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

Genetic factors affecting postnatal gamma -globin expression-a major modifi er of the severity of both beta -thalassemia and sickle cell anemia-have be en difficult to study. This is especially so in mice, an organism lacking a globin gene with an expression pattern equivalent to that of human gamma - globin. To model the human beta -cluster in mice, with the goal of screenin g for loci affecting human gamma -globin expression in vivo, we introduced a human beta -globin cluster YAC transgene into the genome of FVB/N mice. T he beta -cluster contained a Greek hereditary persistence of fetal hemoglob in (HPFH) gamma allele, resulting in postnatal expression of human gamma -g lobin in transgenic mice. The level of human gamma -globin for various F-1 hybrids derived from crosses between the FVB/N transgenics and other inbred mouse strains was assessed. The gamma -globin level of the (C3HeB/FeJ x FV B/N)F-1 transgenic mice was noted to be significantly elevated. To map gene s affecting postnatal gamma -globin expression, we performed a 20-centiMorg an (cM) genome scan of a (C3HeB/FeJ x FVB/N)F-1 transgenics x FVB/N back-cr oss, followed by high-resolution marker analysis of promising loci. From th is 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 gamma -globin le vel. Combining transgenic modeling of the human beta -globin gene cluster w ith quantitative trait analysis, we have identified and mapped a murine loc us that impacts on human gamma -globin level in vivo.