The pattern of HLA-A, -B and -DRB1 alleles and haplotypes of four Malay sub-ethnic groups namely Kelantan,Champa, Patani and Mandailing Malays of Peninsular Malaysia

“Bumiputra” or “son of the soil” is a term used to represent the Malays and other indigenous populations of Malaysia. The Malays are Austronesian speaking population and originated from different parts of the Indo-Malay Archipelago. The migration of Malay population from different parts of Indo-Malay Archipelago were mainly due to trading purposes which shaped the current Malay sub-ethnic groups with unique culture and with distinctive dialects. In this study, HLA typing was carried out using Sequence-based Typing (SBT) method on 109 individuals comprising of four Malay sub-ethnic groups namely Kelantan (n = 28), Champa (n = 29), Patani (n = 25) and Mandailing (n = 27) Malays. The HLA data is available in the Allele Frequencies Net Database (AFND).     

Next-generation sequencing characterization of HLA in multi-generation families of Kuwaiti descent

The frequency of HLA genes in one population may not accurately represent frequencies in other populations. In this study, we characterized extended human leukocyte antigen (HLA) haplotypes in several families of Kuwaiti descent by high-resolution typing using next-generation technology. A total 81 members (including patients and related donors) from 21 families were enrolled. No haplotypes were shared among multiple families. Of 77 haplotypes identified, 23 were not listed in the HaploStats database. Two haplotypes were most common in African Americans, six in Asian Pacific Islanders, three in Caucasians, three in Hispanics, and three in Native Americans. The remaining identified haplotypes were not among the most common 200 HLA haplotypes in any of the five major populations. This cohort had 202 (19%) unique alleles, including 20 rare alleles, 16 very rare alleles, and 2 novel ones. Furthermore, no frequency data were available for 30% (23/77) of the observed haplotypes, and 6% (3/49) of B?～?C blocks identified were not available in the HaploStats database. Kuwaiti individuals carry unique HLA haplotypes that are not shared by the majority of individuals historically reported to the US National Marrow Donor Program registry.     

In-silico study of influence of HLA heterogeneity on CTL responses across ethnicities to SARS-CoV-2

Differences in outcome to COVID-19 infection in different individuals is largely attributed to genetic heterogeneity leading to differential immune responses across individuals and populations. HLA is one such genetic factor that varies across individuals leading to differences in how T-cell responses are triggered against SARS-CoV-2, directly influencing disease susceptibility. HLA alleles that influence COVID-19 outcome, by virtue of epitope binding and presentation, have been identified in cohorts worldwide. However, the heterogeneity in HLA distribution across ethnic groups limits the generality of such association. In this study, we address this limitation by comparing the recognition of CTL epitopes across HLA genotypes and ethnic groups. Using HLA allele frequency data for ethnic groups from Allele Frequency Net Database (AFND), we construct synthetic populations for each ethnic group and show that CTL epitope strength varies across HLA genotypes and populations. We also observe that HLA genotypes, in certain cases, can have high CTL epitope strengths in the absence of top-responsive HLA alleles. Finally, we show that the theoretical estimate of responsiveness and hence protection offered by a HLA allele is bound to vary across ethnic groups, due to the influence of other HLA alleles within the HLA genotype on CTL epitope recognition. This emphasizes the need for studying HLA-disease associations at the genotype level rather than at a single allele level.     

Allele Frequencies Net Database: Improvements for storage of individual genotypes and analysis of existing data

The Allele Frequencies Net Database (AFND) is a freely accessible database which stores population frequencies for alleles or genes of the immune system in worldwide populations. Herein we introduce two new tools. We have defined new classifications of data (gold, silver and bronze) to assist users in identifying the most suitable populations for their tasks. The gold standard datasets are defined by allele frequencies summing to 1, sample sizes >50 and high resolution genotyping, while silver standard datasets do not meet gold standard genotyping resolution and/or sample size criteria. The bronze standard datasets are those that could not be classified under the silver or gold standards. The gold standard includes >500 datasets covering over 3 million individuals from >100 countries at one or more of the following loci: HLA-A, -B, -C, -DPA1, -DPB1, -DQA1, -DQB1 and -DRB1 – with all loci except DPA1 present in more than 220 datasets. Three out of 12 geographic regions have low representation (the majority of their countries having less than five datasets) and the Central Asia region has no representation. There are 18 countries that are not represented by any gold standard datasets but are represented by at least one dataset that is either silver or bronze standard. We also briefly summarize the data held by AFND for KIR genes, alleles and their ligands. Our second new component is a data submission tool to assist users in the collection of the genotypes of the individuals (raw data), facilitating submission of short population reports to Human Immunology, as well as simplifying the submission of population demographics and frequency data.     

Distribution of KIR genes in the Croatian population

The KIR locus with genes involved in immune processes is among the most polymorphic and structurally diverse human loci. KIR genes encode activating and inhibitory receptors that differ in specificity for HLA class I ligands and signaling potential. These receptors are expressed principally by natural killer (NK) cells and subpopulations of T cells. This study represents the first report of the distribution of KIR genes, KIR genotypes and KIR/HLA pairs in 121 unrelated healthy Croatian individuals. Twenty-three different genotypes were observed in the Croatian population and all 16 KIR genes known to date were found. The most frequent KIR genotype was the AA genotype. All individuals had at least one inhibitory KIR/HLA pair with the majority of individuals with three inhibitory KIR/HLA pairs. The most frequent KIR/HLA pair was the KIR2DL3/C1 group. Our results demonstrated the similarity of the Croatian population’s KIR repertoire with other Caucasian populations reported so far.     

Immunogenetics as a tool in anthropological studies

The genes coding for the main molecules involved in the human immune system--immunoglobulins, human leucocyte antigen (HLA) molecules and killer-cell immunoglobulin-like receptors (KIR)--exhibit a very high level of polymorphism that reveals remarkable frequency variation in human populations. 'Genetic marker' (GM) allotypes located in the constant domains of IgG antibodies have been studied for over 40 years through serological typing, leading to the identification of a variety of GM haplotypes whose frequencies vary sharply from one geographic region to another. An impressive diversity of HLA alleles, which results in amino acid substitutions located in the antigen-binding region of HLA molecules, also varies greatly among populations. The KIR differ between individuals according to both gene content and allelic variation, and also display considerable population diversity. Whereas the molecular evolution of these polymorphisms has most likely been subject to natural selection, principally driven by host-pathogen interactions, their patterns of genetic variation worldwide show significant signals of human geographic expansion, demographic history and cultural diversification. As current developments in population genetic analysis and computer simulation improve our ability to discriminate among different--either stochastic or deterministic--forces acting on the genetic evolution of human populations, the study of these systems shows great promise for investigating both the peopling history of modern humans in the time since their common origin and human adaptation to past environmental (e.g. pathogenic) changes. Therefore, in addition to mitochondrial DNA, Y-chromosome, microsatellites, single nucleotide polymorphisms and other markers, immunogenetic polymorphisms represent essential and complementary tools for anthropological studies.     

High-resolution HLA allele and haplotype frequencies in several unrelated populations determined by next generation sequencing: 17th International HLA and Immunogenetics Workshop joint report

The primary goal of the unrelated population HLA diversity (UPHD) component of the 17th International HLA and Immunogenetics Workshop was to characterize HLA alleles at maximum allelic-resolution in worldwide populations and re-evaluate patterns of HLA diversity across populations. The UPHD project included HLA genotype and sequence data, generated by various next-generation sequencing methods, from 4,240 individuals collated from 12 different countries. Population data included well-defined large datasets from the USA and smaller samples from Europe, Australia, and Western Asia. Allele and haplotype frequencies varied across populations from distant geographical regions. HLA genetic diversity estimated at 2- and 4-field allelic resolution revealed that diversity at the majority of loci, particularly for European-descent populations, was lower at the 2-field resolution.Several common alleles with identical protein sequences differing only by intronic substitutions were found in distinct haplotypes, revealing a more detailed characterization of linkage between variants within the HLA region. The examination of coding and non-coding nucleotide variation revealed many examples in which almost complete biunivocal relations between common alleles at different loci were observed resulting in higher linkage disequilibrium. Our reference data of HLA profiles characterized at maximum resolution from many populations is useful for anthropological studies, unrelated donor searches, transplantation, and disease association studies.     

MHC and malaria: the relationship between HLA class II alleles and immune responses to Plasmodium falciparum.

In mice, immune responses to subunits of defined malaria antigens are regulated by genes mapping within the MHC and it has been suggested that such genetic restriction will be a major obstacle in the development of a human malaria vaccine. The relationship between class II human leukocyte antigen (HLA) genes and immune recognition of three candidate antigens for a vaccine against Plasmodium falciparum malaria has been investigated in a human population living in a malaria endemic area of West Africa. The study population was shown to be extremely heterogeneous for HLA class II alleles and marked differences in allelic frequency were detected between members of different ethnic groups. One class II DQA-DQB combination (serological specificity DQw2) was particularly common among members of the Fula ethnic group. This haplotype was significantly associated with higher than average levels of antibody to a peptide epitope, (EENV)6, of the malaria antigen Pf155/RESA. There was little evidence of association between HLA class II genotype and cellular proliferative or interferon gamma responses to the antigens tested. Overall, the number of significant associations between immune responses and specific HLA class II haplotypes was greater than would be expected by chance but less than would be expected if class II-dependent genetic restriction were a major factor governing human immune responses to malaria antigens. Thus, although some qualitative variation in the immune response to vaccine antigens may occur in ethnically different target populations, widespread HLA-associated nonresponsiveness to a multivalent subunit malaria vaccine is unlikely.     

HLA-A, -B, -C, -DQA1, -DQB1, -DRB1, -E, -F and -G genotyping of 130 individuals from Terceira Island,Azores, Portugal

One hundred and thirty unrelated Azorean individuals were randomly selected to study the frequencies of high-resolution HLA alleles and haplotypes in the Azorean (Terceira) population. HLA-A, -B, -Cw, -DRB1, -DQA1 and -DQB1 high-resolution genotyping was performed by polymerase chain reaction using commercial kits. HLA-E, -F and -G alleles, were genotyped by sequence-based typing. All loci were in HWE, showing no locus-level deviations. The genotype data is available in the Allele Frequencies Net Database under the population name “Azores Terceira Island” and the identifier (AFND112579).     

Strategies to work with HLA data in human populations for histocompatibility,clinical transplantation,epidemiology and population genetics: HLA‐NET methodological recommendations

HLA‐NET (a European COST Action) aims at networking researchers working in bone marrow transplantation, epidemiology and population genetics to improve the molecular characterization of the HLA genetic diversity of human populations, with an expected strong impact on both public health and fundamental research. Such improvements involve finding consensual strategies to characterize human populations and samples and report HLA molecular typings and ambiguities; proposing user‐friendly access to databases and computer tools and defining minimal requirements related to ethical aspects. The overall outcome is the provision of population genetic characterizations and comparisons in a standard way by all interested laboratories. This article reports the recommendations of four working groups (WG1‐4) of the HLA‐NET network at the mid‐term of its activities. WG1 (Population definitions and sampling strategies for population genetics’ analyses) recommends avoiding outdated racial classifications and population names (e.g. ‘Caucasian’) and using instead geographic and/or cultural (e.g. linguistic) criteria to describe human populations (e.g. ‘pan‐European’). A standard ‘HLA‐NET POPULATION DATA QUESTIONNAIRE’ has been finalized and is available for the whole HLA community. WG2 (HLA typing standards for population genetics analyses) recommends retaining maximal information when reporting HLA typing results. Rather than using the National Marrow Donor Program coding system, all ambiguities should be provided by listing all allele pairs required to explain each genotype, according to the formats proposed in ‘HLA‐NET GUIDELINES FOR REPORTING HLA TYPINGS’. The group also suggests taking into account a preliminary list of alleles defined by polymorphisms outside the peptide‐binding sites that may affect population genetic statistics because of significant frequencies. WG3 (Bioinformatic strategies for HLA population data storage and analysis) recommends the use of programs capable of dealing with ambiguous data, such as the ‘gene[rate]’ computer tools to estimate frequencies, test for Hardy–Weinberg equilibrium and selective neutrality on data containing any number and kind of ambiguities. WG4 (Ethical issues) proposes to adopt thorough general principles for any HLA population study to ensure that it conforms to (inter)national legislation or recommendations/guidelines. All HLA‐NET guidelines and tools are available through its website http://hla‐net.eu .     

High resolution HLA haplotyping by imputation for a British population bioresource

This study aimed to establish the occurrence and frequency of HLA alleles and haplotypes for a healthy British Caucasian population bioresource from Oxfordshire. We present the results of imputation from HLA SNP genotyping data using SNP2HLA for 5553 individuals from Oxford Biobank, defining one- and two-field alleles together with amino acid polymorphisms. We show that this achieves a high level of accuracy with validation using sequence-specific primer amplification PCR. We define six- and eight-locus HLA haplotypes for this population by Bayesian methods implemented using PHASE. We determine patterns of linkage disequilibrium and recombination for these individuals involving classical HLA loci and show how analysis within a haplotype block structure may be more tractable for imputed data. Our findings contribute to knowledge of HLA diversity in healthy populations and further validate future large-scale use of HLA imputation as an informative approach in population bioresources.     

Distribution of HLA alleles and haplotypes in the Maldivian population

The study of human leukocyte antigen (HLA), allele and haplotype frequencies within populations provides an important source of information for anthropological investigation, organ and hematopoietic stem-cell transplantation purposes as well as disease association studies. As of today, there are no data available in the literature on the HLA structure of the Maldivian population. Altogether 106 families were studied. We used the parents of each family (212 unrelated individuals) to analyze the frequencies of HLA class I and class II allele groups and haplotypes.     

Genome-wide patterns of genetic distances reveal candidate Loci contributing to human population-specific traits

Modern humans originated in Africa before migrating across the world with founder effects and adaptations to new environments contributing to their present phenotypic diversity. Determining the genetic basis of differences between populations may provide clues about our evolutionary history and may have clinical implications. Herein, we develop a method to detect genes and biological processes in which populations most differ by calculating the genetic distance between modern populations and a hypothetical ancestral population. We apply our method to large-scale single nucleotide polymorphism (SNP) data from human populations of African, European and Asian origin. As expected, ancestral alleles were more conserved in the African populations and we found evidence of high divergence in genes previously suggested as targets of selection related to skin pigmentation, immune response, senses and dietary adaptations. Our genome-wide scan also reveals novel candidates for contributing to population-specific traits. These include genes related to neuronal development and behavior that may have been influenced by cultural processes. Moreover, in the African populations, we found a high divergence in genes related to UV protection and to the male reproductive system. Taken together, these results confirm and expand previous findings, providing new clues about the evolution and genetics of human phenotypic diversity.     

Diversity distributions of killer cell immunoglobulin-like receptor genes and their ligands in the Chinese Shaanxi Han population

In the present study, 17 killer cell immunoglobulin-like receptors (KIR) genes and KIR ligands (human leukocyte antigen [HLA] -A and -B) were detected by using a polymerase chain reaction-sequence-specific primer (PCR-SSP) method in 104 unrelated healthy Han individuals living in Shaanxi province, China. The observed carrier frequencies of the 12 KIR genes ranged from 0.14 to 0.96. KIR2DL4, 3DL2, 3DL3, 2DP1 and 3DP1 were found to be present in every individual. A total of 51 different KIR gene profiles were identified, in which 11 gene profiles exclusively belonged to the study population. Neighbor-joining phylogenetic tree between the studing population and its neighboring ethnic groups was constructed using the observed carrier frequencies of 13 KIR loci. The phylogenetic tree shows that the Shaanxi Han population, Han populations in different regions, Yi, Japanese, and Koreans were in the same cluster. KIR/HLA relationships show that KIR3DS1(-)/3DL1(+)/Bw4(+) was the most common association in the population. In conclusion, the present study findings reveal the high polymorphism of KIRs in the Shaanxi Han population, demonstrate the KIR/HLA association in the study population, and enrich the KIR and HLA gene resources. The obtained KIR data will further the understanding of genetic relationships among populations in different geographic areas, and assist in answering questions regarding KIR/HLA relationships.     

Microsatellite evolution in modern humans: a comparison of two data sets from the same populations

We genotyped 64 dinucleotide microsatellite repeats in individuals from populations that represent all inhabited continents. Microsatellite summary statistics are reported for these data, as well as for a data set that includes 28 out of 30 loci studied by Bowcock et al . (1994) in the same individuals. For both data sets, diversity statistics such as heterozygosity, number of alleles per locus, and number of private alleles per locus produced the highest values in Africans, intermediate values in Europeans and Asians, and low values in Americans. Evolutionary trees of populations based on genetic distances separated groups from different continents. Corresponding trees were topologically similar for the two data sets, with the exception that the (δμ)² genetic distance reliably distinguished groups from different continents for the larger data set, but not for the smaller one. Consistent with our results from diversity statistics and from evolutionary trees, population growth statistics S _k and β, which seem particularly useful for indicating recent and ancient population size changes, confirm a model of human evolution in which human populations expand in size and through space following the departure of a small group from Africa.     

Human Leucocyte Antigens in blood transfusion

Human Leucocyte Antigen (HLA) genes and molecules have an important role in transplantation, aetiology of many autoimmune, non‐autoimmune and infection diseases. Due to the extremely high polymorphism of HLA genes and their different frequency distributions in various populations, an increasing probability of HLA non‐compatible blood products, tissues or organs usage exists. For that reason, the aim of this paper was to give a concise overview of the role of HLA antigens and antibodies in adverse reactions caused by administration of transfusion products. The HLA system can cause detrimental immune reactions in transfusion therapy (platelet immune refractoriness, febrile transfusion reaction, transfusion‐related acute lung injury and transfusion‐associated graft versus host disease). Anti‐HLA antibodies present in the patient are responsible for some of these reactions, while anti‐HLA antibodies or HLA reactive cells present in the transfused product are accountable for immune‐reactivity in other cases. In order to avoid or reduce the development of these transfusion‐related events, anti‐HLA antibody‐negative or compatible products should be used. This is increasingly facilitated by introduction of more sensitive and specific techniques to determine anti‐HLA antibodies and gene polymorphisms. In conclusion, the most common adverse reactions related to administration of incompatible HLA transfusion products are discussed. Basic information about HLA genes and antibodies as well as methods for their detection is also provided in order to give sufficient data for safe and efficient administration of transfusion products.     

Distributions of HLA class I alleles and haplotypes in Bulgarians--contribution to understanding the origin of the population

In this study we present for the first time HLA class I allele and haplotype frequencies at DNA level in the Bulgarian population. HLA class I profile of Bulgarians has been compared to other European and Mediterranean populations of common historical background in order to clarify more precisely the origin of our population. Genetic distances, phylogenetic trees and correspondence analyses show that the Bulgarian population is more closely related to the Italian, the Mediterranean, the Armenian and the Romanian population than to the other East and West European population. This is further supported by the analysis of HLA class I haplotypes in Bulgarians. Most of them are also common in Europe. However their frequency pattern in Bulgarians is similar to the South European populations. The presence of some rare alleles and haplotypes indicated Asian genetic inflow. On the basis of HLA class I profile and supported by historical and anthropological data, we suggest that the Bulgarian population is characterized by the features of the Southern European anthropological type with some influence of other groups such as Asians, Turks, Armenians. Migrations and assimilation of many different ethnic groups are the major factor determining the genetic diversity of our population.     

African diversity from the HLA point of view: influence of genetic drift, geography, linguistics, and natural selection.

This study investigates the influence of different evolutionary factors on the patterns of human leukocyte antigen (HLA) genetic diversity within sub-Saharan Africa, and between Africa, Europe, and East Asia. This is done by comparing the significance of several statistics computed on equivalent population data sets tested for two HLA class II loci, DRB1 and DPB1, which strongly differ from each other by the shape of their allelic distributions. Similar results are found for the two loci concerning highly significant correlations between geographic and genetic distances at the world scale, high levels of genetic diversity within sub-Saharan Africa and East Asia, and low within Europe, and low genetic differentiations among the three broad continental areas, with no special divergence of Africa. On the other hand, DPB1 behaves as a neutral polymorphism, although a significant excess of heterozygotes is often observed for DRB1. Whereas the pattern observed for DPB1 is explained by geographic differentiations and genetic drift in isolated populations, balancing selection is likely to have prevented genetic differentiations among populations at the DRB1 locus. However, this selective effect did not disrupt the high correlation found between DRB1 and geography at the world scale, nor between DRB1 and linguistic differentiations at the African level.     

The extensive polymorphism of KIR genes

The functions of human natural killer (NK) cells are controlled by diverse families of antigen receptors. Prominent among these are the killer cell immunoglobulin‐like receptors (KIR), a family of genes clustered in one of the most variable regions of the human genome. Within this review we discuss the vast polymorphism of the KIR gene complex which rivals that of the human leucocyte antigen (HLA) complex. There are several aspects to this polymorphism. Initially there is presence/absence of individual KIR genes, with four of these genes, termed framework genes, being present in all individuals tested to date, except on those very occasional instances when the gene has been deleted. Within each gene, alleles are present at different frequencies. We provide details of a new website that enables convenient searching for data on KIR gene, allele and genotype frequencies in different populations and show how these frequencies vary in different worldwide populations and the high probability of individuals differing in their KIR repertoire when both gene and allele polymorphism is considered. The KIR genes present in an individual may be classified into A and/or B haplotypes, which respectively have a more inhibitory role or a more activating role on the function of the NK cell. Family studies have been used to ascertain the make‐up of these haplotypes, inclusion of allele typing enabling determination of whether one or two copies of a particular gene is present. In addition to genetic diversification the KIR gene complex shows differences at the functional level with different alleles having different protein expression levels and different avidity with their HLA ligand.