Genetics and Genomics
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 gene was first localised to chromosome 1 in 1968 and was the first blood system antigen to be localised. It is a single copy gene spanning over 1500 bases and is in two exons. It encodes a 336 amino acid acidic glycoprotein. The gene carries the antigenic determinants of the Duffy blood group system which consist of four codominant alleles—FY*A and FY*B—coding for the Fy-a and Fy-b antigens respectively, FY*X and FY*Fy, five phenotypes (Fy-a, Fy-b, Fy-o, Fy-x and Fy-y) and five antigens. Fy-x is a form of Fy-b where the Fy-b gene is poorly expressed. Fy-x is also known as Fy-bweak or Fy-bWk.
Fy-a and Fy-b differ by in a single amino acid at position 42: glycine in Fy-a and aspartic acid in Fy-b (guanine in Fy-a and adenosine in Fy-b at position 125). A second mutation causing a Duffy negative phenotype is known: the responsible mutation is G -> A at position 298. The genetic basis for the Fy(a-b-) phenotype is a point mutation in the erythroid specific promoter (a T -> C mutation at position -33 in the GATA box). This mutation occurs in the Fy-b allelle and has been designated Fy-bEs (erythroid silent). Two isotypes have been identified. The Fy-x allelle is characterized by a weak anti-Fy-b reaction and appears to be the result of two separate transitions: Cytosine265Threonine (Arginine89Cysteine) and Guanine298Adenosine (Alanine100Threonine). A third mutation (a transversion) in this gene has also been described - G145T (Alanine49Serine) - that has been associated with the Fy-x phenotype.
Most Duffy negative blacks carry a silent Fy-b allele with a single T to C substitution at nucleotide -46, impairing the promoter activity in erythroid cells by disrupting a binding site for the GATA1 erythroid transcription factor. The gene is still transcribed in non erythroid cells in the presence of this mutation.
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).
The silent allele has evolved at least twice in the black population of Africa and evidence for selection for this allele has been found. The selection pressure involved here appears to be more complex than many text books might suggest. An independent evolution of this phenotype occurred in Papua New Guinea has also been documented.
A comparative study of this gene in seven mammalian species revealed significant differences between species. 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).
Three exons are present in humans and chimpanzees while only two exons occur in the other species. This additional exon is located at the 5' end and is entirely non coding. Both intron and exon size vary considerably between the species examined. Between the chimpanzee and the human 24 differences in the nucleotide sequence were noted. Of these 18 occurred in non coding regions. Of the remaining 6, 3 were synonymous and 3 non synonymous mutations. The significance of these mutations if any is not known.
The mouse ortholog has been cloned and exhibits 63% homology to the human gene at the amino acid level. The mouse gene is located on chromosome 1 between the genetic markers Xmv41 and D1Mit166. The mouse gene has two exons (100 and 1064 nucleotides in length respectively), separated by a 461 base pair intron. In the mouse DARC is expressed during embryonic development between days 9.5 and 12.
In yellow baboons (Papio cynocephalus) mutations in this gene have been associated with protection from infection with species of the genus Hepatocystis.
The ancestral form of extant DARC alleles in humans appears to be the FY*B allele.
The gene appears to be under strong purifying selection. The cause of this selective pressure has not yet been identified.
Read more about this topic: Duffy Antigen System