| 1. |
- Bolivar, Paulina, et al.
(author)
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Biased Inference of Selection Due to GC-Biased Gene Conversion and the Rate of Protein Evolution in Flycatchers When Accounting for It
- 2018
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In: Molecular biology and evolution. - : OXFORD UNIV PRESS. - 0737-4038 .- 1537-1719. ; 35:10, s. 2475-2486
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Journal article (peer-reviewed)abstract
- The rate of recombination impacts on rates of protein evolution for at least two reasons: it affects the efficacy of selection due to linkage and influences sequence evolution through the process of GC-biased gene conversion (gBGC). We studied how recombination, via gBGC, affects inferences of selection in gene sequences using comparative genomic and population genomic data from the collared flycatcher (Ficedula albicollis). We separately analyzed different mutation categories ("strong"-to-"weak" "weak-to-strong," and GC-conservative changes) and found that gBGC impacts on the distribution of fitness effects of new mutations, and leads to that the rate of adaptive evolution and the proportion of adaptive mutations among nonsynonymous substitutions are underestimated by 22-33%. It also biases inferences of demographic history based on the site frequency spectrum. In light of this impact, we suggest that inferences of selection (and demography) in lineages with pronounced gBGC should be based on GC-conservative changes only. Doing so, we estimate that 10% of nonsynonymous mutations are effectively neutral and that 27% of nonsynonymous substitutions have been fixed by positive selection in the flycatcher lineage. We also find that gene expression level, sex-bias in expression, and the number of protein-protein interactions, but not Hill-Robertson interference (HRI), are strong determinants of selective constraint and rate of adaptation of collared flycatcher genes. This study therefore illustrates the importance of disentangling the effects of different evolutionary forces and genetic factors in interpretation of sequence data, and from that infer the role of natural selection in DNA sequence evolution.
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| 2. |
- Bolivar, Paulina, et al.
(author)
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GC-biased gene conversion conceals the prediction of the nearly neutral theory in avian genomes
- 2019
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In: Genome Biology. - : BMC. - 1465-6906 .- 1474-760X. ; 20
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Journal article (peer-reviewed)abstract
- Background: The nearly neutral theory of molecular evolution predicts that the efficacy of natural selection increases with the effective population size. This prediction has been verified by independent observations in diverse taxa, which show that life-history traits are strongly correlated with measures of the efficacy of selection, such as the d(N)/d(S) ratio. Surprisingly, avian taxa are an exception to this theory because correlations between life-history traits and d(N)/d(S) are apparently absent. Here we explore the role of GC-biased gene conversion on estimates of substitution rates as a potential driver of these unexpected observations.Results: We analyze the relationship between d(N)/d(S) estimated from alignments of 47 avian genomes and several proxies for effective population size. To distinguish the impact of GC-biased gene conversion from selection, we use an approach that accounts for non-stationary base composition and estimate d(N)/d(S) separately for changes affected or unaffected by GC-biased gene conversion. This analysis shows that the impact of GC-biased gene conversion on substitution rates can explain the lack of correlations between life-history traits and d(N)/d(S). Strong correlations between life-history traits and d(N)/d(S) are recovered after accounting for GC-biased gene conversion. The correlations are robust to variation in base composition and genomic location.Conclusions: Our study shows that gene sequence evolution across a wide range of avian lineages meets the prediction of the nearly neutral theory,the efficacy of selection increases with effective population size. Moreover, our study illustrates that accounting for GC-biased gene conversion is important to correctly estimate the strength of selection.
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| 3. |
- Bolívar, Paulina
(author)
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Rates and patterns of molecular evolution in avian genomes
- 2019
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Doctoral thesis (other academic/artistic)abstract
- Evolution is the change in inherited characteristics of a population through subsequent generations. The interplay of several evolutionary mechanisms determines the rate at which this change occurs. In short, genetic variation is generated though mutation, and the fate of these mutations in a population is determined mainly by the combined effect of genetic drift, natural selection and recombination. Elucidating the relative impact of these mechanisms is complex; making it a long-standing question in evolutionary biology. In this thesis, I focus on disentangling the relative roles of these evolutionary mechanisms and genetic factors in determining rates and patterns of evolution at the molecular level, by studying variation in the DNA sequence of multiple avian species, and in particular the collared flycatcher (Ficedula albicollis). Specifically, I aim to further our understanding regarding the impact of recombination rate on genome evolution, through its interaction with the efficacy of selection and through the process of GC-biased gene conversion (gBGC), which has been poorly characterized in birds. I demonstrate that gBGC has a pervasive effect on the genome of the collared flycatcher and other avian species, as it increases the substitution rate and affects interpretations of the impact of natural selection and adaptation. Interestingly, its effect is even stronger in neutrally evolving sites compared to sites evolving under selection. After accounting for gBGC, I disentangle the true impact of natural selection versus non-adaptive processes in determining rates of molecular evolution in the collared flycatcher genome, shedding light on the process of adaptation. Finally, I demonstrate the significant role of recombination through its impact on linked selection, along with mutation rate differences, in determining relative levels of genetic diversity and their relationship to the fast-Z effect across the avian phylogeny. This thesis urges future studies to account for the effect of recombination before interpreting patterns of selection in sequence evolution.
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| 4. |
- Bolívar, Paulina, et al.
(author)
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Recombination Rate Variation Modulates Gene Sequence Evolution Mainly via GC-Biased Gene Conversion, Not Hill-Robertson Interference, in an Avian System
- 2016
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In: Molecular biology and evolution. - : Oxford University Press (OUP). - 0737-4038 .- 1537-1719. ; 33:1, s. 216-227
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Journal article (peer-reviewed)abstract
- The ratio of nonsynonymous to synonymous substitution rates (ω) is often used to measure the strength of natural selection. However, ω may be influenced by linkage among different targets of selection, that is, Hill-Robertson interference (HRI), which reduces the efficacy of selection. Recombination modulates the extent of HRI but may also affect ω by means of GC-biased gene conversion (gBGC), a process leading to a preferential fixation of G:C ("strong," S) over A:T ("weak," W) alleles. As HRI and gBGC can have opposing effects on ω, it is essential to understand their relative impact to make proper inferences of ω. We used a model that separately estimated S-to-S, S-to-W, W-to-S, and W-to-W substitution rates in 8,423 avian genes in the Ficedula flycatcher lineage. We found that the W-to-S substitution rate was positively, and the S-to-W rate negatively, correlated with recombination rate, in accordance with gBGC but not predicted by HRI. The W-to-S rate further showed the strongest impact on both dN and dS. However, since the effects were stronger at 4-fold than at 0-fold degenerated sites, likely because the GC content of these sites is farther away from its equilibrium, ω slightly decreases with increasing recombination rate, which could falsely be interpreted as a consequence of HRI. We corroborated this hypothesis analytically and demonstrate that under particular conditions, ω can decrease with increasing recombination rate. Analyses of the site-frequency spectrum showed that W-to-S mutations were skewed toward high, and S-to-W mutations toward low, frequencies, consistent with a prevalent gBGC-driven fixation bias.
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| 5. |
- Dutoit, Ludovic, et al.
(author)
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Sex-biased gene expression, sexual antagonism and levels of genetic diversity in the collared flycatcher (Ficedula albicollis) genome
- 2018
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In: Molecular Ecology. - : Wiley. - 0962-1083 .- 1365-294X. ; 27:18, s. 3572-3581
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Journal article (other academic/artistic)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.
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| 6. |
- Jacques, Florian, et al.
(author)
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Roadmap to the study of gene and protein phylogeny and evolution—A practical guide
- 2023
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 18:2
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Journal article (peer-reviewed)abstract
- Developments in sequencing technologies and the sequencing of an ever-increasing number of genomes have revolutionised studies of biodiversity and organismal evolution. This accumulation of data has been paralleled by the creation of numerous public biological databases through which the scientific community can mine the sequences and annotations of genomes, transcriptomes, and proteomes of multiple species. However, to find the appropriate databases and bioinformatic tools for respective inquiries and aims can be challenging. Here, we present a compilation of DNA and protein databases, as well as bioinformatic tools for phylogenetic reconstruction and a wide range of studies on molecular evolution. We provide a protocol for information extraction from biological databases and simple phylogenetic reconstruction using probabilistic and distance methods, facilitating the study of biodiversity and evolution at the molecular level for the broad scientific community.
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| 7. |
- Reid, Steven E, et al.
(author)
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Cancer-associated fibroblasts rewire the estrogen receptor response in luminal breast cancer, enabling estrogen independence
- 2024
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In: Oncogene. - 1476-5594.
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Journal article (peer-reviewed)abstract
- Advanced breast cancers represent a major therapeutic challenge due to their refractoriness to treatment. Cancer-associated fibroblasts (CAFs) are the most abundant constituents of the tumor microenvironment and have been linked to most hallmarks of cancer. However, the influence of CAFs on therapeutic outcome remains largely unchartered. Here, we reveal that spatial coincidence of abundant CAF infiltration with malignant cells was associated with reduced estrogen receptor (ER)-α expression and activity in luminal breast tumors. Notably, CAFs mediated estrogen-independent tumor growth by selectively regulating ER-α signaling. Whereas most prototypical estrogen-responsive genes were suppressed, CAFs maintained gene expression related to therapeutic resistance, basal-like differentiation, and invasion. A functional drug screen in co-cultures identified effector pathways involved in the CAF-induced regulation of ER-α signaling. Among these, the Transforming Growth Factor-β and the Janus kinase signaling cascades were validated as actionable targets to counteract the CAF-induced modulation of ER-α activity. Finally, genes that were downregulated in cancer cells by CAFs were predictive of poor response to endocrine treatment. In conclusion, our work reveals that CAFs directly control the luminal breast cancer phenotype by selectively modulating ER-α expression and transcriptional function, and further proposes novel targets to disrupt the crosstalk between CAFs and tumor cells to reinstate treatment response to endocrine therapy in patients.
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| 8. |
- Smeds, Linnea, et al.
(author)
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Evolutionary analysis of the female-specific avian W chromosome
- 2015
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
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Journal article (peer-reviewed)abstract
- The typically repetitive nature of the sex-limited chromosome means that it is often excluded from or poorly covered in genome assemblies, hindering studies of evolutionary and population genomic processes in non-recombining chromosomes. Here, we present a draft assembly of the non-recombining region of the collared flycatcher W chromosome, containing 46 genes without evidence of female-specific functional differentiation. Survival of genes during W chromosome degeneration has been highly non-random and expression data suggest that this can be attributed to selection for maintaining gene dose and ancestral expression levels of essential genes. Re-sequencing of large population samples revealed dramatically reduced levels of within-species diversity and elevated rates of between-species differentiation (lineage sorting), consistent with low effective population size. Concordance between W chromosome and mitochondrial DNA phylogenetic trees demonstrates evolutionary stable matrilineal inheritance of this nuclear-cytonuclear pair of chromosomes. Our results show both commonalities and differences between W chromosome and Y chromosome evolution.
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| 9. |
- Smeds, Linnea, et al.
(author)
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Genomic identification and characterization of the pseudoautosomal region in highly differentiated avian sex chromosomes
- 2014
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 5, s. 5448-
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Journal article (peer-reviewed)abstract
- The molecular characteristics of the pseudoautosomal region (PAR) of sex chromosomes remain elusive. Despite significant genome-sequencing efforts, the PAR of highly differentiated avian sex chromosomes remains to be identified. Here we use linkage analysis together with whole-genome re-sequencing to uncover the 630-kb PAR of an ecological model species, the collared flycatcher. The PAR contains 22 protein-coding genes and is GC rich. The genetic length is 64cM in female meiosis, consistent with an obligate crossing-over event. Recombination is concentrated to a hotspot region, with an extreme rate of > 700 cM/Mb in a 67-kb segment. We find no signatures of sexual antagonism and propose that sexual antagonism may have limited influence on PAR sequences when sex chromosomes are nearly fully differentiated and when a recombination hotspot region is located close to the PAR boundary. Our results demonstrate that a very small PAR suffices to ensure homologous recombination and proper segregation of sex chromosomes during meiosis.
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| 10. |
- Uebbing, Severin, et al.
(author)
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Divergence in gene expression within and between two closely related flycatcher species
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Other publication (other academic/artistic)abstract
- Compared to DNA sequence evolution, relatively little is known about the character of gene expression evolution as species diverge. For example, it is unclear if gene expression generally evolves in a clock-like manner (by stabilizing selection or from neutral evolution) or if there are frequent episodes of directional selection. To gain insights into the evolutionary divergence of gene expression patterns, we sequenced and compared the transcriptomes of multiple tissues from population samples of collared (Ficedula albicollis) and pied flycatchers (F. hypoleuca), a species pair which diverged less than one million years ago. Tissues resolved into separate clusters in non-metric multidimensional scaling ordination analysis and samples from the two species generally clustered by tissue rather than by species. Tissues differed in the degrees of expression variance within species and divergence between species. Variance was positively correlated with expression breadth and negatively correlated with protein interactivity, suggesting that pleiotropic constraints reduce gene expression variance within species. Variance was correlated with between-species divergence, consistent with a pattern expected from stabilizing selection and neutral evolution. Using an expression QST approach, we identified genes differentially expressed between species. We also identified 10 genes uniquely expressed in one of the species. For one such gene (DPP7, uniquely expressed in collared flycatcher), the absence of expression in pied flycatchers could be associated with a fixed ≈ 20 kb deletion including 11 out of 13 exons in this species. This study conducted in a young vertebrate speciation model system expands our knowledge of how gene expression evolves in natural populations.
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| 11. |
- Uebbing, Severin, et al.
(author)
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Divergence in gene expression within and between two closely related flycatcher species
- 2016
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In: Molecular Ecology. - : Wiley. - 0962-1083 .- 1365-294X. ; 25:9, s. 2015-2028
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Journal article (peer-reviewed)abstract
- Relatively little is known about the character of gene expression evolution as species diverge. It is for instance unclear if gene expression generally evolves in a clock-like manner (by stabilizing selection or neutral evolution) or if there are frequent episodes of directional selection. To gain insights into the evolutionary divergence of gene expression, we sequenced and compared the transcriptomes of multiple organs from population samples of collared (Ficedula albicollis) and pied flycatchers (F. hypoleuca), two species which diverged less than one million years ago. Ordination analysis separated samples by organ rather than by species. Organs differed in their degrees of expression variance within species and expression divergence between species. Variance was negatively correlated with expression breadth and protein interactivity, suggesting that pleiotropic constraints reduce gene expression variance within species. Variance was correlated with between-species divergence, consistent with a pattern expected from stabilizing selection and neutral evolution. Using an expression PST approach, we identified genes differentially expressed between species and found 16 genes uniquely expressed in one of the species. For one of these, DPP7, uniquely expressed in collared flycatcher, the absence of expression in pied flycatcher could be associated with a ≈ 20 kb deletion including 11 out of 13 exons. This study of a young vertebrate speciation model system expands our knowledge of how gene expression evolves as natural populations become reproductively isolated.
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| 13. |
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