Genome scan identifies a locus affecting gamma-globin level in human beta-cluster YAC transgenic mice

Abstract.

Genetic factors affecting postnatal γ-globin expression—a major modifier of the severity of both β-thalassemia and sickle cell anemia—have been difficult to study. This is especially so in mice, an organism lacking a globin gene with an expression pattern equivalent to that of human γ-globin. To model the human β-cluster in mice, with the goal of screening for loci affecting human γ-globin expression in vivo, we introduced a human β-globin cluster YAC transgene into the genome of FVB/N mice. The β-cluster contained a Greek hereditary persistence of fetal hemoglobin (HPFH) γ allele, resulting in postnatal expression of human γ-globin in transgenic mice. The level of human γ-globin for various F₁ hybrids derived from crosses between the FVB/N transgenics and other inbred mouse strains was assessed. The γ-globin level of the (C3HeB/FeJ × FVB/N)F₁ transgenic mice was noted to be significantly elevated. To map genes affecting postnatal γ-globin expression, we performed a 20-centiMorgan (cM) genome scan of a (C3HeB/FeJ × FVB/N)F₁ transgenics × FVB/N backcross, followed by high-resolution marker analysis of promising loci. From this analysis we mapped a locus within an 18-cM interval of mouse Chromosome (Chr) 1 (LOD = 4.3) that contributes 10.9% of variation in γ-globin level. Combining transgenic modeling of the human β-globin gene cluster with quantitative trait analysis, we have identified and mapped a murine locus that impacts on human γ-globin level in vivo.