25 research outputs found
Shaping Arctic’s Tomorrow through Indigenous Knowledge Engagement and Knowledge Co-Production
No full textThis perspective presents a statement of the 10th International Congress of Arctic Social Sciences Indigenous Knowledge and knowledge co-production panel and discussion group, 20 July 2021. The statement is designed to serve as a characterization of the state-of-the-art and guidance for further advancement of Indigenous Knowledge and knowledge co-production in the Arctic. It identifies existing challenges and provides specific recommendations for researchers, Indigenous communities, and funding agencies on meaningful recognition and engagement of Indigenous Knowledge systems
Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis
No full textUsing the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10−4). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10−8), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals
Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders
No full textElevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets
Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke
No full textGenetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 × 10<sup>−11</sup>; odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28–1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes
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Comparison of ADC metrics and their association with outcome for patients with newly diagnosed glioblastoma being treated with radiation therapy, temozolomide, erlotinib and bevacizumab
No full text© 2014 The Author(s) To evaluate metrics that describe changes in apparent diffusion coefficient (ADC) and to examine their association with clinical outcome for patients with newly diagnosed GBM who were participating in a Phase II clinical trial of trea
Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
No full textApproaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups
Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
No full textMultiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis
Novel Approach Identifies SNPs in SLC2A10 and KCNK9 with Evidence for Parent-of-Origin Effect on Body Mass Index
No full textThe phenotypic effect of some single nucleotide polymorphisms (SNPs) depends on their parental origin. We present a novel approach to detect parent-of-origin effects (POEs) in genome-wide genotype data of unrelated individuals. The method exploits increased phenotypic variance in the heterozygous genotype group relative to the homozygous groups. We applied the method to >56,000 unrelated individuals to search for POEs influencing body mass index (BMI). Six lead SNPs were carried forward for replication in five family-based studies (of ~4,000 trios). Two SNPs replicated: the paternal rs2471083-C allele (located near the imprinted KCNK9 gene) and the paternal rs3091869-T allele (located near the SLC2A10 gene) increased BMI equally (beta = 0.11 (SD), P<0.0027) compared to the respective maternal alleles. Real-time PCR experiments of lymphoblastoid cell lines from the CEPH families showed that expression of both genes was dependent on parental origin of the SNPs alleles (P<0.01). Our scheme opens new opportunities to exploit GWAS data of unrelated individuals to identify POEs and demonstrates that they play an important role in adult obesity. © 2014 Hoggart et al
Evolution of microgastropods (Ellobioidea, Carychiidae): integrating taxonomic, phylogenetic and evolutionary hypotheses
No full textBACKGROUND: Current biodiversity patterns are considered largely the result of past climatic and tectonic changes. In an integrative approach, we combine taxonomic and phylogenetic hypotheses to analyze temporal and geographic diversification of epigean (Carychium) and subterranean (Zospeum) evolutionary lineages in Carychiidae (Eupulmonata, Ellobioidea). We explicitly test three hypotheses: 1) morphospecies encompass unrecognized evolutionary lineages, 2) limited dispersal results in a close genetic relationship of geographical proximally distributed taxa and 3) major climatic and tectonic events had an impact on lineage diversification within Carychiidae.
RESULTS: Initial morphospecies assignments were investigated by different molecular delimitation approaches (threshold, ABGD, GMYC and SP). Despite a conservative delimitation strategy, carychiid morphospecies comprise a great number of unrecognized evolutionary lineages. We attribute this phenomenon to historic underestimation of morphological stasis and phenotypic variability amongst lineages. The first molecular phylogenetic hypothesis for the Carychiidae (based on COI, 16S and H3) reveals Carychium and Zospeum to be reciprocally monophyletic. Geographical proximally distributed lineages are often closely related. The temporal diversification of Carychiidae is best described by a constant rate model of diversification. The evolution of Carychiidae is characterized by relatively few (long distance) colonization events. We find support for an Asian origin of Carychium. Zospeum may have arrived in Europe before extant members of Carychium. Distantly related Carychium clades inhabit a wide spectrum of the available bioclimatic niche and demonstrate considerable niche overlap.
CONCLUSIONS: Carychiid taxonomy is in dire need of revision. An inferred wide distribution and variable phenotype suggest underestimated diversity in Zospeum. Several Carychium morphospecies are results of past taxonomic lumping. By collecting populations at their type locality, molecular investigations are able to link historic morphospecies assignments to their respective evolutionary lineage. We propose that rare founder populations initially colonized a continent or cave system. Subsequent passive dispersal into adjacent areas led to in situ pan-continental or mountain range diversifications. Major environmental changes did not influence carychiid diversification. However, certain molecular delimitation methods indicated a recent decrease in diversification rate. We attribute this decrease to protracted speciation
Plant reproduction in the alpine landscape : reproductive ecology, genetic diversity and gene flow of the rare monocarpic "Campanula thyrsoides" in the Swiss Alps
No full textAims & Objectives
The work presented in this thesis forms part of a larger project “How patchy
habitat and isolation affect alpine plant life: genetic diversity, gene flow and mating
systems”, which includes the PhD studies of Patrick Kuss and the author under the
supervision of Professor Jürg Stöcklin.
This doctoral thesis investigates the consequences of the natural fragmentation
and patchiness of alpine landscapes on the life of alpine plant populations. The central
focus of the thesis is on the mating system, the role of inbreeding and/or outbreeding
depression, genetic diversity and geographic structure within and among populations
of the rare Alpine monocarpic perennial Campanula thyrsoides. The main objectives
and research questions addressed are:
• Is Campanula thyrsoides self-compatible (SI) and if not, does the SI system
break down with flower age? Do inbred C. thyrsoides offspring in the common
garden suffer from inbreeding depression?
• Do we find a distance related inbreeding depression (poorer reproducive
output) or outbreeding depression (increased reproductive output) in field
populations of C. thyrsoides following crosses of different crossing distances
(selfing, 1m, 10m, 100m and among distant populations)?
• How much genetic diversity exists within populations of C. thyrsoides and
how does it relate to population size and altitude? Has the natural habitat
fragmentation let to strong genetic differentiation and restricted gene flow
among populations of C. thyrsoides resulting in a pronounced geographic
structure?
Study species
In order to seek answers to our research questions, we choose to study a
yellow bellflower; Campanula thyrsoides. The choice was based on the information
that C. thyrsoides is a rare plant species, which is only found on calcarious soils
within the European Alps and adjacent mountain ranges (Aeschimann et al. 2005).
The plants selectiveness for carbonate bearing soils together with the fact that its
seeds are not adapted to long-distance dispersal (Tackenberg 2003) are the main
reasons for the isolation and small sizes of many of its populations. These population
characteristics, therefore, made C. thyrsoides a suitable study species. Another
important characteristic of C. thyrsoides, and one of the main reasons for its inclusion
in the study is because it is a monocarpic perennial which flowers once and
subsequently dies (Jäger 2000). Monocarpic plants species, which are more
commonly found in subtropical and tropical mountain systems (e.g. the giant rosettes
of Puya spp, Espeletia spp., Echium spp. etc., Smith & Young 1987; Young &
Augspurger 1991) are rare amidst the temperate alpine flora (for the Alps, see
Aeschimann et al. 2005). Monocarpy can promote genetic differentiation between
populations by reducing the effective population size due to a shorter generation time
and lower density of populations (Loveless & Hamrick 1984; Vitalis et al. 2004).
When studying the effects of population isolation and habitat fragmentation on
plant reproduction (e.g. mating system and inbreeding depression), it is, moreover,
ideal to study a Campanula species. Although most Campanula species are selfincompatible
and allogamous (Nyman 1993), both a break-down in the SI system with
flower age (Vogler et al. 1998) and an evolution towards complete self-compatibility
(Ægisdóttir & Thórhallsdóttir 2006) have been recorded.
Design
We studied the reproductive ecology and genetic diversity of Campanula
thyrsoides by firstly setting up pollination experiments in the common garden and in
the field and secondly by sampling leaf material in 32 field populations in
Switzerland. In the common garden study, we set up a pollination experiment in order
to study the breeding system of C. thyrsoides, including the consequences of selfing,
half-sibling crossings and outcrossing on reproductive output and seedling
performance. Moreover, field experiments in four populations were set up in the
Swiss Alps in order to study the effect of different crossing distances on reproduction
in C. thyrsoides and to see if evidence would be found of hidden inbreeding
depression or outbreeding depression following large-distance crossings compared to
within-population crossings. In addition, we studied the genetic diversity, gene flow
and geographical structure within and among 32 field populations of C. thyrsoides in
Switzerland, covering both large geographical and altitudinal ranges. The genetic
study was conducted using 5 co-dominant microsatellite markers. In addition, we
studied the genetic diversity in C. thyrsoides and two other alpine plants using random
amplified polymorphic DNA (RAPD) marker as well as studing the evolutionary
demography of C. thyrsoides
