In other species: crab-eating macaque , Japanese macaque , Rhesus monkey , olive baboon , agile gibbon , common gibbon , siamang , chimpanzee

Categories: Haematopoietic system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 110300 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: no

Key variant known: yes

Year key variant first reported: 2001

Cross-species summary: Each blood group system consists of a set of blood types, each of which corresponds to a particular antigen (usually a glycoprotein) on the surface of red blood cells. The different types within a system are the result of the action of different alleles at a locus that usually encodes an enzyme that catalyses the creation of the feature of the glycoprotein unique to that type, e.g. the presence of a particular sugar at the end of a short chain of sugars. The ABO blood group system arises from two alleles at a locus that encodes a glycosyltransferase: the A allele encodes alpha 1-3-N-acetylgalactosaminyltransferase; and the B allele encodes alpha 1-3-galactosyltransferase. The B allele transferase catalyses the addition of galactose to a chain of four sugars attached to a protein known as H antigen. The A allele ltransferase catalyses the addition of a derivative of galactose called N-acetylgalactosamine to the same short chain of sugars. The third allele at this locus (the O allele) results in no sugar being added to the chain.

Species-specific description: Pigs have just two alleles at this locus, namely A and O (Yamamoto and Yamamoto, 2001). The A antigen is known as the major xenotransplantation antigen or major xenoantigen. Galactose-alpha-1,3-galactose is the cause of rare allergic reaction to red meat consumption. Variants of this trait have been created artificially: Genetically-modifed organism; GMO.

History: Sprague (1958) was among the first to suggest that pigs may have an ABO-like blood group system (on the basis of the reaction of pig red blood cells to typing sera from cattle). His observations were confirmed by Andresen (1962) and Saison and Imgram (1962).

Molecular basis: By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Yamamoto and Yamamoto (2001) showed that the A allele corresponds to a functional GGTA1 gene, whereas the O allele includes a major deletion of this gene. Nguyen et al. (2011) provided more detail on this deletion: "the 0 allele has a large deletion between exon 7 of the A0 blood group gene and the neighbouring SURF6". Using transcription activator-like effector nucleases (TALENs) to generate GGTA1 knockout fibroblast cell lines, which were then used in somatic cell nuclear transfer, Xin et al. (2013) generated pigs with no effective GGTA1 genes, which "can provide a new organ source for xenotransplantation research". Kan et al. (2016) achieved a similar result with the same technology; Petersen et al. (2016) achieved a similar results with CRISPR/Cas9 technology.

Genetic engineering: Yes - in addition to the occurrence of natural variants, variants have been created artificially, e.g. by genetic engineering or gene editing
Have human generated variants been created, e.g. through genetic engineering and gene editing

Clinical features: The clinical importance of porcine AO antigens relates to the use of pig tissue and organs in transplantation to humans (xenotransplantation): the major cell-surface antigen causing rejection in porcine-human xenotransplantation is the A antigen produced by the enzyme encoded by this locus, i.e. by the enzyme alpha1-3 N-acetyl-D-galactosaminyltransferase (known as "gal transferase [GT]"), encoded by GGTA1. Consequently, as soon as gene knockout and animal cloning technology became available (i.e. in vitro gene knockout, followed by somatic cell nuclear transfer to produce cloned animals), clones of gal-transferase knockout (GTKO) pigs were produced for use as donors in xenotransplantation. The first GTKO pigs were produced by Lai et al. (2002). Furthermore, galactose-alpha-1,3-galactose ("alpha-gal") on the muscle cell surface in pigs, sheep and cattle may induce allergies (alpha-gal syndrome) in humans consuming red meat (Commins et al., 2016). GGTA1 knock out pigs have been approved by the FDA as GalSafe pigs for pork consumption (https://www.fda.gov/news-events/press-announcements/fda-approves-first-its-kind-intentional-genomic-alteration-line-domestic-pigs-both-human-food).

Associated gene: