Hybrid sterility is a common postzygotic reproductive isolation mechanism that appears in the early stages of speciation of various organisms. Mus musculus musculus and Mus musculus domesticus represent two recently separated mouse subspecies particularly suitable for genetic studies of hybrid sterility. Here we show that the introgression of Chr X of M. m. musculus origin (PWD/Ph inbred strain, henceforth PWD) into the genetic background of the C57BL/6J (henceforth B6) inbred strain (predominantly of M. m. domesticus origin) causes male sterility. The X-linked hybrid sterility is associated with reduced testes weight, lower sperm count, and morphological abnormalities of sperm heads. The analysis of recombinant Chr Xs in sterile and fertile males as well as quantitative trait locus (QTL) analysis of several fertility parameters revealed an oligogenic nature of the X-linked hybrid sterility. The Hstx1 locus responsible for male sterility was mapped near DXMit119 in the central part of Chr X. To ensure full sterility, the PWD allele of Hstx1 has to be supported with the PWD allelic form of loci in at least one proximal and/or one distal region of Chr X. Mapping and cloning of Hstx1 and other genes responsible for sterility of B6-X PWD Y B6 males could help to elucidate the special role of Chr X in hybrid sterility and consequently in speciation.

Consomic (chromosome substitution) strains (CSs) represent the most recent addition to the mouse genetic resources aimed to geneticaly analyze complex trait loci (QTLs). In this study, we report the development of a set of 28 mouse intersubspecific CSs. In each CS, we replaced a single chromosome of the C57BL/6J (B6) inbred strain (mostly Mus m. domesticus) with its homolog from the PWD/Ph inbred strain of the Mus m. musculus subspecies. These two progenitor subspecies diverged less than 1 million years ago and accumulated a large number of genetic differences that constitute a rich resource of genetic variation for QTL analyses. Altogether, the 18 consomic, nine subconsomic, and one conplastic strain covered all 19 autosomes, X and Y sex chromosomes, and mitochondrial DNA. Most CSs had significantly lower reproductive fitness compared with the progenitor strains. CSs homosomic for chromosomes 10 and 11, and the C57BL/6J-Chr X males, failed to reproduce and were substituted by less affected subconsomics carrying either a proximal, central, or distal part of the respective chromosome. A genome-wide scan of 965 DNA markers revealed 99.87% purity of the B6 genetic background. Thirty-three nonsynonymous substitutions were uncovered in the protein-coding regions of the mitochondrial DNA of the B6.PWD-mt conplastic strain. A pilot-phenotyping experiment project revealed a high number of variations among B6.PWD consomics.[Supplemental material is available online at www.genome.org. The sequence data from this study have been submitted to GenBank under accession no. DQ874614.]Consomic strains (CSs), also known as chromosome (chr) substitution strains, represent the newest addition to the mouse genetic resources aimed at a genetic analysis of complex traits. To construct a CS, the genomes of two inbred strains are combined so that one chromosome pair of the host strain is replaced by the corresponding chromosome pair of the donor strain (Nadeau et al. 2000). Since the mouse genome is composed of 19 pairs of autosomes, and X and Y gonosomes, 21 CSs constitute the complete set.Nadeau, Lander, and coworkers developed the first set of mouse CSs with the A/J strain as a chromosome donor and C57BL/6J (hereafter B6) as the recipient strain ). Another series of 65 genome-wide congenic (subconsomic) strains was created by transferring segments of individual autosomes of the DBA/2J strain on the background of B6 (Davis et al. 2005) that covered 95% of the autosomal genome. The transfer of sex chromosomes was not reported. Most recently, the same laboratory reported the construction of ∼40 congenic (subconsomic) strains from a CAST/Ei inbred strain of Mus m. castaneus origin (Davis et al. 2007). These strains cover ∼80% of CAST/Ei autosomes. The transfer of sex chromosomes and mitochondrial DNA was not reported. In the accompanying paper in this issue of Genome Research, Takada et al. (2008) describe a full set of consomic strains, using B6 as a background strain and the MSM/ Ms of Mus m. molossinus origin as the chromosome donor....

Missense, nonsense and translationally silent mtuations can inactivate genes by altering the inclusion of mutant exons in messenger RNA, but their overall fraction among disease-causing exonic substitutions is unknown. Here, we have systematically tested missense and silent mutations deposited in the BRCA1 mutation databases of unclassified variants for their effects on exon inclusion in the mRNA experimentally. The introduction of 21 BRCA1 variants in two minigene systems revealed a single example of

Mutations that affect splicing of precursor messenger RNAs play a major role in the development of hereditary diseases. Most splicing mutations have been found to eliminate GT or AG dinucleotides that define the 5 0 and 3 0 ends of introns, leading to exon skipping or cryptic splice-site activation. Although accurate description of the mis-spliced transcripts is critical for predicting phenotypic consequences of these alterations, their exact nature in affected individuals cannot often be determined experimentally. Using a comprehensive collection of exons that sustained cryptic splice-site activation or were skipped as a result of splice-site mutations, we have developed a multivariate logistic discrimination procedure that distinguishes the two aberrant splicing outcomes from DNA sequences. The new algorithm was validated using an independent sample of exons and implemented as a free online utility termed CRYP-SKIP (http://www.dbass.org.uk/cryp-skip/). The web application takes up one or more mutated alleles, each consisting of one exon and flanking intronic sequences, and provides a list of important predictor variables and their values, the overall probability of activating cryptic splice vs exon skipping, and the location and intrinsic strength of predicted cryptic splice sites in the input sequence. These results will facilitate phenotypic prediction of splicing mutations and provide further insights into splicing enhancer and silencer elements and their relative importance for splice-site selection in vivo.