes. In the Warlpiri population the haplotype frequencies were as follows: HYPA, 0.747; LYQA, 0.013; LYPA, 0.229; LXPA, 0.008 and HYPD, 0.003. For the Central Desert population the observed haplotype frequencies were: HYPA, 0.757; LYQA, 0.029; LYPA, 0.180; LXPA, 0.019; LYPB, 0.010 and HYPD, 0.005. The haplotype LYQC (characteristic of sub-Saharan African populations) was not detected in either population. These data are illustrated in Figure 3 in comparison with haplotype frequency information from three other populations studied previously.
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Serum was also available for study from 189 individuals in the Warlpiri cohort and MBL protein levels were determined in these samples using an ELISA procedure (Fig. 4). The population median was 3.07 µg/ml (range 0.13–8.09) with only two individuals having a concentration below 1.00 µg/ml. The median concentrations of HYPA/HYPA individuals (n = 101) and HYPA/LYPA individuals (n = 71) were not significantly different, suggesting that, compared with X/Y, the H/L polymorphism has little effect on protein levels. To date no other population has been described with such high MBL concentrations. However, if individuals with the LYPB haplotype are removed from a previously studied Eskimo population (26) the residual individuals (essentially of HYPA haplotype) have a median MBL concentration of 3.06 µg/ml.
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DISCUSSION |
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The ancestral lands of the Warlpiri people cover 50–60 000 square miles of the central west of the Northern Territory of Australia (29). The subgroup studied here was established in a settlement area of some 200 square miles in the 1940s. As such they represent a more discrete population group than the rather diverse Central Desert population. On the basis of the known HLA profiles of the two populations there is a much lower Caucasian admixture in the Warlpiri compared with the Central Desert group. The MBL structural gene mutation frequency was some six times higher in the latter group (3/104) compared with the Warlpiri (1/190) and the presence of known Caucasian HLA alleles in all four individuals having an MBL mutation strongly suggests that the mutations were probably not present in these indigenous people before European settlement. A possibility of other (unreported) mutations being present and lowering protein levels was ruled out by measuring MBL concentrations in selected sera from the Warlpiri cohort. It is not possible to conclude from this study that the mutations are not present elsewhere amongst other indigenous Australians but, to be meaningful, additional studies will need to identify communities also believed to have minimal Caucasian admixture and preferably include an independent marker of their genetic background such as HLA alleles.
The MBL promoter region polymorphisms were also extremely restricted in both of the study populations. Typing showed that 97% of the Warlpiri and 94% of the Central Desert population were HYPA/HYPA, HYPA/LYPA or LYPA/LYPA. These observations strongly suggest that the ancestral promoter polymorphisms introduced into Australia 50 000 years before present (BP) were HYPA and LYPA. Madsen et al. (23) originally proposed that the ancestral MBL haplotype was a high-producing haplotype such as HYPA, but in a later study this group proposed a lost high-producing haplotype in the evolutionary tree located between the LYQA and LYPA haplotypes (24). Our data on the Australian populations suggest that the HYPA haplotype may have been the dominant haplotype 50 000 BP. This conclusion is supported by the observations that the Eskimo have a high frequency of HYPA. The latter population are descended from ancestral migrants crossing from Eastern Siberia 20–30 000 BP. However, the Eskimo are distinguished from indigenous Australians by the presence of the LYPB haplotype (26), which suggests that the B structural variant arose between 20 000 and 50 000 BP. The geographical isolation of Australia appears to have been complete at the time of the last glaciation and there was no comparable introduction of the B mutation. This hypothesis is illustrated schematically in Figure 5.
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The origins of the Australian Aboriginals are obscure but a generally accepted consensus view is that ‘island hopping’ from SE Asia would have been possible 50 000 years ago because sea levels were then much lower than at present (30). The virtual absence of the three MBL structural gene mutations in indigenous Australians suggests that the mutations were absent in the ancestral migrants from the mainland. An alternative explanation, that one or more of the mutations was originally present and subsequently lost from the gene pool, seems less likely but cannot be discounted.
It is of interest that there was apparently no introduction of the B variant 20 000 BP when glaciation again resulted in a significant lowering of sea levels. It has been suggested that, paradoxically, the associated increased land availability in SE Asia may have reduced both competition for food and the pressures on populations to migrate (30).
Indigenous Australians probably share a common ancestry with the present day Papua New Guinea Highlanders (31) on whom there is no information with respect to MBL polymorphisms. However, in the coastal population of Papua New Guinea the B variant was found at low frequency (0.07) and the C and D variants were not observed (25). This profile is intermediate between the population of mainland SE Asia [Hong Kong Chinese (10)] and the indigenous Australians.
The observed high frequencies of the B and C variants of MBL in many populations has led to the suggestion that these alleles may confer some biological advantage (10,32,33). One suggestion is that MBL deficiency helps to protect the host against infection by intracellular parasites such as mycobacteria and leishmania, which exploit C3b opsonization and subsequent uptake by C3 receptors to invade cells and to parasitize the host (32,33). Another proposal is that the high frequencies of the mutations observed in tropical regions (10,24,26) may serve to reduce the damaging effects of excessive complement activation (10). However, for small bands of hunter-gatherers the spectrum of infectious disease would be different and one might not expect the same biological advantages from low levels of MBL. If the presence of these mutations does indeed reduce infectivity with mycobacteria the very high MBL levels in indigenous Australians may, in part, explain the devastating consequences of the tuberculosis introduced by European settlers in the 19th and 20th centuries. The role of MBL in the immune response to various extracellular pathogens within the indigenous Australian population remains to be established.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Determination of MBL structural gene mutations
PCR product was obtained from standard genomic DNA, sample genomic DNA and from a synthetic MBL Universal Heteroduplex Generator spanning the exon 1 mutations (MBL-UHG) (28). Thermostatic DNA polymerase (Dynazyme), (Finnzymes Oy, Espoo, Finland) was used in a 32 cycle sequence with a 61°C annealing temperature.
Heteroduplexes were prepared and analysed using techniques similar to those described previously (28). Briefly, 15 µl volumes of PCR product from standard DNA or sample DNA were mixed with 15 µl of UHG PCR product. The mixtures were heated to 94°C for 3 min and then cooled to 37°C over 35 min. The mixtures of hetero- and homoduplexes were then analysed immediately using a 20% non-denaturing polyacrylamide mini-gel (Protogel, National Diagnostics, Sydney, Australia). Electrophoresis (200 V, 3 h) was performed at room temperature using a Mini-Protean II tank (Bio-Rad, Sydney, Australia). Heteroduplexes were visualized by staining with ethidium bromide (0.5 mg/ml) and photographed under UV illumination.
Determination of MBL promoter region polymorphisms
A separate heteroduplexing procedure was used to determine the H/L, X/Y and P/Q polymorphisms.
A novel 442 bp UHG spanning the polymorphisms of the MBL promoter region was synthesized by Dr Nigel Wood, University of Bristol, UK, and was used in the present investigations. PCR product from both this generator and genomic DNA was obtained using Amplitaq DNA polymerase (PE Biosystems, Foster City, CA) in a 35 cycle sequence with a 56°C annealing temperature.
For the heteroduplex reaction 15 µl volumes of both PCR products were mixed, heated to 94°C for 5 min and then cooled to room temperature for 30 min. The mixtures of heteroduplexes and homoduplexes were analysed using 10% non-denaturing polyacrylamide mini-gels (Protogel, National Diagnostics). Electrophoresis (200 V for 3.5 h) was performed at 4–6°C using a Mini Protean II tank (Bio-Rad). Heteroduplexes were visualized by staining with ethidium bromide (0.5 mg/ml) and photographed under UV illumination. Band patterns were interpreted by comparison with known reference preparations kindly provided by Dr K. Welsh (Oxford, UK) and Dr P. Garred (Copenhagen, Denmark). The procedure permitted the identification of the following polymorphisms LXP/LXP, LYP/LYP, HYP/HYP, LYQ/LYQ, LXP/LYP, LXP/HYP, LXP/LYQ, LYP/HYP, LYP/LYQ and HYP/LYQ.
Determination of haplotypes
The three known structural gene mutations of MBL are in linkage disequilibrium with promoter region polymorphisms so that the B variant is always linked to LYP, the D variant is always linked to HYP and the C variant is always associated with LYQ (23). These linkages were assumed to hold true for this study and the data obtained by the two heteroduplexing procedures were combined to give complete haplotypes. Each of the structural gene mutations was associated with an appropriate set of promoter region alleles.
HLA typing
HLA class I typing of the Central Desert population was performed at the Tissue Typing Laboratory, ARCBS-SA, using routine serological methods. HLA class I DNA typing of the Warlpiri samples was performed using high resolution PCR–SSOP (sequence specific oligonucleotide) typing protocols as described previously (34).
HLA class II typing was performed by PCR–SSOP methods using 12th International Histocompatibility Workshop primers and probes.
MBL serum protein assays
Serum levels of MBL were determined using commercially available MBL ELISA kits obtained from the Statens Serum Institut, Copenhagen.
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ACKNOWLEDGEMENTS |
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We are indebted to the Warlpiri people and the Yuendumu Land Council for permission to carry out this study. We also thank Vania de Toledo, Nigel Wood, Renata Hamvas, Richard Mead, Peter Bardy and the staff of the ARCBS Tissue Typing Service, Adelaide, South Australia for their valuable contributions. M.W.T. is grateful to the Faculty of Medicine, University of Adelaide for the award of a Senior Visiting Research Fellowship and to the Royal Society for a Travel Fellowship.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +44 20 7829 8844; Fax: +44 20 7813 8494; Email: m.turner@ich.ucl.ac.uk
§ Present address: University of Sheffield Medical School, Sheffield S10 2RX, UK
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REFERENCES |
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