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  • Kess, Tony; Bentzen, Paul; Lehnert, Sarah J.; Sylvester, Emma V.A.; Lien, Sigbjorn; Kent, Matthew P.; Sinclair-Waters, Marion; Morris, Corey J.; Regular, Paul; Fairweather, Robert; Bradbury, Ian R. (2019)
    Chromosome structural variation may underpin ecologically important intraspecific diversity by reducing recombination within supergenes containing linked, coadapted alleles. Here, we confirm that an ancient chromosomal rearrangement is strongly associated with migratory phenotype and individual genetic structure in Atlantic cod (Gadus morhua) across the Northwest Atlantic. We reconstruct trends in effective population size over the last century and reveal declines in effective population size matching onset of industrialized harvest (after 1950). We find different demographic trajectories between individuals homozygous for the chromosomal rearrangement relative to heterozygous or homozygous individuals for the noninverted haplotype, suggesting different selective histories across the past 150 years. These results illustrate how chromosomal structural diversity can mediate fine-scale genetic, phenotypic, and demographic variation in a highly connected marine species and show how overfishing may have led to loss of biocomplexity within Northern cod stock.
  • Näkki, Annu; Kouhia, Sanna T.; Saarela, Janna; Harilainen, Arsi; Tallroth, Kaj; Videman, Tapio; Battie, Michele C.; Kaprio, Jaakko; Peltonen, Leena; Kujala, Urho M. (2010)
    BACKGROUND: In search for genes predisposing to osteoarthritis (OA), several genome wide scans have provided evidence for linkage on 2q. In this study we targeted a 470 kb region on 2q11.2 presenting the locus with most evidence for linkage to severe OA of distal interphalangeal joints (DIP) in our genome wide scan families. METHODS: We genotyped 32 single nucleotide polymorphisms (SNPs) in this 470 kb region comprising six genes belonging to the interleukin 1 superfamily and monitored for association with individual SNPs and SNP haplotypes among severe familial hand OA cases (material extended from our previous linkage study; n = 134), unrelated end-stage bilateral primary knee OA cases (n = 113), and population based controls (n = 436). RESULTS: Four SNPs in the IL1R1 gene, mapping to a 125 kb LD block, provided evidence for association with hand OA in family-based and case-control analysis, the strongest association being with SNP rs2287047 (p-value = 0.0009). CONCLUSIONS: This study demonstrates an association between severe hand OA and IL1R1 gene. This gene represents a highly relevant biological candidate since it encodes protein that is a known modulator of inflammatory processes associated with joint destruction and resides within a locus providing consistent evidence for linkage to hand OA. As the observed association did not fully explain the linkage obtained in the previous study, it is plausible that also other variants in this genome region predispose to hand OA.
  • Holden, Lindsay A.; Arumilli, Meharji; Hytonen, Marjo K.; Hundi, Sruthi; Salojärvi, Jarkko; Brown, Kim H.; Lohi, Hannes (2018)
    Dogs are excellent animal models for human disease. They have extensive veterinary histories, pedigrees, and a unique genetic system due to breeding practices. Despite these advantages, one factor limiting their usefulness is the canine genome reference (CGR) which was assembled using a single purebred Boxer. Although a common practice, this results in many high-quality reads remaining unmapped. To address this whole-genome sequence data from three breeds, Border Collie (n = 26), Bearded Collie (n = 7), and Entlebucher Sennenhund (n = 8), were analyzed to identify novel, non-CGR genomic contigs using the previously validated pseudo-de novo assembly pipeline. We identified 256,957 novel contigs and paired-end relationships together with BLAT scores provided 126,555 (49%) high-quality contigs with genomic coordinates containing 4.6 Mb of novel sequence absent from the CGR. These contigs close 12,503 known gaps, including 2.4 Mb containing partially missing sequences for 11.5% of Ensembl, 16.4% of RefSeq and 12.2% of canFam3.1+ CGR annotated genes and 1,748 unmapped contigs containing 2,366 novel gene variants. Examples for six disease-associated genes (SCARF2, RD3, COL9A3, FAM161A, RASGRP1 and DLX6) containing gaps or alternate splice variants missing from the CGR are also presented. These findings from non-reference breeds support the need for improvement of the current Boxer-only CGR to avoid missing important biological information. The inclusion of the missing gene sequences into the CGR will facilitate identification of putative disease mutations across diverse breeds and phenotypes.
  • Nakki, Annu; Rodriguez-Fontenla, Cristina; Gonzalez, Antonio; Harilainen, Arsi; Leino-Arjas, Paivi; Heliovaara, Markku; Eriksson, Johan G.; Tallroth, Kaj; Videman, Tapio; Kaprio, Jaakko; Saarela, Janna; Kujala, Urho M. (2016)
    Objectives: Osteoarthritis (OA) is a joint disease common in the elderly. There is a prior functional evidence for different matrix metalloproteinases (MMPs), such as MMP8 and MMP9, having a role in the breakdown of cartilage extracellular matrix in OA. Thus, we analyzed whether the common genetic variants of MMP8 and MMP9 contribute to the risk of OA. Materials and methods: In total, 13 common tagging single-nucleotide polymorphisms (SNPs) were studied in a discovery knee OA cohort of 185 cases and 895 controls. For validation, two knee OA replication cohorts and two hand OA replication cohorts were studied (altogether 1369 OA cases, 4445 controls in the five cohorts). The chi(2) test for individual study cohorts and Cochran-Mantel-Haenszel test for combined meta-analysis were calculated using Plink. Results: The rs1940475 SNP in MMP8 showed suggestive association in the discovery cohort (OR = 0.721, 95% CI 0.575-0.906; p = 0.005). Other knee and hand OA replication study cohorts showed similar trend for the predisposing allele without reaching statistical significance in independent replication cohorts nor in their meta-analysis (p > 0.05). Meta-analysis of all five hand and knee OA study cohorts yielded a p-value of 0.027 (OR = 0.904, 95% CI 0.826-0.989). Conclusions: Initial analysis of the MMP8 gene showed suggestive association between rs1940475 and knee OA, but the finding did not replicate in other study cohorts, even though the trend for predisposing allele was similar in all five cohorts. MMP-8 is a good biological candidate for OA, but our study did not find common variants with significant association in the gene.
  • Valtonen, Mia; Palo, Jukka U.; Aspi, Jouni; Ruokonen, Minna; Kunnasranta, Mervi; Nyman, Tommi (2014)
  • Voronova, Angelika; Rendón-Anaya, Martha; Ingvarsson, Pär; Kalendar, Ruslan; Ruņģis, Dainis (2020)
    Sequencing the giga-genomes of several pine species has enabled comparative genomic analyses of these outcrossing tree species. Previous studies have revealed the wide distribution and extraordinary diversity of transposable elements (TEs) that occupy the large intergenic spaces in conifer genomes. In this study, we analyzed the distribution of TEs in gene regions of the assembled genomes of Pinus taeda and Pinus lambertiana using high-performance computing resources. The quality of draft genomes and the genome annotation have significant consequences for the investigation of TEs and these aspects are discussed. Several TE families frequently inserted into genes or their flanks were identified in both species' genomes. Potentially important sequence motifs were identified in TEs that could bind additional regulatory factors, promoting gene network formation with faster or enhanced transcription initiation. Node genes that contain many TEs were observed in multiple potential transposable element-associated networks. This study demonstrated the increased accumulation of TEs in the introns of stress-responsive genes of pines and suggests the possibility of rewiring them into responsive networks and sub-networks interconnected with node genes containing multiple TEs. Many such regulatory influences could lead to the adaptive environmental response clines that are characteristic of naturally spread pine populations.
  • Lemopoulos, Alexandre; Prokkola, Jenni M.; Uusi-Heikkilä, Silva; Vasemägi, Anti; Huusko, Ari; Hyvarinen, Pekka; Koljonen, Marja-Liisa; Koskiniemi, Jarmo; Vainikka, Anssi (2019)
    The conservation and management of endangered species requires information on their genetic diversity, relatedness and population structure. The main genetic markers applied for these questions are microsatellites and single nucleotide polymorphisms (SNPs), the latter of which remain the more resource demanding approach in most cases. Here, we compare the performance of two approaches, SNPs obtained by restriction-site-associated DNA sequencing (RADseq) and 16 DNA microsatellite loci, for estimating genetic diversity, relatedness and genetic differentiation of three, small, geographically close wild brown trout (Salmo trutta) populations and a regionally used hatchery strain. The genetic differentiation, quantified as F-ST, was similar when measured using 16 microsatellites and 4,876 SNPs. Based on both marker types, each brown trout population represented a distinct gene pool with a low level of interbreeding. Analysis of SNPs identified half- and full-siblings with a higher probability than the analysis based on microsatellites, and SNPs outperformed microsatellites in estimating individual-level multilocus heterozygosity. Overall, the results indicated that moderately polymorphic microsatellites and SNPs from RADseq agreed on estimates of population genetic structure in moderately diverged, small populations, but RADseq outperformed microsatellites for applications that required individual-level genotype information, such as quantifying relatedness and individual-level heterozygosity. The results can be applied to other small populations with low or moderate levels of genetic diversity.
  • Wennerström, Annika; Vlachopoulou, Efthymia; Lahtela, L. Elisa; Paakkanen, Riitta; Eronen, Katja T.; Seppänen, Mikko; Lokki, Marja-Liisa (2013)
  • Xue, Yali; Mezzavilla, Massimo; Haber, Marc; McCarthy, Shane; Chen, Yuan; Narasimhan, Vagheesh; Gilly, Arthur; Ayub, Qasim; Colonna, Vincenza; Southam, Lorraine; Finan, Christopher; Massaia, Andrea; Chheda, Himanshu; Palta, Priit; Ritchie, Graham; Asimit, Jennifer; Dedoussis, George; Gasparini, Paolo; Palotie, Aarno; Ripatti, Samuli; Soranzo, Nicole; Toniolo, Daniela; Wilson, James F.; Durbin, Richard; Tyler-Smith, Chris; Zeggini, Eleftheria (2017)
    The genetic features of isolated populations can boost power in complex-trait association studies, and an in-depth understanding of how their genetic variation has been shaped by their demographic history can help leverage these advantageous characteristics. Here, we perform a comprehensive investigation using 3,059 newly generated low-depth whole-genome sequences from eight European isolates and two matched general populations, together with published data from the 1000 Genomes Project and UK10K. Sequencing data give deeper and richer insights into population demography and genetic characteristics than genotype-chip data, distinguishing related populations more effectively and allowing their functional variants to be studied more fully. We demonstrate relaxation of purifying selection in the isolates, leading to enrichment of rare and low-frequency functional variants, using novel statistics, DVxy and SVxy. We also develop an isolation-index (Isx) that predicts the overall level of such key genetic characteristics and can thus help guide population choice in future complex-trait association studies.
  • Arnold, Brian; Sohail, Mashaal; Wadsworth, Crista; Corander, Jukka; Hanage, William P.; Sunyaev, Shamil; Grad, Yonatan H. (2020)
    Identifying genetic variation in bacteria that has been shaped by ecological differences remains an important challenge. For recombining bacteria, the sign and strength of linkage provide a unique lens into ongoing selection. We show that derived alleles
  • Petersen, Jessica L.; Mickelson, James R.; Cothran, E. Gus; Andersson, Lisa S.; Axelsson, Jeanette; Bailey, Ernie; Bannasch, Danika; Binns, Matthew M.; Borges, Alexandre S.; Brama, Pieter; Machado, Artur da Camara; Distl, Ottmar; Felicetti, Michela; Fox-Clipsham, Laura; Graves, Kathryn T.; Guerin, Gerard; Haase, Bianca; Hasegawa, Telhisa; Hemmann, Karin; Hill, Emmeline W.; Leeb, Tosso; Lindgren, Gabriella; Lohi, Hannes; Lopes, Maria Susana; McGivney, Beatrice A.; Mikko, Sofia; Orr, Nicholas; Penedo, M. Cecilia T.; Piercy, Richard J.; Raekallio, Marja; Rieder, Stefan; Roed, Knut H.; Silvestrelli, Maurizio; Swinburne, June; Tozaki, Teruaki; Vaudin, Mark; Wade, Claire M.; McCue, Molly E. (2013)
  • Shikano, Takahito; Järvinen, Antero; Marjamaki, Paula; Kahilainen, Kimmo K.; Merilä, Juha (2015)
    Variation in presumably neutral genetic markers can inform us about evolvability, historical effective population sizes and phylogeographic history of contemporary populations. We studied genetic variability in 15 microsatellite loci in six native landlocked Arctic charr (Salvelinus alpinus) populations in northern Fennoscandia, where this species is considered near threatened. We discovered that all populations were genetically highly (mean F-ST approximate to 0.26) differentiated and isolated from each other. Evidence was found for historical, but not for recent population size bottlenecks. Estimates of contemporary effective population size (N-e) ranged from seven to 228 and were significantly correlated with those of historical N-e but not with lake size. A census size (N-C) was estimated to be approximately 300 individuals in a pond (0.14 ha), which exhibited the smallest N-e (i.e. N-e/N-C = 0.02). Genetic variability in this pond and a connected lake is severely reduced, and both genetic and empirical estimates of migration rates indicate a lack of gene flow between them. Hence, albeit currently thriving, some northern Fennoscandian populations appear to be vulnerable to further loss of genetic variability and are likely to have limited capacity to adapt if selection pressures change.
  • Baison, John; Vidalis, Amaryllis; Zhou, Linghua; Chen, Zhi-Qiang; Li, Zitong; Sillanpää, Mikko J.; Bernhardsson, Carolina; Scofield, Douglas; Forsberg, Nils; Grahn, Thomas; Olsson, Lars; Karlsson, Bo; Wu, Harry; Ingvarsson, Pär K.; Lundqvist, Sven-Olof; Niittylae, Totte; Garcia-Gil, M. Rosario (2019)
    Norway spruce is a boreal forest tree species of significant ecological and economic importance. Hence there is a strong imperative to dissect the genetics underlying important wood quality traits in the species. We performed a functional genome-wide association study (GWAS) of 17 wood traits in Norway spruce using 178 101 single nucleotide polymorphisms (SNPs) generated from exome genotyping of 517 mother trees. The wood traits were defined using functional modelling of wood properties across annual growth rings. We applied a Least Absolute Shrinkage and Selection Operator (LASSO-based) association mapping method using a functional multilocus mapping approach that utilizes latent traits, with a stability selection probability method as the hypothesis testing approach to determine a significant quantitative trait locus. The analysis provided 52 significant SNPs from 39 candidate genes, including genes previously implicated in wood formation and tree growth in spruce and other species. Our study represents a multilocus GWAS for complex wood traits in Norway spruce. The results advance our understanding of the genetics influencing wood traits and identifies candidate genes for future functional studies.
  • Palta, Priit; Kaplinski, Lauris; Nagirnaja, Liina; Veidenberg, Andres; Moels, Maert; Nelis, Mari; Esko, Tonu; Metspalu, Andres; Laan, Maris; Remm, Maido (2015)
    DNA copy number variants (CNVs) that alter the copy number of a particular DNA segment in the genome play an important role in human phenotypic variability and disease susceptibility. A number of CNVs overlapping with genes have been shown to confer risk to a variety of human diseases thus highlighting the relevance of addressing the variability of CNVs at a higher resolution. So far, it has not been possible to deterministically infer the allelic composition of different haplotypes present within the CNV regions. We have developed a novel computational method, called PiCNV, which enables to resolve the haplotype sequence composition within CNV regions in nuclear families based on SNP genotyping microarray data. The algorithm allows to i) phase normal and CNV-carrying haplotypes in the copy number variable regions, ii) resolve the allelic copies of rearranged DNA sequence within the haplotypes and iii) infer the heritability of identified haplotypes in trios or larger nuclear families. To our knowledge this is the first program available that can deterministically phase null, mono-, di-, tri- and tetraploid genotypes in CNV loci. We applied our method to study the composition and inheritance of haplotypes in CNV regions of 30 HapMap Yoruban trios and 34 Estonian families. For 93.6% of the CNV loci, PiCNV enabled to unambiguously phase normal and CNV-carrying haplotypes and follow their transmission in the corresponding families. Furthermore, allelic composition analysis identified the co-occurrence of alternative allelic copies within 66.7% of haplotypes carrying copy number gains. We also observed less frequent transmission of CNV-carrying haplotypes from parents to children compared to normal haplotypes and identified an emergence of several de novo deletions and duplications in the offspring.
  • Vaysse, Amaury; Ratnakumar, Abhirami; Derrien, Thomas; Axelsson, Erik; Pielberg, Gerli Rosengren; Sigurdsson, Snaevar; Fall, Tove; Seppala, Eija H.; Hansen, Mark S. T.; Lawley, Cindy T.; Karlsson, Elinor K.; Bannasch, Danika; Vila, Carles; Lohi, Hannes; Galibert, Francis; Fredholm, Merete; Haggstrom, Jens; Hedhammar, Ake; Andre, Catherine; Lindblad-Toh, Kerstin; Hitte, Christophe; Webster, Matthew T.; LUPA Consortium (2011)
  • Hellquist, Anna; Zucchelli, Marco; Lindgren, Cecilia M.; Saarialho-Kere, Ulpu; Järvinen, Tiina; Koskenmies, Sari; Julkunen, Heikki; Onkamo, Päivi; Skoog, Tiina; Panelius, Jaana; Räisänen-Sokolowski, Anne; Hasan, Taina; Widen, Elisabeth; Gunnarson, Iva; Svenungsson, Elisabet; Padyukov, Leonid; Assadi, Ghazaleh; Berglind, Linda; Mäkelä, Ville-Veikko; Kivinen, Katja; Wong, Andrew; Graham, Deborah S. Cunningham; Vyse, Timothy J.; D'Amato, Mauro; Kere, Juha (2009)
  • Lees, John A.; Mai, T. Tien; Galardini, Marco; Wheeler, Nicole E.; Horsfield, Samuel T.; Parkhill, Julian; Corander, Jukka (2020)
    Discovery of genetic variants underlying bacterial phenotypes and the prediction of phenotypes such as antibiotic resistance are fundamental tasks in bacterial genomics. Genome-wide association study (GWAS) methods have been applied to study these relations, but the plastic nature of bacterial genomes and the clonal structure of bacterial populations creates challenges. We introduce an alignment-free method which finds sets of loci associated with bacterial phenotypes, quantifies the total effect of genetics on the phenotype, and allows accurate phenotype prediction, all within a single computationally scalable joint modeling framework. Genetic variants covering the entire pangenome are compactly represented by extended DNA sequence words known as unitigs, and model fitting is achieved using elastic net penalization, an extension of standard multiple regression. Using an extensive set of state-of-the-art bacterial population genomic data sets, we demonstrate that our approach performs accurate phenotype prediction, comparable to popular machine learning methods, while retaining both interpretability and computational efficiency. Compared to those of previous approaches, which test each genotype-phenotype association separately for each variant and apply a significance threshold, the variants selected by our joint modeling approach overlap substantially. IMPORTANCE Being able to identify the genetic variants responsible for specific bacterial phenotypes has been the goal of bacterial genetics since its inception and is fundamental to our current level of understanding of bacteria. This identification has been based primarily on painstaking experimentation, but the availability of large data sets of whole genomes with associated phenotype metadata promises to revolutionize this approach, not least for important clinical phenotypes that are not amenable to laboratory analysis. These models of phenotype-genotype association can in the future be used for rapid prediction of clinically important phenotypes such as antibiotic resistance and virulence by rapid-turnaround or point-of-care tests. However, despite much effort being put into adapting genome-wide association study (GWAS) approaches to cope with bacterium-specific problems, such as strong population structure and horizontal gene exchange, current approaches are not yet optimal. We describe a method that advances methodology for both association and generation of portable prediction models.
  • Kudinov, A. A.; Mantysaari, E. A.; Aamand, G. P.; Uimari, P.; Stranden, I. (2020)
  • Fang, Bohao; Kemppainen, Petri; Momigliano, Paolo; Feng, Xueyun; Merilä, Juha (2020)
    The three-spined stickleback (Gasterosteus aculeatus) is an important model system for the study of parallel evolution in the wild, having repeatedly colonized and adapted to freshwater from the sea throughout the northern hemisphere. Previous studies identified numerous genomic regions showing consistent genetic differentiation between freshwater and marine ecotypes but these had typically limited geographic sampling and mostly focused on the Eastern Pacific region. We analysed population genomic data from global samples of the three-spined stickleback marine and freshwater ecotypes to detect loci involved in parallel evolution at different geographic scales. Most signatures of parallel evolution were unique to the Eastern Pacific and trans-oceanic marine-freshwater differentiation was restricted to a limited number of shared genomic regions, including three chromosomal inversions. On the basis of simulations and empirical data, we demonstrate that this could result from the stochastic loss of freshwater-adapted alleles during the invasion of the Atlantic basin and selection against freshwater-adapted variants in the sea, both of which can reduce standing genetic variation available for freshwater adaptation outside the Eastern Pacific region. Moreover, the elevated linkage disequilibrium associated with marine-freshwater differentiation in the Eastern Pacific is consistent with secondary contact between marine and freshwater populations that evolved in isolation from each other during past glacial periods. Thus, contrary to what earlier studies from the Eastern Pacific region have led us to believe, parallel marine-freshwater differentiation in sticklebacks is far less prevalent and pronounced in all other parts of the species global distribution range. Population genomic data from a global dataset of three-spined sticklebacks show that parallel signatures of marine to freshwater differentiation are less common than previously thought.
  • Okser, Sebastian; Pahikkala, Tapio; Airola, Antti; Salakoski, Tapio; Ripatti, Samuli; Aittokallio, Tero (2014)