Mutation in p300 causes suppression of Mpl^−/− thrombocytopenia. (A) To map the chromosomal location of Plt6, a (C57BL/6 × 129/Sv)F₂ cohort was bled and phenotypically categorized as having platelet counts typical of unmutated Mpl^−/−, Plt6/+, or Plt6/Plt6 mice and then genotyped using simple sequence length polymorphisms (SSLPs) spaced evenly throughout the genome. Markers found to be homozygous 129/Sv are shown in white; heterozygous, in gray; and homozygous C57BL/6, in black. The number of animals with each haplotype is shown below. Plt6 was localized between D15AahA10 and D15AahA3. (B) Sequence of PCR-amplified genomic DNA from representative Plt6/Plt6, Plt6/+, and wild-type mice showing a T to A mutation in exon 10 of Plt6 mice resulting in a Tyr to Asn substitution at amino acid 630. (C) Model of the p300 KIX domain indicating the Plt6 mutation site (red) and potentially disrupted contacts (blue), as well as residues previously mutated⁶  in mice (Y631, A635, and Y639; green). Modeled using FUGUE⁹  by homology with pdb file, 1KDX, the solution structure of mouse CREB-binding protein KIX domain.