Unexpected complexity in the haplotypes of commonly used inbred strains of laboratory mice.

Investigation of sequence variation in common inbred mouse strains has revealed a segmented pattern in which regions of high and low variant density are intermixed. Furthermore, it has been suggested that allelic strain distribution patterns also occur in well defined blocks and consequently could be used to map quantitative trait loci (QTL) in comparisons between inbred strains. We report a detailed analysis of polymorphism distribution in multiple inbred mouse strains over a 4.8-megabase region containing a QTL influencing anxiety. Our analysis indicates that it is only partly true that the genomes of inbred strains exist as a patchwork of segments of sequence identity and difference. We show that the definition of haplotype blocks is not robust and that methods for QTL mapping may fail if they assume a simple block-like structure.

[1]  E. Myers,et al.  Basic local alignment search tool. , 1990, Journal of molecular biology.

[2]  J. Flint,et al.  The relationship between chromosome structure and function at a human telomeric region , 1997, Nature Genetics.

[3]  M. Soller,et al.  A Simple Method to Calculate Resolving Power and Confidence Interval of QTL Map Location , 1997, Behavior genetics.

[4]  P. Green,et al.  Base-calling of automated sequencer traces using phred. I. Accuracy assessment. , 1998, Genome research.

[5]  David W. Fulker,et al.  High-resolution mapping of quantitative trait loci in outbred mice , 1999, Nature Genetics.

[6]  E. Boerwinkle,et al.  Cladistic structure within the human Lipoprotein lipase gene and its implications for phenotypic association studies. , 2000, Genetics.

[7]  A. C. Collins,et al.  A method for fine mapping quantitative trait loci in outbred animal stocks. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[8]  P. D. de Jong,et al.  Bacterial artificial chromosome libraries for mouse sequencing and functional analysis. , 2000, Genome research.

[9]  Janan T. Eppig,et al.  Genealogies of mouse inbred strains , 2000, Nature Genetics.

[10]  Eric S. Lander,et al.  Large-scale discovery and genotyping of single-nucleotide polymorphisms in the mouse , 2000, Nature Genetics.

[11]  G. Peltz,et al.  In Silico Mapping of Complex Disease-Related Traits in Mice , 2001, Science.

[12]  Parvaneh Saeedi,et al.  A physical map of the mouse genome , 2002, Nature.

[13]  M. Waterman,et al.  A dynamic programming algorithm for haplotype block partitioning , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[14]  S. Gabriel,et al.  The Structure of Haplotype Blocks in the Human Genome , 2002, Science.

[15]  J. Flint,et al.  Multiple Cross Mapping (MCM) markedly improves the localization of a QTL for ethanol‐induced activation , 2002, Genes, brain, and behavior.

[16]  William H. Majoros,et al.  A Comparison of Whole-Genome Shotgun-Derived Mouse Chromosome 16 and the Human Genome , 2002, Science.

[17]  E. Birney,et al.  Analysis of the mouse transcriptome based on functional annotation of 60,770 full-length cDNAs , 2002, Nature.

[18]  Eric S. Lander,et al.  The mosaic structure of variation in the laboratory mouse genome , 2002, Nature.

[19]  G. Abecasis,et al.  Using haplotype blocks to map human complex trait loci. , 2003, Trends in genetics : TIG.

[20]  Richard J. Mural,et al.  Genome-wide single-nucleotide polymorphism analysis defines haplotype patterns in mouse , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[21]  A. Monaco,et al.  Genomic studies of gene expression: regulation of the Wilson disease gene. , 2003, Genomics.

[22]  B. J. Carey,et al.  Chromosome-wide distribution of haplotype blocks and the role of recombination hot spots , 2003, Nature Genetics.

[23]  J. Wall,et al.  Haplotype blocks and linkage disequilibrium in the human genome , 2003, Nature Reviews Genetics.