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

Abstract

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.

Fig. 1.

Haplotype structure of 1,450 diallelic variants with SDP frequency >1% between eight inbred strains across a 4.8-Mb region of mouse chromosome 1. The region is represented along the horizontal axis and scaled such that the nth coordinate from the left edge corresponds to the nth variant, broken into two parts for clarity with the top section showing the first 725 variants and the bottom showing the remainder. (a) The alternating gray and white tracks show the spatial arrangement of the 13 most common SDP arranged from top to bottom in the same order as in Table 4 (so that the top SDP is 01000101 and the bottom SDP is 00101110). Each track represents one SDP, with a bar on the track at points where the corresponding variant has that SDP. (b) The gray and orange bands show the block partitioning produced by a dynamic programming algorithm that identifies an optimal partition that minimizes the SDP heterogeneity within each block, subject to a block transition cost C = 8 (see Methods). The strains are (top to bottom) A/J, AKR, BALB/c, C3H, C57BL/6, DBA/2, I, and RIII. Block boundaries are white vertical lines. Within each block, the major SDP is indicated by the black and orange horizontal bands. Strains with the same color have the same allele. (c) The optimal block partitioning for C = 0, i.e., perfect SDP fidelity within each block. Boundaries are not shown because many blocks have a length of 1 bp and would therefore be invisible.