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 modifier of the severity of both beta-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 gamma-globin. To model the human beta-cluster in mice, with the goal of screening 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. The beta-cluster contained a Greek hereditary persistence of fetal hemoglobin (HPFH) gamma allele, resulting in postnatal expression of human gamma-globin in transgenic mice. The level of human gamma-globin for various F1 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 FVB/N)F1 transgenic mice was noted to be significantly elevated. To map genes affecting postnatal y-globin expression, we performed a 20-centiMorgan (cM) genome scan of a (C3HeB/FeJ x FVB/N)F1 transgenics x 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 gamma-globin level. Combining transgenic modeling of the human beta-globin gene cluster with quantitative trait analysis, we have identified and mapped a murine locus that impacts on human gamma-globin level in vivo.
Lin
S D
SD
Genome Science Department, Lawrence Berkeley National Laboratory, California 94720, USA.
Cooper
P
P
Fung
J
J
Weier
H U
HU
Rubin
E M
EM
D000818:Animals; D000831:Animals, Newborn; D002874:Chromosome Mapping; D018244:Chromosomes, Artificial, Yeast; D002878:Chromosomes, Human, Pair 1; D005319:Fetal Hemoglobin / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D023281:Genomics / Q000379:methods*; D006801:Humans; D008126:Lod Score; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic / Q000235:genetics*; D005719:gamma-Globulins / Q000235:genetics*
D005719:gamma-Globulins; D005319:Fetal Hemoglobin