The Third Human Homolog of a Murine Gene Encoding an Inhibitor of Stem Cell Proliferation Is Truncated and Linked to a CpG Island-Containing Upstream Sequence

Abstract

The murine gene, MIP1 alpha, encodes a cytokine (macrophage inflammatory protein 1 alpha) that inhibits the proliferation of bone marrow stem cells. Two human homologs have been characterized, G0S19-1 and G0S19-2. Like MIP1 alpha, these genes contain three exons, the first of which encodes a hydrophobic signal sequence. The existence of a third human G0S19 gene, present in one in four individuals, has been predicted from restriction enzyme analyses. This paper reports that a previously identified human genomic clone containing a G0S19 sequence (G0S19-3), corresponds to the third gene. However, the first G0S19 exon is missing. The sequence differs from those of G0S19-1 and G0S19-2 upstream of a point 31 nucleotides from the junction of the first intron with the second exon. This upstream sequence contains a CpG island and is named "CpG island-containing upstream sequence," CUS. Apart from the G0S19-3-associated copy found only in individuals with the third G0S19 gene, all individuals have one DNA species hybridizing strongly to a CUS-specific probe and at least two less strongly hybridizing species. The CUS has potential binding sites for transcription factors AP-1, AP-2, AP-3, AP-4, and Sp1, a Donehower conserved repetitive element, and motifs characteristic of cytokine, oncogene, and retroviral promoters. Thus, the CUS might promote the transcription of sequences with which it became associated. We suggest that the CUS-G0S19-3 sequence was generated by recombination between a G0S19-2 gene and a member of a novel CUS-associated gene family.