One type, a genetic linkage map, is based on careful analysis of human inheritance patterns. It indicates for each chromosome the whereabouts of genes or other "heritable markers," with distances measured in centimorgans, a measure of recombination frequency. During the formation of sperm and egg cells, a process of genetic recombination -- or "crossing over" -- occurs in which pieces of genetic material are swapped between paired chromosomes. This process of chromosomal scrambling accounts for the differences invariably seen even in siblings (apart from identical twins, whose genomes are equivalent). Logically, the closer two genes are to each other on a single chromosome, the less likely they are to get split up during genetic recombination. When they are close enough that the chances of being separated are only one in a hundred, they are said to be separated by a distance of one centimorgan.
The role of human pedigrees now becomes clear. By studying family trees and tracing the inheritance of diseases and physical traits, or even unique segments of DNA identifiable only in the laboratory, geneticists can begin to pin down the relative positions of these genetic markers. By the end of 1994, a comprehensive map was available that included more than 5800 such markers, including genes implicated in cystic fibrosis, myotonic dystrophy, Huntington disease, @Tay-@Sachs disease, several cancers, and many other maladies. The average gap between markers was about 0.7 centimorgan.
Other maps are known as physical maps, so called because the distances between features are measured not in genetic terms, but in "real" physical units, typically, numbers of base pairs. A close analogy can thus be drawn between physical maps and the road maps familiar to us all. Indeed, the analogy can be extended further. Just as small-scale road maps may show only large cities and indicate distances only between major features, so a low-resolution physical map includes only a relative sprinkling of chromosomal landmarks. A well-known low-resolution physical map, for example, is the familiar chromosomal map, showing the distinctive staining patterns that can be seen in the light microscope. Further, by a process known as in situ hybridization, specific segments of DNA can be targeted in intact chromosomes by using complementary strands synthesized in the laboratory. These laboratory-made "probes" carry a fluorescent or radioactive label, which can then be detected and thus pinpointed on a specific region of the chromosome. Fishing for genes shows some results of fluorescence in situ hybridization (FISH). Of particular interest are probes known as @cDNA (for complementary DNA), which are synthesized by using molecules of messenger RNA as templates. These molecules of cDNA thus hybridize to "expressed" chromosomal regions -- regions that directly dictate the synthesis of proteins. However, a physical map that depended only on in situ hybridization would be a fairly coarse one. Fluorescent tags on intact chromosomes cannot be resolved into separate spots unless they are two to five million base pairs apart.
Fortunately, means are also available to produce physical maps of much higher resolution -- analogous to large-scale county maps that show every village and farm road, and indicate distances at a similar level of detail. Just such a detailed physical map is one that emerges from the use of restriction enzymes -- DNA-cleaving enzymes that serve as highly selective cleavers of the genetic material. A typical restriction enzyme known as @EcoRI, for example, recognizes the DNA sequence @GAATTC and selectively cuts the double helix at that site. One use of these handy tools involves cutting up a selected chromosome into small pieces, then cloning and ordering the resulting fragments. The cloning, or copying, process is a product of recombinant DNA technology, in which the natural reproductive machinery of a "host" organism -- a bacterium or a yeast, for example -- replicates a "parasitic" fragment of human DNA, thus producing the multiple copies needed for further study.
By cloning enough such fragments, each overlapping the next and together spanning long segments (or even the entire length) of the chromosome, workers can eventually produce an ordered library of clones. Each contiguous block of ordered clones is known as a contig, and the resulting map is a contig map. If a gene can be localized to a single fragment within a contig map, its physical location is thereby accurately pinned down. Further, these conveniently sized clones become resources for further studies by researchers around the world -- as well as the natural starting points for systematic sequencing efforts.
Once the DNA has been mapped, and all the genes placed within the chromosomal framework, the real work begins û making sense of the information encoded within those genes. Specifically, this involves determining whether the genes code for a particular protein, and if so, which one, or whether they are involved in the regulation of other genes. The task then falls to understanding what the proteins' functions are within the body, so that effective therapies can be developed for instances when they malfunction. While much progress has been made in the mapping of the human genome, it is clear to all involved that there is clearly much work yet to be done to gain a full understanding of the complex functioning of the human genetic material.
