mousemap6-rmott.doc - A high resolution single nucleotide...

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A high resolution single nucleotide polymorphism genetic map of the mouse genome Sagiv Shifman 1 , Jordana Tzenova 1 Richard R. Copley 1 , Robert W. Williams 2 , Richard Mott 1 , Jonathan Flint 1 1 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford Roosevelt Drive Oxford OX3 7BN UK, 2 University of Tennessee Health Science Center, 855 Monroe Avenue, Memphis, Tennessee 38163, USA. 1
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Abstract We report the highest density genetic map yet created for any organism, except humans. Using more then 10,000 single nucleotide polymorphisms evenly spaced, we have constructed genetic maps based on outbred and inbred mice and separately for male and females. Recombination rates are highly correlated in outbred and inbred mice but show relatively low correlation between males and females. Our data suggest a high degree of homology between mouse and human in recombination process. Differences between males and females recombination maps and the sequence features associated with recombination are strikingly similar to those observed in humans. The high resolution map will potentially serve as an important resource for genetic mapping and for studies of recombination. 2
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Introduction The large number of inbred strains, the wealth of spontaneous and induced mutations, together with our ability to engineer its genome, have guaranteed the mouse its place as the most important model organism for understanding mammalian biology, disease and evolution. Genetic methodologies are highly developed in the mouse; the availability of its complete genome sequence, coupled with inventories of transcripts and sequence polymorphisms, make it an ideal organism for identifying the molecular basis of complex traits, which continues to be a challenging goal for genetics. Despite the wealth of new genomic information that has accrued recently, the genetic map of the mouse is still based on data from crosses between inbred strains that were carried out using microsatellite markers in the late 1990s (Dietrich et al. 1996). The most recent and still the most comprehensive map was created by backcrossing Mus spretus to C57BL/6 and mapping the position of 3,368 markers on 982 progeny. The map consists of 2,302 genetically separated bins, with an average distance between bins of 0.61 cM (Rhodes et al. 1998). The genetic map was a critical resource for the construction of the physical map of the mouse genome and it continues to serve as a tool for mapping fully penetrant mutations. For many applications it is possible to convert the known physical distance between two sequences in the genome into a genetic distance, using the established metric that 1 centimorgan (cM) corresponds to approximately 2 megabases (Mb). For example it is possible in this way to infer genetic distances between the many thousands of single nucleotide polymorphisms that have not been mapped in crosses. However, the absence of higher resolution maps limits our appreciation of the relationship between physical and genetic distance in the mouse. It is unclear how variation in rates of 3
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