Introduction 
transcribed: while still present, they remain si- 
lent and ineffective. 
Since it plays such a central role in regulating 
the expression of genetic information, it is not 
surprising that the study of transcription is one of 
the most active areas in modern genetic research 
(Figure 13). Investigators have taken two success- 
ful approaches in an effort to understand this pro- 
cess. One involves the study of mutations that 
disrupt regulation in a variety of organisms. The 
other is biochemical and involves isolating spe- 
cific proteins that are parts of the transcription 
machinery and then determining their mode of 
action at a molecular level. The ultimate goals of 
both approaches are to provide a complete ac- 
count, in chemical terms, of the processing of 
genetic information and to provide a sound basis 
for our understanding of the types of disturbances 
in this process that can lead to various genetic 
defects and many diseases in adult life. 
It is perhaps worth commenting on the broad 
spectrum of organisms that are currently used as 
models in genetic investigations. Yeast, worms, 
fruit flies, bacteria, viruses, mice, and human be- 
ings all provide instructive paradigms. For exam- 
ple, because the structure of the nervous system 
is relatively well understood in the primitive 
worm, Caenorhabditis elegans, it has proved to 
be particularly useful for elucidating the genetic 
program that directs the formation of the nervous 
system. The fruit fly Drosophila tnelanogaster, 
which has an uncommonly rich background of 
genetic variation, has proved to be the most valu- 
able organism for studying the genes involved in 
early embryonic development. Similarly, the 
mouse, with a generation time of just a few 
months, is a convenient stand-in for genetic ex- 
periments that cannot be contemplated in most 
mammals or human beings. Thus it has become 
an everyday technique to introduce new genes 
into the genetic makeup of mice. Many of the 
resulting animals, called transgenic mice, have 
proved to be powerful models for certain human 
diseases. Transgenic mice that are genetically 
cancer-prone or that have sickle cell anemia have 
been generated recently and are proving useful 
not only for understanding the molecular bases of 
these disorders but also for exploring possible 
means for their treatment. Complementing this 
approach has been the development of tech- 
niques that allow one to knock out specific genes 
selectively and to generate mice of essentially any 
specified genotype. The power of this new meth- 
odology (that involves homologous recombi- 
nation) for understanding mammalian develop- 
ment, for studying the function of the nervous 
system, and for modeling known human diseases 
has already captured the attention of many genet- 
icists, including several in the HHMI Genetics 
Program. At the other end of the spectrum, the 
simple baker's yeast, Saccharomyces cerevisiae, 
is proving to be especially useful for cloning 
large segments of mammalian chromosomes. Spe- 
cial carrier elements called YACs (yeast artificial 
chromosomes) have been developed that can ac- 
commodate up to 500,000 base pairs of DNA. 
Since this is more than 20 times as large as the 
fragments that have traditionally been cloned in 
bacteria and viruses, this approach and the asso- 
ciated method for separating large DNA fragments 
are beginning to play an important part in the 
international effort to map the human genome. 
The development of a complete map of the 
human genome is one of the great challenges 
engaging the attention of geneticists worldwide, 
including several HHMI investigators. Such a map 
will permit the identification of genes that are 
close to, or responsible for, a large number of as 
yet uncharacterized genetic diseases. Further- 
more, knowledge of the map will allow the devel- 
opment of easily identifiable genetic markers for 
specific diseases. These genetic markers, called 
restriction fragment length polymorphisms 
(RFLPs), can be used to detect carriers of many 
genetic disorders, to determine paternity, and to 
identify individuals for forensic purposes (a pro- 
cess commonly referred to in the press as DNA 
fingerprinting) . 
Four or five years ago an extremely sensitive 
technique for detecting these DNA marker frag- 
ments was developed. This technique (the poly- 
merase chain reaction [PGR]) greatly amplifies 
the genetic signal and has made these studies 
both simpler and faster. With this and other 
emerging technologies, the structures of the ge- 
nomes of several simple bacteria should be 
known in the near future, and the way is already 
clear to begin the systematic structural analysis of 
the genomes of a number of more complex organ- 
isms, such as the nematode worm C. elegans and 
the fruit fly Drosophila. It is confidently pre- 
dicted that with further improvements in the 
technology for sequencing genes, the complete 
structure of the human genome should be known 
within 12 or 15 years. 
While the new genetics has opened the door to 
an understanding of an important range of funda- 
mental problems such as the mechanism of ch«-o- 
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