A comparative assessment of mandible shape in a consomic strain panel of the house mouse (Mus musculus) - implications for epistasis and evolvability of quantitative traits

<p>Abstract</p> <p>Background</p> <p>Expectations of repeatedly finding associations between given genes and phenotypes have been borne out by studies of parallel evolution, especially for traits involving absence or presence of characters. However, it has rarely been asked whether the genetic basis of quantitative trait variation is conserved at the intra- or even at the interspecific level. This question is especially relevant for shape, where the high dimensionality of variation seems to require a highly complex genetic architecture involving many genes.</p> <p>Results</p> <p>We analyse here the genetic effects of chromosome substitution strains carrying <it>M. m. musculus </it>chromosomes in a largely <it>M. m. domesticus </it>background on mandible shape and compare them to the results of previously published QTL mapping data between <it>M. m. domesticus </it>strains. We find that the distribution of genetic effects and effect sizes across the genome is consistent between the studies, while the specific shape changes associated with the chromosomes are different. We find also that the sum of the effects from the different <it>M. m. musculus </it>chromosomes is very different from the shape of the strain from which they were derived, as well as all known wild type shapes.</p> <p>Conclusions</p> <p>Our results suggest that the relative chromosome-wide effect sizes are comparable between the long separated subspecies <it>M. m. domesticus </it>and <it>M. m. musculus</it>, hinting at a relative stability of genes involved in this complex trait. However, the absolute effect sizes and the effect directions may be allele-dependent, or are context dependent, i.e. epistatic interactions appear to play an important role in controlling shape.</p

Segmental Trisomy of Mouse Chromosome 17: Introducing an Alternative Model of Down’s Syndrome

All of the mouse models of human trisomy 21 syndrome that have been studied so far are based on segmental trisomies, encompassing, to a varying extent, distal chromosome 16. Their comparison with one or more unrelated and non-overlapping segmental trisomies may help to distinguish the effects of specific triplicated genes from the phenotypes caused by less specific developmental instability mechanisms. In this paper, the Ts43H segmental trisomy of mouse chromosome 17 is presented as such an alternative model. The trisomy stretches over 32.5 Mb of proximal chromosome 17 and includes 486 genes. The triplicated interval carries seven blocks of synteny with five human chromosomes. The block syntenic to human chromosome 21 contains 20 genes

Genetically enhanced asynapsis of autosomal chromatin promotes transcriptional dysregulation and meiotic failure

During meiosis, pairing of homologous chromosomes and their synapsis are essential prerequisites for normal male gametogenesis. Even limited autosomal asynapsis often leads to spermatogenic impairment, the mechanism of which is not fully understood. The present study was aimed at deliberately increasing the size of partial autosomal asynapsis and analysis of its impact on male meiosis. For this purpose, we studied the effect of t12 haplotype encompassing four inversions on chromosome 17 on mouse autosomal translocation T(16;17)43H (abbreviated T43H). The T43H/T43H homozygotes were fully fertile in both sexes, while +/T43H heterozygous males, but not females, were sterile with meiotic arrest at late pachynema. Inclusion of the t12 haplotype in trans to the T43H translocation resulted in enhanced asynapsis of the translocated autosome, ectopic phosphorylation of histone H2AX, persistence of RAD51 foci, and increased gene silencing around the translocation break. Increase was also on colocalization of unsynapsed chromatin with sex body. Remarkably, we found that transcriptional silencing of the unsynapsed autosomal chromatin precedes silencing of sex chromosomes. Based on the present knowledge, we conclude that interference of meiotic silencing of unsynapsed autosomes with meiotic sex chromosome inactivation is the most likely cause of asynapsis-related male sterility

Differential Expression of Non-Coding RNAs and Continuous Evolution of the X Chromosome in Testicular Transcriptome of Two Mouse Species

BACKGROUND: Tight regulation of testicular gene expression is a prerequisite for male reproductive success, while differentiation of gene activity in spermatogenesis is important during speciation. Thus, comparison of testicular transcriptomes between closely related species can reveal unique regulatory patterns and shed light on evolutionary constraints separating the species. METHODOLOGY/PRINCIPAL FINDINGS: Here, we compared testicular transcriptomes of two closely related mouse species, Mus musculus and Mus spretus, which diverged more than one million years ago. We analyzed testicular expression using tiling arrays overlapping Chromosomes 2, X, Y and mitochondrial genome. An excess of differentially regulated non-coding RNAs was found on Chromosome 2 including the intronic antisense RNAs, intergenic RNAs and premature forms of Piwi-interacting RNAs (piRNAs). Moreover, striking difference was found in the expression of X-linked G6pdx gene, the parental gene of the autosomal retrogene G6pd2. CONCLUSIONS/SIGNIFICANCE: The prevalence of non-coding RNAs among differentially expressed transcripts indicates their role in species-specific regulation of spermatogenesis. The postmeiotic expression of G6pdx in Mus spretus points towards the continuous evolution of X-chromosome silencing and provides an example of expression change accompanying the out-of-the X-chromosomal retroposition

The Nucleoside Diphosphate Kinase Gene Nme3 Acts as Quantitative Trait Locus Promoting Non-Mendelian Inheritance

The t-haplotype, a variant form of the t-complex region on mouse chromosome 17, acts as selfish genetic element and is transmitted at high frequencies (>95%) from heterozygous (t/+) males to their offspring. This phenotype is termed transmission ratio distortion (TRD) and is caused by the interaction of the t-complex responder (Tcr) with several quantitative trait loci (QTL), the t-complex distorters (Tcd1 to Tcd4), all located within the t-haplotype region. Current data suggest that the distorters collectively impair motility of all sperm derived from t/+ males; t-sperm is rescued by the responder, whereas +-sperm remains partially dysfunctional. Recently we have identified two distorters as regulators of RHO small G proteins. Here we show that the nucleoside diphosphate kinase gene Nme3 acts as a QTL on TRD. Reduction of the Nme3 dosage by gene targeting of the wild-type allele enhanced the transmission rate of the t-haplotype and phenocopied distorter function. Genetic and biochemical analysis showed that the t-allele of Nme3 harbors a mutation (P89S) that compromises enzymatic activity of the protein and genetically acts as a hypomorph. Transgenic overexpression of the Nme3 t-allele reduced t-haplotype transmission, proving it to be a distorter. We propose that the NME3 protein interacts with RHO signaling cascades to impair sperm motility through hyperactivation of SMOK, the wild-type form of the responder. This deleterious effect of the distorters is counter-balanced by the responder, SMOKTcr, a dominant-negative protein kinase exclusively expressed in t-sperm, thus permitting selfish behaviour and preferential transmission of the t-haplotype. In addition, the previously reported association of NME family members with RHO signaling in somatic cell motility and metastasis, in conjunction with our data involving RHO signaling in sperm motility, suggests a functional conservation between mechanisms for motility control in somatic cells and spermatozoa

Controlling complexity: the clinical relevance of mouse complex genetics.

Experimental animal models are essential to obtain basic knowledge of the underlying biological mechanisms in human diseases. Here, we review major contributions to biomedical research and discoveries that were obtained in the mouse model by using forward genetics approaches and that provided key insights into the biology of human diseases and paved the way for the development of novel therapeutic approaches

Conserved alternative and antisense transcripts at the programmed cell death 2 locus

<p>Abstract</p> <p>Background</p> <p>The programmed cell death 2 (<it>Pdcd2</it>) gene on mouse chromosome 17 was evaluated as a member of a highly conserved synteny, a candidate for an imprinted locus, and a candidate for the Hybrid sterility 1 (<it>Hst1</it>) gene.</p> <p>Results</p> <p>New mouse transcripts were identified at this locus: an alternative <it>Pdcd2 </it>mRNA skipping the last two coding exons and two classes of antisense RNAs. One class of the antisense RNA overlaps the alternative exon and the other the entire <it>Pdcd2 </it>gene. The antisense RNAs are alternative transcripts of the neighboring TATA-binding protein gene (<it>Tbp</it>) that are located mainly in the cell nucleus. Analogous alternative PDCD2 forms truncating the C-terminal domain were also detected in human and chicken. Alternative transcripts of the chicken <it>PDCD2 </it>and <it>TBP </it>genes also overlap. No correlation in the transcription of the alternative and overlapping mRNAs was detected. Allelic sequencing and transcription studies did not reveal any support for the candidacy of <it>Pdcd2 </it>for <it>Hst1</it>. No correlated expression of <it>Pdcd2 </it>with the other two genes of the highly conserved synteny was observed. <it>Pdcd2</it>, <it>Chd1</it>, and four other genes from this region were not imprinted in the embryo.</p> <p>Conclusion</p> <p>The conservation of alternative transcription of the <it>Pdcd2 </it>gene in mouse, human and chicken suggests the biological importance of such truncated protein. The biological function of the alternative <it>PDCD2 </it>is likely to be opposite to that of the constitutive form. The ratio of the constitutive and alternative <it>Pdcd2 </it>mRNAs differs in the tissues, suggesting a developmental role.</p> <p>The identified <it>Tbp-</it>alternative <it>Pdcd2</it>-antisense transcripts may interfere with the transcription of the <it>Pdcd2 </it>gene, as they are transcribed at a comparable level. The conservation of the <it>Pdcd2</it>/<it>Tbp </it>sense-antisense overlap in the mouse and chicken points out its biological relevance. Our results also suggest that some cDNAs in databases labeled as noncoding are incomplete alternative cDNAs of neighboring protein-coding genes.</p