Browsing by Subject "Genomics"

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  • Sagath, L.; Lehtokari, V.-L.; Välipakka, S.; Udd, B.; Wallgren-Pettersson, C.; Pelin, K.; Kiiski, K. (2018)
    Background: Our previous array, the Comparative Genomic Hybridisation design (CGH-array) for nemaline myopathy (NM), named the NM-CGH array, revealed pathogenic copy number variation (CNV) in the genes for nebulin (NEB) and tropomyosin 3 (TPM3), as well as recurrent CNVs in the segmental duplication (SD), i.e. triplicate, region of NEB (TRI, exons 82-89, 90-97, 98-105). In the light of this knowledge, we have designed and validated an extended CGH array, which includes a selection of 187 genes known to cause neuromuscular disorders (NMDs). Objective: Our aim was to develop a reliable method for CNV detection in genes related to neuromuscular disorders for routine mutation detection and analysis, as a much-needed complement to sequencing methods. Methods: We have developed a novel custom-made 4×180 k CGH array for the diagnostics of NMDs. It includes the same tiled ultra-high density coverage of the 12 known or putative NM genes as our 8×60 k NM-CGH-array but also comprises a selection of 175 additional genes associated with NMDs, including titin (TTN), at a high to very high coverage. The genes were divided into three coverage groups according to known and potential pathogenicity in neuromuscular disorders. Results: The array detected known and putative CNVs in all three gene coverage groups, including the repetitive regions of NEB and TTN. Conclusions: The targeted neuromuscular disorder 4×180 k array-CGH (NMD-CGH-array v1.0) design allows CNV detection for a broader spectrum of neuromuscular disorders at a high resolution. © 2018 - IOS Press and the authors. All rights reserved.
  • Sipola, Aleksi (Helsingin yliopisto, 2020)
    Most of the standard statistical inference methods rely on the evaluating so called likelihood functions. But in some cases the phenomenon of interest is too complex or the relevant data inapplicable and as a result the likelihood function cannot be evaluated. Such a situation blocks frequentist methods based on e.g. maximum likelihood estimation and Bayesian inference based on estimating posterior probabilities. Often still, the phenomenon of interest can be modeled with a generative model that describes supposed underlying processes and variables of interest. In such scenarios, likelihood-free inference, such as Approximate Bayesian Computation (ABC), can provide an option for overcoming the roadblock. Creating a simulator that implements such a generative model provides a way to explore the parameter space and approximate the likelihood function based on similarity between real world data and the data simulated with various parameter values. ABC provides well defined and studied framework for carrying out such simulation-based inference with Bayesian approach. ABC has been found useful for example in ecology, finance and astronomy, in situations where likelihood function is not practically computable but models and simulators for generating simulated data are available. One such problem is the estimation of recombination rates of bacterial populations from genetic data, which often is unsuitable for typical statistical methods due to infeasibly massive modeling and computation requirements. Overcoming these hindrances should provide valuable insight into evolution of bacteria and possibly aid in tackling significant challenges such as antimicrobial resistance. Still, ABC inference is not without its limitations either. Often considerable effort in defining distance functions, summary statistics and threshold for similarity is required to make the comparison mechanism successful. High computational costs can also be a hindrance in ABC inference; As increasingly complex phenomena and thus models are studied, the computations that are needed for sufficient exploration of parameter space with the simulation-comparison cycles can get too time- and resource-consuming. Thus efforts have been made to improve the efficiency of ABC inference. One improvement here has been the Bayesian Optimization for Likelihood-Free Inference algorithm (BOLFI), which provides efficient method to optimize the exploration of parameter space, reducing the amount of needed simulation-comparison cycles by up to several magnitudes. This thesis aims to describe some of the theoretical and applied aspects of the complete likelihood-free inference pipelines using both Rejection ABC and BOLFI methods. The thesis presents also use case where the neutral evolution recombination rate in Streptococcus pneumoniae population is inferred from well-studied real world genome data set. This inference task is used to provide context and concrete examples for the theoretical aspects, and demonstrations for numerous applied aspects. The implementations, experiments and acquired results are also discussed in some detail.
  • Ostrander, E.A.; Lohi, H.; Dog10K Consortium (2019)
    Dogs are the most phenotypically diverse mammalian species, and they possess more known heritable disorders than any other non-human mammal. Efforts to catalog and characterize genetic variation across well-chosen populations of canines are necessary to advance our understanding of their evolutionary history and genetic architecture. To date, no organized effort has been undertaken to sequence the world's canid populations. The Dog10K Consortium (http://www.dog10kgenomes.org) is an international collaboration of researchers from across the globe who will generate 20× whole genomes from 10 000 canids in 5 years. This effort will capture the genetic diversity that underlies the phenotypic and geographical variability of modern canids worldwide. Breeds, village dogs, niche populations and extended pedigrees are currently being sequenced, and de novo assemblies of multiple canids are being constructed. This unprecedented dataset will address the genetic underpinnings of domestication, breed formation, aging, behavior and morphological variation. More generally, this effort will advance our understanding of human and canine health. © 2019 The Author(s) 2019. Published by Oxford University Press on behalf of China Science Publishing & Media Ltd.
  • Seppälä, Toni; Meretoja, Tuomo (2019)
  • Juteau, Susanna; Koljonen, Virve; Kytölä, Soili (2019)
  • Gershony, Liza C.; Belanger, Janelle M.; Hytonen, Marjo K.; Lohi, Hannes; Famula, Thomas R.; Oberbauer, Anita M. (2020)
    Background Primary hypoadrenocorticism (or Addison's disease, AD) is an autoimmune disease that results in destruction of the adrenal cortex and consequent adrenal insufficiency. The disease has been described in purebred and mixed breed dogs, although some breeds, including the Bearded Collie, are at increased risk for AD. Candidate gene approaches have yielded few associations that appear to be breed-specific. A single other genome-wide association study reported no significant regions of association for AD in Standard Poodles. The present study aimed to identify genomic regions of association for canine AD in Bearded Collies. Results Our study consists of the first genome-wide association analysis to identify a genome-wide significant region of association with canine AD (CFA18). Peaks of suggestive association were also noted on chromosomes 11, 16 and 29. Logistic regression analysis supported an additive effect of risk genotypes at these smaller effect loci on the probability of disease associated with carrying a risk genotype on CFA18. Potential candidate genes involved in adrenal steroidogenesis, regulation of immune responses and/or inflammation were identified within the associated regions of chromosomes 11 and 16. The gene-poor regions of chromosomes 18 and 29 may, however, harbor regulatory sequences that can modulate gene expression and contribute to disease susceptibility. Conclusion Our findings support the polygenic and complex nature of canine AD and identified a strongly associated locus on CFA18 that, when combined with three other smaller effect loci, was predictive of disease. The results offer progress in the identification of susceptibility loci for canine AD in the Bearded Collie. Further studies are needed to confirm association with the suggested candidate genes and identify actual causative mutations involved with AD susceptibility in this breed.
  • Gershony, Liza C; Belanger, Janelle M; Hytönen, Marjo K; Lohi, Hannes; Famula, Thomas R; Oberbauer, Anita M (BioMed Central, 2020)
    Abstract Background Primary hypoadrenocorticism (or Addison’s disease, AD) is an autoimmune disease that results in destruction of the adrenal cortex and consequent adrenal insufficiency. The disease has been described in purebred and mixed breed dogs, although some breeds, including the Bearded Collie, are at increased risk for AD. Candidate gene approaches have yielded few associations that appear to be breed-specific. A single other genome-wide association study reported no significant regions of association for AD in Standard Poodles. The present study aimed to identify genomic regions of association for canine AD in Bearded Collies. Results Our study consists of the first genome-wide association analysis to identify a genome-wide significant region of association with canine AD (CFA18). Peaks of suggestive association were also noted on chromosomes 11, 16 and 29. Logistic regression analysis supported an additive effect of risk genotypes at these smaller effect loci on the probability of disease associated with carrying a risk genotype on CFA18. Potential candidate genes involved in adrenal steroidogenesis, regulation of immune responses and/or inflammation were identified within the associated regions of chromosomes 11 and 16. The gene-poor regions of chromosomes 18 and 29 may, however, harbor regulatory sequences that can modulate gene expression and contribute to disease susceptibility. Conclusion Our findings support the polygenic and complex nature of canine AD and identified a strongly associated locus on CFA18 that, when combined with three other smaller effect loci, was predictive of disease. The results offer progress in the identification of susceptibility loci for canine AD in the Bearded Collie. Further studies are needed to confirm association with the suggested candidate genes and identify actual causative mutations involved with AD susceptibility in this breed.
  • Safdar, Luqman Bin; Almas, Fakhrah; Rehman, Attiq Ur; Umer, Muhammad Jawad; Shah, Syed Mashab Ali; Uddin, Siraj; Ashfaq, Shomaila; Rahman, Hamid Ur; Quraishi, Umar Masood (2020)
    Excess Ni intake has harmful implications on human health, which include chronic bronchitis, reduced lung function, and cancer of lung and nasal sinuses. Like other toxic metals, higher Ni accumulation in grains leads to excess intake by humans when the contaminated grains are consumed as food. There is little information about the genetic factors that regulate Ni uptake in plants. To investigate genetic architecture of Ni uptake in leaf and translocation to grain, we performed a genome-wide association study with genotyping from 90 K array in a historical bread wheat diversity panel from Pakistan. We observed that Ni toxicity caused more than 50 % reductions in biological yield and grain yield, other agronomic traits were also partly or severely affected. Genetic association study helped identify 23 SNP-trait associations involved in Ni uptake in leaf and translocation to grains. These 23 SNPs covered 15 genomic loci at chromosomes 1A, 2D, 3B, 4A and 4B of wheat. The favorable alleles of these SNPs were randomly distributed in subpopulations indicating no selection pressure for this trait during breeding improvement. These regions had 283 low-confidence and 248 high-confidence protein coding genes. Among these, 156 were annotated using databases of wheat and closely related grass species. Since there is no previous report on genetic information of Ni uptake and translocation, these results provide sufficient grounds for further research of candidate genes and varietal development.
  • Mäkinen, Mari; Kuuskeri, Jaana; Laine, Pia; Smolander, Olli-Pekka; Kovalchuk, Andriy; Zeng, Zhen; Asiegbu, Fred; Paulin, Lars; Auvinen, Petri; Lundell, Taina (2019)
    Background The white rot fungus Phlebia radiata, a type species of the genus Phlebia, is an efficient decomposer of plant cell wall polysaccharides, modifier of softwood and hardwood lignin, and is able to produce ethanol from various waste lignocellulose substrates. Thus, P. radiata is a promising organism for biotechnological applications aiming at sustainable utilization of plant biomass. Here we report the genome sequence of P. radiata isolate 79 originally isolated from decayed alder wood in South Finland. To better understand the evolution of wood decay mechanisms in this fungus and the Polyporales phlebioid clade, gene content and clustering of genes encoding specific carbohydrate-active enzymes (CAZymes) in seven closely related fungal species was investigated. In addition, other genes encoding proteins reflecting the fungal lifestyle including peptidases, transporters, small secreted proteins and genes involved in secondary metabolism were identified in the genome assembly of P. radiata. Results The PACBio sequenced nuclear genome of P. radiata was assembled to 93 contigs with 72X sequencing coverage and annotated, revealing a dense genome of 40.4 Mbp with approximately 14 082 predicted protein-coding genes. According to functional annotation, the genome harbors 209 glycoside hydrolase, 27 carbohydrate esterase, 8 polysaccharide lyase, and over 70 auxiliary redox enzyme-encoding genes. Comparisons with the genomes of other phlebioid fungi revealed shared and specific properties among the species with seemingly similar saprobic wood-decay lifestyles. Clustering of especially GH10 and AA9 enzyme-encoding genes according to genomic localization was discovered to be conserved among the phlebioid species. In P. radiata genome, a rich repertoire of genes involved in the production of secondary metabolites was recognized. In addition, 49 genes encoding predicted ABC proteins were identified in P. radiata genome together with 336 genes encoding peptidases, and 430 genes encoding small secreted proteins. Conclusions The genome assembly of P. radiata contains wide array of carbohydrate polymer attacking CAZyme and oxidoreductase genes in a composition identifiable for phlebioid white rot lifestyle in wood decomposition, and may thus serve as reference for further studies. Comparative genomics also contributed to enlightening fungal decay mechanisms in conversion and cycling of recalcitrant organic carbon in the forest ecosystems.
  • Lundell, Taina K.; Mäkelä, Miia R.; de Vries, Ronald P.; Hilden, Kristiina S. (Academic Press, 2014)
    Advances in Botanical Research
    Saprobic (saprotrophic and saprophytic) wood-decay fungi are in majority species belonging to the fungal phylum Basidiomycota, whereas saprobic plant litter-decomposing fungi are species of both the Basidiomycota and the second Dikarya phylum Ascomycota. Wood-colonizing white rot and brown rot fungi are principally polypore, gilled pleurotoid, or corticioid Basidiomycota species of the class Agaricomycetes, which also includes forest and grassland soil-inhabiting and litter-decomposing mushroom species. In this chapter, examples of lignocellulose degradation patterns are presented in the current view of genome sequencing and comparative genomics of fungal wood-decay enzymes. Specific attention is given to the model white rot fungus, lignin-degrading species Phanerochaete chrysosporium and its wood decay-related gene expression (transcriptomics) on lignocellulose substrates. Types of fungal decay patterns on wood and plant lignocellulose are discussed in the view of fungal lifestyle strategies. Potentiality of the plant biomass-decomposing Basidiomycota species, their secreted enzymes and respective lignocellulose-attacking genes is evaluated in regard to development of biotechnological and industrial applications.
  • Porkka, Kimmo; Niemi, Mikko; Leppä, Elli; Västrik, Imre; Partanen, Jukka; Ihalainen, Jarkko; Jokiranta, Sakari; Pöllänen, Pasi (2017)
  • Jokiranta, Sakari; Hotakainen, Kristina; Salonen, Iiris; Pöllänen, Pasi; Hänninen, Kai-Petri; Forsström, Jari; Kunnamo, Ilkka (2017)
  • Salavirta, Heikki; Oksanen, Ilona; Kuuskeri, Jaana; Makela, Miia; Laine, Pia; Paulin, Lars; Lundell, Taina (2014)
    Mitochondria are eukaryotic organelles supporting individual life-style via generation of proton motive force and cellular energy, and indispensable metabolic pathways. As part of genome sequencing of the white rot Basidiomycota species Phlebia radiata, we first assembled its mitochondrial genome (mtDNA). So far, the 156 348 bp mtDNA is the second largest described for fungi, and of considerable size among eukaryotes. The P. radiata mtDNA assembled as single circular dsDNA molecule containing genes for the large and small ribosomal RNAs, 28 transfer RNAs, and over 100 open reading frames encoding the 14 fungal conserved protein subunits of the mitochondrial complexes I, III, IV, and V. Two genes (atp6 and tRNA-IleGAU) were duplicated within 6.1 kbp inverted region, which is a unique feature of the genome. The large mtDNA size, however, is explained by the dominance of intronic and intergenic regions (sum 80% of mtDNA sequence). The intergenic DNA stretches harness short (≤200 nt) repetitive, dispersed and overlapping sequence elements in abundance. Long self-splicing introns of types I and II interrupt eleven of the conserved genes (cox1,2,3; cob; nad1,2,4,4L,5; rnl; rns). The introns embrace a total of 57 homing endonucleases with LAGLIDADGD and GYI-YIG core motifs, which makes P. radiata mtDNA to one of the largest known reservoirs of intron-homing endonucleases. The inverted duplication, intergenic stretches, and intronic features are indications of dynamics and genetic flexibility of the mtDNA, not fully recognized to this extent in fungal mitochondrial genomes previously, thus giving new insights for the evolution of organelle genomes in eukaryotes.
  • Kääriäinen, Helena; Varilo, Teppo (2019)
    Suomalainen tautiperintö tarkoittaa harvinaisia, yhden geenin virheestä johtuvia tauteja, jotka ovat Suomessa yleisempiä kuin muualla. Käsite sisältää sen, että eräitä muualla yleisiä vastaavia tauteja puuttuu suomalaisilta lähes täysin. Kaupungistuminen ja globaali liikkuvuus muuttavat näiden tautien esiintymistä. Genomiikka tarjoaa uusia mahdollisuuksia niiden ehkäisyyn
  • Santos-Cortez, R.L.P.; Bhutta, M.F.; Earl, J.P.; Hafrén, Lena; Jennings, M.; Mell, J.C.; Pichichero, M.E.; Ryan, A.F.; Tateossian, Hilda; Ehrlich, G.D. (2020)
    Objective: To review the most recent advances in human and bacterial genomics as applied to pathogenesis and clinical management of otitis media. Data sources: PubMed articles published since the last meeting in June 2015 up to June 2019. Review methods: A panel of experts in human and bacterial genomics of otitis media was formed. Each panel member reviewed the literature in their respective fields and wrote draft reviews. The reviews were shared with all panel members, and a merged draft was created. The panel met at the 20th International Symposium on Recent Advances in Otitis Media in June 2019, discussed the review and refined the content. A final draft was made, circulated, and approved by the panel members. Conclusion: Trans-disciplinary approaches applying pan-omic technologies to identify human susceptibility to otitis media and to understand microbial population dynamics, patho-adaptation and virulence mechanisms are crucial to the development of novel, personalized therapeutics and prevention strategies for otitis media. Implications for practice: In the future otitis media prevention strategies may be augmented by mucosal immunization, combination vaccines targeting multiple pathogens, and modulation of the middle ear microbiome. Both treatment and vaccination may be tailored to an individual's otitis media phenotype as defined by molecular profiles obtained by using rapidly developing techniques in microbial and host genomics. © 2020 Elsevier B.V.
  • Widén, Elisabeth; Ripatti, Samuli (2017)
  • Palotie, Aarno; Ripatti, Samuli (2017)
  • Snell, Karoliina; Helén, Ilpo (2017)