| 1. |
- Burri, Reto, et al.
(författare)
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Linked selection and recombination rate variation drive the evolution of the genomic landscape of differentiation across the speciation continuum of Ficedula flycatchers
- 2015
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 25:11, s. 1656-1665
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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.
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| 2. |
- Böhme, Ulrike, et al.
(författare)
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Complete avian malaria parasite genomes reveal features associated with lineage-specific evolution in birds and mammals
- 2018
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory Press (CSHL). - 1088-9051 .- 1549-5469. ; 28:4, s. 547-560
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Tidskriftsartikel (refereegranskat)abstract
- Avian malaria parasites are prevalent around the world and infect a wide diversity of bird species. Here, we report the sequencing and analysis of high-quality draft genome sequences for two avian malaria species, Plasmodium relictum and Plasmodium gallinaceum. We identify 50 genes that are specific to avian malaria, located in an otherwise conserved core of the genome that shares gene synteny with all other sequenced malaria genomes. Phylogenetic analysis suggests that the avian malaria species form an outgroup to the mammalian Plasmodium species, and using amino acid divergence between species, we estimate the avian- and mammalian-infective lineages diverged in the order of 10 million years ago. Consistent with their phylogenetic position, we identify orthologs of genes that had previously appeared to be restricted to the clades of parasites containing Plasmodium falciparum and Plasmodium vivax, the species with the greatest impact on human health. From these orthologs, we explore differential diversifying selection across the genus and show that the avian lineage is remarkable in the extent to which invasion-related genes are evolving. The subtelomeres of the P. relictum and P. gallinaceum genomes contain several novel gene families, including an expanded surf multigene family. We also identify an expansion of reticulocyte binding protein homologs in P. relictum, and within these proteins, we detect distinct regions that are specific to nonhuman primate, humans, rodent, and avian hosts. For the first time in the Plasmodium lineage, we find evidence of transposable elements, including several hundred fragments of LTR-retrotransposons in both species and an apparently complete LTR-retrotransposon in the genome of P. gallinaceum.
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| 3. |
- Chen, G, et al.
(författare)
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Single-cell analyses of X Chromosome inactivation dynamics and pluripotency during differentiation
- 2016
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Ingår i: Genome research. - : Cold Spring Harbor Laboratory. - 1549-5469 .- 1088-9051. ; 26:10, s. 1342-1354
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Tidskriftsartikel (refereegranskat)abstract
- Pluripotency, differentiation, and X Chromosome inactivation (XCI) are key aspects of embryonic development. However, the underlying relationship and mechanisms among these processes remain unclear. Here, we systematically dissected these features along developmental progression using mouse embryonic stem cells (mESCs) and single-cell RNA sequencing with allelic resolution. We found that mESCs grown in a ground state 2i condition displayed transcriptomic profiles diffused from preimplantation mouse embryonic cells, whereas EpiStem cells closely resembled the post-implantation epiblast. Sex-related gene expression varied greatly across distinct developmental states. We also identified novel markers that were highly enriched in each developmental state. Moreover, we revealed that several novel pathways, including PluriNetWork and Focal Adhesion, were responsible for the delayed progression of female EpiStem cells. Importantly, we “digitalized” XCI progression using allelic expression of active and inactive X Chromosomes and surprisingly found that XCI states exhibited profound variability in each developmental state, including the 2i condition. XCI progression was not tightly synchronized with loss of pluripotency and increase of differentiation at the single-cell level, although these processes were globally correlated. In addition, highly expressed genes, including core pluripotency factors, were in general biallelically expressed. Taken together, our study sheds light on the dynamics of XCI progression and the asynchronicity between pluripotency, differentiation, and XCI.
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| 4. |
- Chen, Jenny, et al.
(författare)
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A quantitative framework for characterizing the evolutionary history of mammalian gene expression
- 2019
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 29:1, s. 53-63
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Tidskriftsartikel (refereegranskat)abstract
- The evolutionary history of a gene helps predict its function and relationship to phenotypic traits. Although sequence conservation is commonly used to decipher gene function and assess medical relevance, methods for functional inference from comparative expression data are lacking. Here, we use RNA-seq across seven tissues from 17 mammalian species to show that expression evolution across mammals is accurately modeled by the Ornstein-Uhlenbeck process, a commonly proposed model of continuous trait evolution. We apply this model to identify expression pathways under neutral, stabilizing, and directional selection. We further demonstrate novel applications of this model to quantify the extent of stabilizing selection on a gene's expression, parameterize the distribution of each gene's optimal expression level, and detect deleterious expression levels in expression data from individual patients. Our work provides a statistical framework for interpreting expression data across species and in disease.
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| 5. |
- Corcoran, Padraic, et al.
(författare)
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Introgression maintains the genetic integrity of the mating-type determining chromosome of the fungus Neurospora tetrasperma.
- 2016
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 26:4, s. 486-498
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Tidskriftsartikel (refereegranskat)abstract
- Genome evolution is driven by a complex interplay of factors, including selection, recombination, and introgression. The regions determining sexual identity are particularly dynamic parts of eukaryotic genomes that are prone to molecular degeneration associated with suppressed recombination. In the fungus Neurospora tetrasperma, it has been proposed that this molecular degeneration is counteracted by the introgression of nondegenerated DNA from closely related species. In this study, we used comparative and population genomic analyses of 92 genomes from eight phylogenetically and reproductively isolated lineages of N. tetrasperma, and its three closest relatives, to investigate the factors shaping the evolutionary history of the genomes. We found that suppressed recombination extends across at least 6 Mbp (similar to 63%) of the mating-type (mat) chromosome in N. tetrasperma and is associated with decreased genetic diversity, which is likely the result primarily of selection at linked sites. Furthermore, analyses of molecular evolution revealed an increased mutational load in this region, relative to recombining regions. However, comparative genomic and phylogenetic analyses indicate that the mat chromosomes are temporarily regenerated via introgression from sister species; six of eight lineages show introgression into one of their mat chromosomes, with multiple Neurospora species acting as donors. The introgressed tracts have been fixed within lineages, suggesting that they confer an adaptive advantage in natural populations, and our analyses support the presence of selective sweeps in at least one lineage. Thus, these data strongly support the previously hypothesized role of introgression as a mechanism for the maintenance of mating-type determining chromosomal regions.
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| 6. |
- Edmonson, MN, et al.
(författare)
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Pediatric Cancer Variant Pathogenicity Information Exchange (PeCanPIE): a cloud-based platform for curating and classifying germline variants
- 2019
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Ingår i: Genome research. - : Cold Spring Harbor Laboratory. - 1549-5469 .- 1088-9051. ; 29:9, s. 1555-1565
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Tidskriftsartikel (refereegranskat)abstract
- Variant interpretation in the era of massively parallel sequencing is challenging. Although many resources and guidelines are available to assist with this task, few integrated end-to-end tools exist. Here, we present the Pediatric Cancer Variant Pathogenicity Information Exchange (PeCanPIE), a web- and cloud-based platform for annotation, identification, and classification of variations in known or putative disease genes. Starting from a set of variants in variant call format (VCF), variants are annotated, ranked by putative pathogenicity, and presented for formal classification using a decision-support interface based on published guidelines from the American College of Medical Genetics and Genomics (ACMG). The system can accept files containing millions of variants and handle single-nucleotide variants (SNVs), simple insertions/deletions (indels), multiple-nucleotide variants (MNVs), and complex substitutions. PeCanPIE has been applied to classify variant pathogenicity in cancer predisposition genes in two large-scale investigations involving >4000 pediatric cancer patients and serves as a repository for the expert-reviewed results. PeCanPIE was originally developed for pediatric cancer but can be easily extended for use for nonpediatric cancers and noncancer genetic diseases. Although PeCanPIE's web-based interface was designed to be accessible to non-bioinformaticians, its back-end pipelines may also be run independently on the cloud, facilitating direct integration and broader adoption. PeCanPIE is publicly available and free for research use.
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| 7. |
- Elvers, Ingegerd, et al.
(författare)
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Exome sequencing of lymphomas from three dog breeds reveals somatic mutation patterns reflecting genetic background
- 2015
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 25:11, s. 1634-1645
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Tidskriftsartikel (refereegranskat)abstract
- Lymphoma is the most common hematological malignancy in developed countries. Outcome is strongly determined by molecular subtype, reflecting a need for new and improved treatment options. Dogs spontaneously develop lymphoma, and the predisposition of certain breeds indicates genetic risk factors. Using the dog breed structure, we selected three lymphoma predisposed breeds developing primarily T-cell (boxer), primarily B-cell (cocker spaniel), and with equal distribution of B- and T-cell lymphoma (golden retriever), respectively. We investigated the somatic mutations in B- and T-cell lymphomas from these breeds by exome sequencing of tumor and normal pairs. Strong similarities were evident between B-cell lymphomas from golden retrievers and cocker spaniels, with recurrent mutations in TRAF3-MAP3K14 (28% of all cases), FBXW7 (25%), and POT1 (17%). The FBXW7 mutations recurrently occur in a specific codon; the corresponding codon is recurrently mutated in human cancer. In contrast, T-cell lymphomas from the predisposed breeds, boxers and golden retrievers, show little overlap in their mutation pattern, sharing only one of their 15 most recurrently mutated genes. Boxers, which develop aggressive T-cell lymphomas, are typically mutated in the PTEN-mTOR pathway. T-cell lymphomas in golden retrievers are often less aggressive, and their tumors typically showed mutations in genes involved in cellular metabolism. We identify genes with known involvement in human lymphoma and leukemia, genes implicated in other human cancers, as well as novel genes that could allow new therapeutic options.
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| 8. |
- Fabbri, M, et al.
(författare)
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Decrypting noncoding RNA interactions, structures, and functional networks
- 2019
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Ingår i: Genome research. - : Cold Spring Harbor Laboratory. - 1549-5469 .- 1088-9051. ; 29:9, s. 1377-1388
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Tidskriftsartikel (refereegranskat)abstract
- The world of noncoding RNAs (ncRNAs) is composed of an enormous and growing number of transcripts, ranging in length from tens of bases to tens of kilobases, involved in all biological processes and altered in expression and/or function in many types of human disorders. The premise of this review is the concept that ncRNAs, like many large proteins, have a multidomain architecture that organizes them spatially and functionally. As ncRNAs are beginning to be imprecisely classified into functional families, we review here how their structural properties might inform their functions with focus on structural architecture–function relationships. We will describe the properties of “interactor elements” (IEs) involved in direct physical interaction with nucleic acids, proteins, or lipids and of “structural elements” (SEs) directing their wiring within the “ncRNA interactor networks” through the emergence of secondary and/or tertiary structures. We suggest that spectrums of “letters” (ncRNA elements) are assembled into “words” (ncRNA domains) that are further organized into “phrases” (complete ncRNA structures) with functional meaning (signaling output) through complex “sentences” (the ncRNA interactor networks). This semiotic analogy can guide the exploitation of ncRNAs as new therapeutic targets through the development of IE-blockers and/or SE-lockers that will change the interactor partners’ spectrum of proteins, RNAs, DNAs, or lipids and consequently influence disease phenotypes.
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| 9. |
- Forsberg, Lars A., et al.
(författare)
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Signatures of post-zygotic structural genetic aberrations in the cells of histologically normal breast tissue that can predispose to sporadic breast cancer
- 2015
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 25:10, s. 1521-1535
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Tidskriftsartikel (refereegranskat)abstract
- Sporadic breast cancer (SBC) is a common disease without robust means of early risk prediction in the population. We studied 282 females with SBC, focusing on copy number aberrations in cancer-free breast tissue (uninvolved margin, UM) outside the primary tumor (PT). In total, 1162 UMs (1-14 per breast) were studied. Comparative analysis between UM(s), PT(s), and blood/skin from the same patient as a control is the core of the study design. We identified 108 patients with at least one aberrant UM, representing 38.3% of cases. Gains in gene copy number were the principal type of mutations in microscopically normal breast cells, suggesting that oncogenic activation of genes via increased gene copy number is a predominant mechanism for initiation of SBC pathogenesis. The gain of ERBB2, with overexpression of HER2 protein, was the most common aberration in normal cells. Five additional growth factor receptor genes (EGFR, FGFR1, IGF1R, LIFR, and NGFR) also showed recurrent gains, and these were occasionally present in combination with the gain of ERBB2. All the aberrations found in the normal breast cells were previously described in cancer literature, suggesting their causative, driving role in pathogenesis of SBC. We demonstrate that analysis of normal cells from cancer patients leads to identification of signatures that may increase risk of SBC and our results could influence the choice of surgical intervention to remove all predisposing cells. Early detection of copy number gains suggesting a predisposition toward cancer development, long before detectable tumors are formed, is a key to the anticipated shift into a preventive paradigm of personalized medicine for breast cancer.
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| 10. |
- Gandin, V, et al.
(författare)
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nanoCAGE reveals 5' UTR features that define specific modes of translation of functionally related MTOR-sensitive mRNAs
- 2016
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Ingår i: Genome research. - : Cold Spring Harbor Laboratory. - 1549-5469 .- 1088-9051. ; 26:5, s. 636-648
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Tidskriftsartikel (refereegranskat)abstract
- The diversity of MTOR-regulated mRNA translation remains unresolved. Whereas ribosome-profiling suggested that MTOR almost exclusively stimulates translation of the TOP (terminal oligopyrimidine motif) and TOP-like mRNAs, polysome-profiling indicated that MTOR also modulates translation of mRNAs without the 5′ TOP motif (non-TOP mRNAs). We demonstrate that in ribosome-profiling studies, detection of MTOR-dependent changes in non-TOP mRNA translation was obscured by low sensitivity and methodology biases. Transcription start site profiling using nano-cap analysis of gene expression (nanoCAGE) revealed that not only do many MTOR-sensitive mRNAs lack the 5′ TOP motif but that 5′ UTR features distinguish two functionally and translationally distinct subsets of MTOR-sensitive mRNAs: (1) mRNAs with short 5′ UTRs enriched for mitochondrial functions, which require EIF4E but are less EIF4A1-sensitive; and (2) long 5′ UTR mRNAs encoding proliferation- and survival-promoting proteins, which are both EIF4E- and EIF4A1-sensitive. Selective inhibition of translation of mRNAs harboring long 5′ UTRs via EIF4A1 suppression leads to sustained expression of proteins involved in respiration but concomitant loss of those protecting mitochondrial structural integrity, resulting in apoptosis. Conversely, simultaneous suppression of translation of both long and short 5′ UTR mRNAs by MTOR inhibitors results in metabolic dormancy and a predominantly cytostatic effect. Thus, 5′ UTR features define different modes of MTOR-sensitive translation of functionally distinct subsets of mRNAs, which may explain the diverse impact of MTOR and EIF4A inhibitors on neoplastic cells.
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