Department of Genetics, Case Western Reserve University School of Medicine and Center for Human Genetics, University Hospitals of Cleveland, Cleveland, Ohio 44106, USA. jhn4@po.cwru.edu
At the forefront of the Genomics Revolution are seven model organisms:
viruses, bacteria, fungi, Arabidopsis thaliana, Caenorhabditis elegans
, Drosophila melanogaster and the laboratory mouse. Recent advances,
now crowned by a study presented by Takeshi Watanabe, Michael James and colleagues on page 27 of this issue, suggest that the rat should
now be admitted to this Genome 7 (G7) community.
With respect to incentives, characteristics and goals, the Genomics Revolution
shares striking and instructive parallels with the Industrial Revolution.
Beginning in England and then spreading to many other countries, the Industrial
Revolution inevitably and irreversibly changed societies. Cottage and agricultural
communities were converted to urban industrial societies. Factories that manufactured
commodities for global markets largely replaced simple machines and handwork
that generated goods in homes and shops for local sales. International financiers
emerged to provide capital to build factories, purchase raw materials, pay
labour and distribute goods. Transportation by water, rail and road moved
raw materials and manufactured goods. Laws were periodically passed and repealed
to limit production and protect industries. The Revolution was not based on
science, invention or capital individually, but rather on the combination
of these forces. Luddites opposed these technological and cultural changes,
but failed to stop the Industrial Revolution.
Genomics is revolutionizing biomedical research in similar ways. Where
genetics research was once a cottage enterprise initiated and managed by individual
scientists, genome centres, like factories, have brought together resources,
technologies, information and a highly skilled workforce in an integrated,
high-throughput manner. Where genes were once individually mapped, cloned
and sequenced, and then described in separate research papers, sequence data
are now deposited wholesale into public databases. Where protein expression
patterns and functions were once studied individually, gene expression patterns
and protein functions are now being surveyed and reported on a genomic scale.
Funding agencies work closely with genome centres to accomplish shared goals.
Electronic networks transmit the main commodity of genomics research—information.
Intellectual property considerations and material transfer agreements are
commonplace. Finally, opponents view the Genomics Revolution as a threat to
traditional research.
To join the revolution, model species must develop their own reagent and
information resources. Although the genomic resources of the rat have been
steadily accumulating2,
3,
4,
5,
6,
7, the data provided by
Watanabe et al. represent a significant landmark, with the most comprehensive
physical (radiation hybrid) map and comparative map of the rat genome yet
reported. The authors report 3,019 new microsatellite (CAn dinucleotide
repeats) markers that can be typed with PCR assays and used to build genetic
and physical maps and sequences that will serve as navigation beacons in genomic
sequencing.
The centrepiece of their study is a radiation hybrid (RH) map, a map derived
from data obtained from irradiated cells containing fragments of rat chromosomes.
Each cell line contains a unique combination of these fragments. By typing
the genetic markers in a panel of these cell lines, the relative location
of markers can be determined by noting the correlated occurrence of markers—which
reflects their close physical proximity on the same DNA fragment. The advantage
of the RH approach is the level of resolution; RH maps stand at the interface
between the genetic map and the more detailed physical maps under development.
Watanabe et al. also make a significant contribution to comparative
maps. These indicate the location of homologous genes in different species
and provide a powerful means of transferring genomic information and reagents
from map-rich to map-poor species. They also shed light on genome organization
and evolution. By comparing the chromosomal location of homologous genes,
chromosome segments that have remained intact during evolution can be identified
and the location of chromosome rearrangement breakpoints documented. Key to
navigating these maps is the ability to cross-reference between a substantial
number of homologous genes that are widely distributed across the genome.
Nearly 500 of the markers in the current map are within genes whose homologues
have been identified in other species. These genes reveal 145 (20)
conserved segments in the rat-human comparative map, and 48 (7) conserved
segments in the rat-mouse comparative map. Cumulatively, these conserved segments
cover more than one-half of the rat-human comparative map and more than 80%
of the rat-mouse map—which demonstrates that a modest number of genes
are sufficient to identify most conserved segments and that the rat comparative
map is rapidly approaching completion.
Perhaps the most important, and unappreciated, outcome of both the Industrial
and Genomics Revolutions is the enhanced, rather than diminished, vitality
of small companies and research laboratories. Despite the profound changes
consequent to industrialization, small companies remain an important part
of vigorous economies. In the same way, conventional research laboratories
are essential for exploiting genomic information, reagents and technologies
for functional studies. Genomic information is a catalogue whose meaning can
only be established through traditional research based on testing specific
hypotheses; it is easier to centralize raw materials in a few centres than
to concentrate intuition, imagination and insight. A balance between genome
centres and small laboratories is a strength of the research community. The
principal threat to success is that small labs are denied access to the products
of the Genomics Revolution. Without access, biomedical research may well devolve
into feudal societies composed of 'haves' and 'have-nots'. In this context,
it is noteworthy that the data obtained by Watanabe et al. have been
made freely available in publicly accessible databases.
For years, the rat has been the premier species for many physiological,
behavioural and pharmacological studies. With these maps and mapping reagents,
the rat community is now well positioned to identify genes that control physiological
traits and diseases. And with these maps and reagents, it is time to consider
sequencing the rat genome. The nature of the corresponding cultural changes
remains to be determined. These benefits and risks now face the rat community
as they bid to join the G7.
20)
conserved segments in the rat-human comparative map, and 48 (
