Genotype, Serotype and Supertype Classification

Table of genotypes, serotypes and supertypes

Find below a table (Table 1) showing the currently available human leucocyte antigen (HLA) class I and II serotypes and genotypes, as well as the HLA class I supertypes that have been defined.

Alleles, chromosomes and genotypes

An individual's genotype for a gene is the set of alleles, which the gene contains. In a diploid organism, one that has two copies of each chromosome, two alleles make up the individual's genotype. An allele is the specification of a gene that is located at a particular position (locus) on a chromosome. Put differently, the two copies of the gene in diploid organisms are the alleles. The fact that, in diploid organisms, a gene exists in two copies makes for possible variations in phenotype, the expressed characteristics (e.g. blue or brown eyes). An organism in which the two copies of the gene are identical, i.e. have the same allele, is called homozygous for that gene. An organism, which has two different alleles of the gene, is called heterozygous.

How serotypes are defined

HLA genes that encode immune-associated glycoproteins are located on chromosome 6p21. HLA class I and II genes are known to be highly polymorphic, i.e. they exist in many different forms among humans. HLA class I and II genes are individually found at HLA-A, -B and -C and well as HLA-DR, -DQ and -DP loci. The initial discovery of HLA gene products was made in the late 1960s by observing that serum samples from transplanted patients exhibit reactivities against lymphoid cells of other subjects. The actual definition of HLA serotypes was established through a series of refined analyses of these earlier results in combination with the use of antiserum panels that exhibit greater specificities against HLA molecules. This method requires to have the right antibodies to the HLA proteins. Sero means antibody here. Therefore, a HLA serotype is the HLA protein (expressed from the respective HLA gene) that is detected by the respective antibody which is available. Because antibodies to HLA class I or II proteins do not exist in similar versatile numbers and/or are not detected easily, the number of HLA serotypes is less than the number of associated genotypes.

At the moment, antibodies to many HLA class I proteins are reliable, i.e. they are specific for particular HLA class I proteins. Reliable antibodies to HLA class II proteins are not easily available, but most HLA class II genes are also defined as serotypes today (see Table 1 below). Despite the advances in defining HLA serotypes, a given HLA serotype represents only a rough collection of proteins expressed by the respective HLA gene. In addition, some serotypes still exhibit cross-reactivity towards other serotypes. Such examples are found among HLA-A9, -23 and -24.

Genotyping DNA sequences

Due to the uniqueness of individual DNA sequences, probes and primers complementary to HLA genes have been used for genotyping of both HLA class I and II genes. The Sequence Specific Oligonucleotide Probes (SSOP) method has been used for genotyping of HLA-class II genes and for finding alleles that exist in HLA class I serotypes. On this basis, many of the sequences of the HLA class I and II locus were found to consist of multiple families of alleles, which have been grouped e.g. into the HLA-A2 family. Within HLA-A2, there are at least 25 genotypes, i.e. at least 25 HLA class I (A2) genes are different. So, a HLA class I or II genotype is one particular HLA form defined by its DNA sequence.

What are supertypes?

The principle function of HLA class I and II molecules are to present antigenic peptides derived from intracellular processing of native proteins to CD8+ and CD4+ lymphocytes. Binding patterns obtained from studies of individual HLA class I molecules have revealed that some of them within a given allele family share binding specificities towards the same panel of peptides. This property is reflected by some common structural features of the peptide-binding grooves of these HLA class I molecules, which accommodate these peptides. The collection of HLA class I molecules that exhibit this property is designated as a supertype. Under this structural classification, a few HLA class I supertypes are defined for the numerous allele family that are now known to exist.

References

The composition of serotype equivalents is due to Schreuder GM, Hurley CK, Marsh SG, et al. HLA dictionary 2004: summary of HLA-A, -B, -C, -DRB1/3/4/5, -DQB1 alleles and their association with serologically defined HLA-A, -B, -C, -DR, and -DQ antigens. Hum Immunol 2005. 66(2):170-210. The supertype classification is from Sette A, Sidney J. Nine major HLA Class I supertypes account for the vast preponderance of HLA-A and -B polymorphism. Immunogenetics 1999. 50(3-4):201-212.