Dynamic instability of the Major Urinary Protein gene family revealed by genomic and phenotypic comparisons between C57 and 129 strain mice

Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB101SA, UK.
Genome biology (Impact Factor: 10.81). 02/2008; 9(5):R91. DOI: 10.1186/gb-2008-9-5-r91
Source: PubMed


The major urinary proteins (MUPs) of Mus musculus domesticus are deposited in urine in large quantities, where they bind and release pheromones and also provide an individual 'recognition signal' via their phenotypic polymorphism. Whilst important information about MUP functionality has been gained in recent years, the gene cluster is poorly studied in terms of structure, genic polymorphism and evolution.
We combine targeted sequencing, manual genome annotation and phylogenetic analysis to compare the Mup clusters of C57BL/6J and 129 strains of mice. We describe organizational heterogeneity within both clusters: a central array of cassettes containing Mup genes highly similar at the protein level, flanked by regions containing Mup genes displaying significantly elevated divergence. Observed genomic rearrangements in all regions have likely been mediated by endogenous retroviral elements. Mup loci with coding sequences that differ between the strains are identified--including a gene/pseudogene pair--suggesting that these inbred lineages exhibit variation that exists in wild populations. We have characterized the distinct MUP profiles in the urine of both strains by mass spectrometry. The total MUP phenotype data is reconciled with our genomic sequence data, matching all proteins identified in urine to annotated genes.
Our observations indicate that the MUP phenotypic polymorphism observed in wild populations results from a combination of Mup gene turnover coupled with currently unidentified mechanisms regulating gene expression patterns. We propose that the structural heterogeneity described within the cluster reflects functional divergence within the Mup gene family.

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    • "All are synthesised as preproteins , but the signal peptide is removed precisely to reveal a conserved N-terminus. Mouse MUPs contain a single disulphide bond but only two have consensus sites for N-linked glycosylation (MUP3 and MUP21) of which one has been proven to be glycosylated [3]. Of these 21 genes, the central 15 show very high sequence homology, and the peripheral six are more variable in their sequence. "

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    • "Initially, four chromosomes sequenced at the Wellcome Trust Sanger Institute (2, 4, 11, and X) were systematically annotated on a clone-by-clone basis during the assembly phase. Secondly , numerous genomic regions and gene families considered of particular interest to the wider community had their annotation prioritized, for example, the major histocompatibility complex on chr17 (unpublished), the Major Urinary Proteins gene cluster on chr 4 (Mudge et al. 2008) and the large complement of immunoglobulin loci found at several sites across the genome (unpublished). The HAVANA group has also been involved in several collaborative projects over the years that have required annotation on a gene-by-gene basis. "
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    ABSTRACT: Annotation on the reference genome of the C57BL6/J mouse has been an ongoing project ever since the draft genome was first published. Initially, the principle focus was on the identification of all protein-coding genes, although today the importance of describing long non-coding RNAs, small RNAs, and pseudogenes is recognized. Here, we describe the progress of the GENCODE mouse annotation project, which combines manual annotation from the HAVANA group with Ensembl computational annotation, alongside experimental and in silico validation pipelines from other members of the consortium. We discuss the more recent incorporation of next-generation sequencing datasets into this workflow, including the usage of mass-spectrometry data to potentially identify novel protein-coding genes. Finally, we will outline how the C57BL6/J genebuild can be used to gain insights into the variant sites that distinguish different mouse strains and species.
    Mammalian Genome 07/2015; 26(9). DOI:10.1007/s00335-015-9583-x · 3.07 Impact Factor
    • "The protein component of mouse urine is comprised almost exclusively of major urinary proteins (MUPs). MUPs are encoded by roughly 20 linked loci and are integral to social communication (Mudge et al., 2008) by providing a signature of genetic identity and relatedness (Cheetham et al., 2007; Sherborne et al., 2007; Kaur et al., 2014). MUPs bind and slowly release many volatile urinary compounds (Hurst et al., 1998); the maleexpressed MUP darcin is the primary carrier of SBT (Armstrong et al., 2005), and darcin by itself influences the formation of social memory, particularly in females (Roberts et al., 2010, 2012). "
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    ABSTRACT: Communication signals are key regulators of social networks, and are thought to be under selective pressure to honestly reflect social status, including dominance status. The odors of dominants and nondominants differentially influence behavior, and identification of the specific pheromones associated with, and predictive of, dominance status is essential for understanding the mechanisms of network formation and maintenance. In mice, major urinary proteins (MUPs) are excreted in extraordinary large quantities and expression level has been hypothesized to provide an honest signal of dominance status. Here, we evaluate whether MUPs are associated with dominance in wild-derived mice by analyzing expression levels before, during, and after competition for reproductive resources over three days. During competition, dominant males have 24% greater urinary MUP expression than nondominants. The MUP darcin, a pheromone that stimulates female attraction, is predictive of dominance status: dominant males have higher darcin expression before competition. Dominants also have a higher ratio of darcin to other MUPs before and during competition. These differences appear transient, because there are no differences in MUPs or darcin after competition. We also find MUP expression is affected by sire dominance status: socially naive sons of dominant males have lower MUP expression, but this apparent repression is released during competition. A requisite condition for the evolution of communication signals is honesty, and we provide novel insight into pheromones and social networks by showing that MUP and darcin expression is a reliable signal of dominance status, a primary determinant of male fitness in many species. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Evolutionary Biology 04/2015; 28(6). DOI:10.1111/jeb.12643 · 3.23 Impact Factor
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