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Human Genome News, April-June 1996; 7(6)

Santa Fe '96

Leaping Across Genomes

Comparing Mouse and Human DNA

Luckily for researchers trying to find and understand human genes, nature does not reinvent the wheel. Many genes that are important for basic life functions are spared major evolutionary changes, with similarities retained across species, often even the order of the genes along the chromosomes.

The mouse, having long been used as a model for genetic studies, offers a highly characterized genetic system with many established inbred strains available for study. Within the best-mapped homologous mouse and human regions, the presence and location of specific genes and gene families can be predicted in one species based on mapping results obtained in the other.

Information on gene function derived from analyzing human hereditary traits or mapped murine mutations can be applied from one species to another. Side-by-side genome sequencing enables close comparisons that provide insights into the evolutionary mechanisms underlying overall gene organization.

Some highlights follow of workshop presentations focusing on different aspects of mouse-human comparison studies.

Homologous Regions: Mouse Chromosome 7 and Human Chromosome 19
Lisa Stubbs [Oak Ridge National Laboratory (ORNL)] described collaborations with Lawrence Livermore National Laboratory. New methods are being explored to exploit mouse-human genomic relationships, using LLNL's collection of contiguous cosmid and YAC clones spanning human chromosome 19.

Work has focused initially on one of the largest regions of homology found for the two species: the proximal portion of mouse chromosome 7 and the entire long arm of human chromosome 19. Stubbs described the results of these comparative analyses.

Gene content, order, and spacing are remarkably well conserved throughout the length of this 23-cM to 29-Mb region of mouse-human homology, except for five major rearrangements clustered in two sites. Because of an almost perfect megabase-to-centimorgan relationship, mapping information can be extrapolated between maps of the two species. Recent mapping studies have been extended to include other regions, and work is under way to define borders of mouse-human syntenic segments on a broader, genome-wide scale.

ORNL investigators have also developed a highly efficient method of isolating exons and conserved regulatory sequences, using overlapping human cosmids and parallel sets of mouse P1 or BAC clones. (For reports of collaborative studies on human and mouse DNA repair genes, see the related LLNL article, in "Progress at the DOE Labs")

Human Genome Postdoctoral fellows Evan Eichler (LLNL) and Mark Shannon (ORNL) discussed, respectively, the identification and characterization of three additional zinc finger genes in a 2-Mb cluster on 19p12 and structural and functional analysis of a conserved zinc-finger gene cluster. The cluster is located distal to XRCC1 in human chromosome 19q13.2 and in the related interval in proximal mouse chromosome 7. Zinc fingers are protein regions that fold around a zinc atom and may be involved with their binding to nucleic acids.

Immune System Genes
Lee Rowen (University of Washington, Seattle) discussed the analysis of over 1 Mb of sequence from T-cell receptor (TCR) beta loci of both human and mouse [see Science 272, 1755-62 (June 21, 1996)]. TCRs play a major role in immunity and autoimmune disease. About half the human TCR beta locus is composed of long homologous repeats in which members of multigene subfamilies are embedded; a portion has even been translocated to another chromosome. These repeats suggest a mechanism for divergence of gene function. By contrast, the mouse locus contains far less repeated DNA. TCR beta variable gene segments in human are twice as numerous as in mouse, even though both species have about the same number of subfamilies.

The most surprising result, Rowen said, was finding two gene families inhabiting the same genomic address: the genes for human and mouse TCRs and for pancreatic trypsinogen. She discussed the evolutionary changes and possible origins of the gene families. In contrast with the situation in the variable beta gene segments described above, the mouse locus has undergone a greater expansion in the number and variety of trypsinogen genes than its human counterpart.

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Human Genome Program, U.S. Department of Energy, Human Genome News (v7n6).

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