Genome-wide association analysis reveals distinct genetic architectures for single and combined stress responses in Arabidopsis thaliana
Davila Olivas, Nelson H. ; Kruijer, Willem ; Gort, Gerrit ; Wijnen, Cris L. ; Loon, Joop J.A. van; Dicke, Marcel - \ 2017
New Phytologist 213 (2017)2. - ISSN 0028-646X - p. 838 - 851.
abiotic stress - biotic stress - combined stresses - genome-wide association - specialist herbivores
Plants are commonly exposed to abiotic and biotic stresses. We used 350 Arabidopsis thaliana accessions grown under controlled conditions. We employed genome-wide association analysis to investigate the genetic architecture and underlying loci involved in genetic variation in resistance to: two specialist insect herbivores, Pieris rapae and Plutella xylostella; and combinations of stresses, i.e. drought followed by P. rapae and infection by the fungal pathogen Botrytis cinerea followed by infestation by P. rapae. We found that genetic variation in resistance to combined stresses by drought plus P. rapae was limited compared with B. cinerea plus P. rapae or P. rapae alone. Resistance to the two caterpillars is controlled by different genetic components. There is limited overlap in the quantitative trait loci (QTLs) underlying resistance to combined stresses by drought plus P. rapae or B. cinerea plus P. rapae and P. rapae alone. Finally, several candidate genes involved in the biosynthesis of aliphatic glucosinolates and proteinase inhibitors were identified to be involved in resistance to P. rapae and P. xylostella, respectively. This study underlines the importance of investigating plant responses to combinations of stresses. The value of this approach for breeding plants for resistance to combinatorial stresses is discussed.
Replicated analysis of the genetic architecture of quantitative traits in two wild great tit populations
Santure, Anna W. ; Poissant, Jocelyn ; Cauwer, Isabelle De; Oers, Kees van; Robinson, Matthew R. ; Quinn, John L. ; Groenen, M.A.M. ; Visser, M.E. ; Sheldon, Ben C. ; Slate, Jon - \ 2015
Molecular Ecology 24 (2015)24. - ISSN 0962-1083 - p. 6148 - 6162.
chromosome partitioning - genome-wide association - genomics - GWAS - QTL mapping - quantitative genetics
Currently, there is much debate on the genetic architecture of quantitative traits in wild populations. Is trait variation influenced by many genes of small effect or by a few genes of major effect? Where is additive genetic variation located in the genome? Do the same loci cause similar phenotypic variation in different populations? Great tits (Parus major) have been studied extensively in long-term studies across Europe and consequently are considered an ecological 'model organism'. Recently, genomic resources have been developed for the great tit, including a custom SNP chip and genetic linkage map. In this study, we used a suite of approaches to investigate the genetic architecture of eight quantitative traits in two long-term study populations of great tits - one in the Netherlands and the other in the United Kingdom. Overall, we found little evidence for the presence of genes of large effects in either population. Instead, traits appeared to be influenced by many genes of small effect, with conservative estimates of the number of contributing loci ranging from 31 to 310. Despite concordance between population-specific heritabilities, we found no evidence for the presence of loci having similar effects in both populations. While population-specific genetic architectures are possible, an undetected shared architecture cannot be rejected because of limited power to map loci of small and moderate effects. This study is one of few examples of genetic architecture analysis in replicated wild populations and highlights some of the challenges and limitations researchers will face when attempting similar molecular quantitative genetic studies in free-living populations.
Natural genetic variation for acclimation of photosynthetic light use efficiency to growth irradiance in Arabidopsis
Rooijen, R. van; Aarts, M.G.M. ; Harbinson, J. - \ 2015
Plant Physiology 167 (2015)4. - ISSN 0032-0889 - p. 1412 - 1429.
genome-wide association - chlorophyll fluorescence - photosystem-ii - supramolecular organization - protein-phosphorylation - plant photosynthesis - electron-transport - barley leaves - quantum yield - green plants
Plants are known to be able to acclimate their photosynthesis to the level of irradiance. Here we present the analysis of natural genetic variation for photosynthetic light use efficiency (FPSII) in response to five light environments among 12 genetically diverse Arabidopsis thaliana accessions. We measured acclimation of FPSII to constant growth irradiances of four different levels (100, 200, 400, and 600 µmol m-2 s-1) by imaging chlorophyll fluorescence after 24 days of growth, and compared these results to acclimation of FPSII to a step-wise change in irradiance where the growth irradiance was increased from 100 to 600 µmol m-2 s-1 after 24 days of growth. Genotypic variation for FPSII is shown by calculating heritability for short-term FPSII response to different irradiance levels, as well as for the relation of FPSII measured at light saturation (a measure of photosynthetic capacity) to growth irradiance level, and for the kinetics of the response to a step-wise increase in irradiance from 100 to 600 µmol m-2 s-1. A genome-wide association study for FPSII measured one hour after a step-wise increase in irradiance identified several new candidate genes controlling this trait. In conclusion, the different photosynthetic responses to a changing light environment displayed by different Arabidopsis are due to genetic differences and we have identified candidate genes for the photosynthetic response to an irradiance change. The genetic variation for photosynthetic acclimation to irradiance found in this study will allow future identification and analysis of the causal genes for the regulation of FPSII in plants
Quantitative trait loci and candidate genes underlying genotype by environment interaction in the response of Arabidopsis thaliana to drought
El-Soda, M. ; Kruijer, Willem ; Malosetti, M. ; Koornneef, M. ; Aarts, M.G.M. - \ 2015
Plant, Cell & Environment 38 (2015)3. - ISSN 0140-7791 - p. 585 - 599.
genome-wide association - natural variation - abiotic stress - inbred lines - qtl analysis - growth - reveals - protein - genetics - adaptation
Drought stress was imposed on two sets of Arabidopsis thaliana genotypes grown in sand under short-day conditions and analysed for several shoot and root growth traits. The response to drought was assessed for quantitative trait locus (QTL) mapping in a genetically diverse set of Arabidopsis accessions using genome-wide association (GWA) mapping, and conventional linkage analysis of a recombinant inbred line (RIL) population. Results showed significant genotype by environment interaction (G×E) for all traits in response to different watering regimes. For the RIL population, the observed G×E was reflected in 17 QTL by environment interactions (Q×E), while 17 additional QTLs were mapped not showing Q×E. GWA mapping identified 58 single nucleotide polymorphism (SNPs) associated with loci displaying Q×E and an additional 16 SNPs associated with loci not showing Q×E. Many candidate genes potentially underlying these loci were suggested. The genes for RPS3C and YLS7 were found to contain conserved amino acid differences when comparing Arabidopsis accessions with strongly contrasting drought response phenotypes, further supporting their candidacy. One of these candidate genes co-located with a QTL mapped in the RIL population
Marker-Based Estimation of Heritability in Immortal Populations
Kruijer, W.T. ; Boer, M.P. ; Malosetti, M. ; Flood, P.J. ; Engel, B. ; Kooke, R. ; Keurentjes, J.J.B. ; Eeuwijk, F.A. van - \ 2015
Genetics 199 (2015)2. - ISSN 0016-6731 - p. 379 - 398.
genome-wide association - multi-environment trials - quantitative trait loci - plant-breeding trials - linear mixed models - arabidopsis-thaliana - missing heritability - complex traits - selection - prediction
Heritability is a central parameter in quantitative genetics, both from an evolutionary and a breeding perspective. For plant traits heritability is traditionally estimated by comparing within and between genotype variability. This approach estimates broad-sense heritability, and does not account for different genetic relatedness. With the availability of high-density markers there is growing interest in marker based estimates of narrow-sense heritability, using mixed models in which genetic relatedness is estimated from genetic markers. Such estimates have received much attention in human genetics but are rarely reported for plant traits. A major obstacle is that current methodology and software assume a single phenotypic value per genotype, hence requiring genotypic means. An alternative that we propose here, is to use mixed models at individual plant or plot level. Using statistical arguments, simulations and real data we investigate the feasibility of both approaches, and how these affect genomic prediction with G-BLUP and genome-wide association studies. Heritability estimates obtained from genotypic means had very large standard errors and were sometimes biologically unrealistic. Mixed models at individual plant or plot level produced more realistic estimates, and for simulated traits standard errors were up to 13 times smaller. Genomic prediction was also improved by using these mixed models, with up to a 49% increase in accuracy. For GWAS on simulated traits, the use of individual plant data gave almost no increase in power. The new methodology is applicable to any complex trait where multiple replicates of individual genotypes can be scored. This includes important agronomic crops, as well as bacteria and fungi.
Inter-ethnic differences in genetic variants within the transmembrane protease, serine 6 (TMPRSS6) gene associated with iron status indicators: a systematic review with meta-analyses
Gichohi, W.N. ; Towers, G.W. ; Swinkels, D.W. ; Zimmermann, M.B. ; Feskens, E.J.M. ; Boonstra, A. - \ 2015
Genes & Nutrition 10 (2015). - ISSN 1555-8932 - 15 p.
genome-wide association - deficiency anemia - african-americans - matriptase-2 tmprss6 - serum hepcidin - transferrin saturation - caucasian populations - racial-differences - common variants - united-states
Transmembrane protease, serine 6 (TMPRSS6), is likely to be involved in iron metabolism through its pleiotropic effect on hepcidin concentrations. Recently, genome-wide association studies have identified common variants in the TMPRSS6 gene to be linked to anaemia and low iron status. To get a more precise evaluation of identified TMPRSS6 single nucleotide polymorphism associations with iron status in cohorts of differing continental ancestry, we conducted a systematic review with meta-analyses. We searched the literature using HuGE Navigator, Pubmed and Scopus databases for primarily genome-wide association studies using TMPRSS6 as a free term. Fixed-effects meta-analysis was used to obtain summary estimates of associations. Eleven studies comprised Caucasian populations, four included an Asian population and one study included an African-American population. Differences in minor allele frequencies of 8 TMPRSS6 SNPs (rs855791, rs4820268, rs2111833, rs1421312, rs228921, rs228918, rs228919 and rs575620) across ethnic groups were observed, with the MAF of rs855791 significantly higher in Asian populations than in Caucasians (0.55 vs 0.42, P <0.0001). In the meta-analysis, the A allele of rs855791 was associated with lower Hb and ferritin concentrations in all populations. This allele was also associated with increased serum transferrin receptor and transferrin concentrations. We observed similar associations for the G allele in rs4820268. Clear disparities in associations were found for the African-American population, although not statistically significant. Associations between TMPRSS6 SNPs and anaemia are consistent across Caucasian and Asian populations. This study highlights the need to conduct studies in African populations where iron deficiency is of utmost public health significance.
Genetic resources for quantitative trait analysis: novelty and efficiency in design from an Arabidopsis perspective
Wijnen, C.L. ; Keurentjes, J.J.B. - \ 2014
Current Opinion in Plant Biology 18 (2014). - ISSN 1369-5266 - p. 103 - 109.
genome-wide association - inbred line population - functional genomics - thaliana accession - induced mutations - natural variation - identification - plant - mutagenesis - phenotypes
The use of genetic resources for the analysis of quantitative traits finds its roots in crop breeding but has seen a rejuvenation in Arabidopsis thaliana thanks to specific tools and genomic approaches. Although widely used in numerous crop and natural species, many approaches were first developed in this reference plant. We will discuss the scientific background and historical use of mapping populations in Arabidopsis and highlight the technological innovations that drove the development of novel strategies. We will especially lay emphasis on the methodologies used to generate the diverse population types and designate possible applications. Finally we highlight some of the most recent developments in generating genetic mapping resources and suggest specific usage for these novel tools and concepts.
Prioritization of candidate genes in QTL regions based on associations between traits and biological processes
Bargsten, J.W. ; Nap, J.P.H. ; Sanchez Perez, G.F. ; Dijk, A.D.J. van - \ 2014
BMC Plant Biology 14 (2014). - ISSN 1471-2229
genome-wide association - protein function prediction - arabidopsis-thaliana - nucleotide polymorphisms - enrichment analysis - flowering time - complex traits - oryza-sativa - rice - architecture
Background Elucidation of genotype-to-phenotype relationships is a major challenge in biology. In plants, it is the basis for molecular breeding. Quantitative Trait Locus (QTL) mapping enables to link variation at the trait level to variation at the genomic level. However, QTL regions typically contain tens to hundreds of genes. In order to prioritize such candidate genes, we show that we can identify potentially causal genes for a trait based on overrepresentation of biological processes (gene functions) for the candidate genes in the QTL regions of that trait. Results The prioritization method was applied to rice QTL data, using gene functions predicted on the basis of sequence- and expression-information. The average reduction of the number of genes was over ten-fold. Comparison with various types of experimental datasets (including QTL fine-mapping and Genome Wide Association Study results) indicated both statistical significance and biological relevance of the obtained connections between genes and traits. A detailed analysis of flowering time QTLs illustrates that genes with completely unknown function are likely to play a role in this important trait. Conclusions Our approach can guide further experimentation and validation of causal genes for quantitative traits. This way it capitalizes on QTL data to uncover how individual genes influence trait variation.
Evaluation of a diagnostic ELISA for insect bite hypersensitivity in horses using recombinant Obsoletus complex allergens
Meide, N.M.A. van der; Savelkoul, H.F.J. ; Meulenbroeks, C. ; Ducro, B.J. ; Tijhaar, E.J. - \ 2014
The Veterinary Journal 200 (2014)1. - ISSN 1090-0233 - p. 31 - 37.
genome-wide association - culicoides-obsoletus - plasma-cells - equine ige - antibodies - responses - expression - extract - skin - ceratopogonidae
Culicoides spp. of the Obsoletus complex belong to the most important species of midge, involved in causing insect bite hypersensitivity (IBH) in horses in The Netherlands. The aim of the current study was to evaluate seven different Obsoletus complex-derived recombinant allergens (Cul o 1–Cul o 7) and to compare these with Obsoletus complex whole body extract (WBE) in an IgE ELISA, using sera of 194 clinically-confirmed cases of IBH and 175 unaffected horses. The highest test accuracy was obtained with WBE, followed by Cul o 2, 3 and 5. Two ELISAs with a combination of recombinant allergens, Combi-1 (Cul o 3, 5 and 7) and Combi-2 (Cul o 1, 2, 5 and 7) were additionally performed and both resulted in high test accuracies close to that obtained with WBE. Combi-1 resulted in the best sensitivity and specificity, both 89%. Both Combi-1 and Combi-2 performed less well with samples collected in winter, but over 70% of the IBH-affected horses could still be identified. In conclusion, a combination of three Obsoletus complex recombinant allergens (Cul o 3, 5 and 7) could potentially replace Obsoletus complex WBE in an IgE ELISA for diagnosis of IBH in horses.
Colorectal cancer risk variants on 11q23 and 15q13 are associated with unexplained adenomatous polyposis
Hes, F.J. ; Ruano, D. ; Nieuwenhuis, M. ; Tops, C.M.J. ; Schrumpf, M. ; Nielsen, M. ; Huijts, P.E. ; Wijnen, J. ; Wagner, A. ; Gomet Garcia, E.B. ; Sijmons, R.H. ; Menko, F.H. ; Letteboer, T.G. ; Hoogerbrugge, N. ; Harryvan, J.L. ; Kampman, E. ; Morreau, H. ; Vasen, H.F. ; Wezel, T.G. van - \ 2014
Journal of Medical Genetics 51 (2014)1. - ISSN 0022-2593 - p. 55 - 60.
genome-wide association - susceptibility loci - genetic-variants - apc - mutations - hereditary - families - metaanalysis - mechanisms - phenotype
Background Colorectal adenomatous polyposis is associated with a high risk of colorectal cancer (CRC) and is frequently caused by germline mutations in APC or MUTYH. However, in about 20–30% of patients no underlying gene defect can be identified. In this study, we tested if recently identified CRC risk variants play a role in patients with >10 adenomas. Methods We analysed a total of 16 SNPs with a reported association with CRC in a cohort of 252 genetically unexplained index patients with >10 colorectal adenomas and 745 controls. In addition, we collected detailed clinical information from index patients and their first-degree relatives (FDRs). Results We found a statistically significant association with two of the variants tested: rs3802842 (at chromosome 11q23, OR=1.60, 95% CI 1.3 to 2.0) and rs4779584 (at chromosome 15q13, OR=1.50, 95% CI 1.2 to 1.9). The majority of index patients (84%) had between 10 and 100 adenomas and 15% had >100 adenomas. Only two index patients (1%), both with >100 adenomas, had FDRs with polyposis. Forty-one per cent of the index patients had one or more FDRs with CRC. Conclusions These SNPs are the first common, low-penetrant variants reported to be associated with adenomatous polyposis not caused by a defect in the APC, MUTYH, POLD1 and POLE genes. Even though familial occurrence of polyposis was very rare, CRC was over-represented in FDRs of polyposis patients and, if confirmed, these relatives will therefore benefit from surveillance.
Asian low-androstenone haplotype on pig chromosome 6 does not unfavorably affect production and reproduction traits.
Hidalgo, A.M. ; Bastiaansen, J.W.M. ; Harlizius, B. ; Knol, E.F. ; Lopes, M.S. ; Koning, D.J. De; Groenen, M. - \ 2014
Animal Genetics 45 (2014)6. - ISSN 0268-9146 - p. 874 - 877.
genome-wide association - boar taint - level - fertility - skatole - loci
European pigs that carry Asian haplotypes of a 1.94-Mbp region on pig chromosome 6 have lower levels of androstenone, one of the two main compounds causing boar taint. The objective of our study was to examine potential pleiotropic effects of the Asian low-androstenone haplotypes. A single nucleotide polymorphism marker, rs81308021, distinguishes the Asian from European haplotypes and was used to investigate possible associations of androstenone with production and reproduction traits. Eight traits were available from three European commercial breeds. For the two sow lines studied, a favorable effect on number of teats was detected for the low-androstenone haplotype. In one of these sow lines, a favorable effect on number of spermatozoa per ejaculation was detected for the low-androstenone haplotype. No unfavorable pleiotropic effects were found, which suggests that selection for low-androstenone haplotypes within the 1.94 Mbp would not unfavorably affect the other eight relevant traits.
Comined effects of smoking and alcohol on metabolic syndrome: the lifelines cohort study
Slagter, S.N. ; Vliet-Ostaptchouk, J.V. ; Vonk, J.M. ; Boezen, H.M. ; Dullaart, R.P.F. ; Muller Kobold, A.C. ; Feskens, E.J.M. ; Beek, A.P. van; Klauw, M.M. van der; Wolffenbuttel, B.H.R. - \ 2014
PLoS ONE 9 (2014)4. - ISSN 1932-6203 - 9 p.
genome-wide association - nutrition examination survey - coronary-heart-disease - body-mass index - blood-pressure - waist circumference - cigarette-smoking - physical-activity - national-health - dietary-intake
Introduction - The development of metabolic syndrome (MetS) is influenced by environmental factors such as smoking and alcohol consumption. We determined the combined effects of smoking and alcohol on MetS and its individual components. Methods - 64,046 participants aged 18–80 years from the LifeLines Cohort study were categorized into three body mass index (BMI) classes (BMI1 drink/day) and tobacco showed higher triglycerides levels. Up to 2 drinks/day was associated with a smaller waist circumference in overweight and obese individuals. Consumption of >2 drinks/day increased blood pressure, with the strongest associations found for heavy smokers. The overall metabolic profile of wine drinkers was better than that of non-drinkers or drinkers of beer or spirits/mixed drinks. Conclusion - Light alcohol consumption may moderate the negative associations of smoking with MetS. Our results suggest that the lifestyle advice that emphasizes smoking cessation and the restriction of alcohol consumption to a maximum of 1 drink/day, is a good approach to reduce the prevalence of MetS. Figures
Fine mapping of a quantitative trait locus for bovine milk fat composition on Bos taurus autosome 19
Bouwman, A.C. ; Visker, M.H.P.W. ; Arendonk, J.A.M. van; Bovenhuis, H. - \ 2014
Journal of Dairy Science 97 (2014)2. - ISSN 0022-0302 - p. 1139 - 1149.
genome-wide association - stearoyl-coa desaturase - dairy-cattle - acid-composition - genotype imputation - genetic-parameters - missense mutation - fasn gene - polymorphisms - yield
A major quantitative trait locus (QTL) for milk fat content and fatty acids in both milk and adipose tissue has been detected on Bos taurus autosome 19 (BTA19) in several cattle breeds. The objective of this study was to refine the location of the QTL on BTA19 for bovine milk fat composition using a denser set of markers. Opportunities for fine mapping were provided by imputation from 50,000 genotyped single nucleotide polymorphisms (SNP) toward a high-density SNP panel with up to 777,000 SNP. The QTL region was narrowed down to a linkage disequilibrium block formed by 22 SNP covering 85,007 bp, from 51,303,322 to 51,388,329 bp on BTA19. This linkage disequilibrium block contained 2 genes: coiled-coil domain containing 57 (CCDC57) and fatty acid synthase (FASN). The gene CCDC57 is minimally characterized and has not been associated with bovine milk fat previously, but is expressed in the mammary gland. The gene FASN has been associated with bovine milk fat and fat in adipose tissue before. This gene is a likely candidate for the QTL on BTA19 because of its involvement in de novo fat synthesis. Future studies using sequence data of both CCDC57 and FASN, and eventually functional studies, will have to be pursued to assign the causal variant(s).
Imputation of non-genotyped individuals based on genotyped relatives: assessing the imputation accuracy of a real case scenario in dairy cattle
Bouwman, A.C. ; Hickey, J.M. ; Calus, M.P.L. ; Veerkamp, R.F. - \ 2014
Genetics, Selection, Evolution 46 (2014). - ISSN 0999-193X - 11 p.
genome-wide association - density genotypes - populations - selection - animals - pedigree - information - simulation - prediction - algorithm
Background Imputation of genotypes for ungenotyped individuals could enable the use of valuable phenotypes created before the genomic era in analyses that require genotypes. The objective of this study was to investigate the accuracy of imputation of non-genotyped individuals using genotype information from relatives. Methods Genotypes were simulated for all individuals in the pedigree of a real (historical) dataset of phenotyped dairy cows and with part of the pedigree genotyped. The software AlphaImpute was used for imputation in its standard settings but also without phasing, i.e. using basic inheritance rules and segregation analysis only. Different scenarios were evaluated i.e.: (1) the real data scenario, (2) addition of genotypes of sires and maternal grandsires of the ungenotyped individuals, and (3) addition of one, two, or four genotyped offspring of the ungenotyped individuals to the reference population. Results The imputation accuracy using AlphaImpute in its standard settings was lower than without phasing. Including genotypes of sires and maternal grandsires in the reference population improved imputation accuracy, i.e. the correlation of the true genotypes with the imputed genotype dosages, corrected for mean gene content, across all animals increased from 0.47 (real situation) to 0.60. Including one, two and four genotyped offspring increased the accuracy of imputation across all animals from 0.57 (no offspring) to 0.73, 0.82, and 0.92, respectively. Conclusions At present, the use of basic inheritance rules and segregation analysis appears to be the best imputation method for ungenotyped individuals. Comparison of our empirical animal-specific imputation accuracies to predictions based on selection index theory suggested that not correcting for mean gene content considerably overestimates the true accuracy. Imputation of ungenotyped individuals can help to include valuable phenotypes for genome-wide association studies or for genomic prediction, especially when the ungenotyped individuals have genotyped offspring.
On the relationship between an Asian haplotype on chromosome 6 that reduces androstenone levels in boars and the differential expression of SULT2A1 in the testis
Hidalgo, A.M. ; Bastiaansen, J.W.M. ; Harlizius, B. ; Megens, H.J.W.C. ; Madsen, O. ; Crooijmans, R.P.M.A. ; Groenen, M.A.M. - \ 2014
BMC Genetics 15 (2014). - ISSN 1471-2156
genome-wide association - quantitative trait loci - 16-androstene steroids - pig genomes - taint - gene - domestication - reveals - sulfoconjugation - visualization
Background Androstenone is one of the major compounds responsible for boar taint, a pronounced urine-like odor produced when cooking boar meat. Several studies have identified quantitative trait loci (QTL) for androstenone level on Sus scrofa chromosome (SSC) 6. For one of the candidate genes in the region SULT2A1, a difference in expression levels in the testis has been shown at the protein and RNA level. Results Haplotypes were predicted for the QTL region and their effects were estimated showing that haplotype 1 was consistently related with a lower level, and haplotype 2 with a higher level of androstenone. A recombinant haplotype allowed us to narrow down the QTL region from 3.75 Mbp to 1.94 Mbp. An RNA-seq analysis of the liver and testis revealed six genes that were differentially expressed between homozygotes of haplotypes 1 and 2. Genomic sequences of these differentially expressed genes were checked for variations within potential regulatory regions. We identified one variant located within a CpG island that could affect expression of SULT2A1 gene. An allele-specific expression analysis in the testis did not show differential expression between the alleles of SULT2A1 located on the different haplotypes in heterozygous animals. However a synonymous mutation C166T (SSC6: 49,117,861 bp in Sscrofa 10.2; C/T) was identified within the exon 2 of SULT2A1 for which the haplotype 2 only had the C allele which was higher expressed than the T allele, indicating haplotype-independent allelic-imbalanced expression between the two alleles. A phylogenetic analysis for the 1.94 Mbp region revealed that haplotype 1, associated with low androstenone level, originated from Asia. Conclusions Differential expression could be observed for six genes by RNA-seq analysis. No difference in the ratio of C:T expression of SULT2A1 for the haplotypes was found by the allele-specific expression analysis, however, a difference in expression between the C over T allele was found for a variation within SULT2A1, showing that the difference in androstenone levels between the haplotypes is not caused by the SNP in exon 2.
Genotype x environment interaction QTL mapping in plants: lessons from Arabidopsis
El-Soda, M. ; Malosetti, M. ; Zwaan, B.J. ; Koornneef, M. ; Aarts, M.G.M. - \ 2014
Trends in Plant Science 19 (2014)6. - ISSN 1360-1385 - p. 390 - 398.
quantitative trait loci - genome-wide association - adaptive phenotypic plasticity - flowering time - natural variation - mixed-model - missing heritability - drought tolerance - complex traits - life-history
Plant growth and development are influenced by the genetic composition of the plant (G), the environment (E), and the interaction between them (G × E). To produce suitable genotypes for multiple environments, G × E should be accounted for and assessed in plant-breeding programs. Here, we review the genetic basis of G × E and its consequence for quantitative trait loci (QTL) mapping in biparental and genome-wide association (GWA) mapping populations. We also consider the implications of G × E for understanding plant fitness trade-offs and evolutionary ecology
Genetic diversity and linkage disequilibrium analysis in elite sugar beet breeding lines and wild beet accessions
Adetunji, I. ; Willems, G. ; Tschoep, H. ; Bürkholz, A. ; Barnes, S. ; Boer, M.P. ; Malosetti, M. ; Horemans, S. ; Eeuwijk, F. van - \ 2014
Theoretical and Applied Genetics 127 (2014)3. - ISSN 0040-5752 - p. 559 - 571.
beta-vulgaris l. - genome-wide association - yellow-vein-virus - population-structure - ssp maritima - rhizomania resistance - restorer gene - markers - map - dna
Linkage disequilibrium decay in sugar beet is strongly affected by the breeding history, and varies extensively between and along chromosomes, allowing identification of known and unknown signatures of selection. Genetic diversity and linkage disequilibrium (LD) patterns were investigated in 233 elite sugar beet breeding lines and 91 wild beet accessions, using 454 single nucleotide polymorphisms (SNPs) and 418 SNPs, respectively. Principal coordinate analysis suggested the existence of three groups of germplasm, corresponding to the wild beets, the seed parent and the pollen parent breeding pool. LD was investigated in each of these groups, with and without correction for genetic relatedness. Without correction for genetic relatedness, in the pollen as well as the seed parent pool, LD persisted beyond 50 centiMorgan (cM) on four (2, 3, 4 and 5) and three chromosomes (2, 4 and 6), respectively; after correction for genetic relatedness, LD decayed after
Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease
Meurs, J.B.J. van; Pare, G. ; Schwartz, S.M. ; Hazra, A. ; Tanaka, T. ; Vermeulen, S.H. ; Cotlarciuc, I. ; Yuan, X. ; Malarstig, A. ; Bandinelli, S. ; Bis, J.C. ; Morn, H. ; Brown, M.J. ; Chen, C. ; Chen, Y.D. ; Clarke, R.J. ; Dehghan, A. ; Erdmann, J. ; Ferrucci, L. ; Hamsten, A. ; Hofman, A. ; Hunten, D.J. ; Goel, A. ; Johnson, A.D. ; Kathiresan, S. ; Kampman, E. ; Kiel, D.P. ; Kiemeney, L.A. ; Chambers, J.C. ; Kraft, P. ; Lindemans, J. ; McKnight, B. ; Nelson, C.P. ; O'Donnell, C.J. ; Psaty, B.M. ; Ridken, P.M. ; Rivadeneira, F. ; Rose, L.M. ; Seedoif, U. ; Siscovick, D.S. ; Schunkert, H. ; Selhub, J. ; Ueland, P.M. ; Vollenweiden, P. ; Waeben, G. ; Waterworth, D.M. ; Watkins, H. ; Witteman, J.C.M. ; Heijen, M. den; Jacques, P. ; Uitterlinden, A.G. ; Koonet, J.S. ; Rader, D.J. ; Reilly, M.P. ; Moose, V. ; Chasman, D.I. ; Samani, N.J. ; Ahmadi, K.R. - \ 2013
American Journal of Clinical Nutrition 98 (2013)3. - ISSN 0002-9165 - p. 668 - 676.
genome-wide association - cardiovascular-disease - mendelian randomization - heart-disease - expression - metaanalysis - mthfr - polymorphism - women - identification
Background: The strong observational association between total homocysteine (tHcy) concentrations and risk of coronary artery disease (CAD) and the null associations in the homocysteinelowering trials have prompted the need to identify genetic variants associated with homocysteine concentrations and risk of CAD. Objective: We tested whether common genetic polymorphisms associated with variation in tlicy are also associated with CAD. Design: We conducted a meta-analysis of genome-wide association studies (GWAS) on tHcy concentrations in 44,147 individuals of European descent. Polymolphisms associated with tHcy (P <10(-8)) were tested for association with CAD in 31,400 cases and 92,927 controls. Results: Common variants at 13 loci, explaining 5.9% of the variation in tHcy, were associated with tHcy concentrations, including 6 novel loci in or near MMACHC (2.1 X 10(-9)), SLC17A3 (1.0 x 10(-8)), GTPB10 (1.7 X 10(-8)), CUBN (7.5 X 10(-1)), HNFlA (1.2 x 10(-12)), and FUT2 (6.6 x 10(-9)), and variants previously reported at or near the MTHFR, MTR, CPS1, MUT, NOX4, DPEP1, and CBS genes. Individuals within the highest 10% of the genotype risk score (GRS) had 3-gmol/L higher mean tHcy concentrations than did those within the lowest 10% of the GRS (P = 1 X 10(-36)). The GRS was not associated with risk of CAD (OR: 1.01; 95% CI: 0.98, 1.04; P = 0.49). Conclusions: We identified several novel loci that influence plasma tHcy concentrations. Overall, common genetic variants that influence plasma tHcy concentrations are not associated with risk of CAD in white populations, which further refutes the causal relevance of moderately elevated tHey concentrations and tHcy-related pathways for CAD.
A Next-Generation Sequencing Method for Genotyping-by-Sequencing of Highly Heterozygous Autotetraploid Potato
Uitdewilligen, J.G.A.M.L. ; Wolters, A.M.A. ; hoop, B.B. D'; Borm, T.J.A. ; Visser, R.G.F. ; Eck, H.J. van - \ 2013
PLoS ONE 8 (2013)5. - ISSN 1932-6203 - 14 p.
single-nucleotide polymorphisms - genome-wide association - chloroplast dna - solanum-tuberosum - agronomic traits - hybrid selection - discovery - enrichment - resistance - diversity
Assessment of genomic DNA sequence variation and genotype calling in autotetraploids implies the ability to distinguish among five possible alternative allele copy number states. This study demonstrates the accuracy of genotyping-by-sequencing (GBS) of a large collection of autotetraploid potato cultivars using next-generation sequencing. It is still costly to reach sufficient read depths on a genome wide scale, across the cultivated gene pool. Therefore, we enriched cultivar-specific DNA sequencing libraries using an in-solution hybridisation method (SureSelect). This complexity reduction allowed to confine our study to 807 target genes distributed across the genomes of 83 tetraploid cultivars and one reference (DM 1–3 511). Indexed sequencing libraries were paired-end sequenced in 7 pools of 12 samples using Illumina HiSeq2000. After filtering and processing the raw sequence data, 12.4 Gigabases of high-quality sequence data was obtained, which mapped to 2.1 Mb of the potato reference genome, with a median average read depth of 63× per cultivar. We detected 129,156 sequence variants and genotyped the allele copy number of each variant for every cultivar. In this cultivar panel a variant density of 1 SNP/24 bp in exons and 1 SNP/15 bp in introns was obtained. The average minor allele frequency (MAF) of a variant was 0.14. Potato germplasm displayed a large number of relatively rare variants and/or haplotypes, with 61% of the variants having a MAF below 0.05. A very high average nucleotide diversity (p = 0.0107) was observed. Nucleotide diversity varied among potato chromosomes. Several genes under selection were identified. Genotyping-by-sequencing results, with allele copy number estimates, were validated with a KASP genotyping assay. This validation showed that read depths of ~60–80× can be used as a lower boundary for reliable assessment of allele copy number of sequence variants in autotetraploids. Genotypic data were associated with traits, and alleles strongly influencing maturity and flesh colour were identified.
Increased protein expression of LHCG receptor and 17a-hydroxylase/17,20-lyase in human polycystic ovaries
Comim, F.V. ; Teerds, K.J. ; Hardy, K. ; Franks, S. - \ 2013
Human Reproduction 28 (2013)11. - ISSN 0268-1161 - p. 3086 - 3092.
luteinizing-hormone receptor - genome-wide association - adrenal androgen excess - chromosome 2p16.3 - granulosa-cells - theca cells - follicle - steroidogenesis - women - prevalence
STUDY QUESTION Does the expression of LHCG receptor (LHCGR) protein and key enzymes in the androgen biosynthetic pathway differ in normal human versus polycystic ovarian tissue? SUMMARY ANSWER LHCGR and 17a-hydroxylase/17-20-lyase (CYP17A1) protein levels are increased in polycystic ovaries (PCOs). WHAT IS KNOWN ALREADY The predominant source of excess androgen secretion in women with polycystic ovary syndrome (PCOS) is ovarian theca cells but few studies have directly assessed the presence and abundance of protein for key molecules involved in androgen production by theca, including LHCGR and the rate-limiting enzyme in androgen production, CYP17A1. STUDY DESIGN, SIZE, DURATION This is a laboratory-based, cross-sectional study comparing protein expression of key molecules in the androgen biosynthetic pathway in archived ovarian tissue from women with normal ovaries (n = 10) with those with PCOs (n = 16). PARTICIPANTS/MATERIALS, SETTING, METHODS A quantitative morphometric study was performed using sections of archived human ovaries (n = 26) previously characterized as normal or polycystic. The distribution and abundance of LHCGR, CYP17A1, 3ß-hydroxysteroid dehydrogenase type 2 (3ßHSDII) and 17ß-hydroxysteroid dehydrogenase type 5 (17ßHSD5) proteins were evaluated by immunohistochemistry and quantified. MAIN RESULTS AND THE ROLE OF CHANCE A higher proportion of theca cells from anovulatory PCO expressed LHCGR protein when compared with control ovaries (P = 0.01). A significant increase in the intensity of immunostaining for CYP17A1 was identified in antral follicles in sections of PCO compared with ovaries from normal women (P = 0.04). LIMITATIONS, REASONS FOR CAUTION As the study used formalin-fixed ovarian tissue sections, it was not possible to carry out studies ‘in vitro’ using the same ovarian tissues in order to also demonstrate increased functional activity of LHCGR and CYP17A1. WIDER IMPLICATIONS OF THE FINDINGS The data are in keeping with the results of previous studies in isolated theca cells and support the notion of an intrinsic abnormality of theca cell androgen production in women with PCOS. STUDY FUNDING/COMPETING INTEREST(S) The research was supported by a Programme Grant, G0802782, from the Medical Research Council (MRC) UK and by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London. F.V.C was supported by Capes Foundation (Brazilian Ministry of Education). The authors have no conflicts of interest to disclose.