Protein Complex Evolution Does Not Involve Extensive Network Rewiring

The formation of proteins into stable protein complexes plays a fundamental role in the operation of the cell. The study of the degree of evolutionary conservation of protein complexes between species and the evolution of protein-protein interactions has been hampered by lack of comprehensive coverage of the high-throughput (HTP) technologies that measure the interactome. We show that new high-throughput datasets on protein co-purification in yeast have a substantially lower false negative rate than previous datasets when compared to known complexes. These datasets are therefore more suitable to estimate the conservation of protein complex membership than hitherto possible. We perform comparative genomics between curated protein complexes from human and the HTP data in Saccharomyces cerevisiae to study the evolution of co-complex memberships. This analysis revealed that out of the 5,960 protein pairs that are part of the same complex in human, 2,216 are absent because both proteins lack an ortholog in S. cerevisiae, while for 1,828 the co-complex membership is disrupted because one of the two proteins lacks an ortholog. For the remaining 1,916 protein pairs, only 10% were never co-purified in the large-scale experiments. This implies a conservation level of co-complex membership of 90% when the genes coding for the protein pairs that participate in the same protein complex are also conserved. We conclude that the evolutionary dynamics of protein complexes are, by and large, not the result of network rewiring (i.e. acquisition or loss of co-complex memberships), but mainly due to genomic acquisition or loss of genes coding for subunits. We thus reveal evidence for the tight interrelation of genomic and network evolution

The relationship between retinal vessel calibre and knee cartilage and BMLs

10.1186/1471-2474-13-255BMC Musculoskeletal Disorders13

Species Specificity in Major Urinary Proteins by Parallel Evolution

Species-specific chemosignals, pheromones, regulate social behaviors such as aggression, mating, pup-suckling, territory establishment, and dominance. The identity of these cues remains mostly undetermined and few mammalian pheromones have been identified. Genetically-encoded pheromones are expected to exhibit several different mechanisms for coding 1) diversity, to enable the signaling of multiple behaviors, 2) dynamic regulation, to indicate age and dominance, and 3) species-specificity. Recently, the major urinary proteins (Mups) have been shown to function themselves as genetically-encoded pheromones to regulate species-specific behavior. Mups are multiple highly related proteins expressed in combinatorial patterns that differ between individuals, gender, and age; which are sufficient to fulfill the first two criteria. We have now characterized and fully annotated the mouse Mup gene content in detail. This has enabled us to further analyze the extent of Mup coding diversity and determine their potential to encode species-specific cues

Development of a Bead-Based Multiplex Genotyping Method for Diagnostic Characterization of HPV Infection

The accurate genotyping of human papillomavirus (HPV) is clinically important because the oncogenic potential of HPV is dependent on specific genotypes. Here, we described the development of a bead-based multiplex HPV genotyping (MPG) method which is able to detect 20 types of HPV (15 high-risk HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68 and 5 low-risk HPV types 6, 11, 40, 55, 70) and evaluated its accuracy with sequencing. A total of 890 clinical samples were studied. Among these samples, 484 were HPV positive and 406 were HPV negative by consensus primer (PGMY09/11) directed PCR. The genotyping of 484 HPV positive samples was carried out by the bead-based MPG method. The accuracy was 93.5% (95% CI, 91.0–96.0), 80.1% (95% CI, 72.3–87.9) for single and multiple infections, respectively, while a complete type mismatch was observed only in one sample. The MPG method indiscriminately detected dysplasia of several cytological grades including 71.8% (95% CI, 61.5–82.3) of ASCUS (atypical squamous cells of undetermined significance) and more specific for high grade lesions. For women with HSIL (high grade squamous intraepithelial lesion) and SCC diagnosis, 32 women showed a PPV (positive predictive value) of 77.3% (95% CI, 64.8–89.8). Among women >40 years of age, 22 women with histological cervical cancer lesions showed a PPV of 88% (95% CI, 75.3–100). Of the highest risk HPV types including HPV-16, 18 and 31 positive women of the same age groups, 34 women with histological cervical cancer lesions showed a PPV of 77.3% (95% CI, 65.0–89.6). Taken together, the bead-based MPG method could successfully detect high-grade lesions and high-risk HPV types with a high degree of accuracy in clinical samples

Effects of Degraded Optical Conditions on Behavioural Responses to Alarm Cues in a Freshwater Fish

Prey organisms often use multiple sensory cues to gain reliable information about imminent predation threat. In this study we test if a freshwater fish increases the reliance on supplementary cues when the reliability of the primary cue is reduced. Fish commonly use vision to evaluate predation threat, but may also use chemical cues from predators or injured conspecifics. Environmental changes, such as increasing turbidity or water colour, may compromise the use of vision through changes in the optical properties of water. In an experiment we tested if changes in optical conditions have any effects on how crucian carp respond to chemical predator cues. In turbidity treatments we added either clay or algae, and in a brown water colour treatment we added water with a high humic content. We found that carp reduced activity in response to predator cues, but only in the turbidity treatments (clay, algae), whereas the response in the brown water treatment was intermediate, and not significantly different from, clear and turbid water treatments. The increased reliance on chemical cues indicates that crucian carp can compensate for the reduced information content from vision in waters where optical conditions are degraded. The lower effect in brown water may be due to the reduction in light intensity, changes in the spectral composition (reduction of UV light) or to a change in chemical properties of the cue in humic waters

Selection upon Genome Architecture: Conservation of Functional Neighborhoods with Changing Genes

An increasing number of evidences show that genes are not distributed randomly across eukaryotic chromosomes, but rather in functional neighborhoods. Nevertheless, the driving force that originated and maintains such neighborhoods is still a matter of controversy. We present the first detailed multispecies cartography of genome regions enriched in genes with related functions and study the evolutionary implications of such clustering. Our results indicate that the chromosomes of higher eukaryotic genomes contain up to 12% of genes arranged in functional neighborhoods, with a high level of gene co-expression, which are consistently distributed in phylogenies. Unexpectedly, neighborhoods with homologous functions are formed by different (non-orthologous) genes in different species. Actually, instead of being conserved, functional neighborhoods present a higher degree of synteny breaks than the genome average. This scenario is compatible with the existence of selective pressures optimizing the coordinated transcription of blocks of functionally related genes. If these neighborhoods were broken by chromosomal rearrangements, selection would favor further rearrangements reconstructing other neighborhoods of similar function. The picture arising from this study is a dynamic genomic landscape with a high level of functional organization

Selection upon Genome Architecture: Conservation of Functional Neighborhoods with Changing Genes

An increasing number of evidences show that genes are not distributed randomly across eukaryotic chromosomes, but rather in functional neighborhoods. Nevertheless, the driving force that originated and maintains such neighborhoods is still a matter of controversy. We present the first detailed multispecies cartography of genome regions enriched in genes with related functions and study the evolutionary implications of such clustering. Our results indicate that the chromosomes of higher eukaryotic genomes contain up to 12% of genes arranged in functional neighborhoods, with a high level of gene co-expression, which are consistently distributed in phylogenies. Unexpectedly, neighborhoods with homologous functions are formed by different (non-orthologous) genes in different species. Actually, instead of being conserved, functional neighborhoods present a higher degree of synteny breaks than the genome average. This scenario is compatible with the existence of selective pressures optimizing the coordinated transcription of blocks of functionally related genes. If these neighborhoods were broken by chromosomal rearrangements, selection would favor further rearrangements reconstructing other neighborhoods of similar function. The picture arising from this study is a dynamic genomic landscape with a high level of functional organization

CRF1-R Activation of the Dynorphin/Kappa Opioid System in the Mouse Basolateral Amygdala Mediates Anxiety-Like Behavior

Stress is a complex human experience and having both rewarding and aversive motivational properties. The adverse effects of stress are well documented, yet many of underlying mechanisms remain unclear and controversial. Here we report that the anxiogenic properties of stress are encoded by the endogenous opioid peptide dynorphin acting in the basolateral amygdala. Using pharmacological and genetic approaches, we found that the anxiogenic-like effects of Corticotropin Releasing Factor (CRF) were triggered by CRF1-R activation of the dynorphin/kappa opioid receptor (KOR) system. Central CRF administration significantly reduced the percent open-arm time in the elevated plus maze (EPM). The reduction in open-arm time was blocked by pretreatment with the KOR antagonist norbinaltorphimine (norBNI), and was not evident in mice lacking the endogenous KOR ligand dynorphin. The CRF1-R agonist stressin 1 also significantly reduced open-arm time in the EPM, and this decrease was blocked by norBNI. In contrast, the selective CRF2-R agonist urocortin III did not affect open arm time, and mice lacking CRF2-R still showed an increase in anxiety-like behavior in response to CRF injection. However, CRF2-R knockout animals did not develop CRF conditioned place aversion, suggesting that CRF1-R activation may mediate anxiety and CRF2-R may encode aversion. Using a phosphoselective antibody (KORp) to identify sites of dynorphin action, we found that CRF increased KORp-immunoreactivity in the basolateral amygdala (BLA) of wildtype, but not in mice pretreated with the selective CRF1-R antagonist, antalarmin. Consistent with the concept that acute stress or CRF injection-induced anxiety was mediated by dynorphin release in the BLA, local injection of norBNI blocked the stress or CRF-induced increase in anxiety-like behavior; whereas norBNI injection in a nearby thalamic nucleus did not. The intersection of stress-induced CRF and the dynorphin/KOR system in the BLA was surprising, and these results suggest that CRF and dynorphin/KOR systems may coordinate stress-induced anxiety behaviors and aversive behaviors via different mechanisms