particularly well (described in more detail below). In the mouse, mutations can be obtained efficiently by targeted recombination of mutant DNA constructs introduced into the germ line (described in more detail below). In flies (Drosophila) and nematodes (C. elegans), the desired mutant individual can be screened from a large population after random transposon insertion or chemical mutagenesis.

  1. Once mutations are obtained, they can be subjected to any of the genetic analyses described above.

Again, emerging technologies, such as microchips carrying ordered arrays of cDNAs to allow rapid analysis of how a mutation affects mRNA populations, will accelerate and enhance the above approaches.

Extrapolation to Humans

For many genes identified by forward or reverse genetics in model animals such as the mouse, and particularly for genes relevant to human disease states, the next step is to isolate and characterize the corresponding (orthologous) gene in humans. Several recent developments have simplified the task of cloning human homologs for molecular analysis. Extensive and detailed maps of molecular markers are now available for many areas of the human genome, and rapid progress is being made on the remainder in connection with the Human Genome Project. Comparison of mouse and human maps demonstrate extensive linkage conservation (synteny) between the two genomes (i.e., the arrangement of orthologous genes has been conserved over large regions from the last common ancestor). Considerable linkage conservation is found even between fish and mammals. As ancestral species diverged hundreds of millions of years ago and evolved into present-day species, local gene order in most instances has been maintained while large blocks of contiguous genes have been rearranged. For example, genes A-B-C-D-E found on mouse chromosome 12 might be found as A-B-C-D-E or, in reverse order, as E-D-C-B-A on human chromosome 7. As a result, if the chromosomal location of a gene responsible for a trait in the mouse is known, it is now possible to predict quite accurately the chromosomal location of its ortholog in humans (see Web site at http://www.informatics.jax.org, under mammalian homology and comparative maps). This approach will also be useful in defining human genes that affect responses to developmental toxicants (e.g., the genes for various enzymes that metabolize exogenous chemicals).

There also are large libraries (expressed sequence tag (EST) libraries) of sequences representing pieces of mRNAs transcribed from genes at various times and tissues in the human (see description of EST methods in Chapter 5). Transcripts from almost 90% of all human genes are estimated to be sequenced and present in these libraries. The transcripts are of great value for isolating the human homologs of genes and gene products that have been well characterized in other organisms.



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