Browsing by Subject "PHENOTYPES"

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  • Hisinger-Mölkänen, Hanna; Honkamäki, Jasmin; Kankaanranta, Hannu; Tuomisto, Leena; Backman, Helena; Andersen, Heidi; Lindqvist, Ari; Lehtimäki, Lauri; Sovijärvi, Anssi; Rönmark, Eva; Pallasaho, Paula; Ilmarinen, Pinja; Piirilä, Päivi (2022)
    Background: Although asthma may begin at any age, knowledge about relationship between asthma age of onset and the prevalence and character of different symptoms is scarce. Objectives: The aim of this study was to investigate if adult-diagnosed asthma is associated with more symptoms and different symptom profiles than child-diagnosed asthma.Methods: A FinEsS postal survey was conducted in a random sample of 16 000 20-69-year-old Finnish adults in 2016. Those reporting physician-diagnosed asthma and age at asthma diagnosis were included. Age 18 years was chosen to delineate child-and adult-diagnosed asthma.Results: Of responders (N = 8199, 51.5%), 842 (10.3%) reported asthma diagnosis. Adult -diagnosed asthma was reported by 499 (59.3%) and child-diagnosed by 343 (40.7%). Of re-sponders with adult-diagnosed and child-diagnosed asthma, 81.8% versus 60.6% used asthma medication (p < 0.001), respectively. Current asthma was also more prevalent in adult-diagnosed asthma (89.2% versus 72.0%, p < 0.001). Risk factors of attacks of breathlessness during the last 12 months were adult-diagnosis (OR = 2.41, 95% CI 1.64-3.54, p < 0.001), female gender (OR = 1.49, 1.07-2.08, p = 0.018), family history of asthma (OR = 1.48, 1.07-2.04, p = 0.018) and allergic rhinitis (OR = 1.49, 1.07-2.09, p = 0.019). All the analysed asthma symptoms, except dyspnea in exercise, were more prevalent in adult-diagnosed asthma in age-and gender-adjusted analyses (p = 0.032-
  • Bauer, Witold; Veijola, Riitta; Lempainen, Johanna; Kiviniemi, Minna; Härkönen, Taina; Toppari, Jorma; Knip, Mikael; Gyenesei, Attila; Ilonen, Jorma (2019)
    Context: Children with initial autoantibodies to either insulin (IAA) or glutamic acid decarboxylase (GADA) differ in peak age of seroconversion and have different type 1 diabetes (T1D) risk gene associations, suggesting heterogeneity in the disease process. Objective: To compare the associations of age at seroconversion, HLA risk, and specificity of secondary autoantibodies with the progression of islet autoimmunity between children with either IAA or GADA as their first autoantibody. Design and methods: A cohort of 15,253 children with HLA-associated increased risk of T1D participated in a follow-up program in which islet autoantibodies were regularly measured. The median follow-up time was 6.7 years. Spearman correlation, Kaplan-Meier survival plots, and Cox proportional-hazard models were used for statistical analyses. Results: Persistent positivity for at least one of the tested autoantibodies was detected in 998 children; 388 of children progressed to clinical T1D. Young age at initial seroconversion was associated with a high probability of expansion of IAA-initiated autoimmunity and progression to clinical diabetes, whereas expansion of GADA-initiated autoimmunity and progression to diabetes were not dependent on initial seroconversion age. The strength of HLA risk affected the progression of both IAA- and GADA-initiated autoimmunity. The simultaneous appearance of two other autoantibodies increased the rate of progression to diabetes compared with that of a single secondary autoantibody among subjects with GADA-initiated autoimmunity but not among those with IAA as the first autoantibody. Conclusions: Findings emphasize the differences in the course of islet autoimmunity initiated by either IAA or GADA supporting heterogeneity in the pathogenic process.
  • Pakkasela, Johanna; Ilmarinen, Pinja; Honkamäki, Jasmin; Tuomisto, Leena E.; Andersen, Heidi; Piirilä, Päivi; Hisinger-Mölkänen, Hanna; Sovijärvi, Anssi; Backman, Helena; Lundbäck, Bo; Rönmark, Eva; Kankaanranta, Hannu; Lehtimäki, Lauri (2020)
    Background Onset of allergic asthma has a strong association with childhood but only a few studies have analyzed incidence of asthma from childhood to late adulthood in relation to allergy. The purpose of the study was to assess age-specific incidence of allergic and non-allergic asthma. Methods Questionnaires were sent to 8000 randomly selected recipients aged 20-69 years in Finland in 2016. The response rate was 52.3% (n = 4173). The questionnaire included questions on e.g. atopic status, asthma and age at asthma diagnosis. Asthma was classified allergic if also a physician-diagnosed allergic rhinitis was reported. Results The prevalence of physician-diagnosed asthma and allergic rhinitis were 11.2 and 17.8%, respectively. Of the 445 responders with physician-diagnosed asthma, 52% were classified as allergic and 48% as non-allergic. Median ages at diagnosis of allergic and non-allergic asthma were 19 and 35 years, respectively. Among subjects with asthma diagnosis at ages 0-9, 10-19, 20-29, 30-39, 40-49, 50-59 and 60-69 years, 70, 62, 58, 53, 38, 19 and 33%, respectively, were allergic. For non-allergic asthma, the incidence rate was lowest in children and young adults (0.7/1000/year). It increased after middle age and was highest in older age groups (2.4/1000/year in 50-59 years old). Conclusions The incidence of allergic asthma is highest in early childhood and steadily decreases with advancing age, while the incidence of non-allergic asthma is low until it peaks in late adulthood. After approximately 40 years of age, most of the new cases of asthma are non-allergic.
  • Honkamäki, Jasmin; Piirilä, Päivi; Hisinger-Mölkänen, Hanna; Tuomisto, Leena E.; Andersen, Heidi; Huhtala, Heini; Sovijärvi, Anssi; Lindqvist, Ari; Backman, Helena; Lundbäck, Bo; Rönmark, Eva; Lehtimäki, Lauri; Pallasaho, Paula; Ilmarinen, Pinja; Kankaanranta, Hannu (2021)
    BACKGROUND: Child-onset asthma is known to remit with high probability, but remission in adult-onset asthma is seem-ingly less frequent. Reports of the association between remission and asthma age of onset up to late adulthood are scarce. OBJECTIVE: To evaluate the association between asthma remission, age at diagnosis and gender, and assess risk factors of nonremission. METHODS: In 2016, a random sample of 16,000 subjects aged 20 to 69 years from Helsinki and Western Finland were sent a FinEsS questionnaire. Physician-diagnosed asthma was catego-rized by age at diagnosis to early-(0-11 years), intermediate-(12-39 years), and late-diagnosed (40-69 years) asthma. Asthma remission was defined by not having had asthma symptoms and not having used asthma medication in the past 12 months. RESULTS: Totally, 8199 (51.5%) responded, and 879 reported physician-diagnosed asthma. Remission was most common in early-diagnosed (30.2%), followed by intermediate-diagnosed (17.9%), and least common in late-diagnosed asthma (5.0%) (P < .001), and the median times from diagnosis were 27, 18.5, and 10 years, respectively. In males, the corresponding remission rates were 36.7%, 20.0%, and 3.4%, and in females, 20.4%, 16.6%, and 5.9% (gender difference P < .001). In multivariable binary logistic regression analysis, signifi-cant risk factors of asthma nonremission were intermediate (odds ratio [OR] = 2.15, 95% confidence interval: 1.373.36) and late diagnosis (OR = 11.06, 4.82-25.37) compared with early diagnosis, chronic obstructive pulmonary disease (COPD) (OR = 5.56, 1.26-24.49), allergic rhinitis (OR = 2.28, 1.50-3.46), and family history of asthma (OR = 1.86, 1.22-2.85). Results were similar after excluding COPD. CONCLUSION: Remission was rare in adults diagnosed with asthma after age 40 years in both genders. Late-diagnosed asthma was the most significant independent risk factor for nonremission. (C) 2020 American Academy of Allergy, Asthma & Immunology
  • Heinla, Indrek; Åhlgren, Johanna; Vasar, Eero; Voikar, Vootele (2018)
    Developing reliable mouse models for social behaviour is challenging. Different tests have been proposed, but most of them consist of rather artificial confrontations of unfamiliar mice in novel arenas or are relying on social stress induced by aggressive conspecifics. Natural social interaction in home cage in laboratory has not been investigated well. IntelliCage is a fully automated home-cage system, where activity of the group-housed mice can be monitored along with various cognitive tasks. Here we report the behavioural profile of C57BL/6N (86) and BALB/c (BALB) female mice in IntelliCage when separated by strain, followed by monitoring of activity and formation of 'home-base' after mixing two strains. For that purpose, 3 cages were connected. Significant differences between the strains were established in baseline behaviour in conventional tests and in IntelliCage. The B6 mice showed reduced anxiety-like behaviour in open field and light-dark box, slightly enhanced exploratory activity in IntelliCage during initial adaptation and clearly distinct circadian activity. Mixing of two strains resulted in reduction of body weight and anhedonia in B6 mice. In addition, the B6 mice showed clear preference to previous home-cage, and formed a new home-base faster than BALB mice. In contrast, BALB mice showed enhanced activity and moving between the cages without showing any preference to previous home-cage. It could be argued that social challenge caused changes in both strains and different coping styles are responsible for behavioural manifestations. Altogether, this approach could be useful in modelling and validating mouse models for disorders with disturbed social behaviour.
  • Syrjänen, Leo; Valanne, Susanna; Kuuslahti, Marianne; Tuomela, Tea; Sriram, Ashwin; Sanz, Alberto; Jacobs, Howard T.; Rämet, Mika; Parkkila, Seppo (2015)
    Background: Carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous enzymes that catalyze the reversible hydration reaction of carbon dioxide. CAs are present as six structurally divergent enzyme families: alpha, beta, gamma, delta, zeta and eta. beta-CAs have a wide distribution across different species including invertebrates. Previously, we showed that Drosophila melanogaster beta-CA is a highly active mitochondrial enzyme. In this study, we investigated the function of Drosophila beta-CA by silencing the expression of the beta-CA gene using UAS/GAL4-based RNA interference (RNAi) in Drosophila in vivo. Results: Crossing beta-CA RNAi lines over ubiquitous Actin driver flies did not produce any viable progeny, indicating that beta-CA expression is required for fly development. RNAi silencing of beta-CA ubiquitously in adult flies did not affect their survival rate or function of mitochondrial electron transport chain. Importantly, beta-CA RNAi led to impaired reproduction. All beta-CA knockdown females were sterile, and produced few or no eggs. Whole ovaries of knockdown females looked normal but upon cadherin staining, there was an apparent functional defect in migration of border cells, which are considered essential for normal fertilization. Conclusions: These results indicate that although Drosophila beta-CA is dispensable for survival of adult flies, it is essential for female fertility.
  • Morandin, Claire; Brendel, Volker P.; Sundstrom, Liselotte; Helantera, Heikki; Mikheyev, Alexander S. (2019)
    Social insects provide systems for studying epigenetic regulation of phenotypes, particularly with respect to differentiation of reproductive and worker castes, which typically arise from a common genetic background. The role of gene expression in caste specialization has been extensively studied, but the role of DNA methylation remains controversial. Here, we perform well replicated, integrated analyses of DNA methylation and gene expression in brains of an ant (Formica exsecta) with distinct female castes using traditional approaches (tests of differential methylation) combined with a novel approach (analysis of co-expression and co-methylation networks). We found differences in expression and methylation profiles between workers and queens at different life stages, as well as some overlap between DNA methylation and expression at the functional level. Large portions of the transcriptome and methylome are organized into "modules" of genes, some significantly associated with phenotypic traits of castes and developmental stages. Several gene co-expression modules are preserved in co-methylation networks, consistent with possible regulation of caste-specific gene expression by DNA methylation. Surprisingly, brain co-expression modules were highly preserved when compared with a previous study that examined whole-body co-expression patterns in 16 ant species, suggesting that these modules are evolutionarily conserved and for specific functions in various tissues. Altogether, these results suggest that DNA methylation participates in regulation of caste specialization and age-related physiological changes in social insects.
  • Holman, Luke; Helantera, Heikki; Trontti, Kalevi; Mikheyev, Alexander S. (2019)
    Queen pheromones are chemical signals that mediate reproductive division of labor in eusocial animals. Remarkably, queen pheromones are composed of identical or chemically similar compounds in some ants, wasps and bees, even though these taxa diverged > 150MYA and evolved queens and workers independently. Here, we measure the transcriptomic consequences of experimental exposure to queen pheromones in workers from two ant and two bee species (genera: Lasius, Apis, Bombus), and test whether they are similar across species. Queen pheromone exposure affected transcription and splicing at many loci. Many genes responded consistently in multiple species, and the set of pheromone-sensitive genes was enriched for functions relating to lipid biosynthesis and transport, olfaction, production of cuticle, oogenesis, and histone (de)acetylation. Pheromone-sensitive genes tend to be evolutionarily ancient, positively selected, peripheral in the gene coexpression network, hypomethylated, and caste-specific in their expression. Our results reveal how queen pheromones achieve their effects, and suggest that ants and bees use similar genetic modules to achieve reproductive division of labor.
  • van Zanten, Sophie E. M. Veldhuijzen; Baugh, Joshua; Chaney, Brooklyn; De Jongh, Dennis; Aliaga, Esther Sanchez; Barkhof, Frederik; Noltes, Johan; De Wolf, Ruben; Van Dijk, Jet; Cannarozzo, Antonio; Damen-Korbijn, Carin M.; Lieverst, Jan A.; Colditz, Niclas; Hoffmann, Marion; Warmuth-Metz, Monika; Bison, Brigitte; Jones, David T. W.; Sturm, Dominik; Gielen, Gerrit H.; Jones, Chris; Hulleman, Esther; Calmon, Raphael; Castel, David; Varlet, Pascale; Giraud, Geraldine; Slavc, Irene; Van Gool, Stefaan; Jacobs, Sandra; Jadrijevic-Cvrlje, Filip; Sumerauer, David; Nysom, Karsten; Pentikäinen, Virve; Kivivuori, Sanna-Maria; Leblond, Pierre; Entz-Werle, Natasha; von Bueren, Andre O.; Kattamis, Antonis; Hargrave, Darren R.; Hauser, Peter; Garami, Miklos; Thorarinsdottir, Halldora K.; Pears, Jane; Gandola, Lorenza; Rutkauskiene, Giedre; Janssens, Geert O.; Torsvik, Ingrid K.; Perek-Polnik, Marta; Gil-da-Costa, Maria J.; Zheludkova, Olga; Shats, Liudmila; SIOPE DIPG Network (2017)
    Diffuse intrinsic pontine glioma (DIPG) is a rare and deadly childhood malignancy. After 40 years of mostly single-center, often non-randomized trials with variable patient inclusions, there has been no improvement in survival. It is therefore time for international collaboration in DIPG research, to provide new hope for children, parents and medical professionals fighting DIPG. In a first step towards collaboration, in 2011, a network of biologists and clinicians working in the field of DIPG was established within the European Society for Paediatric Oncology (SIOPE) Brain Tumour Group: the SIOPE DIPG Network. By bringing together biomedical professionals and parents as patient representatives, several collaborative DIPG-related projects have been realized. With help from experts in the fields of information technology, and legal advisors, an international, web-based comprehensive database was developed, The SIOPE DIPG Registry and Imaging Repository, to centrally collect data of DIPG patients. As for April 2016, clinical data as well as MR-scans of 694 patients have been entered into the SIOPE DIPG Registry/Imaging Repository. The median progression free survival is 6.0 months (95% Confidence Interval (CI) 5.6-6.4 months) and the median overall survival is 11.0 months (95% CI 10.5-11.5 months). At two and five years post-diagnosis, 10 and 2% of patients are alive, respectively. The establishment of the SIOPE DIPG Network and SIOPE DIPG Registry means a paradigm shift towards collaborative research into DIPG. This is seen as an essential first step towards understanding the disease, improving care and (ultimately) cure for children with DIPG.
  • Leppaaho, Eemeli; Renvall, Hanna; Salmela, Elina; Kere, Juha; Salmelin, Riitta; Kaski, Samuel (2019)
    Brain structure and many brain functions are known to be genetically controlled, but direct links between neuroimaging measures and their underlying cellular-level determinants remain largely undiscovered. Here, we adopt a novel computational method for examining potential similarities in high-dimensional brain imaging data between siblings. We examine oscillatory brain activity measured with magnetoencephalography (MEG) in 201 healthy siblings and apply Bayesian reduced-rank regression to extract a low-dimensional representation of familial features in the participants' spectral power structure. Our results show that the structure of the overall spectral power at 1-90Hz is a highly conspicuous feature that not only relates siblings to each other but also has very high consistency within participants' own data, irrespective of the exact experimental state of the participant. The analysis is extended by seeking genetic associations for low-dimensional descriptions of the oscillatory brain activity. The observed variability in the MEG spectral power structure was associated with SDK1 (sidekick cell adhesion molecule 1) and suggestively with several other genes that function, for example, in brain development. The current results highlight the potential of sophisticated computational methods in combining molecular and neuroimaging levels for exploring brain functions, even for high-dimensional data limited to a few hundred participants.
  • Lemmetyinen, Riikka; Karjalainen, Jussi; But, Anna; Renkonen, Risto; Pekkanen, Juha; Haukka, Jari; Toppila-Salmi, Sanna (2021)
    Objectives Many comorbidities are associated with adult asthma and may exacerbate the asthma burden of disease. This study aims to investigate the risk for major oral diseases or oral-manifesting diseases in asthmatic compared with non-asthmatic adults. Design We conducted a population-based matched cohort study with a 13.8-year follow-up. Setting A baseline questionnaire was completed by participants in 1997 and follow-up data were extracted from the national hospital discharge registry of the National Institute for Health and Welfare in Finland from 1997 to 2014. Participants A total of 1394 adults with asthma were matched with 2398 adults without asthma based on sex, age and area of residence. Asthmatic adults were identified from the Drug Reimbursement Register of the Finnish Social Insurance Institution based on a special drug reimbursement right resulting from asthma. Participants without asthma were identified from the Population Register. Main outcomes and measures Oral health-related primary diagnoses were retrieved using codes from the International Classification of Diseases, 10th edition and divided into groups of diseases. Cox's proportional hazards models stratified by matching unit and models matched and adjusted for pack-years, education level and body mass index (when possible) were used to evaluate the matched and further adjusted HRs for diseases comparing asthmatic and non-asthmatic cohorts. Results Adult asthma was associated with a higher risk for any oral-manifesting disease (adjusted HR 1.41, 95% CI 1.11 to 1.80), herpes zoster (adjusted HR 6.18, 95% CI 1.21 to 31.6), benign tumours of the oral cavity and pharynx (matched HR 1.94, 95% CI 1.05 to 3.56) and dermatological diseases (pemphigus, pemphigoid, dermatitis herpetiformis, psoriasis and lichen planus, HR 1.67, 95% CI 1.01 to 2.78). Conclusions In this study, adult asthmatics experienced a higher risk for a major oral disease or oral-manifesting disease.
  • Tani, Haruna; Mito, Takayuki; Velagapudi, Vidya; Ishikawa, Kaori; Umehara, Moe; Nakada, Kazuto; Suomalainen, Anu; Hayashi, Jun-Ichi (2019)
    In a previous study, we proposed that age-related mitochondrial respiration defects observed in elderly subjects are partially due to age-associated downregulation of nuclear-encoded genes, including serine hydroxymethyltransferase 2 (SHMT2), which is involved in mitochondrial one-carbon (1C) metabolism. This assertion is supported by evidence that the disruption of mouse Shmt2 induces mitochondrial respiration defects in mouse embryonic fibroblasts generated from Shmt2-knockout E13.5 embryos experiencing anaemia and lethality. Here, we elucidated the potential mechanisms by which the disruption of this gene induces mitochondrial respiration defects and embryonic anaemia using Shmt2-knockout E13.5 embryos. The livers but not the brains of Shmt2-knockout E13.5 embryos presented mitochondrial respiration defects and growth retardation. Metabolomic profiling revealed that Shmt2 deficiency induced foetal liver-specific downregulation of 1C-metabolic pathways that create taurine and nucleotides required for mitochondrial respiratory function and cell division, respectively, resulting in the manifestation of mitochondrial respiration defects and growth retardation. Given that foetal livers function to produce erythroblasts in mouse embryos, growth retardation in foetal livers directly induced depletion of erythroblasts. By contrast, mitochondrial respiration defects in foetal livers also induced depletion of erythroblasts as a consequence of the inhibition of erythroblast differentiation, resulting in the manifestation of anaemia in Shmt2-knockout E13.5 embryos.
  • Xu, Cheng-Jian; Soderhall, Cilla; Bustamante, Mariona; Baiz, Nour; Gruzieva, Olena; Gehring, Ulrike; Mason, Dan; Chatzi, Leda; Basterrechea, Mikel; Llop, Sabrina; Torrent, Maties; Forastiere, Francesco; Fantini, Maria Pia; Carlsen, Karin C. Lodrup; Haahtela, Tari; Morin, Andreanne; Kerkhof, Marjan; Merid, Simon Kebede; van Rijkom, Bianca; Jankipersadsing, Soesma A.; Bonder, Marc Jan; Ballereau, Stephane; Vermeulen, Cornelis J.; Aguirre-Gamboa, Raul; de Jongste, Johan C.; Smit, Henriette A.; Kumar, Ashish; Pershagen, Goran; Guerra, Stefano; Garcia-Aymerich, Judith; Greco, Dario; Reinius, Lovisa; McEachan, Rosemary R. C.; Azad, Raf; Hovland, Vegard; Mowinckel, Petter; Alenius, Harri; Fyhrquist, Nanna; Lemonnier, Nathanael; Pellet, Johann; Auffray, Charles; van der Vlies, Pieter; van Diemen, Cleo C.; Li, Yang; Wijmenga, Cisca; Netea, Mihai G.; Moffatt, Miriam F.; Cookson, William O. C. M.; Anto, Josep M.; Kere, Juha (2018)
    Background DNA methylation profiles associated with childhood asthma might provide novel insights into disease pathogenesis. We did an epigenome-wide association study to assess methylation profiles associated with childhood asthma. Methods We did a large-scale epigenome-wide association study (EWAS) within the Mechanisms of the Development of ALLergy (MeDALL) project. We examined epigenome-wide methylation using Illumina Infinium Human Methylation450 BeadChips (450K) in whole blood in 207 children with asthma and 610 controls at age 4-5 years, and 185 children with asthma and 546 controls at age 8 years using a cross-sectional case-control design. After identification of differentially methylated CpG sites in the discovery analysis, we did a validation study in children (4-16 years; 247 cases and 2949 controls) from six additional European cohorts and meta-analysed the results. We next investigated whether replicated CpG sites in cord blood predict later asthma in 1316 children. We subsequently investigated cell-type-specific methylation of the identified CpG sites in eosinophils and respiratory epithelial cells and their related gene-expression signatures. We studied cell-type specificity of the asthma association of the replicated CpG sites in 455 respiratory epithelial cell samples, collected by nasal brushing of 16-year-old children as well as in DNA isolated from blood eosinophils (16 with asthma, eight controls [age 2-56 years]) and compared this with whole-blood DNA samples of 74 individuals with asthma and 93 controls (age 1-79 years). Whole-blood transcriptional profiles associated with replicated CpG sites were annotated using RNA-seq data of subsets of peripheral blood mononuclear cells sorted by fluorescence-activated cell sorting. Findings 27 methylated CpG sites were identified in the discovery analysis. 14 of these CpG sites were replicated and passed genome-wide significance (p Interpretation Reduced whole-blood DNA methylation at 14 CpG sites acquired after birth was strongly associated with childhood asthma. These CpG sites and their associated transcriptional profiles indicate activation of eosinophils and cytotoxic T cells in childhood asthma. Our findings merit further investigations of the role of epigenetics in a clinical context.
  • Bannasch, Danika L.; Kaelin, Christopher B.; Letko, Anna; Loechel, Robert; Hug, Petra; Jagannathan, Vidhya; Henkel, Jan; Roosje, Petra; Hytönen, Marjo K.; Lohi, Hannes; Arumilli, Meharji; Minor, Katie M.; Mickelson, James R.; Drogemuller, Cord; Barsh, Gregory S.; Leeb, Tosso (2021)
    Distinctive colour patterns in dogs are an integral component of canine diversity. Colour pattern differences are thought to have arisen from mutation and artificial selection during and after domestication from wolves but important gaps remain in understanding how these patterns evolved and are genetically controlled. In other mammals, variation at the ASIP gene controls both the temporal and spatial distribution of yellow and black pigments. Here, we identify independent regulatory modules for ventral and hair cycle ASIP expression, and we characterize their action and evolutionary origin. Structural variants define multiple alleles for each regulatory module and are combined in different ways to explain five distinctive dog colour patterns. Phylogenetic analysis reveals that the haplotype combination for one of these patterns is shared with Arctic white wolves and that its hair cycle-specific module probably originated from an extinct canid that diverged from grey wolves more than 2 million years ago. Natural selection for a lighter coat during the Pleistocene provided the genetic framework for widespread colour variation in dogs and wolves. Dogs exhibit remarkable variation in colour patterns. Here, the authors identify structural variants of independent regulatory modules for ventral and hair cycle expression of the ASIP gene that explain five distinctive dog colour patterns and trace back the origin of one colour pattern to an extinct canid.
  • Nikkola, Elina; Ko, Arthur; Alvarez, Marcus; Cantor, Rita M.; Garske, Kristina; Kim, Elliot; Gee, Stephanie; Rodriguez, Alejandra; Muxel, Reinhard; Matikainen, Niina; Soderlund, Sanni; Motazacker, Mahdi M.; Boren, Jan; Lamina, Claudia; Kronenberg, Florian; Schneider, Wolfgang J.; Palotie, Aarno; Laakso, Markku; Taskinen, Marja-Riitta; Pajukanta, Paivi (2017)
    Background and aims: Hypercholesterolemia confers susceptibility to cardiovascular disease (CVD). Both serum total cholesterol (TC) and LDL-cholesterol (LDL-C) exhibit a strong genetic component (heritability estimates 0.41-0.50). However, a large part of this heritability cannot be explained by the variants identified in recent extensive genome-wide association studies (GWAS) on lipids. Our aim was to find genetic causes leading to high LDL-C levels and ultimately CVD in a large Austrian family presenting with what appears to be autosomal dominant inheritance for familial hypercholesterolemia (FH). Methods: We utilized linkage analysis followed by whole-exome sequencing and genetic risk score analysis using an Austrian multi-generational family with various dyslipidemias, including elevated TC and LDL-C, and one family branch with elevated lipoprotein (a) (Lp(a)). Results: We did not find evidence for genome-wide significant linkage for LDL-C or apparent causative variants in the known FH genes rather, we discovered a particular family-specific combination of nine GWAS LDL-C SNPs (p = 0.02 by permutation), and putative less severe familial hypercholesterolemia mutations in the LDLR and APOB genes in a subset of the affected family members. Separately, high Lp(a) levels observed in one branch of the family were explained primarily by the LPA locus, including short (<23) Kringle IV repeats and rs3798220. Conclusions: Taken together, some forms of FH may be explained by family-specific combinations of LDL-C GWAS SNPs. (c) 2017 Elsevier B.V. All rights reserved.
  • Mahajan, Anubha; Taliun, Daniel; Thurner, Matthias; Robertson, Neil R.; Torres, Jason M.; Rayner, N. William; Payne, Anthony J.; Steinthorsdottir, Valgerdur; Scott, Robert A.; Grarup, Niels; Cook, James P.; Schmidt, Ellen M.; Wuttke, Matthias; Sarnowski, Chloe; Magill, Reedik; Nano, Jana; Gieger, Christian; Trompet, Stella; Lecoeur, Cecile; Preuss, Michael H.; Prins, Bram Peter; Guo, Xiuqing; Bielak, Lawrence F.; Below, Jennifer E.; Bowden, Donald W.; Chambers, John Campbell; Kim, Young Jin; Ng, Maggie C. Y.; Petty, Lauren E.; Sim, Xueling; Zhang, Weihua; Bennett, Amanda J.; Bork-Jensen, Jette; Brummett, Chad M.; Canouil, Mickael; Kardt, Kai-Uwe Ec; Fischer, Krista; Kardia, Sharon L. R.; Kronenberg, Florian; Lall, Kristi; Liu, Ching-Ti; Locke, Adam E.; Luan, Jian'an; Ntalla, Loanna; Nylander, Vibe; Schoenherr, Sebastian; Schurmann, Claudia; Yengo, Loic; Bottinger, Erwin P.; Brandslund, Ivan; Christensen, Cramer; Dedoussis, George; Florez, Jose C.; Ford, Ian; France, Oscar H.; Frayling, Timothy M.; Giedraitis, Vilmantas; Hackinger, Sophie; Hattersley, Andrew T.; Herder, Christian; Ikram, M. Arfan; Ingelsson, Martin; Jorgensen, Marit E.; Jorgensen, Torben; Kriebel, Jennifer; Kuusisto, Johanna; Ligthart, Symen; Lindgren, Cecilia M.; Linneberg, Allan; Lyssenko, Valeriya; Mamakou, Vasiliki; Meitinger, Thomas; Mohlke, Karen L.; Morris, Andrew D.; Nadkarni, Girish; Pankow, James S.; Peters, Annette; Sattar, Naveed; Stancakova, Alena; Strauch, Konstantin; Taylor, Kent D.; Thorand, Barbara; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Tuomilehto, Jaakko; Witte, Daniel R.; Dupuis, Josee; Peyser, Patricia A.; Zeggini, Eleftheria; Loos, Ruth J. F.; Froguel, Philippe; Ingelsson, Erik; Lind, Lars; Groop, Leif; Laakso, Markku; Collins, Francis S.; Jukema, J. Wouter; Palmer, Colin N. A.; Grallert, Harald; Metspalu, Andres; Dehghan, Abbas; Koettgen, Anna; Abecasis, Goncalo R.; Meigs, James B.; Rotter, Jerome; Marchini, Jonathan; Pedersen, Oluf; Hansen, Torben; Langenberg, Claudia; Wareham, Nicholas J.; Stefansson, Kari; Gloyn, Anna L.; Morris, Andrew P.; Boehnke, Michael; McCarthy, Mark (2018)
    We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci,135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency 2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).
  • Silventoinen, Karri; Maia, José; Jelenkovic, Aline; Pereira, Sara; Gouveia, Élvio; Antunes, António; Thomis, Martine; Lefevre, Johan; Kaprio, Jaakko; Freitas, Duarte (2021)
    Objectives To analyze the influence of genetic and environmental factors on the variation in somatotype, physical fitness, and their mutual associations. Methods Twins from 214 pairs (87 monozygotic) of the Autonomous Region of Madeira, Portugal, from 3 to 18 years of age (51% girls) were assessed in anthropometry and physical fitness tests. We estimated endomorphy, mesomorphy, and ectomorphy based on anthropometric measures and physical fitness using the Eurofit test battery. Two age categories were analyzed: children (3-11 years) and adolescents (12-18 years). Genetic and environmental variations were estimated using quantitative genetic twin modeling. Results No genetic sex differences were found, thus boys and girls were pooled in all genetic analyses. Heritability estimates were high for somatotype (a(2)= 0.80-0.93), physical fitness traits (a(2)= 0.67-0.83), and largely similar in children and adolescents. Positive correlations were found for ectomorphy with motor ability and cardiorespiratory endurance as well as for endomorphy and mesomorphy with muscular strength (r= 0.25-0.37). In contrast, negative associations were found for ectomorphy with muscular strength, as well as for endomorphy and mesomorphy with motor ability and cardiorespiratory endurance (-0.46 to -0.26). Twin modeling indicated that these associations were explained mostly by genetic factors in common to the two associated traits (84% or more). Conclusions Associations between somatotype and physical fitness tests are mainly explained by common genetic background in children and adolescents. Therefore, interventions in youth should consider that a child's performance in physical fitness tests partly reflects their inherited physique.
  • Fitak, Robert Rodgers; Mohandesan, Elmira; Corander, Jukka; Yadamsuren, Adiya; Chuluunbat, Battsetseg; Abdelhadi, Omer; Raziq, Abdul; Nagy, Peter; Walzer, Chris; Faye, Bernard; Burger, Pamela Anna (2020)
    Domestication begins with the selection of animals showing less fear of humans. In most domesticates, selection signals for tameness have been superimposed by intensive breeding for economical or other desirable traits. Old World camels, conversely, have maintained high genetic variation and lack secondary bottlenecks associated with breed development. By re-sequencing multiple genomes from dromedaries, Bactrian camels, and their endangered wild relatives, here we show that positive selection for candidate genes underlying traits collectively referred to as 'domestication syndrome' is consistent with neural crest deficiencies and altered thyroid hormone-based signaling. Comparing our results with other domestic species, we postulate that the core set of domestication genes is considerably smaller than the pan-domestication set - and overlapping genes are likely a result of chance and redundancy. These results, along with the extensive genomic resources provided, are an important contribution to understanding the evolutionary history of camels and the genomic features of their domestication. Robert R. Fitak et al. investigate the genetic basis for domestication in camels. They found that the positive selection of candidate domestication genes is consistent with neural crest deficiencies and altered thyroid hormone-based signaling. Their work provides insights to the evolutionary history of camels and genetics of domestication.
  • Montiglio, P. O.; Gotanda, K. M.; Kratochwil, C. F.; Laskowski, K. L.; Farine, D. R. (2020)
    Because genes and phenotypes are embedded within individuals, and individuals within populations, interactions within one level of biological organization are inherently linked to interactors at others. Here, we expand the network paradigm to consider that nodes can be embedded within other nodes, and connections (edges) between nodes at one level of organization form "bridges" for connections between nodes embedded within them. Such hierarchically embedded networks highlight two central properties of biological systems: 1) processes occurring across multiple levels of organization shape connections among biological units at any given level of organization and 2) ecological effects occurring at a given level of organization can propagate up or down to additional levels. Explicitly considering the embedded structure of evolutionary and ecological networks can capture otherwise hidden feedbacks and generate new insights into key biological phenomena, ultimately promoting a broader understanding of interactions in evolutionary theory. Lay Summary: Interactions are ubiquitous across biological systems. Modeling their consequences requires capturing how units are organized across biological scales: gene and protein interactions shape phenotypic traits within individuals, individuals are embedded within populations, populations within communities, and communities within ecosystems. Doing so reveals how indirect connections among units arise from the structure of connections at higher or lower levels of organization, and how effects at one level of the network propagate across neighboring levels.
  • Vaattovaara, Aleksia Fanni Maria; Leppälä, Johanna Maria; Salojärvi, Jarkko Tapani; Wrzaczek, Michael Alois (2019)
    The use of draft genomes of different species and re-sequencing of accessions and populations are now a common tool for plant biology research. The de novo assembled draft genomes make it possible to identify pivotal divergence points in the plant lineage and provide an opportunity to investigate the genomic basis and timing of biological innovations by inferring orthologs between species. Furthermore, re-sequencing facilitates the mapping and subsequent molecular characterization of causative loci for traits including plant stress tolerance or development. In both cases high quality gene annotation, the identification of protein-coding regions, gene promoters and 5’ and 3’ untranslated regions, is critical for investigation of gene function. Annotations are constantly improving but automated gene annotations still require manual curation and experimental validation. This is particularly important for genes with large introns, genes located in regions rich with transposable elements or repeats, large gene families and segmentally duplicated genes. In this opinion paper we highlight the impact of annotation quality on evolutionary analyses, genome-wide association studies and the identification of orthologous genes in plants. Furthermore, we predict that incorporating the accurate information from manual curation into databases will dramatically improve the performance of automated gene predictors.