Complex patterns of intragenic polymorphism at the PDGFA locus

The human platelet-derived growth factor A chain gene (PDGFA) on chromosome 7p22 encodes an important mitogen. Within PDGFA lies a complex minisatelli te structure that results in partial duplications of exon 4 and the IVS4 sp lice donor site. Here, we show that the PDGFA genes of four ape species and an Old-World monkey all have similar complex minisatellites at this positi on. Comparison of their structures suggests evolutionary constraints result ing from the protein-coding function of the minisatellite. Nonetheless, the IVS4 minisatellite seems to have undergone independent expansion events in different primate lineages. Within the human IVS4 minisatellite, an embedd ed pentanucleotide repeat, based on the sequence (CCTCC)(n), shows frequent subunit sequence variation but only rare length polymorphism. In contrast, within IVS3 of human PDGFA, we have discovered a second minisatellite whic h, unlike the IVS4 minisatellite, is highly polymorphic. The subunit sequen ces of these two minisatellites, which lie less than 0.5 kb apart, are non- identical, but share a CnT-rich core. Two new single nucleotide polymorphis ms (SNPs), in exon 3 and IVS4, are in linkage disequilibrium, despite flank ing the two minisatellite regions. Reverse transcription-polymerase chain r eaction analysis of the exon 3 SNP in human foetal tissues demonstrated bia llelic expression of PDGFA in all tissues examined. The unusual location of PDGFA exon 3 between two minisatellite sequences, together with its partia l duplication, may have functional implications, particularly for the splic ing of the gene. The high level of polymorphism demonstrated in this region will also be valuable for disease-association and linkage studies of the P DGFA locus.