Most traits and disorders have a multifactorial background indicating that they are controlled by environmental factors as well as an unknown number of quantitative trait loci (QTLs). The identification of mutations underlying QTLs is a challenge because each locus explains only a fraction of the phenotypic variation. A paternally expressed QTL affecting muscle growth, fat deposition and size of the heart in pigs maps to the IGF2 (insulin-like growth factor 2) region. Here we show that this QTL is caused by a nucleotide substitution in intron 3 of IGF2. The mutation occurs in an evolutionarily conserved CpG island that is hypomethylated in skeletal muscle. The mutation abrogates in vitro interaction with a nuclear factor, probably a repressor, and pigs inheriting the mutation from their sire have a threefold increase in IGF2 messenger RNA expression in postnatal muscle. Our study establishes a causal relationship between a single-base-pair substitution in a non-coding region and a QTL effect. The result supports the long-held view that regulatory mutations are important for controlling phenotypic variation.

Here, we report the sequence characterization of the bovine pseudoautosomal boundary (PAB) and its neighborhood. We demonstrate that it maps to the 5Ј end of the GPR143 gene, which has concomitantly lost upstream noncoding exons on the Y chromosome. We show that the bovine PAB was created ∼20.7 million years ago by illegitimate intrachromatid recombination between inverted, ruminant-specific Bov-tA repeats. Accordingly, we demonstrate that cattle share their PAB with all other examined ruminants including sheep, but not with cetaceans or more distantly related mammals. We provide evidence that, since its creation, the ancestral ruminant PAB has been displaced by attrition, which occurs at variable rates in different species, and that it is capable of retreat by attrition erasure. We have estimated the ratio of male to female mutation rates in the Bovidae family as ∼1.7, and we provide evidence that the mutation rate is higher in the recombining pseudoautosomal region than in the adjacent, nonrecombining gonosome-specific sequences.[Supplemental material is available online at www.genome.org. The sequence data from this study have been submitted to GenBank under accession nos. FJ195351-FJ195356 and FJ195359-FJ195366.] Maleness in placental mammals and marsupials is determined by the SRY gene located on the Y chromosome. This major sex determinant arose ∼166 million years ago (Mya) on an ancestral autosome as an allele of the SOX3 gene (Veyrunes et al. 2008). As is commonly observed for chromosomes carrying sexdetermining genes (Ohno 1967), the Y has since undergone progressive degeneration, being reduced in present-day man to a mere 25 Mb of euchromatin harboring no more than 27 distinct protein-coding genes or gene families, appended with an approximately equal amount of dispensable heterochromatin (Skaletsky et al. 2003). These numbers are to be compared with the ∼155 Mb and 1100 genes of its ancestral partner, the X chromosome (Ross et al. 2005).The decay of the Y is thought to result from the successive selection of male-beneficial/female-deleterious alleles embedded in haplotypes that lost the ability to recombine with the X and are hence confined to males (Charlesworth 1991). Absence of recombination causes rapid degeneration by mutation, deletion, and transposon invasion accumulating as a result of a higher mutation rate in the male versus the female germline (due to the larger number of cell divisions required to produce male vs. female gametes), inefficient repair (e.g., Muller's ratchet), and inefficient selection (e.g., shielding of deleterious recessives and Hill-Robertson interference) (e.g., Charlesworth et al. 2005;Bachtrog 2006;Graves 2006).The most commonly invoked recombination-blocking mechanism is chromosomal inversion. The observation of a stepwise increase in sequence similarity between genes ordered on the human X with their gametologs on the Y ("evolutionary strata") suggests that five such recombination-blocking inversions have occurred in the human lineage (Lahn and Page 1999;Ross et ...

IGF2 is the major candidate gene for a paternally expressed Quantitative Trait Locus (QTL) in the pig primarily affecting muscle development. Here we report two sequence contigs together comprising almost 90 kb containing the INS-IGF2 and H19 genes. A comparative sequence analysis of the pig, human, and mouse genomic sequences was conducted to identify the exon/intron organization, all promoters, and other evolutionarily conserved elements. RT-PCR analysis showed that IGF2 transcripts originated from four different promoters and included various combinations of seven untranslated exons together with three coding exons, in agreement with previous findings in other mammals. The observed sequence similarity in intronic and intragenic regions among the three species is remarkable and is most likely explained by the complicated regulation of imprinting and expression of these genes. The general trend was, as expected, a higher sequence similarity between human and pig than between these species and the mouse, but a few exceptions to this rule were noted. This genomic region exhibits several striking features, including a very high GC content, many CpG islands, and a low amount of interspersed repeats. The high GC and CpG content were more pronounced in the pig than in the two other species. The results will facilitate the further characterization of this important QTL in the pig.

Usutu virus (USUV) is a neurotropic flavivirus closely related to West Nile virus (WNV). Its enzootic cycle mainly involves mosquitoes and birds. Human infection can occur with occasional, but sometimes severe, neurological complications. Since its emergence and spread in Europe over the last two decades, USUV has been linked to significant avian outbreaks, especially among Passeriformes, including European blackbirds (Turdus merula). Strikingly, no in vivo avian model exists so far to study this arbovirus. The domestic canary (Serinus canaria) is a passerine, which is considered as a highly susceptible model of infection by WNV. Here, we experimentally challenged domestic canaries with two different doses of USUV. All inoculated birds presented detectable amounts of viral RNA in the blood and RNA shedding via feathers and droppings during the early stages of the infection, as determined by RT-qPCR. Mortality occurred in both infected groups (1/5 and 2/5, respectively) and was not necessarily correlated to a pure neurological disease. Subsequent analyses of samples from dead birds showed histopathological changes and virus tropism mimicking those reported in naturally infected birds. A robust seroconversion followed the infection in almost all the surviving canaries. Altogether, these results demonstrate that domestic canaries constitute an interesting experimental model for the study of USUV pathogenesis and transmission.