Retroviral Replication and Human Gene Mapping 
now readily study the catalytic activities, which 
include the sequence-specific processing of the 
viral DNA ends and the joining of these ends to a 
target DNA molecule. 
Studies are under way to define the structure of 
the integrase proteins, the molecular mechanism 
by which they carry out their catalytic functions, 
and the means by which they recognize and bind 
their two distinct classes of DNA substrates. The 
ease with which genetic manipulations of inte- 
grase can be accomplished in the bacterial ex- 
pression system will enable us to carry out a ge- 
netic dissection of the many activities of the HIV 
and MLV integrases. Moreover, this system should 
facilitate our efforts to develop genetically al- 
tered integrases with properties more favorable 
for therapeutic applications. For example, we 
would like to develop an integrase that can selec- 
tively integrate the viral DNA into predetermined 
sites in the target DNA. 
The ultimate goal of our work on integration is 
to understand in molecular detail how the pro- 
teins of the integration machinery recognize the 
viral DNA, form an active complex, recognize the 
target DNA, and finally catalyze the DNA breakage 
and joining reactions that lead to integration of 
the provirus. It is hoped that this understanding 
will lead to the development of new agents for 
inhibiting the replication of pathogenic retrovi- 
ruses, and to improved systems for the therapeu- 
tic introduction of genes into mammalian cells. 
New Methods for Linkage Mapping in 
Complex Genomes 
A major impediment to defining and character- 
izing the genes that influence complex human 
traits has been the difficulty of collecting suitable 
large families in which the trait segregates. Such 
families are generally needed to find the genes by 
conventional linkage mapping. The same genes 
could in principle be mapped by an alternative 
strategy that involves collecting and analyzing 
pairs of relatives that share a trait of interest. In 
the case of rare recessive traits, just a few affected 
inbred individuals could suffice, and such small 
sets of affected relatives are generally easier to 
collect than large pedigrees. However, linkage 
mapping with small sets of relatives generally re- 
quires analysis of a large number of closely 
spaced, highly polymorphic genetic markers, 
which makes this strategy impractical with 
current technology. 
We are developing a new set of genetic tools 
that should facilitate widespread application of 
these highly efficient linkage mapping methods. 
Experiments are in progress to test our new map- 
ping procedure, using as test systems the nema- 
tode Caenorhabditis elegans and some well- 
characterized human families. We hope to be 
able soon to apply this technology to map genes 
for a number of complex human traits that have 
resisted conventional approaches. 
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