Using the realized relationship matrix to disentangle confounding factors for the estimation of genetic variance components of complex traits

Background

In the analysis of complex traits, genetic effects can be confounded with non-genetic effects, especially when using full-sib families. Dominance and epistatic effects are typically confounded with additive genetic and non-genetic effects. This confounding may cause the estimated genetic variance components to be inaccurate and biased.

Methods

In this study, we constructed genetic covariance structures from whole-genome marker data, and thus used realized relationship matrices to estimate variance components in a heterogenous population of ~ 2200 mice for which four complex traits were investigated. These mice were genotyped for more than 10,000 single nucleotide polymorphisms (SNP) and the variances due to family, cage and genetic effects were estimated by models based on pedigree information only, aggregate SNP information, and model selection for specific SNP effects.

Results and conclusions

We show that the use of genome-wide SNP information can disentangle confounding factors to estimate genetic variances by separating genetic and non-genetic effects. The estimated variance components using realized relationship were more accurate and less biased, compared to those based on pedigree information only. Models that allow the selection of individual SNP in addition to fitting a relationship matrix are more efficient for traits with a significant dominance variance.     

Drosophilid Assemblages at Different Urbanization Levels in the City of Porto Alegre, State of Rio Grande do Sul, Southern Brazil

The present study analyzed the drosophilid assemblages in different levels of urbanization in the city of Porto Alegre, Rio Grande do Sul, Brazil. Collections were carried out in 2008 in three different environments: a highly urbanized area????Jardim Botanico,?? a forested area with intermediary urbanization????Parque Gabriel Knijnik,?? and in a relatively well-preserved forested area, although threatened by the urban growth????Morro Santana.?? In Jardim Botanico, 36 species belonging to four genera were found, with high abundance of exotic species as Drosophila simulans Sturtevant and Zaprionus indianus (Gupta). In Parque Gabriel Knijnik, 33 species that belonged to four genera were found, with higher abundances of native species belonging to the Drosophila tripunctata species group and Drosophila willistoni species subgroup, and lower abundance of exotic species. As for Morro Santana, 32 species and three genera were found, with higher abundances of native groups, low representativeness of exotic species, and absence of Zaprionus indianus. The analysis of the Jaccard index showed higher similarity in the species composition between samples collected in summer and autumn, and between samples collected in winter and spring. On the other hand, the Morisita index differentiated Jardim Botanico from the other two studied sites. Our results show that Morro Santana is an important area of native biodiversity, reinforcing, therefore, the inclusion of this area in the project for the creation of an ecological corridor as proposed by the Ministry of the Environment of Brazil.     

Clinical features and predictors for disease natural progression in adults with Pompe disease: a nationwide prospective observational study

Background

Due partly to physicians’ unawareness, many adults with Pompe disease are diagnosed with great delay. Besides, it is not well known which factors influence the rate of disease progression, and thus disease outcome. We delineated the specific clinical features of Pompe disease in adults, and mapped out the distribution and severity of muscle weakness, and the sequence of involvement of the individual muscle groups. Furthermore, we defined the natural disease course and identified prognostic factors for disease progression.

Methods

We conducted a single-center, prospective, observational study. Muscle strength (manual muscle testing, and hand-held dynamometry), muscle function (quick motor function test), and pulmonary function (forced vital capacity in sitting and supine positions) were assessed every 3–6 months and analyzed using repeated-measures ANOVA.

Results

Between October 2004 and August 2009, 94 patients aged between 25 and 75 years were included in the study. Although skeletal muscle weakness was typically distributed in a limb-girdle pattern, many patients had unfamiliar features such as ptosis (23%), bulbar weakness (28%), and scapular winging (33%). During follow-up (average 1.6 years, range 0.5-4.2 years), skeletal muscle strength deteriorated significantly (mean declines of ?1.3% point/year for manual muscle testing and of ?2.6% points/year for hand-held dynamometry; both p<0.001). Longer disease duration (>15 years) and pulmonary involvement (forced vital capacity in sitting position <80%) at study entry predicted faster decline. On average, forced vital capacity in supine position deteriorated by 1.3% points per year (p=0.02). Decline in pulmonary function was consistent across subgroups. Ten percent of patients declined unexpectedly fast.

Conclusions

Recognizing patterns of common and less familiar characteristics in adults with Pompe disease facilitates timely diagnosis. Longer disease duration and reduced pulmonary function stand out as predictors of rapid disease progression, and aid in deciding whether to initiate enzyme replacement therapy, or when.

     

Genetic homogeneity among breeding grounds and nursery areas of an exploited Lake Malawi cichlid fish

1. Nursery areas are commonly recognized as important habitats for the management and conservation of fish stocks. Here we report the use of nursery areas by an exploited offshore cichlid in Lake Malawi, Rhamphochromis longiceps .
2. Like all haplochromine cichlids that have been studied, the species is a maternal mouthbrooder that broods eggs for several weeks following spawning. We found evidence that during this brooding period females migrate from open water to release juveniles in three shallow peripheral waterbodies (Chia Lagoon, Unaka Lagoon, Lake Malombe). However, it was unclear whether there is geographical population structuring within the species, which could indicate stock differences in their use of these nursery habitats, or if the lake contains a genetically panmictic population that employs nursery habitats opportunistically.
3. To investigate spatial and temporal population structuring within the lake we genotyped populations at seven microsatellite DNA loci. Overall, we found no significant spatial structuring among juveniles from the peripheral lagoons or among breeding males within the main lake body. Moreover, we found no evidence of temporal structuring among males on the breeding grounds within Lake Malawi or females entering Chia lagoon. Together, these results suggest that Lake Malawi contains a genetically homogeneous population of R. longiceps .
4. At present we know little of the distribution of juvenile R. longiceps elsewhere in the Lake Malawi basin, but their absence from surveyed rocky and sandy littoral habitats makes it possible that the species is dependent upon a small number of nearshore nursery areas, including these lagoons. As such, conservation of lagoon habitats and monitoring of exploited fish stocks within them may be important for effective preservation of biodiversity within the catchment.     

Integrated responses of hydraulic architecture, water and carbon relations of western hemlock to dwarf mistletoe infection

Dwarf mistletoe (Arceuthobium spp.) is a hemiparasite that is said to be the single‐most destructive pathogen of commercially valuable coniferous trees in many regions of the world. Although its destructive nature is well documented in many respects, its effects on the physiology of its host are poorly understood. In the present study, water and carbon relations were characterized over a range of scale from leaf to whole tree in large (40‐ to 50‐m‐tall) individuals of western hemlock (Tsuga heterophylla (Raf.) Sarg.) that were either heavily infected, or uninfected with hemlock dwarf mistletoe (Arceuthobium tsugense). Specific hydraulic conductivity (k_s) of infected branches was approximately half that of uninfected branches, yet leaf‐specific conductivity (k_L) was similar because leaf area : sapwood area ratios (A_L : A_S) of infected branches were lower. Pre‐dawn and minimum leaf water potential and stomatal conductance (g_s) were similar among infected and uninfected trees because adjustments in hydraulic architecture of infected trees maintained k_L despite reduced k_s. Maximum whole‐tree water use was substantially lower in infected trees (approximately 55 kg d^?1) than in uninfected trees (approximately 90 kg d^?1) because reduced numbers of live branches in infected trees reduced whole‐tree A_L : A_S in a manner consistent with that observed in infected branches. Maximum photosynthetic rates of heavily infected trees were approximately half those of uninfected trees. Correspondingly, leaf nitrogen content was 35% lower in infected trees. Foliar δ¹³C values were 2.8‰ more negative in infected than in uninfected individuals, consistent with the absence of stomatal adjustment to diminished photosynthetic capacity. Adjustments in hydraulic architecture of infected trees thus contributed to homeostasis of water transport efficiency and transpiration on a leaf area basis, whereas both carbon accumulation and photosynthetic water use efficiency were sharply reduced at both the leaf and whole‐tree scale.     

Autoantibody systems in rheumatoid arthritis: specificity, sensitivity and diagnostic value

This review focuses on the mechanisms of stress response in the synovial tissue of rheumatoid arthritis. The major stress factors, such as heat stress, shear stress, proinflammatory cytokines and oxidative stress, are discussed and reviewed, focusing on their potential to induce a stress response in the synovial tissue. Several pathways of stress signalling molecules are found to be activated in the synovial membrane of rheumatoid arthritis; of these the most important examples are heat shock proteins, mitogen-activated protein kinases, stress-activated protein kinases and molecules involved in the oxidative stress pathways. The expression of these pathways in vitro and in vivo as well as the consequences of stress signalling in the rheumatoid synovium are discussed. Stress signalling is part of a cellular response to potentially harmful stimuli and thus is essentially involved in the process of synovitis. Stress signalling pathways are therefore new and promising targets of future anti-rheumatic therapies.