Browsing by Subject "SINGLE NUCLEOTIDE POLYMORPHISMS"

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  • Gutierrez, Alejandro P.; Bean, Tim P.; Hooper, Chantelle; Stenton, Craig A.; Sanders, Matthew B.; Paley, Richard K.; Rastas, Pasi; Bryrom, Michaela; Matika, Oswald; Houston, Ross D. (2018)
    Ostreid herpesvirus (OsHV) can cause mass mortality events in Pacific oyster aquaculture. While various factors impact on the severity of outbreaks, it is clear that genetic resistance of the host is an important determinant of mortality levels. This raises the possibility of selective breeding strategies to improve the genetic resistance of farmed oyster stocks, thereby contributing to disease control. Traditional selective breeding can be augmented by use of genetic markers, either via marker-assisted or genomic selection. The aim of the current study was to investigate the genetic architecture of resistance to OsHV in Pacific oyster, to identify genomic regions containing putative resistance genes, and to inform the use of genomics to enhance efforts to breed for resistance. To achieve this, a population of approximate to 1,000 juvenile oysters were experimentally challenged with a virulent form of OsHV, with samples taken from mortalities and survivors for genotyping and qPCR measurement of viral load. The samples were genotyped using a recently-developed SNP array, and the genotype data were used to reconstruct the pedigree. Using these pedigree and genotype data, the first high density linkage map was constructed for Pacific oyster, containing 20,353 SNPs mapped to the ten pairs of chromosomes. Genetic parameters for resistance to OsHV were estimated, indicating a significant but low heritability for the binary trait of survival and also for viral load measures (h2 0.12 - 0.25). A genome-wide association study highlighted a region of linkage group 6 containing a significant QTL affecting host resistance. These results are an important step toward identification of genes underlying resistance to OsHV in oyster, and a step toward applying genomic data to enhance selective breeding for disease resistance in oyster aquaculture.
  • Kjaerner-Semb, Erik; Edvardsen, Rolf B.; Ayllon, Fernando; Vogelsang, Petra; Furmanek, Tomasz; Rubin, Carl Johan; Veselov, Alexey E.; Nilsen, Tom Ole; McCormick, Stephen D.; Primmer, Craig R.; Wargelius, Anna (2021)
    Most Atlantic salmon (Salmo salarL.) populations follow an anadromous life cycle, spending early life in freshwater, migrating to the sea for feeding, and returning to rivers to spawn. At the end of the last ice age similar to 10,000 years ago, several populations of Atlantic salmon became landlocked. Comparing their genomes to their anadromous counterparts can help identify genetic variation related to either freshwater residency or anadromy. The objective of this study was to identify consistently divergent loci between anadromous and landlocked Atlantic salmon strains throughout their geographical distribution, with the long-term aim of identifying traits relevant for salmon aquaculture, including fresh and seawater growth, omega-3 metabolism, smoltification, and disease resistance. We used a Pool-seq approach (n = 10-40 individuals per population) to sequence the genomes of twelve anadromous and six landlocked Atlantic salmon populations covering a large part of the Northern Hemisphere and conducted a genomewide association study to identify genomic regions having been under different selection pressure in landlocked and anadromous strains. A total of 28 genomic regions were identified and includedcadm1on Chr 13 andppargc1aon Chr 18. Seven of the regions additionally displayed consistently reduced heterozygosity in fish obtained from landlocked populations, including the genes gpr132, cdca4, and sertad2 on Chr 15. We also found 16 regions, includingigf1on Chr 17, which consistently display reduced heterozygosity in the anadromous populations compared to the freshwater populations, indicating relaxed selection on traits associated with anadromy in landlocked salmon. In conclusion, we have identified 37 regions which may harbor genetic variation relevant for improving fish welfare and quality in the salmon farming industry and for understanding life-history traits in fish.
  • Kringel, Dario; Kaunisto, Mari A.; Lippmann, Catharina; Kalso, Eija; Lötsch, Jörn (2018)
    Background: Many gene variants modulate the individual perception of pain and possibly also its persistence. The limited selection of single functional variants is increasingly being replaced by analyses of the full coding and regulatory sequences of pain-relevant genes accessible by means of next generation sequencing (NGS). Methods: An NGS panel was created for a set of 77 human genes selected following different lines of evidence supporting their role in persisting pain. To address the role of these candidate genes, we established a sequencing assay based on a custom AmpliSeq (TM) panel to assess the exomic sequences in 72 subjects of Caucasian ethnicity. To identify the systems biology of the genes, the biological functions associated with these genes were assessed by means of a computational over-representation analysis. Results: Sequencing generated a median of 2.85 . 10(6) reads per run with a mean depth close to 200 reads, mean read length of 205 called bases and an average chip loading of 71%. A total of 3,185 genetic variants were called. A computational functional genomics analysis indicated that the proposed NGS gene panel covers biological processes identified previously as characterizing the functional genomics of persisting pain. Conclusion: Results of the NGS assay suggested that the produced nucleotide sequences are comparable to those earned with the classical Sanger sequencing technique. The assay is applicable for small to large-scale experimental setups to target the accessing of information about any nucleotide within the addressed genes in a study cohort.
  • Ho, Tho H.; Dang, Kien X.; Lintula, Susanna; Hotakainen, Kristina; Feng, Lin; Olkkonen, Vesa M.; Verschuren, Emmy W.; Tenkanen, Tuomas; Haglund, Caj; Kolho, Kaija-Leena; Stenman, Ulf-Hakan; Stenman, Jakob (2015)
  • Tenhu, Elina; Teräsjärvi, Johanna; Cruzeiro, Manuel Leite; Savonius, Okko; Rugemalira, Emilie; Roine, Irmeli; He, Qiushui; Pelkonen, Tuula (2020)
    Bacterial meningitis (BM) is a severe disease caused by various bacterial pathogens. Toll-like receptors (TLRs) protect humans from invading pathogens. In this study, we determined whether single nucleotide polymorphisms (SNPs) ofTLR4andTLR9are associated with susceptibility to and outcome of BM in Angolan children. Samples were taken from 241 patients and 265 age-matched ethnic controls. The SNPsTLR4rs4986790 (896A > G) andTLR9rs187084 (-1486T > C) were determined by high-resolution melting analysis (HRMA). The frequency of variant genotypes inTLR4was significantly higher in patients withHaemophilus influenzaemeningitis than controls (odds ratio (OR), 2.5; 95% confidence interval (CI), 1.2-5.4;p= 0.021), whereas the frequency of variant genotypes inTLR9was significantly lower in patients withH. influenzaemeningitis than controls (OR, 0.4; 95% CI, 0.2-0.9;p= 0.036). No such differences were found with other causative pathogens, such asStreptococcus pneumoniaeandNeisseria meningitidis. At the time of discharge, patients with meningitis caused by Gram-negative bacteria who were carriers of variantTLR4genotypes had a higher risk of ataxia (OR, 12.91; 95% CI, 1.52-109.80;p= 0.019) and other neurological sequelae (OR, 11.85; 95% CI, 1.07-131.49;p= 0.044) than those with the wild-typeTLR4genotype. Our study suggests an association betweenH. influenzaemeningitis and genetic variation betweenTLR4andTLR9in Angolan children.
  • Hyvarinen, Kati; Ritari, Jarmo; Koskela, Satu; Niittyvuopio, Riitta; Nihtinen, Anne; Volin, Liisa; Gallardo, David; Partanen, Jukka (2017)
    Despite detailed human leukocyte antigen (HLA) matching and modern immunosuppressive therapy, severe graft-versus-host disease (GvHD) remains a major hurdle for successful allogeneic hematopoietic stem cell transplantation (HSCT). As the genetic diversity in GvHD complicates the systematic discovery of associated variants across populations, we studied 122 GvHD-associated single nucleotide polymorphisms (SNPs) in 492 HLA-matched sibling HSCT donor-recipient pairs from Finland and Spain. The association between these candidate SNPs and grade III-IV acute GvHD and extensive chronic GvHD was assessed. The functional effects of the variants were determined using expression and cytokine quantitative trait loci (QTL) database analyses. Clear heterogeneity was observed in the associated markers between the two populations. Interestingly, the majority of markers, such as those annotated to IL1, IL23R, TLR9, TNF, and NOD2 genes, are related to the immunological response by monocytes-macrophages to microbes, a step that precedes GvHD as a result of intestinal lesions. Furthermore, cytokine QTL analysis showed that the GvHD-associated markers regulate IL1 beta, IFN gamma, and IL6 responses. These results support a crucial role for the anti-microbial response in GvHD risk. Furthermore, despite apparent heterogeneity in the genetic markers associated with GvHD, it was possible to identify a biological pathway shared by most markers in both populations.
  • Prasad, Rashmi B.; Groop, Leif (2015)
    Type 2 diabetes (T2D) is a complex disease that is caused by a complex interplay between genetic, epigenetic and environmental factors. While the major environmental factors, diet and activity level, are well known, identification of the genetic factors has been a challenge. However, recent years have seen an explosion of genetic variants in risk and protection of T2D due to the technical development that has allowed genome-wide association studies and next-generation sequencing. Today, more than 120 variants have been convincingly replicated for association with T2D and many more with diabetes-related traits. Still, these variants only explain a small proportion of the total heritability of T2D. In this review, we address the possibilities to elucidate the genetic landscape of T2D as well as discuss pitfalls with current strategies to identify the elusive unknown heritability including the possibility that our definition of diabetes and its subgroups is imprecise and thereby makes the identification of genetic causes difficult.
  • Einarsdottir, Elisabet; Hafren, Lena; Leinonen, Eira; Bhutta, Mahmood F.; Kentala, Erna; Kere, Juha; Mattila, Petri S. (2016)
    To identify genetic risk factors of childhood otitis media (OM), a genome-wide association study was performed on Finnish subjects, 829 affected children, and 2118 randomly selected controls. The most significant and validated finding was an association with an 80 kb region on chromosome 19. It includes the variants rs16974263 (P = 1.77 x 10(-7), OR = 1.59), rs268662 (P = 1.564 x 10(-6), OR = 1.54), and rs4150992 (P = 3.37 x 10(-6), OR = 1.52), and harbors the genes PLD3, SERTAD1, SERTAD3, HIPK4, PRX, and BLVRB, all in strong linkage disequilibrium. In a sub-phenotype analysis of the 512 patients with chronic otitis media with effusion, one marker reached genome-wide significance (rs16974263, P = 2.92 x 10(-8)). The association to this locus was confirmed but with an association signal in the opposite direction, in a UK family cohort of 4860 subjects (rs16974263, P = 3.21 x 10(-4), OR = 0.72; rs4150992, P = 1.62 x 10(-4), OR = 0.71). Thus we hypothesize that this region is important for COME risk in both the Finnish and UK populations, although the precise risk variants or haplotype background remain unclear. Our study suggests that the identified region on chromosome 19 includes a novel and previously uncharacterized risk locus for OM.
  • Ahonen, Saija J.; Pietilä (ent.Rusanen), Elina Maria; Mellersh, Cathryn S.; Tiira, Katriina; Hansen, Liz; Johnson, Gary S.; Lohi, Hannes (2013)
  • Ritari, J.; Hyvärinen, K.; Koskela, S.; Itälä-Remes, M.; Niittyvuopio, R.; Nihtinen, A.; Salmenniemi, U.; Putkonen, M.; Volin, L.; Kwan, T.; Pastinen, T.; Partanen, J. (2019)
    Allogeneic haematopoietic stem cell transplantation currently represents the primary potentially curative treatment for cancers of the blood and bone marrow. While relapse occurs in approximately 30% of patients, few risk-modifying genetic variants have been identified. The present study evaluates the predictive potential of patient genetics on relapse risk in a genome-wide manner. We studied 151 graft recipients with HLA-matched sibling donors by sequencing the whole-exome, active immunoregulatory regions, and the full MHC region. To assess the predictive capability and contributions of SNPs and INDELs, we employed machine learning and a feature selection approach in a cross-validation framework to discover the most informative variants while controlling against overfitting. Our results show that germline genetic polymorphisms in patients entail a significant contribution to relapse risk, as judged by the predictive performance of the model (AUC = 0.72 [95% CI: 0.63-0.81]). Furthermore, the top contributing variants were predictive in two independent replication cohorts (n = 258 and n = 125) from the same population. The results can help elucidate relapse mechanisms and suggest novel therapeutic targets. A computational genomic model could provide a step toward individualized prognostic risk assessment, particularly when accompanied by other data modalities.
  • Lazary, Judit; Dome, Peter; Csala, Iren; Kovacs, Gabor; Faludi, Gabor; Kaunisto, Mari; Dome, Balazs (2014)
  • Hyvärinen, Kati; Koskela, Satu; Niittyvuopio, Riitta; Nihtinen, Anne; Volin, Liisa; Salmenniemi, Urpu; Putkonen, Mervi; Buño, Ismael; Gallardo, David; Itälä-Remes, Maija; Partanen, Jukka; Ritari, Jarmo (2020)
    Graft-vs.-host disease (GvHD) is a major complication after allogeneic hematopoietic stem cell transplantation that causes mortality and severe morbidity. Genetic disparities in human leukocyte antigens between the recipient and donor are known contributors to the risk of the disease. However, the overall impact of genetic component is complex, and consistent findings across different populations and studies remain sparse. To gain a comprehensive understanding of the genes responsible for GvHD, we combined genome-wide association studies (GWAS) from two distinct populations with previously published gene expression studies on GvHD in a single gene-level meta-analysis. We hypothesized that genes driving GvHD should be associated in both data modalities and therefore could be detected more readily through their combined effects in the integrated analysis rather than in separate analyses. The meta-analysis yielded a total of 51 acute GvHD-associated genes (false detection rate [FDR]