Regulators of complement activity mediate inhibitory mechanisms through a common C3b‐binding mode

Regulators of complement activation (RCA) inhibit complement‐induced immune responses on healthy host tissues. We present crystal structures of human RCA (MCP, DAF, and CR1) and a smallpox virus homolog (SPICE) bound to complement component C3b. Our structural data reveal that up to four consecutive homologous CCP domains (i–iv), responsible for inhibition, bind in the same orientation and extended arrangement at a shared binding platform on C3b. Large sequence variations in CCP domains explain the diverse C3b‐binding patterns, with limited or no contribution of some individual domains, while all regulators show extensive contacts with C3b for the domains at the third site. A variation of ~100° rotation around the longitudinal axis is observed for domains binding at the fourth site on C3b, without affecting the overall binding mode. The data suggest a common evolutionary origin for both inhibitory mechanisms, called decay acceleration and cofactor activity, with variable C3b binding through domains at sites ii, iii, and iv, and provide a framework for understanding RCA disease‐related mutations and immune evasion.     

Efficiency of population structures for mapping of Mendelian and imprinted quantitative trait loci in outbred pigs using variance component methods

In a simulation study different designs for a pure line pig population were compared for efficiency of mapping QTL using the variance component method. Phenotypes affected by a Mendelian QTL, a paternally expressed QTL, a maternally expressed QTL or by a QTL without an effect were simulated. In all alternative designs 960 progeny were phenotyped. Given the limited number of animals there is an optimum between the number of families and the family size. Estimation of Mendelian and parentally expressed QTL is more efficient in a design with large family sizes. Too small a number of sires should be avoided to minimize chances of sires to be non-segregating. When a large number of families is used, the number of haplotypes increases which reduces the accuracy of estimating the QTL effect and thereby reduces the power to show a significant QTL and to correctly position the QTL. Dense maps allow for smaller family size due to exploitation of LD-information. Given the different possible modes of inheritance of the QTL using 8 to16 boars, two litters per dam was optimal with respect to determining significance and correct location of the QTL for a data set consisting of 960 progeny. The variance component method combining linkage disequilibrium and linkage analysis seems to be an appropriate choice to analyze data sets which vary in marker density and which contain complex family structures.     

The effect of using approximate gametic variance covariance matrices on marker assisted selection by BLUP

Under additive inheritance, the Henderson mixed model equations (HMME) provide an efficient approach to obtaining genetic evaluations by marker assisted best linear unbiased prediction (MABLUP) given pedigree relationships, trait and marker data. For large pedigrees with many missing markers, however, it is not feasible to calculate the exact gametic variance covariance matrix required to construct HMME. The objective of this study was to investigate the consequences of using approximate gametic variance covariance matrices on response to selection by MABLUP. Two methods were used to generate approximate variance covariance matrices. The first method (Method A) completely discards the marker information for individuals with an unknown linkage phase between two flanking markers. The second method (Method B) makes use of the marker information at only the most polymorphic marker locus for individuals with an unknown linkage phase. Data sets were simulated with and without missing marker data for flanking markers with 2, 4, 6, 8 or 12 alleles. Several missing marker data patterns were considered. The genetic variability explained by marked quantitative trait loci (MQTL) was modeled with one or two MQTL of equal effect. Response to selection by MABLUP using Method A or Method B were compared with that obtained by MABLUP using the exact genetic variance covariance matrix, which was estimated using 15 000 samples from the conditional distribution of genotypic values given the observed marker data. For the simulated conditions, the superiority of MABLUP over BLUP based only on pedigree relationships and trait data varied between 0.1% and 13.5% for Method A, between 1.7% and 23.8% for Method B, and between 7.6% and 28.9% for the exact method. The relative performance of the methods under investigation was not affected by the number of MQTL in the model.     

Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin

Cleavage of huntingtin (htt) has been characterized in vitro, and accumulation of caspase cleavage fragments represents an early pathological change in brains of Huntington's disease (HD) patients. However, the relationship between htt proteolysis and the pathogenesis of HD is unknown. To determine whether caspase cleavage of htt is a key event in the neuronal dysfunction and selective neurodegeneration in HD, we generated YAC mice expressing caspase-3- and caspase-6-resistant mutant htt. Mice expressing mutant htt, resistant to cleavage by caspase-6 but not caspase-3, maintain normal neuronal function and do not develop striatal neurodegeneration. Furthermore, caspase-6-resistant mutant htt mice are protected against neurotoxicity induced by multiple stressors including NMDA, quinolinic acid (QA), and staurosporine. These results are consistent with proteolysis of htt at the caspase-6 cleavage site being an important event in mediating neuronal dysfunction and neurodegeneration and highlight the significant role of htt proteolysis and excitotoxicity in HD.     

Breeding value prediction for production traits in layer chickens using pedigree or genomic relationships in a reduced animal model

Background

Genomic selection involves breeding value estimation of selection candidates based on high-density SNP genotypes. To quantify the potential benefit of genomic selection, accuracies of estimated breeding values (EBV) obtained with different methods using pedigree or high-density SNP genotypes were evaluated and compared in a commercial layer chicken breeding line.

Methods

The following traits were analyzed: egg production, egg weight, egg color, shell strength, age at sexual maturity, body weight, albumen height, and yolk weight. Predictions appropriate for early or late selection were compared. A total of 2,708 birds were genotyped for 23,356 segregating SNP, including 1,563 females with records. Phenotypes on relatives without genotypes were incorporated in the analysis (in total 13,049 production records).The data were analyzed with a Reduced Animal Model using a relationship matrix based on pedigree data or on marker genotypes and with a Bayesian method using model averaging. Using a validation set that consisted of individuals from the generation following training, these methods were compared by correlating EBV with phenotypes corrected for fixed effects, selecting the top 30 individuals based on EBV and evaluating their mean phenotype, and by regressing phenotypes on EBV.

Results

Using high-density SNP genotypes increased accuracies of EBV up to two-fold for selection at an early age and by up to 88% for selection at a later age. Accuracy increases at an early age can be mostly attributed to improved estimates of parental EBV for shell quality and egg production, while for other egg quality traits it is mostly due to improved estimates of Mendelian sampling effects. A relatively small number of markers was sufficient to explain most of the genetic variation for egg weight and body weight.     

Local spread of classical swine fever upon virus introduction into The Netherlands: Mapping of areas at high risk

Background

In the recent past, the introduction of Classical Swine Fever Virus (CSFV) followed by between-herd spread has given rise to a number of large epidemics in The Netherlands and Belgium. Both these countries are pork-exporting countries. Particularly important in these epidemics has been the occurrence of substantial "neighborhood transmission" from herd to herd in the presence of base-line control measures prescribed by EU legislation. Here we propose a calculation procedure to map out "high-risk areas" for local between-herd spread of CSFV as a tool to support decision making on prevention and control of CSFV outbreaks. In this procedure the identification of such areas is based on an estimated inter-herd distance dependent probability of neighborhood transmission or "local transmission". Using this distance-dependent probability, we derive a threshold value for the local density of herds. In areas with local herd density above threshold, local transmission alone can already lead to epidemic spread, whereas in below-threshold areas this is not the case. The first type of area is termed 'high-risk' for spread of CSFV, while the latter type is termed 'low-risk'.

Results

As we show for the case of The Netherlands, once the distance-dependent probability of local transmission has been estimated from CSFV outbreak data, it is possible to produce a map of the country in which areas of high-risk herds and of low-risk herds are identified. We made these maps even more informative by estimating border zones between the two types of areas. In these border zones the risk of local transmission of infection to a nearby high-risk area exceeds a certain level.

Conclusion

The risk maps provide an easily understandable visualization of the spatial heterogeneities in transmission risk. They serve as a tool for area-specific designs of control strategies, and possibly also for spatial planning of areas where livestock farming is allowed. Similar risk maps can in principle be constructed for other highly-transmissible livestock infections that spread via neighborhood transmission.

     

<Emphasis Type="Italic">α</Emphasis>-Amylase inhibitor-1 gene from <Emphasis Type="Italic">Phaseolus vulgaris</Emphasis> expressed in <Emphasis Type="Italic">Coffea arabica</Emphasis>plants inhibits α-amylases from the coffee berry borer pest

Background  

Coffee is an important crop and is crucial to the economy of many developing countries, generating around US70 billion per year. There are 115 species in the < i > Coffea < /i > genus, but only two, < i > C. arabica < /i > and < i > C. canephora < /i > , are commercially cultivated. Coffee plants are attacked by many pathogens and insect-pests, which affect not only the production of coffee but also its grain quality, reducing the commercial value of the product. The main insect-pest, the coffee berry borer ( < i > Hypotheneumus hampei < /i > ), is responsible for worldwide annual losses of around US70 billion per year. There are 115 species in the Coffea genus, but only two, C. arabica and C. canephora, are commercially cultivated. Coffee plants are attacked by many pathogens and insect-pests, which affect not only the production of coffee but also its grain quality, reducing the commercial value of the product. The main insect-pest, the coffee berry borer (Hypotheneumus hampei), is responsible for worldwide annual losses of around US500 million. The coffee berry borer exclusively damages the coffee berries, and it is mainly controlled by organochlorine insecticides that are both toxic and carcinogenic. Unfortunately, natural resistance in the genus Coffea to H. hampei has not been documented. To overcome these problems, biotechnological strategies can be used to introduce an α-amylase inhibitor gene (α-AI1), which confers resistance against the coffee berry borer insect-pest, into C. arabica plants.