Inside Mickey: the mouse genome

Before Reading
We are going to read an article on SNP’s. What are SNP’s? In your own words explain what SNP’s are.
Task 1: With a partner make a list of nouns that you might in an article about SNP’s.
Task 2: Now make a list of verbs that you might in an article about SNP’s.
Task 3: Now make a list of adjectives that you might in an article about SNP’s.
Compare your lists with another pair.

Reading
The following article from the scientific magazine ‘Nature’ is not a ‘real’ scientific paper but it follows some of the conventions in scientific writing.
Task 1: Skim the passage to get an overview and try to find which parts correspond to the Introduction, Methods, Results and Discussion sections of a real scientific paper. In groups compare your answers.
Task 2: Look at what you identified as the methods and results section and highlight any words that are related to time sequences e.g. words like next or later
Compare your words with another pair.
Task 3: Now fill in the chart below

Task 4: Now read the article again and highlight all the words and phrases you are unsure of. Discuss these with your partner.
Task 5 grammar: Find all examples of the passive verb form in the text. Change them to active forms. Why do you think the author used passive form in these cases?

The Mouse Genome
Nature 420, 517 - 518 (05 December 2002)
Single nucleotide polymorphisms: Tackling complexity
JOSEPH H. NADEAU
Joseph H. Nadeau is in the Department of Genetics, BRB 624, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106-4955, USA.
e-mail: jhn4@po.cwru.edu

Many traits, including susceptibilities to some diseases, are under complex genetic control. A new way of analysing the mouse genome will be a great help in understanding the interactions involved.

Like Passepartout with Phileas Fogg in their 80-day travels, mice have tagged along with humans in a 10,000-year journey around the world. But these animals have been more than fellow travellers — along the way, new types of mice with unusual features were occasionally found. These genetic variants were collected and much prized, whether for their unique coat colours or patterns, waltzing behaviour, small size or other unusual characteristics. Keeping and breeding such fancy mice has long been a hobby with international appeal. In the eighteenth century, during the Edo period in Japan, the book Chingan Sodategusa was published as a guide to mouse breeding. And more recently, around the beginning of the twentieth century, clubs set up by mouse fanciers proliferated in North America and Europe1.

The transition of fancy mice to laboratory mice began in 1909, with the recognition by C. C. Little that these rich collections, especially when taken as genetically homogeneous inbred strains, could become a powerful resource for biomedical research2. Twenty years later, Little founded the Jackson Laboratory in Bar Harbor, Maine, and subsequent work there and elsewhere has shown that the mouse is genetically closer to us than had been imagined3-5. Hence the value of the laboratory mouse both for basic research and as a model of human disease, and the significance of the report by Wade et al.6 (page 574 of this issue), which
extends the prospects for detailed investigations of mouse genetics.
Fig.1 C. C. Little, an innovator in genetics

The characteristics of some fancy mice result from genes operating in a mendelian fashion; this is the simplest form of inheritance, in which a trait is controlled by two variants, or alleles, of a single gene. Most traits, however, have a genetically complex background and are the subject of considerable attention. For instance, the Mouse Phenome Project is a community effort to characterize the phenotypes — the morphological, physiological and behavioural traits — of inbred strains of mice7, 8. The project, which aims to be both comprehensive and systematic, is revealing remarkable phenotypic variability, most of which is probably controlled by numerous genes. Identifying the genes concerned will not only provide insight into fundamental biology, but also new ways of understanding genetically complex human diseases — obesity, hypertension, diabetes and cardiovascular diseases, for example, as well as drug addiction and the biological underpinnings of learning and memory.

Wade et al.6 have pioneered a new form of gene mapping in mice that will greatly accelerate gene discovery, especially for genes that control complex traits. Their approach is based on single nucleotide polymorphisms (SNPs) — these are differences of just one nucleotide base in sequences of DNA. Identification of mendelian variants in mice is now routine. But the discovery of genes involved in complex traits is just beginning9, and the study of SNPs will help greatly in that endeavour.

The point of departure for Wade et al. was the 'finished' DNA sequence of the genome of the C57BL/6J mouse strain. This is the most widely used inbred strain, and the complete sequence of the genome is published formally only now — see page 520 of this issue10. (Celera Genomics has also produced a genome sequence, as well as a collection of mouse SNPs, but the data have not been deposited in public databases5, 11.)

Wade et al. compared the C57BL/6J sequence with 59 'finished' segments of the genome of a different (129/Sv) inbred strain, and found nearly 70,000 SNPs. These SNPs were located in blocks of high SNP density, of 1 million base pairs or more, that were separated by blocks of low variability. The authors estimate that 67% of these genomes are SNP poor, with an average of 0.5 SNPs per 10 kilobases, and 33% are SNP rich, with 40 SNPs per 10 kilobases. There is a sharp transition from high to low SNP density, implying that the difference results from recombination among the chromosomes of the common ancestor12, 13, a process in which stretches of DNA are swapped between sister chromosomes.

Wade et al. then surveyed a panel of inbred mouse strains and found striking evidence that segments of chromosomes with distinct combinations of SNPs (haplotypes) were shared among common inbred strains. This observation is consistent with both the historical record and genetic evidence from mitochondrial DNA and the Y chromosome that inbred strains have a small number of progenitors14-16. Typically, at any given genomic location, only two or three different haplotypes were found in this panel of strains, suggesting that there is much less genetic variability between them than had been thought. Finally, a survey of strains derived recently from wild mice showed that 67% of each of these genomes are derived from European mice (Mus musculus domesticus) and 33% from Asian mice (M. m. musculus).

Study of mouse SNPs will accelerate discovery of the genes that underlie complex traits in two ways — by genetic mapping of crosses between phenotypically distinct strains, and by associating a particular phenotype with particular genotypes in surveys of inbred strains. The apparently limited genetic heterogeneity among the various strains will facilitate the task of dissecting controls of phenotypic variation. And given that the genomes of humans and mice contain fewer protein-coding genes than had been expected, as Mark Boguski describes in an accompanying News and Views article (page 515), complexity probably arises from the numerous ways in which a modest number of genes and alleles interact, rather than from the mass action of a large number of genes and alleles. Finally, because chromosome segments with high SNP density occupy only about 33% of the genome, the 'search space' for genes controlling complex traits is greatly reduced and the prospects for gene discovery are likewise increased.

Previous technical innovations in research on mouse genetics have delivered striking advances in our understanding. First there was analysis of visible phenotypes; then came study of isoenzyme variation; and since the advent of molecular biology we have had the ability to exploit restriction-fragment-length and simple-sequence-length polymorphisms17. These innovations facilitated the construction of rudimentary genetic maps, then mapping of sequenced genes and positional cloning of mendelian variants, and now the genetic characterization of complex traits.

We must remember that discoveries in mice do not necessarily lead to corresponding insights in humans — despite the many genetic similarities, humans are humans and mice are mice. But SNP analysis will without doubt prove revolutionary, and we can have every hope that the resulting discoveries about complex genetic traits will in time produce significant improvements in human health.

References
1.  Moriwaki, K. in Genetics in Wild Mice (eds Moriwaki, K., hiroishi, T. & Yonekawa, H.) xiii-xxv (Karger, New York, 1994).
2. Russell, E. S. in Origins of Inbred Mice (ed. Morse, H. C.) 33-43 (Academic, New York, 1978).
3. Nadeau, J. H. & Taylor, B. A. Proc. Natl Acad. Sci. USA 81, 814-818 (1984).
4. Makalowski, W. & Boguski, M. S. Proc. Natl Acad. Sci. USA 95, 9407-9412 (1998). | Article |
5. Mural, R. J. et al. Science 296, 1661-1671 (2002). | Article |
6. Wade, C. M. et al. Nature 420, 574-578 (2002). | Article |
7. Paigen, K. & Eppig, J. T. Mammal. Genome 11, 715-717 (2000). | Article |
8. http://www.jax.org/phenome
9. Glazier, A. M., Nadeau, J. H. & Aitman, T. J. Science (in the press).
10. Mouse Genome Sequencing Consortium Nature 420, 520-562 (2002). | Article |
11. http://www.celera.org
12. Weiss, K. M. & Clark, A. G. Trends Genet. 18, 19-24 (2002). | Article |
13. Reich, D. E. et al. Nature Genet. 32, 135-142 (2002). | Article |
14. Morse, H. C. (ed.) Origins of Inbred Mice (Academic, New York, 1978).
15. Ferris, S. D., Sage, R. D. & Wilson, A. C. Nature 295, 163-165 (1982).
16. Bishop, C. E., Boursot, P., Baron, B., Bonhomme, F. & Hatat, D. Nature 325, 70-72 (1985).
17. Lyon, M. F. Annu. Rev. Genomics Hum. Genet. 3, 1-16 (2002). | Article |
 
After Reading
Task 1: We have noted some of the things that Wade et al did in their study. How do you think they actually did these things? What techniques or procedures did they use? Your teacher doesn’t know. Could you explain them to him?
Task 2: Look at the articles listed in the references. Do any of them look interesting to you? Which ones and why? If none, why not?