What use is the human genome for understanding the mouse?
© BioMed Central Ltd 2001
Published: 22 October 2001
Having a working draft of the human genome sequence is proving invaluable to mouse genetic and genomic studies, providing a useful stepping-stone towards the finished sequence of the mouse genome.
All over the world, mouse geneticists have applauded the publication of the initial analysis of the human genome sequence(s) [1,2]. Why? One simplistic answer is that mouse and human are two flavors of mammal, and a genome sequence for one is a surrogate for the other. So perhaps the pertinent question then becomes: how can mouse geneticists make use of the human sequence? In this article, we briefly describe some ways in which the human working draft sequence can be used as a tool in mouse genomics, not only for assembling the mouse genome but also for identifying conserved sequence elements and providing new insights into genome evolution.
Before the genome
Mice suffer from diseases similar to those of humans. Furthermore, this biological similarity can extend to defects in the same molecules: for example, mutations in the leptin gene cause morbid obesity  and in myosin VII cause deafness , both in humans and in mice. In complex genetic diseases, such as diabetes, or where mutations may be subtle rather than obviously deleterious, the mouse is of particular importance as it allows experimental testing of the validity of candidate mutations, by targeted mutagenesis. From the outset, the Human Genome Project recognized the importance of model organisms, from bacteria to mouse, and devoted funding to developing resources for their genetic and physical mapping . As a genetically malleable social mammal, well suited to living and breeding in (relatively) modest space, the mouse has become the premier genetic model for humans. A secondary aspect of the publicly funded Human Genome Project that has been immensely valuable to scientists working on model organisms is the policy of rapid data release. This has meant that data could be used prior to formal publication.
Building mouse genome sequence using a human scaffold
The version of the contig data generated in the last of these ways is made particularly powerful by the way in which it links together data from several sources: the sequence-tagged site (STS) content of the contigs, plus assemblies of expressed sequence tags (ESTs) in the database of transcribed sequences (DOTS)  and data from radiation hybrid (RH) maps. In some cases, this helps to confirm anchoring of mouse BAC contigs and also to orient the contigs on the mouse chromosome (M. Bucan, personal communication). Furthermore, a refinement of this approach has been used recently to produce a physical map of the whole mouse genome .
Identifying and visualizing conserved sequences
Turning the idea of comparative analysis on its head, we can use the human genome to find areas of the mouse genome where conservation of gene content and order breaks down. What happens in these evolutionary 'breakpoint' regions? Studies of this kind are still quite rare, but there are suggestions of an emerging consensus. A correlation has been noted between genetic instability and sites that are rich in repetitive elements and may, therefore, be more prone to rearrangement through inappropriate homologous recombination . Transposition events, leading to both insertion and deletion, are also apparent in regions of chromosomal rearrangements [24,25,26]. The evolutionary breakpoint disrupting the conservation of human 19p13.3 with mouse chromosomes 10 and 17, for example, is rich in simple tandem repeats , and repetitive elements were identified in the section of mouse chromosome 10 bridging the junction between conserved syntenic regions of human chromosomes 21 and 22 . Indeed, many of the breaks in conservation of human chromosome 19 relative to mouse chromosomes seem to be associated with localized repetitive elements, such as tandemly repeated gene families . As more extensive mouse genome sequence becomes available, it will be interesting to assess whether the prediction that regions rich in repetitive elements are associated with genome rearrangements holds up.
Finishing the mouse genome?
Finally, we would like to argue the case for producing a finished mouse genomic sequence. When mouse genome sequencing first became a serious endeavor, it was unclear what the quality of the 'product' might be. Some suggested that all that was needed was a low-to-medium coverage whole-genome shotgun (about 3-6-fold sequencing depth), which could be assembled and aligned with the finished human genome. Indeed, unassembled, low-coverage mouse shotgun sequence can be used efficiently to find exons in the human working draft sequence  and is a valuable resource for gene and marker discovery . Lack of long-range contiguity hampers accurate prediction of mouse gene structure, however, and accurate prediction is invaluable for efficient mutation scanning. Studies of two critical classes of mutations would benefit from high-quality, finished sequence: point mutations such as those induced by the supermutagen ethylnitrosourea (ENU) , and mutations responsible for quantitative traits, as it is believed that many of the latter may be found in regulatory elements . Despite the unequivocal utility of a draft human genome sequence [1,2], it is clear that draft sequence has limitations . Even with a finished human genome sequence, interpretation of genome function will be enhanced by access to a second, finished mammalian genome. As the premier genetic model mammal, it makes sense to finish the mouse.
We thank Steve Brown for improvements to the manuscript.
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