[citation needed] Several other types were later discovered bringing the current total up to 6: Fya, Fyb, Fy3, Fy4, Fy5 and Fy6.

[citation needed] The Duffy antigen/chemokine receptor gene (gp-Fy; CD234) is located on the long arm of chromosome 1 (1.q22-1.q23) and was cloned in 1993.

The Fy-x allele is characterized by a weak anti-Fy-b reaction and appears to be the result of two separate transitions: Cytosine265Threonine (Arginine89Cysteine) and Guanine298Adenosine (Alanine100Threonine).

The Duffy negative phenotype occurs at low frequency among whites (~3.5%) and is due to a third mutation that results in an unstable protein (Arg89Cys: cytosine -> thymidine at position 265).

[16] The species examined included Pan troglodytes (chimpanzee), Macaca mulatta (rhesus monkey), Pongo pygmaeus (orangutan), Rattus norvegicus (brown rat), Mus musculus (mouse), Monodelphis domestica (opossum), Bos taurus (cow) and Canis familiaris (dog).

The mouse ortholog has been cloned and exhibits 63% homology to the human gene at the amino acid level.

[citation needed] In yellow baboons (Papio cynocephalus) mutations in this gene have been associated with protection from infection with species of the genus Hepatocystis.

Biochemical analysis of the Duffy antigen has shown that it has a high content of α-helical secondary structure - typical of chemokine receptors.

[20] Its N-glycans are mostly of the triantennary complex type terminated with α2-3- and α2-6-linked sialic acid residues with bisecting GlcNAc and α1-6-linked fucose at the core.

[21] While the Duffy antigen is expressed on bone marrow erythroblasts and circulating erythrocytes it is also found on Purkinje cells of the cerebellum,[22] endothelial cells of thyroid capillaries, the post-capillary venules of some organs including the spleen, liver and kidney[23] and the large pulmonary venules.

Alignment with other seven transmembrane G-protein-coupled receptors shows that DARC lacks the highly conserved DRY motif in the second intracellular loop of the protein that is known to be associated with G-protein signaling.

Consistent with this finding ligand binding by DARC does not induce G-protein coupled signal transduction nor a Ca2+ flux unlike other chemokine receptors.

While the function of the Duffy antigen remains presently (2006) unknown, evidence is accumulating that suggests a role in neutrophil migration from the blood into the tissues[33] and in modulating the inflammatory response.

The formation of this heterodimer impairs chemotaxis and calcium flux through CCR5, whereas internalization of CCR5 in response to ligand binding remains unchanged.

Phenotype frequencies are: While a possible role in the protection of humans from malaria had been previously suggested, this was only confirmed clinically in 1976.

This sweep appears to have occurred between 6,500 and 97,200 years ago (95% confidence interval)[13] The distribution within India has been studied in some detail.

On erythrocytes, the Duffy antigen acts as a receptor for invasion by the human malarial parasites P. vivax and P. knowlesi.

[78] The critical DARC binding residues are concentrated at the dimer interface and along a relatively flat surface spanning portions of two subdomains.

The absence of erythroid DARC alters hematopoiesis including stem and progenitor cells, which ultimately gives rise to phenotypically distinct neutrophils.

[82] Therefore, alternative physiological patterns of hematopoiesis and bone marrow cell outputs depend on the expression of DARC in the erythroid lineage.

[81][82] Failure to recognize that individuals with African ancestry often have healthy Duffy-null antigen-associated neutrophil counts instead of neutropenia has historically contributed to inequity in access to medications that require blood monitoring due to risk of neutropenia, including chemotherapy and the antipsychotic medication clozapine.

[89] In human breast cancer samples low expression of the DARC protein is significantly associated with estrogen receptor status, both lymph node and distant metastasis and poor survival.

A study of 142 black South African high-risk female sex workers over 2 years revealed a seroconversion rate of 19.0%.

[95] In the Sardinian population, an association of several variants in the DARC gene (coding and non-coding) correlates with increased serum levels of monocyte chemoattractant protein (MCP -1).

A new variant in this population, consisting of the amino acid substitution of arginine for a cysteine at position 89 of the protein diminishes the ability to bind chemokines.

[96] DARC has also been linked to rheumatoid arthritis (RA), possibly displaying chemokines such as CXCL5 on the surface of endothelial cells within the synovium, increasing the recruitment of neutrophils in the disease state.

[98] An increased incidence of Duffy antigen has been reported in patients with multiple myeloma compared with healthy controls.

Its expression is increased in the vascular beds and alveolar septa of the lung parenchyma during suppurative pneumonia.

However, the contribution of DARC to this increased risk has been tested in Jamaican males of black African descent.

Anti-Fya is a common antibody while anti-Fyb is approximately 20 times less common.,[106][107] They are reactive at body temperature and are therefore clinically significant, although they do not typically bind complement.