Genetic and functional investigation of inherited neuropathies

With the discovery of next generation sequencing techniques the landscape of pathogenic gene discovery has shifted drastically over the last ten years. For the purpose of this thesis, focus was applied on finding genetic causes of inherited neuropathies, mainly Charcot-Marie-Tooth disease, by using both old and new genetic techniques and the accompanying functional investigations to prove the pathogenicity of these variants. Mutations in ATPase 6, the first mitochondrially encoded gene responsible for an isolated neuropathy, were found in five families with CMT2 by a traditional Sanger sequencing approach. The same approach was used to expand the phenotype associated with FIG4 mutations, known as CMT4J. Compound heterozygous mutations were found in a patient with a proximal and asymmetric weakness and rapid deterioration of strength in a single limb, mimicking CIDP. Several appropriate cohorts were screened for mutations in candidate genes with the traditional Sanger sequencing approach; however, no new pathogenic genes were found. In the case of the HINT1 gene, the originally stated frequency of 11% could not be replicated and a founder effect was suggested, underlying the importance of considering the ethnic background of a patient when screening for mutations in neuropathy-related genes. After the incorporation of exome sequencing, five CMT families were provided with a genetic diagnosis due to mutations in three novel genes and two previously known pathogenic genes. Many more families are currently under investigation and candidate genes have been found in some. Lastly, a series of divergent functional techniques was used to investigate the pathogenicity of IGHMBP2 mutations in 11 families with CMT2. IGHMBP2 mutations normally lead to SMARD1 and fibroblast and lymphoblast studies indicate that the IGHMBP2 protein levels are significantly higher in CMT2 than SMARD1, but lower than controls, suggesting that the clinical phenotype differences correlate to the IGHMBP2 protein levels

Reconciling seascape genetics and fisheries science in three codistributed flatfishes

Uncertainty hampers innovative mixed‐fisheries management by the scales at which connectivity dynamics are relevant to management objectives. The spatial scale of sustainable stock management is species‐specific and depends on ecology, life history and population connectivity. One valuable approach to understand these spatial scales is to determine to what extent population genetic structure correlates with the oceanographic environment. Here, we compare the level of genetic connectivity in three codistributed and commercially exploited demersal flatfish species living in the North East Atlantic Ocean. Population genetic structure was analysed based on 14, 14 and 10 neutral DNA microsatellite markers for turbot, brill and sole, respectively. We then used redundancy analysis (RDA) to attribute the genetic variation to spatial (geographical location), temporal (sampling year) and oceanographic (water column characteristics) components. The genetic structure of turbot was composed of three clusters and correlated with variation in the depth of the pycnocline, in addition to spatial factors. The genetic structure of brill was homogenous, but correlated with average annual stratification and spatial factors. In sole, the genetic structure was composed of three clusters, but was only linked to a temporal factor. We explored whether the management of data poor commercial fisheries, such as in brill and turbot, might benefit from population‐specific information. We conclude that the management of fish stocks has to consider species‐specific genetic structures and may benefit from the documentation of the genetic seascape and life‐history traits.publishedVersionUnit Licence Agreemen

Reconciling seascape genetics and fisheries science in three codistributed flatfishes

Uncertainty hampers innovative mixed‐fisheries management by the scales at which connectivity dynamics are relevant to management objectives. The spatial scale of sustainable stock management is species‐specific and depends on ecology, life history and population connectivity. One valuable approach to understand these spatial scales is to determine to what extent population genetic structure correlates with the oceanographic environment. Here, we compare the level of genetic connectivity in three codistributed and commercially exploited demersal flatfish species living in the North East Atlantic Ocean. Population genetic structure was analysed based on 14, 14 and 10 neutral DNA microsatellite markers for turbot, brill and sole, respectively. We then used redundancy analysis (RDA) to attribute the genetic variation to spatial (geographical location), temporal (sampling year) and oceanographic (water column characteristics) components. The genetic structure of turbot was composed of three clusters and correlated with variation in the depth of the pycnocline, in addition to spatial factors. The genetic structure of brill was homogenous, but correlated with average annual stratification and spatial factors. In sole, the genetic structure was composed of three clusters, but was only linked to a temporal factor. We explored whether the management of data poor commercial fisheries, such as in brill and turbot, might benefit from population‐specific information. We conclude that the management of fish stocks has to consider species‐specific genetic structures and may benefit from the documentation of the genetic seascape and life‐history traits.publishedVersionUnit Licence Agreemen

The distribution of pond snail communities across a landscape: separating out the influence of spatial position from local habitat quality for ponds in south-east Northumberland, UK

Ponds support a rich biodiversity because the heterogeneity of individual ponds creates, at the landscape scale, a diversity of habitats for wildlife. The distribution of pond animals and plants will be influenced by both the local conditions within a pond and the spatial distribution of ponds across the landscape. Separating out the local from the spatial is difficult because the two are often linked. Pond snails are likely to be affected by both local conditions, e.g. water hardness, and spatial patterns, e.g. distance between ponds, but studies of snail communities struggle distinguishing between the two. In this study, communities of snails were recorded from 52 ponds in a biogeographically coherent landscape in north-east England. The distribution of snail communities was compared to local environments characterised by the macrophyte communities within each pond and to the spatial pattern of ponds throughout the landscape. Mantel tests were used to partial out the local versus the landscape respective influences. Snail communities became more similar in ponds that were closer together and in ponds with similar macrophyte communities as both the local and the landscape scale were important for this group of animals. Data were collected from several types of ponds, including those created on nature reserves specifically for wildlife, old field ponds (at least 150 years old) primarily created for watering livestock and subsidence ponds outside protected areas or amongst coastal dunes. No one pond type supported all the species. Larger, deeper ponds on nature reserves had the highest numbers of species within individual ponds but shallow, temporary sites on farm land supported a distinct temporary water fauna. The conservation of pond snails in this region requires a diversity of pond types rather than one idealised type and ponds scattered throughout the area at a variety of sites, not just concentrated on nature reserves

Local Factors Determine Plant Community Structure on Closely Neighbored Islands

Despite the recent popularity of the metacommunity concept, ecologists have not evaluated the applicability of different metacommunity frameworks to insular organisms. We surveyed 50 closely spaced islands in the Thousand-Island Lake of China to examine the role of local (environmental) and regional (dispersal) factors in structuring woody plant assemblages (tree and shrub species) on these islands. By partitioning the variation in plant community structure into local and regional causes, we showed that local environmental conditions, specifically island morphometric characteristics, accounted for the majority of the variation in plant community structure among the studied islands. Spatial variables, representing the potential importance of species dispersal, explained little variation. We conclude that one metacommunity framework–species sorting–best characterizes these plant communities. This result reinforces the idea that the traditional approach of emphasizing the local perspective when studying ecological communities continues to hold its value

Truncating and missense mutations in IGHMBP2 cause Charcot-Marie Tooth disease type 2.

Using a combination of exome sequencing and linkage analysis, we investigated an English family with two affected siblings in their 40s with recessive Charcot-Marie Tooth disease type 2 (CMT2). Compound heterozygous mutations in the immunoglobulin-helicase-μ-binding protein 2 (IGHMBP2) gene were identified. Further sequencing revealed a total of 11 CMT2 families with recessively inherited IGHMBP2 gene mutations. IGHMBP2 mutations usually lead to spinal muscular atrophy with respiratory distress type 1 (SMARD1), where most infants die before 1 year of age. The individuals with CMT2 described here, have slowly progressive weakness, wasting and sensory loss, with an axonal neuropathy typical of CMT2, but no significant respiratory compromise. Segregating IGHMBP2 mutations in CMT2 were mainly loss-of-function nonsense in the 5' region of the gene in combination with a truncating frameshift, missense, or homozygous frameshift mutations in the last exon. Mutations in CMT2 were predicted to be less aggressive as compared to those in SMARD1, and fibroblast and lymphoblast studies indicate that the IGHMBP2 protein levels are significantly higher in CMT2 than SMARD1, but lower than controls, suggesting that the clinical phenotype differences are related to the IGHMBP2 protein levels

A comparative analysis reveals weak relationships between ecological factors and beta diversity of stream insect metacommunities at two spatial levels.

The hypotheses that beta diversity should increase with decreasing latitude and increase with spatial extent of a region have rarely been tested based on a comparative analysis of multiple datasets, and no such study has focused on stream insects. We first assessed how well variability in beta diversity of stream insect metacommunities is predicted by insect group, latitude, spatial extent, altitudinal range, and dataset properties across multiple drainage basins throughout the world. Second, we assessed the relative roles of environmental and spatial factors in driving variation in assemblage composition within each drainage basin. Our analyses were based on a dataset of 95 stream insect metacommunities from 31 drainage basins distributed around the world. We used dissimilarity-based indices to quantify beta diversity for each metacommunity and, subsequently, regressed beta diversity on insect group, latitude, spatial extent, altitudinal range, and dataset properties (e.g., number of sites and percentage of presences). Within each metacommunity, we used a combination of spatial eigenfunction analyses and partial redundancy analysis to partition variation in assemblage structure into environmental, shared, spatial, and unexplained fractions. We found that dataset properties were more important predictors of beta diversity than ecological and geographical factors across multiple drainage basins. In the within-basin analyses, environmental and spatial variables were generally poor predictors of variation in assemblage composition. Our results revealed deviation from general biodiversity patterns because beta diversity did not show the expected decreasing trend with latitude. Our results also call for reconsideration of just how predictable stream assemblages are along ecological gradients, with implications for environmental assessment and conservation decisions. Our findings may also be applicable to other dynamic systems where predictability is low

Strong Neutral Spatial Effects Shape Tree Species Distributions across Life Stages at Multiple Scales

Traditionally, ecologists use lattice (regional summary) count data to simulate tree species distributions to explore species coexistence. However, no previous study has explicitly compared the difference between using lattice count and basal area data and analyzed species distributions at both individual species and community levels while simultaneously considering the combined scenarios of life stage and scale. In this study, we hypothesized that basal area data are more closely related to environmental variables than are count data because of strong environmental filtering effects. We also address the contribution of niche and the neutral (i.e., solely dependent on distance) factors to species distributions. Specifically, we separately modeled count data and basal area data while considering life stage and scale effects at the two levels with simultaneous autoregressive models and variation partitioning. A principal coordinates of neighbor matrix (PCNM) was used to model neutral spatial effects at the community level. The explained variations of species distribution data did not differ significantly between the two types of data at either the individual species level or the community level, indicating that the two types of data can be used nearly identically to model species distributions. Neutral spatial effects represented by spatial autoregressive parameters and the PCNM eigenfunctions drove species distributions on multiple scales, different life stages and individual species and community levels in this plot. We concluded that strong neutral spatial effects are the principal mechanisms underlying the species distributions and thus shape biodiversity spatial patterns

Inferring Ecological Processes from Taxonomic, Phylogenetic and Functional Trait β-Diversity

Understanding the influences of dispersal limitation and environmental filtering on the structure of ecological communities is a major challenge in ecology. Insight may be gained by combining phylogenetic, functional and taxonomic data to characterize spatial turnover in community structure (β-diversity). We develop a framework that allows rigorous inference of the strengths of dispersal limitation and environmental filtering by combining these three types of β-diversity. Our framework provides model-generated expectations for patterns of taxonomic, phylogenetic and functional β-diversity across biologically relevant combinations of dispersal limitation and environmental filtering. After developing the framework we compared the model-generated expectations to the commonly used “intuitive” expectation that the variance explained by the environment or by space will, respectively, increase monotonically with the strength of environmental filtering or dispersal limitation. The model-generated expectations strongly departed from these intuitive expectations: the variance explained by the environment or by space was often a unimodal function of the strength of environmental filtering or dispersal limitation, respectively. Therefore, although it is commonly done in the literature, one cannot assume that the strength of an underlying process is a monotonic function of explained variance. To infer the strength of underlying processes, one must instead compare explained variances to model-generated expectations. Our framework provides these expectations. We show that by combining the three types of β-diversity with model-generated expectations our framework is able to provide rigorous inferences of the relative and absolute strengths of dispersal limitation and environmental filtering. Phylogenetic, functional and taxonomic β-diversity can therefore be used simultaneously to infer processes by comparing their empirical patterns to the expectations generated by frameworks similar to the one developed here