Behçet disease, new insights in disease associations and manifestations: a next-generation sequencing study.

Behçet disease is a multi-system disease associated with human leukocyte antigen (HLA) class I polymorphism. High-resolution next-generation sequencing (NGS) with haplotype analysis has not been performed previously for this disease. Sixty Egyptian patients diagnosed according to the International Study Group (ISG) criteria for Behçet disease and 160 healthy geographic and ethnic-matched controls were genotyped for HLA class I loci (HLA-A, B, C). For HLA class II loci (DRB1, DRB3/4/5, DQA1, DQB1, DPA1, DPB1), 40 control samples were genotyped. High-resolution HLA genotyping was performed using NGS and the results were analyzed. Clinical manifestations were oral ulcers (100%), genital ulcers (100%), eye (55%) and neurological (28%) and vascular involvement (35%). HLA-B*51:08 [odds ratio (OR) = 19·75, 95% confidence interval (CI) = 6·5-79; P < 0·0001], HLA-B*15:03 (OR = 12·15, 95% CI = 3·7-50·7; P < 0·0001), HLA-C*16:02 (OR = 6·53, 95% CI = 3-14; P < 0·0001), HLA-A*68:02 (OR = 3·14, 95% CI = 1·1-8·9; P < 0·01) were found to be associated with Behçet disease, as were HLA-DRB1*13:01 and HLA-DQB1*06:03 (OR = 3·39, 95% CI = 0·9-18·9; P = 0·04 for both). By contrast, HLA-A*03:01 (OR = 0·13, 95% CI = 0-0·8; P = 0·01) and HLA-DPB1*17:01 were found to be protective (OR = 0·27, 95% CI = 0·06-1·03; P = 0·02). We identified strong linkage disequilibrium between HLA-B*51:08 and C*16:02 and A*02:01 in a haplotype associated with Behçet disease. HLA-B*51:08 was significantly associated with legal blindness (OR = 2·98, 95% CI = 1·06-8·3; P = 0·01). In Egyptian Behçet patients, HLA-B*51:08 is the most common susceptibility allele and holds poor prognosis for eye involvement.

Significant variation between SNP-based HLA imputations in diverse populations: the last mile is the hardest.

Four single nucleotide polymorphism (SNP)-based human leukocyte antigen (HLA) imputation methods (e-HLA, HIBAG, HLA*IMP:02 and MAGPrediction) were trained using 1000 Genomes SNP and HLA genotypes and assessed for their ability to accurately impute molecular HLA-A, -B, -C and -DRB1 genotypes in the Human Genome Diversity Project cell panel. Imputation concordance was high (>89%) across all methods for both HLA-A and HLA-C, but HLA-B and HLA-DRB1 proved generally difficult to impute. Overall, <27.8% of subjects were correctly imputed for all HLA loci by any method. Concordance across all loci was not enhanced via the application of confidence thresholds; reliance on confidence scores across methods only led to noticeable improvement (+3.2%) for HLA-DRB1. As the HLA complex is highly relevant to the study of human health and disease, a standardized assessment of SNP-based HLA imputation methods is crucial for advancing genomic research. Considerable room remains for the improvement of HLA-B and especially HLA-DRB1 imputation methods, and no imputation method is as accurate as molecular genotyping. The application of large, ancestrally diverse HLA and SNP reference data sets and multiple imputation methods has the potential to make SNP-based HLA imputation methods a tractable option for determining HLA genotypes.

The killer immunoglobulin-like receptor KIR3DL1 in combination with HLA-Bw4 is protective against multiple sclerosis in African Americans.

We investigated the role of the KIR loci and their HLA class I ligands in a large cohort of African American multiple sclerosis (MS) patients (N=907) and controls (N=1456). No significant differences in carrier frequencies for any KIR locus or haplotype were observed between cases and controls. However, examination of KIR in the context of their cognate HLA ligands revealed a strong protective effect for KIR3DL1 in combination with HLA-A and -B alleles bearing the Bw4 motif (P=10(-8); odds ratio (OR)=0.60, confidence interval (CI)=0.50-0.71) and the Bw4 ligand alone (P<10(-6); OR=0.63, CI=0.53-0.75). The observed effect cannot be explained by either a specific HLA-B allele or by linkage disequilibrium with HLA-DRB1 or HLA-A. The protective effect was observed only in individuals who were not positive for the MS risk allele HLA-DRB1*15:01 (P<10(-6); OR=0.61, CI=0.51-0.74). Our study, the first investigation of KIR and MS in African Americans, confirms and refines previous findings in a European cohort.

KIR haplotypes are associated with late-onset type 1 diabetes in European-American families.

Classical human leukocyte antigens (HLA) genes confer the strongest, but not the only, genetic susceptibility to type 1 diabetes. Killer cell immunoglobulin-like receptors (KIR), on natural killer (NK) cells, bind ligands including class I HLA. We examined presence or absence, with copy number, of KIR loci in 1698 individuals, from 339 multiplex type 1 diabetes families, from the Human Biological Data Interchange, previously genotyped for HLA. Combining family data with KIR copy number information allowed assignment of haplotypes using identity by descent. This is the first disease study to use KIR copy number typing and unambiguously define haplotypes by gene transmission. KIR A1 haplotypes were positively associated with T1D in the subset of patients without the high T1D risk HLA genotype, DR3/DR4 (odds ratio=1.29, P=0.0096). The data point to a role for KIR in type 1 diabetes risk in late-onset patients. In the top quartile (age of onset>14), KIR A2 haplotype was overtransmitted (63.4%, odds ratio=1.73, P=0.024) and KIR B haplotypes were undertransmitted (41.1%, odds ratio=0.70, P=0.0052) to patients. The data suggest that inhibitory 'A' haplotypes are predisposing and stimulatory 'B' haplotypes confer protection in both DR3/DR4-negative and late-onset patient groups.

Validation of statistical imputation of allele-level multilocus phased genotypes from ambiguous HLA assignments.

Genetic matching for loci in the human leukocyte antigen (HLA) region between a donor and a patient in hematopoietic stem cell transplantation (HSCT) is critical to outcome; however, methods for HLA genotyping of donors in unrelated stem cell registries often yield results with allelic and phase ambiguity and/or do not query all clinically relevant loci. We present and evaluate a statistical method for in silico imputation of HLA alleles and haplotypes in large ambiguous population data from the Be The Match(®) Registry. Our method builds on haplotype frequencies estimated from registry populations and exploits patterns of linkage disequilibrium (LD) across HLA haplotypes to infer high resolution HLA assignments. We performed validation on simulated and real population data from the Registry with non-trivial ambiguity content. While real population datasets caused some predictions to deviate from expectation, validations still showed high percent recall for imputed results with average recall >76% when imputing HLA alleles from registry data. We simulated ambiguity generated by several HLA genotyping methods to evaluate the imputation performance on several levels of typing resolution. On average, imputation percent recall of allele-level HLA haplotypes was >95% for allele-level typing, >92% for intermediate resolution typing and >58% for serology (low-resolution) typing. Thus, allele-level HLA assignments can be imputed through the application of a set of statistical and population genetics inferences and with knowledge of haplotype frequencies and self-identified race and ethnicities.

Genotype List String: a grammar for describing HLA and KIR genotyping results in a text string.

Knowledge of an individual's human leukocyte antigen (HLA) genotype is essential for modern medical genetics, and is crucial for hematopoietic stem cell and solid-organ transplantation. However, the high levels of polymorphism known for the HLA genes make it difficult to generate an HLA genotype that unambiguously identifies the alleles that are present at a given HLA locus in an individual. For the last 20 years, the histocompatibility and immunogenetics community has recorded this HLA genotyping ambiguity using allele codes developed by the National Marrow Donor Program (NMDP). While these allele codes may have been effective for recording an HLA genotyping result when initially developed, their use today results in increased ambiguity in an HLA genotype, and they are no longer suitable in the era of rapid allele discovery and ultra-high allele polymorphism. Here, we present a text string format capable of fully representing HLA genotyping results. This Genotype List (GL) String format is an extension of a proposed standard for reporting killer-cell immunoglobulin-like receptor (KIR) genotype data that can be applied to any genetic data that use a standard nomenclature for identifying variants. The GL String format uses a hierarchical set of operators to describe the relationships between alleles, lists of possible alleles, phased alleles, genotypes, lists of possible genotypes, and multilocus unphased genotypes, without losing typing information or increasing typing ambiguity. When used in concert with appropriate tools to create, exchange, and parse these strings, we anticipate that GL Strings will replace NMDP allele codes for reporting HLA genotypes.

Common and well-documented HLA alleles: 2012 update to the CWD catalogue.

We have updated the catalogue of common and well-documented (CWD) human leukocyte antigen (HLA) alleles to reflect current understanding of the prevalence of specific allele sequences. The original CWD catalogue designated 721 alleles at the HLA-A, -B, -C, -DRB1, -DRB3/4/5, -DQA1, -DQB1, and -DPB1 loci in IMGT (IMmunoGeneTics)/HLA Database release 2.15.0 as being CWD. The updated CWD catalogue designates 1122 alleles at the HLA-A, -B, -C, -DRB1, -DRB3/4/5, -DQA1, -DQB1, -DPA1 and -DPB1 loci as being CWD, and represents 14.3% of the HLA alleles in IMGT/HLA Database release 3.9.0. In particular, we identified 415 of these alleles as being 'common' (having known frequencies) and 707 as being 'well-documented' on the basis of ~140,000 sequence-based typing observations and available HLA haplotype data. Using these allele prevalence data, we have also assigned CWD status to specific G and P designations. We identified 147/151 G groups and 290/415 P groups as being CWD. The CWD catalogue will be updated on a regular basis moving forward, and will incorporate changes to the IMGT/HLA Database as well as empirical data from the histocompatibility and immunogenetics community. This version 2.0.0 of the CWD catalogue is available online at cwd.immunogenomics.org, and will be integrated into the Allele Frequencies Net Database, the IMGT/HLA Database and National Marrow Donor Program's bioinformatics web pages.

16(th) IHIW: immunogenomic data-management methods. report from the immunogenomic data analysis working group (IDAWG).

SUMMARY: The goal of the immunogenomic data analysis working group (IDAWG) is to facilitate the consistent analysis of HLA and KIR data, and the sharing of those data among the immunogenomic and larger genomic communities. However, the data management approaches currently applied by immunogenomic researchers are not widely discussed or reported in the literature, and the effect of different approaches on data analyses is not known. With ASHI's support, the IDAWG developed a 45 question survey on HLA and KIR data generation, data management and data analysis practices. Survey questions detailed the loci genotyped, typing systems used, nomenclature versions reported, computer operating systems and software used to manage and transmit data, the approaches applied to resolve HLA ambiguity and the methods used for basic population-level analyses. Respondents were invited to demonstrate their HLA ambiguity resolution approaches in simulated data sets. By May 2012, 156 respondents from 35 nations had completed the survey. These survey respondents represent a broad sampling of the Immunogenomic community; 52% were European, 30% North American, 10% Asian, 4% South American and 4% from the Pacific. The project will continue in conjunction with the 17th Workshop, with the aim of developing community data sharing standards, ambiguity resolution documentation formats, single-task data Management tools and novel data analysis methods and applications. While additional project details and plans for the 17th IHIW will be forthcoming, we welcome the input and participation in these projects from the histocompatibility and immunogenetics community.

16(th) IHIW: population global distribution of killer immunoglobulin-like receptor (KIR) and ligands.

In the last fifteen years, published reports have described KIR gene-content frequency distributions in more than 120 populations worldwide. However, there have been limited studies examining these data in aggregate to detect overall patterns of variation at regional and global levels. Here, we present a summary of the collection of KIR gene-content data for 105 worldwide populations collected as part of the 15th and 16th International Histocompatibility and Immunogenetics Workshops, and preliminary results for data analysis.

16(th) IHIW: extending the number of resources and bioinformatics analysis for the investigation of HLA rare alleles.

Continuing a project presented at the 15th International HLA and Immunogenetics Workshop (IHIWS) on the rarity of HLA alleles, we sought to expand the number of data sources and bioinformatics tools available in the Allele Frequencies Net Database website (AFND, www.allelefrequencies.net). In this 16th IHIWS Rare Alleles project, HLA alleles described in the latest IMGT/HLA Database (release 3.8.0) were queried against different sources including data from registries (stem cell) and from 74 different laboratories around the world. We demonstrated that approximately 40% of the alleles officially named in the IMGT/HLA Database have been reported only once across all different sources. To facilitate the large-scale analysis of rare alleles, we have produced an online tool called the Rare Allele Detector that simplifies the detection of alleles that are considered to be 'very rare', 'rare' or 'frequent'. Tools and associated data can be accessed via the www.allelefrequencies.net website.

A community standard for immunogenomic data reporting and analysis: proposal for a STrengthening the REporting of Immunogenomic Studies statement.

Modern high-throughput HLA and KIR typing technologies are generating a wealth of immunogenomic data with the potential to revolutionize the fields of histocompatibility and immune-related disease association and population genetic research, much as SNP-based approaches have revolutionized association research. The STrengthening the REporting of Genetic Association studies (STREGA) statement provides community-based data reporting and analysis standards for genomic disease-association studies, identifying specific areas in which adoption of reporting guidelines can improve the consistent interpretation of genetic studies. While aspects of STREGA can be applied to immunogenomic studies, HLA and KIR research requires additional consideration, as the high levels of polymorphism associated with immunogenomic data pose unique methodological and computational challenges to the synthesis of information across datasets. Here, we outline the principle challenges to consistency in immunogenomic studies, and propose that an immunogenomic-specific analog to the STREGA statement, a STrengthening the REporting of Immunogenomic Studies (STREIS) statement, be developed as part of the 16th International HLA and Immunogenetics Workshop. We propose that STREIS extends at least four of the 22 elements of the STREGA statement to specifically address issues pertinent to immunogenomic data: HLA and KIR nomenclature, data-validation, ambiguity resolution, and the analysis of highly polymorphic genetic systems. As with the STREGA guidelines, the intent behind STREIS is not to dictate the design of immunogenomic studies, but to ensure consistent and transparent reporting of research, facilitating the synthesis of HLA and KIR data across studies.

Association of HLA alleles with Plasmodium falciparum severity in Malian children.

Pre-erythrocytic immunity to Plasmodium falciparum malaria is likely to be mediated by T-cell recognition of malaria epitopes presented on infected host cells via class I and II major histocompatibility complex (MHC) antigens. To test for associations of human leukocyte antigen (HLA) alleles with disease severity, we performed high-resolution typing of HLA class I and II loci and compared the distributions of alleles of HLA-A, -B, -C and -DRB1 loci in 359 Malian children of Dogon ethnicity with uncomplicated or severe malaria. We observed that alleles A*30:01 and A*33:01 had higher frequency in the group of patients with cerebral disease compared to patients with uncomplicated disease [A*30:01: gf = 0.2031 vs gf = 0.1064, odds ratio (OR) = 3.17, P = 0.004, confidence interval (CI) (1.94-5.19)] and [A*33:01: gf = 0.0781 vs gf = 0.0266, 4.21, P = 0.005, CI (1.89-9.84)], respectively. The A*30:01 and A*33:01 alleles share some sequence motifs and A*30:01 appears to have a unique peptide binding repertoire compared to other A*30 group alleles. Computer algorithms predicted malaria peptides with strong binding affinity for HLA-A*30:01 and HLA-A*33:01 but not to closely related alleles. In conclusion, we identified A*30:01 and A*33:01 as potential susceptibility factors for cerebral malaria, providing further evidence that polymorphism of MHC genes results in altered malaria susceptibility.

Allele Name Translation Tool and Update NomenCLature: software tools for the automated translation of HLA allele names between successive nomenclatures.

In this brief communication, we describe the Allele Name Translation Tool (antt) and Update NomenCLature (uncl), free programs developed to facilitate the translation of human leukocyte antigen (HLA) allele names recorded using the December 2002 version of the HLA allele nomenclature (e.g. A*01010101) to those recorded using the colon-delimited version of the HLA allele nomenclature (e.g. A*01:01:01:01) that was adopted in April 2010. In addition, the antt and uncl translate specific HLA allele-name changes (e.g. DPB1*0502 is translated to DPB1*104:01), as well as changes to the locus prefix for HLA-C (i.e. Cw* is translated to C*). The antt and uncl will also translate allele names that have been truncated to two, four, or six digits, as well as ambiguous allele strings. The antt is a locally installed and run application, while uncl is a web-based tool that requires only an Internet connection and a modern browser. The antt accepts a variety of HLA data-presentation and allele-name formats. In addition, the antt can translate using user-defined conversion settings (e.g. the names of alleles that encode identical peptide binding domains can be translated to a common 'P-code'), and can serve as a preliminary data-sanity tool. The antt is available for download, and uncl for use, at www.igdawg.org/software.

Report from the killer immunoglobulin-like receptor (KIR) anthropology component of the 15th International Histocompatibility Workshop: worldwide variation in the KIR loci and further evidence for the co-evolution of KIR and HLA.

The killer immunoglobulin-like receptor (KIR) anthropology component of the 15th International Histocompatibility Workshop (IHIWS) sought to explore worldwide population variation in the KIR loci, and to examine the relationship between KIR genes and their human leukocyte antigen (HLA) ligands. Fifteen laboratories submitted KIR genotype and HLA ligand data in 27 populations from six broad ethnic groups. Data were analyzed for correlations between the frequencies of KIR and their known HLA ligands. In addition, allelic typing was performed for KIR2DL2 and 3DL1 in a subset of populations. Strong and significant correlations were observed between KIR2DL2, 2DL3 genotype frequencies and the frequency of their ligand, HLA-C1. In contrast, only weak associations were seen for 3DL1, 3DS1 and the HLA-Bw4 ligand. Although some aspects of the correlations observed here differ from those reported in other populations, these data provide additional evidence of linked evolutionary histories for some KIR and HLA loci. Investigation of allele-level variation for the B haplotype locus KIR 2DL2 showed that two alleles, *001 and *003, predominate in all populations in this study. Much more allelic variation was observed for the A haplotype locus 3DL1, with several alleles observed at moderate frequencies and extensive variation observed between populations.

HLA class I (A, B, C) and class II (DRB1, DQA1, DQB1, DPB1) alleles and haplotypes in the Han from southern China.

In this study, polymerase chain reaction-sequence-specific oligonucleotide prode (SSOP) typing results for the human leukocyte antigen (HLA) class I (A, B, and C) and class II (DRB1, DQA1, DQB1, and DPB1) loci in 264 individuals of the Han ethnic group from the Canton region of southern China are presented. The data are examined at the allele, genotype, and haplotype level. Common alleles at each of the loci are in keeping with those observed in similar populations, while the high-resolution typing methods used give additional details about allele frequency distributions not shown in previous studies. Twenty distinct alleles are seen at HLA-A in this population. The locus is dominated by the A*1101 allele, which is found here at a frequency of 0.266. The next three most common alleles, A*2402, A*3303, and A*0203, are each seen at frequencies of greater than 10%, and together, these four alleles account for roughly two-thirds of the total for HLA-A in this population. Fifty alleles are observed for HLA-B, 21 of which are singleton copies. The most common HLA-B alleles are B*4001 (f= 0.144), B*4601 (f= 0.119), B*5801 (f= 0.089), B*1301 (f= 0.068), B*1502 (f= 0.073), and B*3802 (f= 0.070). At the HLA-C locus, there are a total of 20 alleles. Four alleles (Cw*0702, Cw*0102, Cw*0801, and Cw*0304) are found at frequencies of greater than 10%, and together, these alleles comprise over 60% of the total. Overall, the class II loci are somewhat less diverse than class I. Twenty-eight distinct alleles are seen at DRB1, and the most common three, DRB1*0901, *1202, and *1501, are each seen at frequencies of greater than 10%. The DR4 lineage also shows extensive expansion in this population, with seven subtypes, representing one quarter of the diversity at this locus. Eight alleles are observed at DQA1; DQA1*0301 and 0102 are the most common alleles, with frequencies over 20%. The DQB1 locus is dominated by four alleles of the 03 lineage, which make up nearly half of the total. The two most common DQB1 alleles in this population are DQB1*0301 (f= 0.242) and DQB1*0303 (f= 0.15). Eighteen alleles are observed at DPB1; DPB1*0501 is the most common allele, with a frequency of 37%. The class I allele frequency distributions, expressed in terms of Watterson's (homozygosity) F-statistic, are all within expectations under neutrality, while there is evidence for balancing selection at DRB1, DQA1, and DQB1. Departures from Hardy-Weinberg expectations are observed for HLA-C and DRB1 in this population. Strong individual haplotypic associations are seen for all pairs of loci, and many of these occur at frequencies greater than 5%. In the class I region, several examples of HLA-B and -C loci in complete or near complete linkage disequilibrium (LD) are present, and the two most common, B*4601-Cw*0102 and B*5801-Cw*0302 account for more than 20% of the B-C haplotypes. Similarly, at class II, nearly all of the most common DR-DQ haplotypes are in nearly complete LD. The most common DRB1-DQB1 haplotypes are DRB1*0901-DQB1*0303 (f= 0.144) and DRB1*1202-DQB1*0301 (f= 0.131). The most common four locus class I and class II combined haplotypes are A*3303-B*5801-DRB1*0301-DPB1*0401 (f= 0.028) and A*0207-B*4601-DRB1*0901-DPB1*0501 (f= 0.026). The presentation of complete DNA typing for the class I loci and haplotype analysis in a large sample such as this can provide insights into the population history of the region and give useful data for HLA matching in transplantation and disease association studies in the Chinese population.

Genetic variability and linkage disequilibrium within the HLA-DP region: analysis of 15 different populations.

In order to understand the forces governing the evolution of the genetic diversity in the HLA-DP molecule, polymerase chain reaction (PCR)-based methods were used to characterize genetic variation at the DPA1 and DPB1 loci encoding this heterodimer on 2,807 chromosomes from 15 different populations including individuals of African, Asian, Amerindian, Indian and European origin. These ethnically diverse samples represent a variety of population substructures and include small, isolated populations as well as larger, presumably admixed populations. Ten DPA1 and 39 DPB1 alleles were identified and observed on 87 distinct DP haplotypes, 34 of which were found to be in significant positive linkage disequilibrium in at least one population. Some haplotypes were found in all ethnic groups while others were confined to a single ethnic group or population. Strong positive global linkage disequilibrium (Wn) between DPA1 and DPB1 was present in all 15 populations. The African populations displayed the lowest values of Wn whereas the Amerindian populations displayed near absolute disequilibrium. Analysis of the distribution of haplotypes using the normalized deviate of the Ewens-Watterson homozygosity statistic, F, suggests that DP haplotypes encoding the functional heterodimer are subject to much lower degrees of balancing selection than other loci within the HLA region. Finally, neighbor joining tree analyses demonstrate the power of haplotype diversity for inferring the relationships between the different populations.

Analysis of the frequencies of HLA-A, B, and C alleles and haplotypes in the five major ethnic groups of the United States reveals high levels of diversity in these loci and contrasting distribution patterns in these populations.

The HLA system is the most polymorphic of all human genetic systems. The frequency of HLA class I alleles and their linkage disequilibrium patterns differ significantly among human populations as shown in studies using serologic methods. Many DNA-defined alleles with identical serotypes may have variable frequencies in different populations. We typed HLA-A, B, and C loci at the allele level by PCR-based methods in 1,296 unrelated subjects from five major outbred groups living in the U.S.A (African, AFAM; Caucasians, CAU; Asian, ORI; Hispanic, HIS, and North American Natives, NAI). We detected 46, 100 and 32 HLA-A, B, and C alleles, respectively. ORI and HIS presented more alleles at each of these loci. There was lack of correlation between the levels of heterozygosity and the number of alleles detected in each population. In AFAM, heterozygosity (>90%) is maximized at all class I loci. HLA-A had the lowest heterozygosity in all populations but CAU. Tight LD was observed between HLA-B and C alleles. AFAM had weaker or nonexistent associations between alleles of HLA-A and B than other populations. Analysis of the genetic distances between these and other populations showed a close relationship between specific US populations and a population from their original continents. ORI exhibited the largest genetic distance with all the other U.S. groups and were closer to NAI. Evidence of admixture with CAU was observed for AFAM and HIS. HIS also had significant frequencies of AFAM and Mexican Indian alleles. Differences in both LD and heterozygosity levels suggest distinct evolutionary histories of the HLA loci in the geographical regions from where the U.S. populations originated.

HLA diversity, differentiation, and haplotype evolution in Mesoamerican Natives.

Genetic variation of the Human Leukocyte Antigen region (HLA) in three Amerindian populations from the Southern Mexican state of Oaxaca, the Zapotec, Mixtec and the Mixe is examined. Individuals were typed using PCR-SSOP for four class II loci (DRB1, DQA1, DQB1, DPB1) and three class I loci (HLA-A, -B, and -C). Based on known HLA distributions, European admixture ranged from 1% to 10%. Individuals with European alleles were excluded from subsequent analysis. New alleles were revealed at each of the class I loci. In general, genotype frequencies were in Hardy-Weinberg equilibrium, although some deviations were detected. Allele frequency distributions at the DRB1, DQA1, DQB1 and HLA-A loci in all populations were more even than expected under neutrality, supporting a model of balancing selection at these loci. A history of directional selection for DPB1 in all three populations was indicated, as homozygosity values were significantly above expected values. Allele frequency distributions at HLA-B and HLA-C did not differ significantly from neutrality expectations. The data also provide evidence from linkage disequilibrium that strong haplotypic associations are present across the entire HLA region in each of the populations. Significant overall linkage disequilibrium exists between all pairs of loci typed in these populations, except those which include the DPB1 locus. These associations exist despite the fact that the recombination fraction between HLA-A, in the class I region, and DQB1, in the class II region, may exceed 0.02. One explanation is that selective pressures are maintaining the relationships between particular alleles at these loci in these populations. These relationships are maintained in general across the entire HLA region in the Oaxacan Amerindians, with the exception of DPB1.

Hardy-Weinberg testing for HLA class II (DRB1, DQA1, DQB1, and DPB1) loci in 26 human ethnic groups.

Testing the fit of population data to Hardy-Weinberg proportions is crucial in the validation of many current approaches in population genetic studies. In this paper, we tested fit to Hardy-Weinberg proportions using exact approaches for both the overall and individual heterozygote genotype data of four HLA Class II loci: DRB1, DQA1, DQB1, and DPB1, from 26 human populations. Eighty of 99 overall tests fit the Hardy-Weinberg expectation (73% for DRB1, 89% for DQA1, 81% for DQB1 and 81% for DPB1). Deviations from Hardy-Weinberg proportions were both locus and group specific. Although we could not rule out other mechanisms at work, the individual test results indicated that the departure was possibly partly due to recent admixture. Evidence for selection and other sources of deviation are also discussed.

Natural course of the human bite wound: incidence of infection and complications in 434 bites and 803 lacerations in the same group of patients.

Human bites and common lacerations are frequent in certain residential groups in institutions for the care of developmentally disabled individuals. We screened the records of such an institution and studied the course and outcome of 434 human bite wounds and 803 lacerations in the same group of clients. Infection developed in 13.4% of the lacerations, and 17.7% of the bite wounds (chi 2 = 3.474; p greater than 0.06). Prophylactic antibiotics were administered after 14.0% of the bite wounds, and 3.2% of the lacerations. Infection supervened after prophylactic antibiotics in 29.5% of the bites and 34.6% of the lacerations. No patient with a bite wound required debridement, initial or subsequent surgical intervention other than wound closure, admission to hospital, or intravenous antibiotics. There is no recorded instance of a bite wound complication other than immediate loss of tissue. These data substantiate a higher incidence of infection in human bite wounds, but they are scant support for admonition that such wounds are indication for routine antimicrobial prophylaxis or aggressive surgical intervention.