the receptor's peptide-binding cleft tend to produce molecules with different binding capability. however, the gene frequencies of the most common alleles (>5%) of hla-a, -b, -c and hla-dpa1, -dpb1, -dqa1, -dqb1, and -drb1 from south america have been reported from the typing and sequencing carried out in genetic diversity studies and cases and controls. in addition, information on the allele frequencies of hla-i and hla-ii genes for the european population has been compiled. in both cases the distribution of allele frequencies reveals a regional variation related with the history of the populations. tables of variant alleles number of variant alleles at class i loci according to the imgt-hla database, last updated october 2018: mhc class i locus # major antigens hla a 4,340 hla b 5,212 hla c 3,930 minor antigens hla e 27 hla f 31 hla g 61 number of variant alleles at class ii loci (dm, do, dp, dq, and dr): mhc class ii hla -a1 -b1 -b3 to -b51 theor. possible locus ### combinations dm- 713 91 do- 1213 156 dp- 671,014 16,036 dq- 951,257 34,528 dr- 72,593312 11,431 1drb3, drb4, drb5 have variable presence in humans sequence feature variant type (sfvt) the large extent of variability in hla genes poses significant challenges in investigating the role of hla genetic variations in diseases. disease association studies typically treat each hla allele as a single complete unit, which does not illuminate the parts of the molecule associated with disease. karp d. r. et al. describes a novel sequence feature variant type (sfvt) approach for hla genetic analysis that categorizes hla proteins into biologically relevant smaller sequence features (sfs), and their variant types (vts). sequence features are combinations of amino acid sites defined based on structural information (e.g., beta-sheet 1), functional information (e.g., peptide antigen-binding), and polymorphism. these sequence features can be overlapping and continuous or discontinuous in the linear sequence. variant types for each sequence feature are defined based upon all known polymorphisms in the hla locus being described. sfvt categorization of hla is applied in genetic association analysis so that the effects and roles of the epitopes shared by several hla alleles can be identified. sequence features and their variant types have been described for all classical hla proteins; the international repository of hla sfvts will be maintained at imgt/hla database. a tool to convert hla alleles into their component sfvts can be found on the immunology database and analysis portal (immport) website. common, well-documented and rare alleles although the number of individual hla alleles that have been identified is large, approximately 40% of these alleles appear to be unique, having only been identified in single individuals. roughly a third of alleles have been reported more than three times in unrelated individuals. because of this variation in the rate at which of individual hla alleles are detected, attempts have been made to categorize alleles at each expressed hla locus in terms of their prevalence. the result is a catalog of common and well-documented (cwd) hla alleles, and a catalogue of rare and very rare hla alleles. common hla alleles are defined as having been observed with a frequency of at least 0.001 in reference populations of at least 1500 individuals. well-documented hla alleles were originally defined as having been reported at least three times in unrelated individuals, and are now defined as having been detected at least five times in unrelated individuals via the application of a sequence-based typing (sbt) method, or at least three times via a sbt method and in a specific haplotype in unrelated individuals. rare alleles are defined as those that have been reported one to four times, and very rare alleles as those reported only once. table of hla alleles in each prevalence category while the current cwd and rare or very rare designations were developed using different datasets and different versions of the imgt/hla database, the approximate fraction of alleles at each hla locus in each category is shown below. hlalocusno. commonalleles % commonallelesno. well-documentedalleles % well-documentedallelesno. rarealleles % rareallelesno. very rarealleles % very rarealleles % allelescategorized a683.4%1788.8%14521.5%28041.6%~75% b1254.8%2429.3%19017.6%46843.5%~75% c442.8%1026.6%7721.4%15442.8%~74% drb1796.8%14712.7%13322.7%20635.2%~77% drb358.6%712.1%~21% drb4640.0%213.3%~53% drb5525.0%315.0%~40% dqa11531.9%48.5%926.5%720.6%~88% dqb12212.5%84.5%2628.9%4245.2%~91% dpa1617.6%00.0%414.8%1555.6%~88% dpb14028.8%149.0%2922.7%2932.8%~90% all loci4155.3%7079.0%61320.6%121440.8%~76% serotype and allele names there are two parallel systems of nomenclature that are applied to hla. the first, and oldest, system is based on serological (antibody based) recognition. in this system, antigens were eventually assigned letters and numbers (e.g., hla-b27 or, shortened, b27). a parallel system that allowed more refined definition of alleles was developed. in this system, an "hla" is used in conjunction with a letter, *, and a four-or-more-digit number (e.g., hla-b*08:01, a*68:01, a*24:02:01n n=null) to designate a specific allele at a given hla locus. hla loci can be further classified into mhc class i and mhc class ii (or rarely, d locus). every two years, a nomenclature is put forth to aid researchers in interpreting serotypes to alleles. serotyping further information: serotype in order to create a typing reagent, blood from animals or humans would be taken, the blood cells allowed to separate from the serum, and the serum diluted to its optimal sensitivity and used to type cells from other individuals or animals. thus, serotyping became a way of crudely identifying hla receptors and receptor isoforms. over the years, serotyping antibodies became more refined as techniques for increasing sensitivity improved and new serotyping antibodies continue to appear. one of the goals of serotype analysis is to fill gaps in the analysis. it is possible to predict based on 'square root','maximum-likelihood' method, or analysis of familial haplotypes to account for adequately typed alleles. these studies using serotyping techniques frequently revealed, in particular for non-european or north east asian populations many null or blank serotypes. this was particularly problematic for the cw locus until recently, and almost half of the cw serotypes went untyped in the 1991 survey of the human population. there are several types of serotypes. a broad antigen serotype is a crude measure of identity of cells. for example, hla a9 serotype recognizes cells of a23- and a24-bearing individuals. it may also recognize cells that a23 and a24 miss because of small variations. a23 and a24 are split antigens, but antibodies specific to either are typically used more often than antibodies to broad antigens. cellular typing a representative cellular assay is the mixed lymphocyte culture (mlc) and used to determine the hla class ii types. the cellular assay is more sensitive in detecting hla differences than serotyping. this is because minor differences unrecognized by alloantisera can stimulate t cells. this typing is designated as dw types. serotyped dr1 has cellularly defined as either of dw1 or of dw20 and so on for other serotyped drs. table shows associated cellular specificities for dr alleles. however, cellular typing has inconsistency in the reaction between cellular-type individuals, sometimes resulting differently from predicted. together with difficulty of cellular assay in generating and maintaining cellular typing reagents, cellular assay is being replaced by dna-based typing method. gene sequencing minor reactions to subregions that show similarity to other types can be observed to the gene products of alleles of a serotype group. the sequence of the antigens determines the antibody reactivities, and so having a good sequencing capability (or sequence-based typing) obviates the need for serological reactions. therefore, different serotype reactions may indicate the need to sequence a person's hla to determine a new gene sequence. broad antigen types are still useful, such as typing very diverse populations with many unidentified hla alleles (africa, arabia, southeastern iran and pakistan, india). africa, southern iran, and arabia show the difficulty in typing areas that were settled earlier. allelic diversity makes it necessary to use broad antigen typing followed by gene sequencing because there is an increased risk of misidentifying by serotyping techniques. in the end, a workshop, based on sequence, decides which new allele goes into which serogroup either by sequence or by reactivity. once the sequence is verified, it is assigned a number. for example, a new allele of b44 may get a serotype (i.e. b44) and allele id i.e. b*44:65, as it is the 65th b44 allele discovered. marsh et al. (2005) can be considered a code book for hla serotypes and genotypes, and a new book biannually with monthly updates in tissue antigens. phenotyping gene typing is different from gene sequencing and serotyping. with this strategy, pcr primers specific to a variant region of dna are used (called sequence-specific primers). if a product of the right size is found, the assumption is that the hla allele has been identified. new gene sequences often result in an increasing appearance of ambiguity. because gene typing is based on ssp-pcr, it is possible that new variants, in particular in the class i and drb1 loci, may be missed. for example, ssp-pcr within the clinical situation is often used for identifying hla phenotypes. an example of an extended phenotype for a person might be: a*01:01/*03:01, c*07:01/*07:02, b*07:02/*08:01, drb1*03:01/*15:01, dqa1*05:01/*01:02, dqb1*02:01/*06:02 in general, this is identical to the extended serotype: a1,a3,b7,b8,dr3,dr15(2), dq2,dq6(1) for many populations, such as the japanese or european populations, so many patients have been typed that new alleles are relatively rare, and thus ssp-pcr is more than adequate for allele resolution. haplotypes can be obtained by typing family members in areas of the world where ssp-pcr is unable to recognize alleles and typing requires the sequencing of new alleles. areas of the world where ssp-pcr or serotyping may be inadequate include central africa, eastern africa, parts of southern africa, arabia, s. iran, pakistan, and india. haplotypes an hla haplotype is a series of hla "genes" (loci-alleles) by chromosome, one passed from the mother and one from the father. the phenotype exampled above is one of the more common in ireland and is the result of two common genetic haplotypes: a*01:01 ; c*07:01 ; b*08:01 ; drb1*03:01 ; dqa1*05:01 ; dqb1*02:01 (by serotyping a1-cw7-b8-dr3-dq2) which is called ' 'super b8' ' or ' 'ancestral haplotype' ' and a*03:01 ; c*07:02 ; b*07:02 ; drb1*15:01 ; dqa1*01:02 ; dqb1*06:02 (by serotyping a3-cw7-b7-dr15-dq6 or the older version "a3-b7-dr2-dq1") these haplotypes can be used to trace migrations in the human population because they are often much like a fingerprint of an event that has occurred in evolution. the super-b8 haplotype is enriched in the western irish, declines along gradients away from that region, and is found only in areas of the world where western europeans have migrated. the "a3-b7-dr2-dq1" is more widely spread, from eastern asia to iberia. the super-b8 haplotype is associated with a number of diet-associated autoimmune diseases. there are 100,000s of extended haplotypes, but only a few show a visible and nodal character in the human population. role of allelic variation studies of humans and animals imply a heterozygous selection mechanism operating on these loci as an explanation for this variability. one proposed mechanism is sexual selection in which females are able to detect males with different hla relative to their own type. while the dq and dp encoding loci have fewer alleles, combinations of a1:b1 can produce a theoretical potential of 7,755 dq and 5,270 dp αβ heterodimers, respectively. while nowhere near this number of isoforms exist in the human population, each individual can carry 4 variable dq and dp isoforms, increasing the potential number of antigens that these receptors can present to the immune system. studies of the variable positions of dp, dr, and dq reveal that peptide antigen contact residues on class ii molecules are most frequently the site of variation in the protein primary structure. therefore, through a combination of intense allelic variation and/or subunit pairing, the class ii peptide receptors are capable of binding an almost endless variation of peptides of 9 amino acids or longer in length, protecting interbreeding subpopulations from nascent or epidemic diseases. individuals in a population frequently have different haplotypes, and this results in many combinations, even in small groups. this diversity enhances the survival of such groups, and thwarts evolution of epitopes in pathogens, which would otherwise be able to be shielded from the immune system. antibodies hla antibodies are typically not naturally occurring, and with few exceptions are formed as a result of an immunologic challenge to a foreign material containing non-self hlas via blood transfusion, pregnancy (paternally inherited antigens), or organ or tissue transplant. antibodies against disease-associated hla haplotypes