Tracking Genes That Cause Human Disease 
and yeast artificial chromosome cloning from 
probes known to map to this interval, we have 
nearly completed an overlapping set of clones of 
the region and are beginning to search for candi- 
date genes. 
A final project is an investigation of the switch 
in production from fetal to adult hemoglobin in 
the human. In this precisely controlled phenome- 
non, fetal hemoglobin genes turn off and adult 
hemoglobin genes turn on at about the time of 
birth. This phenomenon is important for two rea- 
sons. First, it is a model for developmental con- 
trol of gene expression. Second, turning the fetal 
genes back on in an adult with sickle cell anemia 
or thalassemia would be likely to cure these 
blood diseases, which afflict hundreds of thou- 
sands of persons worldwide. 
In attempting to understand this complex pro- 
cess, we have identified a series of mutations in 
the fetal hemoglobin genes responsible for fail- 
ure to turn these genes off completely during 
adult life, which leads to a benign condition 
called hereditary persistence of fetal hemoglobin 
(HPFH). These mutations mark DNA sequences 
important in the developmental switch. We are 
characterizing proteins from the nucleus that 
bind to these sequences and control the expres- 
sion of the hemoglobin genes. 
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