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Sökning: WFRF:(Smeds Linnea)

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  • Husby, Arild, et al. (författare)
  • Genome-wide association mapping in a wild avian population identifies a link between genetic and phenotypic variation in a life-history trait
  • 2015
  • Ingår i: Proceedings of the Royal Society of London. Biological Sciences. - : Royal Society, The. - 0962-8452 .- 1471-2954. ; 282:1806
  • Tidskriftsartikel (refereegranskat)abstract
    • Understanding the genetic basis of traits involved in adaptation is a major challenge in evolutionary biology but remains poorly understood. Here, we use genome-wide association mapping using a custom 50 k single nucleotide polymorphism (SNP) array in a natural population of collared flycatchers to examine the genetic basis of clutch size, an important life-history trait in many animal species. We found evidence for an association on chromosome 18 where one SNP significant at the genome-wide level explained 3.9% of the phenotypic variance. We also detected two suggestive quantitative trait loci (QTLs) on chromosomes 9 and 26. Fitness differences among genotypes were generally weak and not significant, although there was some indication of a sex-by-genotype interaction for lifetime reproductive success at the suggestive QTL on chromosome 26. This implies that sexual antagonism may play a role in maintaining genetic variation at this QTL. Our findings provide candidate regions for a classic avian life-history trait that will be useful for future studies examining the molecular and cellular function of, as well as evolutionary mechanisms operating at, these loci.
  • La Fleur, Linnea, et al. (författare)
  • Mutation patterns in a population-based non-small cell lung cancer cohort and prognostic impact of concomitant mutations in KRAS and TP53 or STK11
  • 2019
  • Ingår i: Lung Cancer. - : Elsevier. - 0169-5002 .- 1872-8332. ; 130, s. 50-58
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVES: Non-small cell lung cancer (NSCLC) is a heterogeneous disease with unique combinations of somatic molecular alterations in individual patients, as well as significant differences in populations across the world with regard to mutation spectra and mutation frequencies. Here we aim to describe mutational patterns and linked clinical parameters in a population-based NSCLC cohort.MATERIALS AND METHODS: Using targeted resequencing the mutational status of 82 genes was evaluated in a consecutive Swedish surgical NSCLC cohort, consisting of 352 patient samples from either fresh frozen or formalin fixed paraffin embedded (FFPE) tissues. The panel covers all exons of the 82 genes and utilizes reduced target fragment length and two-strand capture making it compatible with degraded FFPE samples.RESULTS: We obtained a uniform sequencing coverage and mutation load across the fresh frozen and FFPE samples by adaption of sequencing depth and bioinformatic pipeline, thereby avoiding a technical bias between these two sample types. At large, the mutation frequencies resembled the frequencies seen in other western populations, except for a high frequency of KRAS hotspot mutations (43%) in adenocarcinoma patients. Worse overall survival was observed for adenocarcinoma patients with a mutation in either TP53, STK11 or SMARCA4. In the adenocarcinoma KRAS-mutated group poor survival appeared to be linked to concomitant TP53 or STK11 mutations, and not to KRAS mutation as a single aberration. Similar results were seen in the analysis of publicly available data from the cBioPortal. In squamous cell carcinoma a worse prognosis could be observed for patients with MLL2 mutations, while CSMD3 mutations were linked to a better prognosis.CONCLUSION: Here we have evaluated the mutational status of a NSCLC cohort. We could not confirm any survival impact of isolated driver mutations. Instead, concurrent mutations in TP53 and STK11 were shown to confer poor survival in the KRAS-positive adenocarcinoma subgroup.
  • Burri, Reto, et al. (författare)
  • Linked selection and recombination rate variation drive the evolution of the genomic landscape of differentiation across the speciation continuum of Ficedula flycatchers
  • 2015
  • Ingår i: Genome Research. - 1088-9051 .- 1549-5469. ; 25:11, s. 1656-1665
  • Tidskriftsartikel (refereegranskat)abstract
    • Speciation is a continuous process during which genetic changes gradually accumulate in the genomes of diverging species. Recent studies have documented highly heterogeneous differentiation landscapes, with distinct regions of elevated differentiation ("differentiation islands") widespread across genomes. However, it remains unclear which processes drive the evolution of differentiation islands; how the differentiation landscape evolves as speciation advances; and ultimately, how differentiation islands are related to speciation. Here, we addressed these questions based on population genetic analyses of 200 resequenced genomes from 10 populations of four Ficedula flycatcher sister species. We show that a heterogeneous differentiation landscape starts emerging among populations within species, and differentiation islands evolve recurrently in the very same genomic regions among independent lineages. Contrary to expectations from models that interpret differentiation islands as genomic regions involved in reproductive isolation that are shielded from gene flow, patterns of sequence divergence (d(XY) relative node depth) do not support a major role of gene flow in the evolution of the differentiation landscape in these species. Instead, as predicted by models of linked selection, genome-wide variation in diversity and differentiation can be explained by variation in recombination rate and the density of targets for selection. We thus conclude that the heterogeneous landscape of differentiation in Ficedula flycatchers evolves mainly as the result of background selection and selective sweeps in genomic regions of low recombination. Our results emphasize the necessity of incorporating linked selection as a null model to identify genome regions involved in adaptation and speciation.
  • Dutoit, Ludovic, et al. (författare)
  • Estimation of contemporary effect population size in an island population of the collared flycatcher (Ficedula albicollis) using large-scale genome data
  • Annan publikation (övrigt vetenskapligt)abstract
    • Due to its central importance to many aspects of evolutionary biology and population genetics, the long-term effective population size (Ne) has been estimated for numerous species and populations. However, estimating contemporary Ne is difficult and in practice this parameter is often not known. In principle, contemporary Ne can be estimated using either analyses of temporal changes in allele frequencies or the extent of linkage disequilibrium (LD) between unlinked markers. We applied these approaches for contemporary Ne estimation of a relatively recently founded island population of collared flycatchers (Ficedula albicollis). We sequenced the genomes of 85 birds sampled in 1993 and 2015, and used a method of Jorde & Ryman (2007) to estimate Ne to ≈5,000 based on the amount of genetic drift observed between the two cohorts. This corresponds to an effective size/census size (Ne/Nc) ratio of ≈0.5. An approach based on LD applied to each cohort could not separate from Ne infinity. When individuals from the two cohorts were pooled, Ne was estimated to 10,000-25,000, but these estimates may be sensitive to biases. We conclude that whole-genome sequence data offer new possibilities for estimation of contemporary Ne, but also note that such estimation remains difficult. 
  • Dutoit, Ludovic, et al. (författare)
  • Sex-biased gene expression, sexual antagonism and levels of genetic diversity in the collared flycatcher (Ficedula albicollis) genome
  • 2018
  • Ingår i: Molecular Ecology. - 0962-1083 .- 1365-294X. ; 27:18, s. 3572-3581
  • Tidskriftsartikel (övrigt vetenskapligt)abstract
    • Theoretical work suggests that sexual conflict should promote the maintenance of genetic diversity by the opposing directions of selection on sexually antagonistic mutations in males and females. This prediction, so far not been empirically tested on a genome-wide scale, could potentially contribute towards genomic heterogeneity in levels of genetic diversity. We used large-scale population genomic and transcriptomic data from the collared flycatcher (Ficedula albicollis) to analyse how sex-biased gene expression – one outcome of sexual conflict – relates to genetic variability. Here, we demonstrate that the extent of sex-biased gene expression of both male-biased and female-biased genes is significantly correlated with levels of nucleotide diversity in gene sequences and that this correlation extends to the overall levels of genomic diversity. We find evidence for balancing selection in sex-biased genes, suggesting that sex-biased gene expression could be seen as a component counteracting the diversity-reducing effects of linked positive and purifying selection. The observation of significant genetic differentiation between males and females for male-biased genes indicates ongoing sexual conflict and sex-specific viability selection, potentially driven by sexual selection. Our results thus provide a new perspective on the long-standing question in evolutionary biology of how genomes can remain so genetically variable in face of strong natural and sexual selection.
  • Ekblom, Robert, Docent, 1976-, et al. (författare)
  • Genome sequencing and conservation genomics in the Scandinavian wolverine population
  • 2018
  • Ingår i: Conservation Biology. - : WILEY. - 0888-8892 .- 1523-1739. ; 32:6, s. 1301-1312
  • Tidskriftsartikel (refereegranskat)abstract
    • Genetic approaches have proved valuable to the study and conservation of endangered populations, especially for monitoring programs, and there is potential for further developments in this direction by extending analyses to the genomic level. We assembled the genome of the wolverine (Gulo gulo), a mustelid that in Scandinavia has recently recovered from a significant population decline, and obtained a 2.42 Gb draft sequence representing >85% of the genome and including >21,000 protein-coding genes. We then performed whole-genome resequencing of 10 Scandinavian wolverines for population genomic and demographic analyses. Genetic diversity was among the lowest detected in a red-listed population (mean genome-wide nucleotide diversity of 0.05%). Results of the demographic analyses indicated a long-term decline of the effective population size (N-e) from 10,000 well before the last glaciation to N-e appeared even lower. The genome-wide F-IS level was 0.089 (possibly signaling inbreeding), but this effect was not observed when analyzing a set of highly variable SNP markers, illustrating that such markers can give a biased picture of the overall character of genetic diversity. We found significant population structure, which has implications for population connectivity and conservation. We used an integrated microfluidic circuit chip technology to develop an SNP-array consisting of 96 highly informative markers that, together with a multiplex pre-amplification step, was successfully applied to low-quality DNA from scat samples. Our findings will inform management, conservation, and genetic monitoring of wolverines and serve as a genomic roadmap that can be applied to other endangered species. The approach used here can be generally utilized in other systems, but we acknowledge the trade-off between investing in genomic resources and direct conservation actions.
  • Ekblom, Robert, et al. (författare)
  • Patterns of sequencing coverage bias revealed by ultra-deep sequencing of vertebrate mitochondria
  • 2014
  • Ingår i: BMC Genomics. - 1471-2164 .- 1471-2164. ; 15, s. 467-
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Genome and transcriptome sequencing applications that rely on variation in sequence depth can be negatively affected if there are systematic biases in coverage. We have investigated patterns of local variation in sequencing coverage by utilising ultra-deep sequencing (>100,000X) of mtDNA obtained during sequencing of two vertebrate genomes, wolverine (Gulo gulo) and collared flycatcher (Ficedula albicollis). With such extreme depth, stochastic variation in coverage should be negligible, which allows us to provide a very detailed, fine-scale picture of sequence dependent coverage variation and sequencing error rates. Results: Sequencing coverage showed up to six-fold variation across the complete mtDNA and this variation was highly repeatable in sequencing of multiple individuals of the same species. Moreover, coverage in orthologous regions was correlated between the two species and was negatively correlated with GC content. We also found a negative correlation between the site-specific sequencing error rate and coverage, with certain sequence motifs "CCNGCC" being particularly prone to high rates of error and low coverage. Conclusions: Our results demonstrate that inherent sequence characteristics govern variation in coverage and suggest that some of this variation, like GC content, should be controlled for in, for example, RNA-Seq and detection of copy number variation.
  • Ellegren, Hans, et al. (författare)
  • The genomic landscape of species divergence in Ficedula flycatchers
  • 2012
  • Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 491:7426, s. 756-760
  • Tidskriftsartikel (refereegranskat)abstract
    • Unravelling the genomic landscape of divergence between lineages is key to understanding speciation. The naturally hybridizing collared flycatcher and pied flycatcher are important avian speciation models that show pre-as well as postzygotic isolation. We sequenced and assembled the 1.1-Gb flycatcher genome, physically mapped the assembly to chromosomes using a low-density linkage map and re-sequenced population samples of each species. Here we show that the genomic landscape of species differentiation is highly heterogeneous with approximately 50 'divergence islands' showing up to 50-fold higher sequence divergence than the genomic background. These non-randomly distributed islands, with between one and three regions of elevated divergence per chromosome irrespective of chromosome size, are characterized by reduced levels of nucleotide diversity, skewed allele-frequency spectra, elevated levels of linkage disequilibrium and reduced proportions of shared polymorphisms in both species, indicative of parallel episodes of selection. Proximity of divergence peaks to genomic regions resistant to sequence assembly, potentially including centromeres and telomeres, indicate that complex repeat structures may drive species divergence. A much higher background level of species divergence of the Z chromosome, and a lower proportion of shared polymorphisms, indicate that sex chromosomes and autosomes are at different stages of speciation. This study provides a roadmap to the emerging field of speciation genomics.
  • Jarvis, Erich D., et al. (författare)
  • Whole-genome analyses resolve early branches in the tree of life of modern birds
  • 2014
  • Ingår i: Science. - : American Association for the Advancement of Science. - 0036-8075 .- 1095-9203. ; 346:6215, s. 1320-1331
  • Tidskriftsartikel (refereegranskat)abstract
    • To better determine the history of modern birds, we performed a genome-scale phylogenetic analysis of 48 species representing all orders of Neoaves using phylogenomic methods created to handle genome-scale data. We recovered a highly resolved tree that confirms previously controversial sister or close relationships. We identified the first divergence in Neoaves, two groups we named Passerea and Columbea, representing independent lineages of diverse and convergently evolved land and water bird species. Among Passerea, we infer the common ancestor of core landbirds to have been an apex predator and confirm independent gains of vocal learning. Among Columbea, we identify pigeons and flamingoes as belonging to sister clades. Even with whole genomes, some of the earliest branches in Neoaves proved challenging to resolve, which was best explained by massive protein-coding sequence convergence and high levels of incomplete lineage sorting that occurred during a rapid radiation after the Cretaceous-Paleogene mass extinction event about 66 million years ago.
  • Kawakami, Takeshi, et al. (författare)
  • A high-density linkage map enables a second-generation collared flycatcher genome assembly and reveals the patterns of avian recombination rate variation and chromosomal evolution
  • 2014
  • Ingår i: Molecular Ecology. - 0962-1083 .- 1365-294X. ; 23:16, s. 4035-4058
  • Forskningsöversikt (refereegranskat)abstract
    • Detailed linkage and recombination rate maps are necessary to use the full potential of genome sequencing and population genomic analyses. We used a custom collared flycatcher 50K SNP array to develop a high-density linkage map with 37262 markers assigned to 34 linkage groups in 33 autosomes and the Z chromosome. The best-order map contained 4215 markers, with a total distance of 3132cM and a mean genetic distance between markers of 0.12cM. Facilitated by the array being designed to include markers from most scaffolds, we obtained a second-generation assembly of the flycatcher genome that approaches full chromosome sequences (N50 super-scaffold size 20.2Mb and with 1.042Gb (of 1.116Gb) anchored to and mostly ordered and oriented along chromosomes). We found that flycatcher and zebra finch chromosomes are entirely syntenic but that inversions at mean rates of 1.5-2.0 event (6.6-7.5Mb) per My have changed the organization within chromosomes, rates high enough for inversions to potentially have been involved with many speciation events during avian evolution. The mean recombination rate was 3.1cM/Mb and correlated closely with chromosome size, from 2cM/Mb for chromosomes >100Mb to >10cM/Mb for chromosomes <10Mb. This size dependence seemed entirely due to an obligate recombination event per chromosome; if 50cM was subtracted from the genetic lengths of chromosomes, the rate per physical unit DNA was constant across chromosomes. Flycatcher recombination rate showed similar variation along chromosomes as chicken but lacked the large interior recombination deserts characteristic of zebra finch chromosomes.
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