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Sökning: L773:1553 7404 > (2015-2019) > (2019)

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1.
  • Biasoli, Deborah, et al. (författare)
  • A synonymous germline variant in a gene encoding a cell adhesion molecule is associated with cutaneous mast cell tumour development in Labrador and Golden Retrievers
  • 2019
  • Ingår i: PLOS Genetics. - : PUBLIC LIBRARY SCIENCE. - 1553-7390 .- 1553-7404. ; 15:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Mast cell tumours are the most common type of skin cancer in dogs, representing a significant concern in canine health. The molecular pathogenesis is largely unknown, but breed-predisposition for mast cell tumour development suggests the involvement of inherited genetic risk factors in some breeds. In this study, we aimed to identify germline risk factors associated with the development of mast cell tumours in Labrador Retrievers, a breed with an elevated risk of mast cell tumour development. Using a methodological approach that combined a genome-wide association study, targeted next generation sequencing, and TaqMan genotyping, we identified a synonymous variant in the DSCAM gene on canine chromosome 31 that is associated with mast cell tumours in Labrador Retrievers. DSCAM encodes a cell-adhesion molecule. We showed that the variant has no effect on the DSCAM mRNA level but is associated with a significant reduction in the level of the DSCAM protein, suggesting that the variant affects the dynamics of DSCAM mRNA translation. Furthermore, we showed that the variant is also associated with mast cell tumours in Golden Retrievers, a breed that is closely related to Labrador Retrievers and that also has a predilection for mast cell tumour development. The variant is common in both Labradors and Golden Retrievers and consequently is likely to be a significant genetic contributor to the increased susceptibility of both breeds to develop mast cell tumours. The results presented here not only represent an important contribution to the understanding of mast cell tumour development in dogs, as they highlight the role of cell adhesion in mast cell tumour tumourigenesis, but they also emphasise the potential importance of the effects of synonymous variants in complex diseases such as cancer. Author summary The combination of various genetic and environmental risk factors makes the understanding of the molecular circuitry behind complex diseases, like cancer, a major challenge. The homogeneous nature of pedigree dog breed genomes makes these dogs ideal for the identification of both simple disease-causing genetic variants and genetic risk factors for complex diseases. Mast cell tumours are the most common type of canine skin cancer, and one of the most common cancers affecting dogs of most breeds. Several breeds, including Labrador Retrievers (which represent one of the most popular dog breeds), have an elevated risk of mast cell tumour development. Here, by using a methodological approach that combined different techniques, we identified a common inherited synonymous variant, that predisposes Labrador Retrievers to mast cell tumour development. Interestingly, we showed that this variant, despite its synonymous nature, appears to have an effect on translation dynamics as it is associated with reduced levels of DSCAM, a cell adhesion molecule. The results presented here reveal dysregulation of cell adhesion to be an important factor in mast cell tumour pathogenesis, and also highlight the important role that synonymous variants can play in complex diseases.
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2.
  • Eisfeldt, J., et al. (författare)
  • Comprehensive structural variation genome map of individuals carrying complex chromosomal rearrangements
  • 2019
  • Ingår i: PLOS Genetics. - : NLM (Medline). - 1553-7390 .- 1553-7404. ; 15:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Complex chromosomal rearrangements (CCRs) are rearrangements involving more than two chromosomes or more than two breakpoints. Whole genome sequencing (WGS) allows for outstanding high resolution characterization on the nucleotide level in unique sequences of such rearrangements, but problems remain for mapping breakpoints in repetitive regions of the genome, which are known to be prone to rearrangements. Hence, multiple complementary WGS experiments are sometimes needed to solve the structures of CCRs. We have studied three individuals with CCRs: Case 1 and Case 2 presented with de novo karyotypically balanced, complex interchromosomal rearrangements (46,XX,t(2;8;15)(q35;q24.1;q22) and 46,XY,t(1;10;5)(q32;p12;q31)), and Case 3 presented with a de novo, extremely complex intrachromosomal rearrangement on chromosome 1. Molecular cytogenetic investigation revealed cryptic deletions in the breakpoints of chromosome 2 and 8 in Case 1, and on chromosome 10 in Case 2, explaining their clinical symptoms. In Case 3, 26 breakpoints were identified using WGS, disrupting five known disease genes. All rearrangements were subsequently analyzed using optical maps, linked-read WGS, and short-read WGS. In conclusion, we present a case series of three unique de novo CCRs where we by combining the results from the different technologies fully solved the structure of each rearrangement. The power in combining short-read WGS with long-molecule sequencing or optical mapping in these unique de novo CCRs in a clinical setting is demonstrated.
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3.
  • Fredriksson, Robert, et al. (författare)
  • The polyamine transporter Slc18b1(VPAT) is important for both short and long time memory and for regulation of polyamine content in the brain.
  • 2019
  • Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 15:12
  • Tidskriftsartikel (refereegranskat)abstract
    • SLC18B1 is a sister gene to the vesicular monoamine and acetylcholine transporters, and the only known polyamine transporter, with unknown physiological role. We reveal that Slc18b1 knock out mice has significantly reduced polyamine content in the brain providing the first evidence that Slc18b1 is functionally required for regulating polyamine levels. We found that this mouse has impaired short and long term memory in novel object recognition, radial arm maze and self-administration paradigms. We also show that Slc18b1 KO mice have altered expression of genes involved in Long Term Potentiation, plasticity, calcium signalling and synaptic functions and that expression of components of GABA and glutamate signalling are changed. We further observe a partial resistance to diazepam, manifested as significantly lowered reduction in locomotion after diazepam treatment. We suggest that removal of Slc18b1 leads to reduction of polyamine contents in neurons, resulting in reduced GABA signalling due to long-term reduction in glutamatergic signalling.
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4.
  • Grenville-Briggs Didymus, Laura (författare)
  • Infection mechanisms and putative effector repertoire of the mosquito pathogenic oomycete Pythium guiyangense uncovered by genomic analysis
  • 2019
  • Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 15
  • Tidskriftsartikel (refereegranskat)abstract
    • Pythium guiyangense, an oomycete from a genus of mostly plant pathogens, is an effective biological control agent that has wide potential to manage diverse mosquitoes. However, its mosquito-killing mechanisms are almost unknown. In this study, we observed that P. guiyangense could utilize cuticle penetration and ingestion of mycelia into the digestive system to infect mosquito larvae. To explore pathogenic mechanisms, a high-quality genome sequence with 239 contigs and an N50 contig length of 1,009 kb was generated. The genome assembly is approximately 110 Mb, which is almost twice the size of other sequenced Pythium genomes. Further genome analysis suggests that P. guiyangense may arise from a hybridization of two related but distinct parental species. Phylogenetic analysis demonstrated that P. guiyangense likely evolved from common ancestors shared with plant pathogens. Comparative genome analysis coupled with transcriptome sequencing data suggested that P. guiyangense may employ multiple virulence mechanisms to infect mosquitoes, including secreted proteases and kazal-type protease inhibitors. It also shares intracellular Crinkler (CRN) effectors used by plant pathogenic oomycetes to facilitate the colonization of plant hosts. Our experimental evidence demonstrates that CRN effectors of P. guiyangense can be toxic to insect cells. The infection mechanisms and putative virulence effectors of P. guiyangense uncovered by this study provide the basis to develop improved mosquito control strategies. These data also provide useful knowledge on host adaptation and evolution of the entomopathogenic lifestyle within the oomycete lineage. A deeper understanding of the biology of P. guiyangense effectors might also be useful for management of other important agricultural pests.Author summary Utilization of biocontrol agents has emerged as a promising mosquito control strategy, and Pythium guiyangense has wide potential to manage diverse mosquitoes with high efficiency. However, the molecular mechanisms underlying pathological processes remain almost unknown. We observed that P. guiyangense invades mosquito larvae through cuticle penetration and through ingestion of mycelia via the digestive system, jointly accelerating mosquito larvae mortality. We also present a high-quality genome assembly of P. guiyangense that contains two distinct genome complements, which likely resulted from a hybridization of two parental species. Our analyses revealed expansions of kinases, proteases, kazal-type protease inhibitors, and elicitins that may be important for adaptation of P. guiyangense to a mosquito-pathogenic lifestyle. Moreover, our experimental evidence demonstrated that some Crinkler effectors of P. guiyangense can be toxic to insect cells. Our findings suggest new insights into oomycete evolution and host adaptation by animal pathogenic oomycetes. Our new genome resource will enable better understanding of infection mechanisms, with the potential to improve the biological control of mosquitoes and other agriculturally important pests.
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6.
  • Kryvokhyzha, Dmytro, et al. (författare)
  • Parental legacy, demography, and admixture influenced the evolution of the two subgenomes of the tetraploid Capsella bursa-pastoris (Brassicaceae)
  • 2019
  • Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 15:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Allopolyploidy is generally perceived as a major source of evolutionary novelties and as an instantaneous way to create isolation barriers. However, we do not have a clear understanding of how two subgenomes evolve and interact once they have fused in an allopolyploid species nor how isolated they are from their relatives. Here, we address these questions by analyzing genomic and transcriptomic data of allotetraploid Capsella bursa-pastoris in three differentiated populations, Asia, Europe, and the Middle East. We phased the two subgenomes, one descended from the outcrossing and highly diverse Capsella grandiflora (Cbp(Cg)) and the other one from the selfing and genetically depauperate Capsella orientalis (Cbp(Co)). For each subgenome, we assessed its relationship with the diploid relatives, temporal changes of effective population size (N-e), signatures of positive and negative selection, and gene expression patterns. In all three regions, N-e of the two subgenomes decreased gradually over time and the Cbp(Co) subgenome accumulated more deleterious changes than Cbp(Cg). There were signs of widespread admixture between C. bursa-pastoris and its diploid relatives. The two subgenomes were impacted differentially depending on geographic region suggesting either strong interploidy gene flow or multiple origins of C. bursa-pastoris. Selective sweeps were more common on the Cbp(Cg) subgenome in Europe and the Middle East, and on the Cbp(Co) subgenome in Asia. In contrast, differences in expression were limited with the Cbp(Cg) subgenome slightly more expressed than Cbp(Co) in Europe and the Middle-East. In summary, after more than 100,000 generations of co-existence, the two subgenomes of C. bursa-pastoris still retained a strong signature of parental legacy but their evolutionary trajectory strongly varied across geographic regions. Author summary Allopolyploid species have two or more sets of chromosomes that originate from hybridization of different species. It remains largely unknown how the two genomes evolve in the same organism and how strongly their evolutionary trajectory depends on the initial differences between the two parental species and the specific demographic history of the newly formed allopolyploid species. To address these questions, we analyzed the genomic and gene expression variation of the shepherd's purse, a recent allopolyploid species, in three regions of its natural range. After approximate to 100,000 generations of co-existence within the same species, the two subgenomes had still retained part of the initial difference between the two parental species in the number of deleterious mutations reflecting a history of mating system differences. This difference, as well as differences in patterns of positive selection and levels of gene expression, also strongly depended on the specific histories of the three regions considered. Most strikingly, and unexpectedly, the allopolyploid species showed signs of hybridization with different diploid relatives or multiple origins in different parts of its range. Regardless if it was hybridization or multiple origins, this profoundly altered the relationship between the two subgenomes in different regions. Hence, our study illustrates how both the genomic structure and ecological arena interact to determine the evolutionary trajectories of allopolyploid species.
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7.
  • Kryvokhyzha, Dmytro, et al. (författare)
  • Towards the new normal : Transcriptomic convergence and genomic legacy of the two subgenomes of an allopolyploid weed (Capsella bursa-pastoris)
  • 2019
  • Ingår i: PLOS Genetics. - : PUBLIC LIBRARY SCIENCE. - 1553-7390 .- 1553-7404. ; 15:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Allopolyploidy has played a major role in plant evolution but its impact on genome diversity and expression patterns remains to be understood. Some studies found important genomic and transcriptomic changes in allopolyploids, whereas others detected a strong parental legacy and more subtle changes. The allotetraploid C. bursa-pastoris originated around 100,000 years ago and one could expect the genetic polymorphism of the two subgenomes to follow similar trajectories and their transcriptomes to start functioning together. To test this hypothesis, we sequenced the genomes and the transcriptomes (three tissues) of allotetraploid C. bursa-pastoris and its parental species, the outcrossing C. grandiflora and the self-fertilizing C. orientalis. Comparison of the divergence in expression between subgenomes, on the one hand, and divergence in expression between the parental species, on the other hand, indicated a strong parental legacy with a majority of genes exhibiting a conserved pattern and cis-regulation. However, a large proportion of the genes that were differentially expressed between the two subgenomes, were also under trans-regulation reflecting the establishment of a new regulatory pattern. Parental dominance varied among tissues: expression in flowers was closer to that of C. orientalis and expression in root and leaf to that of C. grandiflora. Since deleterious mutations accumulated preferentially on the C. orientalis subgenome, the bias in expression towards C. orientalis observed in flowers indicates that expression changes could be adaptive and related to the selfing syndrome, while biases in the roots and leaves towards the C. grandiflora subgenome may be reflective of the differential genetic load.
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8.
  • Li, X. L., et al. (författare)
  • Mck1 defines a key S-phase checkpoint effector in response to various degrees of replication threats
  • 2019
  • Ingår i: Plos Genetics. - San Francisco : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 15:8
  • Tidskriftsartikel (refereegranskat)abstract
    • The S-phase checkpoint plays an essential role in regulation of the ribonucleotide reductase (RNR) activity to maintain the dNTP pools. How eukaryotic cells respond appropriately to different levels of replication threats remains elusive. Here, we have identified that a conserved GSK-3 kinase Mck1 cooperates with Dun1 in regulating this process. Deleting MCK1 sensitizes dun1 Delta to hydroxyurea (HU) reminiscent of mec1 Delta or rad53 Delta. While Mck1 is downstream of Rad53, it does not participate in the post-translational regulation of RNR as Dun1 does. Mck1 phosphorylates and releases the Crt1 repressor from the promoters of DNA damage-inducible genes as RNR2-4 and HUG1. Hug1, an Rnr2 inhibitor normally silenced, is induced as a counterweight to excessive RNR. When cells suffer a more severe threat, Mck1 inhibits HUG1 transcription. Consistently, only a combined deletion of HUG1 and CRT1, confers a dramatic boost of dNTP levels and the survival of mck1 Delta dun1 Delta or mec1 Delta cells assaulted by a lethal dose of HU. These findings reveal the division-of-labor between Mck1 and Dun1 at the S-phase checkpoint pathway to fine-tune dNTP homeostasis. Author summary The appropriate amount and balance of four dNTPs are crucial for all cells correctly copying and passing on their genetic material generation by generation. Eukaryotes have developed an alert and response system to deal with the disturbance. Here, we uncovered a second-level effector branch. It is activated by the upstream surveillance kinase cascade, which can induce the expression of dNTP-producing enzymes. It can also reduce the inhibitor of these enzymes to further boost their activity according to the degrees of threats. These findings suggest a multi-level response system to guarantee the appropriate dNTP supply, which is essential to maintain genetic stability under various environmental challenges.
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9.
  • McCoy, Annette M., et al. (författare)
  • Identification and validation of genetic variants predictive of gait in standardbred horses
  • 2019
  • Ingår i: PLOS Genetics. - : PUBLIC LIBRARY SCIENCE. - 1553-7390 .- 1553-7404. ; 15:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Several horse breeds have been specifically selected for the ability to exhibit alternative patterns of locomotion, or gaits. A premature stop codon in the gene DMRT3 is permissive for gaitedness across breeds. However, this mutation is nearly fixed in both American Standardbred trotters and pacers, which perform a diagonal and lateral gait, respectively, during harness racing. This suggests that modifying alleles must influence the preferred gait at racing speeds in these populations. A genome-wide association analysis for the ability to pace was performed in 542 Standardbred horses (n = 176 pacers, n = 366 trotters) with genotype data imputed to similar to 74,000 single nucleotide polymorphisms (SNPs). Nineteen SNPs on nine chromosomes (ECA1, 2, 6, 9, 17, 19, 23, 25, 31) reached genome-wide significance (p < 1.44 x 10(-6)). Variant discovery in regions of interest was carried out via whole-genome sequencing. A set of 303 variants from 22 chromosomes with putative modifying effects on gait was genotyped in 659 Standardbreds (n = 231 pacers, n = 428 trotters) using a high-throughput assay. Random forest classification analysis resulted in an out-of-box error rate of 0.61%. A conditional inference tree algorithm containing seven SNPs predicted status as a pacer or trotter with 99.1% accuracy and subsequently performed with 99.4% accuracy in an independently sampled population of 166 Standardbreds (n = 83 pacers, n = 83 trotters). This highly accurate algorithm could be used by owners/trainers to identify Standardbred horses with the potential to race as pacers or as trotters, according to the genotype identified, prior to initiating training and would enable fine-tuning of breeding programs with designed matings. Additional work is needed to determine both the algorithm's utility in other gaited breeds and whether any of the predictive SNPs play a physiologically functional role in the tendency to pace or tag true functional alleles.
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10.
  • Musharoff, Shaila, et al. (författare)
  • The inference of sex-biased human demography from whole-genome data
  • 2019
  • Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 15:9
  • Tidskriftsartikel (refereegranskat)abstract
    • Sex-biased demographic events (“sex-bias”) involve unequal numbers of females and males. These events are typically inferred from the relative amount of X-chromosomal to autosomal genetic variation and have led to conflicting conclusions about human demographic history. Though population size changes alter the relative amount of X-chromosomal to autosomal genetic diversity even in the absence of sex-bias, this has generally not been accounted for in sex-bias estimators to date. Here, we present a novel method to identify sex-bias from genetic sequence data that models population size changes and estimates the female fraction of the effective population size during each time epoch. Compared to recent sex-bias inference methods, our approach can detect sex-bias that changes on a single population branch without requiring data from an outgroup or knowledge of divergence events. When applied to simulated data, conventional sex-bias estimators are biased by population size changes, especially recent growth or bottlenecks, while our estimator is unbiased. We next apply our method to high-coverage exome data from the 1000 Genomes Project and estimate a male bias in Yorubans (47% female) and Europeans (44%), possibly due to stronger background selection on the X chromosome than on the autosomes. Finally, we apply our method to the 1000 Genomes Project Phase 3 high-coverage Complete Genomics whole-genome data and estimate a female bias in Yorubans (63% female), Europeans (84%), Punjabis (82%), as well as Peruvians (56%), and a male bias in the Southern Han Chinese (45%). Our method additionally identifies a male-biased migration out of Africa based on data from Europeans (20% female). Our results demonstrate that modeling population size change is necessary to estimate sex-bias parameters accurately. Our approach gives insight into signatures of sex-bias in sexual species, and the demographic models it produces can serve as more accurate null models for tests of selection.
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