| 1. |
- Beal, Jacob, et al.
(författare)
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Robust estimation of bacterial cell count from optical density
- 2020
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Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 3:1
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Tidskriftsartikel (refereegranskat)abstract
- Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data.
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| 2. |
- Brindefalk, Björn, et al.
(författare)
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Evolutionary history of the TBP-domain superfamily
- 2013
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 41:5, s. 2832-2845
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Tidskriftsartikel (refereegranskat)abstract
- The TATA binding protein (TBP) is an essential transcription initiation factor in Archaea and Eucarya. Bacteria lack TBP, and instead use sigma factors for transcription initiation. TBP has a symmetric structure comprising two repeated TBP domains. Using sequence, structural and phylogenetic analyses, we examine the distribution and evolutionary history of the TBP domain, a member of the helix-grip fold family. Our analyses reveal a broader distribution than for TBP, with TBP-domains being present across all three domains of life. In contrast to TBP, all other characterized examples of the TBP domain are present as single copies, primarily within multidomain proteins. The presence of the TBP domain in the ubiquitous DNA glycosylases suggests that this fold traces back to the ancestor of all three domains of life. The TBP domain is also found in RNase HIII, and phylogenetic analyses show that RNase HIII has evolved from bacterial RNase HII via TBP-domain fusion. Finally, our comparative genomic screens confirm and extend earlier reports of proteins consisting of a single TBP domain among some Archaea. These monopartite TBP-domain proteins suggest that this domain is functional in its own right, and that the TBP domain could have first evolved as an independent protein, which was later recruited in different contexts.
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| 3. |
- Curtis, Bruce A., et al.
(författare)
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Algal genomes reveal evolutionary mosaicism and the fate of nucleomorphs
- 2012
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 492:7427, s. 59-65
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Tidskriftsartikel (refereegranskat)abstract
- Cryptophyte and chlorarachniophyte algae are transitional forms in the widespread secondary endosymbiotic acquisition of photosynthesis by engulfment of eukaryotic algae. Unlike most secondary plastid-bearing algae, miniaturized versions of the endosymbiont nuclei (nucleomorphs) persist in cryptophytes and chlorarachniophytes. To determine why, and to address other fundamental questions about eukaryote-eukaryote endosymbiosis, we sequenced the nuclear genomes of the cryptophyte Guillardia theta and the chlorarachniophyte Bigelowiella natans. Both genomes have >21,000 protein genes and are intron rich, and B. natans exhibits unprecedented alternative splicing for a single-celled organism. Phylogenomic analyses and subcellular targeting predictions reveal extensive genetic and biochemical mosaicism, with both host-and endosymbiont-derived genes servicing the mitochondrion, the host cell cytosol, the plastid and the remnant endosymbiont cytosol of both algae. Mitochondrion-to-nucleus gene transfer still occurs in both organisms but plastid-to-nucleus and nucleomorph-to-nucleus transfers do not, which explains why a small residue of essential genes remains locked in each nucleomorph.
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| 4. |
- Edvardsson, Sverker, et al.
(författare)
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A search for H/ACA snoRNAs in yeast using MFE secondary structure prediction
- 2003
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Ingår i: Bioinformatics. - : Oxford University Press (OUP). - 1367-4803 .- 1367-4811. ; 19:7, s. 865-873
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Tidskriftsartikel (refereegranskat)abstract
- We develop an algorithm to screen the yeast genome for novel H/ACA snoRNAs. To achieve this, we introduce some new methods for facilitating the search for noncoding RNAs in genomic sequences which are based on properties of predicted minimum free-energy (MFE) secondary structures. The algorithm has been implemented and can be generalized to enable screening of other eukaryote genomes. We find that use of primary sequence alone is insufficient for identifying novel H/ACA snoRNAs. Only the use of secondary structure filters reduces the number of candidates to a manageable size. From genomic context, we identify three strong H/ACA snoRNA candidates. These together with a further 47 candidates obtained by our analysis are being experimentally screened.
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| 5. |
- Gribaldo, Simonetta, et al.
(författare)
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The origin of eukaryotes and their relationship with the Archaea : are we at a phylogenomic impasse?
- 2010
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Ingår i: Nature Reviews Microbiology. - 1740-1526 .- 1740-1534. ; 8:10, s. 743-752
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Tidskriftsartikel (refereegranskat)abstract
- The origin of eukaryotes and their evolutionary relationship with the Archaea is a major biological question and the subject of intense debate. In the context of the classical view of the universal tree of life, the Archaea and the Eukarya have a common ancestor, the nature of which remains undetermined. Alternative views propose instead that the Eukarya evolved directly from a bona fide archaeal lineage. Several recent large-scale phylogenomic studies using an array of approaches are divided in supporting either one or the other scenario, despite analysing largely overlapping data sets of universal genes. We examine the reasons for such a lack of consensus and consider how alternative approaches may enable progress in answering this fascinating and as-yet-unresolved question.
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| 6. |
- Hoeppner, Marc Patrick, 1980-, et al.
(författare)
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Comparative analysis of RNA families reveals distinct repertoires for each domain of life
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Some RNAs may date back to an RNA-rich period in the early evolution of life, butmany RNAs are thought to have more recent evolutionary origins. To chart the broadevolutionary history of known RNA families, we performed comparative genomicanalysis of over 3 million RNA annotations spanning 1446 families from the Rfam 10database. We report that 99% of known RNA families are restricted to a singledomain of life, revealing discrete repertoires for each domain. For the 1% of RNAfamilies/clans present in more than one domain, over half show evidence ofhorizontal gene transfer (HGT), and only six RNAs directly trace to the LastUniversal Common Ancestor (LUCA). These results indicate that cellular RNAinfrastructure evolves in a domain-specific manner.
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| 7. |
- Hoeppner, Marc Patrick, et al.
(författare)
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Comparative Genomics of Eukaryotic Small Nucleolar RNAs Reveals Deep Evolutionary Roots Amidst Ongoing Intragenomic Mobility
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Small nucleolar (sno)RNAs are required for posttranscriptional processing andmodification of ribosomal, spliceosomal and messenger RNAs. There are two broadclasses (C/D and H/ACA), both of which have been characterized in eukaryotes andarchaea. The association with ribosomal RNA processing and modification has led tothe suggestion that snoRNAs are evolutionarily ancient, and date back to the RNAworld. That numerous snoRNAs have been identified in the introns of ribosomalprotein genes has led to alternate views on the origin of this organization. Oneproposal is that intronic snoRNAs predate their surrounding protein-coding exons,the latter being recruited as messenger RNA following the origin of geneticallyencodedprotein synthesis. Another is that intron position reflects selection forcoexpression of snoRNAs and ribosomal components. To gain a clearer insight intothe antiquity of individual snoRNA families and the stability of their genomic location,we examined the evolutionary history of snoRNA families across 44 eukaryotegenomes. Our analysis reveals that dozens of snoRNA families can be traced backto the Last Eukaryotic Common Ancestor (LECA). However, none of the snoRNA1families placed in the LECA are sufficiently similar to characterized archaeal sno-likeRNAs, for us to confidently place specific snoRNA families in the common ancestorof archaea and eukaryotes. In agreement with earlier studies, we can tracenumerous introns to the LECA. However, snoRNAs housed within such positionallyconserved introns are not themselves orthologs. Morevover, our comparativegenomics analysis argues against evolutionarily-stable association betweensnoRNAs and individual host genes — analysis of host gene expression dataindicates that the primary requirement being for hosting intronic snoRNAs is a broadexpression profile. Consistent with mobility over antiquity, we report a case ofdemonstrable intronic snoRNA gain, where an evolutionarily ancient snoRNA hasmigrated into the intron of a mammalian mitochondrial ribosomal protein gene.Together, these data best fit a model wherein snoRNAs are intragenomically mobile,frequently residing in the introns of broadly-expressed protein-coding genes.
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| 8. |
- Hoeppner, Marc P., et al.
(författare)
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Evolutionarily Stable Assiciation of Intronic snoRNAs and microRNAs with Their Host Genes
- 2009
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Ingår i: Genome Biology and Evolution. - : Oxford University Press (OUP). - 1759-6653. ; 1:1, s. 420-428
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Tidskriftsartikel (refereegranskat)abstract
- Small nucleolar RNAs (snoRNAs) and microRNAs (miRNAs) are integral to a range of processes, including ribosome biogenesis and gene regulation. Some are intron encoded, and this organization may facilitate coordinated coexpression of host gene and RNA. However, snoRNAs and miRNAs are known to be mobile, so intron-RNA associations may not be evolutionarily stable. We have used genome alignments across 11 mammals plus chicken to examine positional orthology of snoRNAs and miRNAs and report that 21% of annotated snoRNAs and 11% of miRNAs are positionally conserved across mammals. Among RNAs traceable to the bird–mammal common ancestor, 98% of snoRNAs and 76% of miRNAs are intronic. Comparison of the most evolutionarily stable mammalian intronic snoRNAs with those positionally conserved among primates reveals that the former are more overrepresented among host genes involved in translation or ribosome biogenesis and are more broadly and highly expressed. This stability is likely attributable to a requirement for overlap between host gene and intronic snoRNA expression profiles, consistent with an ancestral role in ribosome biogenesis. In contrast, whereas miRNA positional conservation is comparable to that observed for snoRNAs, intronic miRNAs show no obvious association with host genes of a particular functional category, and no statistically significant differences in host gene expression are found between those traceable to mammalian or primate ancestors. Our results indicate evolutionarily stable associations of numerous intronic snoRNAs and miRNAs and their host genes, with probable continued diversification of snoRNA function from an ancestral role in ribosome biogenesis.
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| 9. |
- Hoeppner, Marc Patrick, et al.
(författare)
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Maintenance of redundant small RNA gene copies over evolutionarytimescales via a retrotransposition motor?
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- We analysed the stability of duplicated, essential RNAs on the backdrop of theirexpression profiles to test whether the data is compatible with functional redundancy ordiversification. Under the former model, the expectation is that copies are equallyexpressed across tissues and subject to high turn-over. The latter model, in contrast,predicts that sub- or neofunctionalization following duplication may lead to a range ofcomplementary expression profiles across tissues. By example of the spliceosomal RNAU1 and snoRNA U3, we find that only few loci are stable over the course of vertebrateevolution and that the majority of copies show little or no expression. We conclude thatthese findings are most compatible with the redundancy model. Interestingly, the deepestloci are associated with a testis-expressed gene, suggesting a possible driving forcebehind the ongoing proliferation that we observe.
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| 10. |
- Hoeppner, Marc Patrick, 1980-
(författare)
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The deep evolutionary roots of non-coding RNA - a comparative genomics approach
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Non-coding RNAs (ncRNA) are a diverse group of genes that do not encode proteins but function exclusively on the level of RNA and were originally suggested to be remnants of a pre-DNA stage of life known as the RNA world. More recent work, however, has uncovered a rich repertoire of previously unknown families with possible consequences for our understanding of the origin and evolution of the modern RNA infrastructure. The main goal of this thesis was therefore to re-examine the evolutionary history of RNAs and theories regarding the transition from an RNA world in light of recent advances in molecular and computational biology. Using comparative genomics approaches and sequence data from all domains of life, my work shows that the majority of known RNAs exhibit a highly domain-specific distribution, compatible with an ongoing emergence rather than deep ancestry. Focusing on small nucleolar RNAs (snoRNA), I find that the eukaryote ancestor possessed a complex snoRNA infrastructure, but that intronic snoRNAs are mobile over larger evolutionary time scales. The latter has consequences for predictions made by the Introns-first hypothesis, a framework to explain the emergence of introns in an RNA world and which we revisited in light of advances in our understanding of the evolutionary dynamics of introns. A more in-depth analysis of ncRNA mobility across vertebrates found intronic copies of both snoRNAs and miRNAs to be more stable than intergenic ones, suggesting that this arrangement may be a consequence of co-expression. Also, snoRNAs are frequently located in highly expressed genes, in line with their role in ribosome biogenesis. Finally, a closer examination of the genomic distribution of two essential ncRNAs, snoRNA U3 and the spliceosomal RNA U1 shows that both are present in numerous copies across vertebrate genomes. Using next-generation sequencing data, I tested whether this is the result of genetic drift or a requirement for having many copies.
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| 11. |
- Hollestelle, Antoinette, et al.
(författare)
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No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer
- 2016
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Ingår i: Gynecologic Oncology. - : Elsevier BV. - 0090-8258 .- 1095-6859. ; 141:2, s. 386-401
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Tidskriftsartikel (refereegranskat)abstract
- Objective Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3′ UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. Methods Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). Results We found no association with risk of ovarian cancer (OR = 0.99, 95% CI 0.94-1.04, p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94-1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97-1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97-1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71-1.13, p = 0.34, breast cancer HR = 1.06, 95% CI 0.94-1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83-1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87-1.06, p = 0.38), and all other previously-reported associations. Conclusions rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.
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| 12. |
- Höppner, Marc P, et al.
(författare)
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Comparative analysis of RNA families reveals distinct repertoires for each domain of life
- 2012
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Ingår i: PloS Computational Biology. - : Public Library of Science (PLoS). - 1553-734X .- 1553-7358. ; 8:11, s. e1002752-
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Tidskriftsartikel (refereegranskat)abstract
- The RNA world hypothesis, that RNA genomes and catalysts preceded DNA genomes and genetically-encoded protein catalysts, has been central to models for the early evolution of life on Earth. A key part of such models is continuity between the earliest stages in the evolution of life and the RNA repertoires of extant lineages. Some assessments seem consistent with a diverse RNA world, yet direct continuity between modern RNAs and an RNA world has not been demonstrated for the majority of RNA families, and, anecdotally, many RNA functions appear restricted in their distribution. Despite much discussion of the possible antiquity of RNA families, no systematic analyses of RNA family distribution have been performed. To chart the broad evolutionary history of known RNA families, we performed comparative genomic analysis of over 3 million RNA annotations spanning 1446 families from the Rfam 10 database. We report that 99% of known RNA families are restricted to a single domain of life, revealing discrete repertoires for each domain. For the 1% of RNA families/clans present in more than one domain, over half show evidence of horizontal gene transfer (HGT), and the rest show a vertical trace, indicating the presence of a complex protein synthesis machinery in the Last Universal Common Ancestor (LUCA) and consistent with the evolutionary history of the most ancient protein-coding genes. However, with limited interdomain transfer and few RNA families exhibiting demonstrable antiquity as predicted under RNA world continuity, our results indicate that the majority of modern cellular RNA repertoires have primarily evolved in a domain-specific manner.
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| 13. |
- Höppner, Marc P., et al.
(författare)
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Comparative genomics of eukaryotic small nucleolar RNAs reveals deep evolutionary ancestry amidst ongoing intragenomic mobility
- 2012
-
Ingår i: BMC Evolutionary Biology. - : Springer Science and Business Media LLC. - 1471-2148. ; 12, s. 183-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Small nucleolar (sno) RNAs are required for posttranscriptional processing and modification of ribosomal, spliceosomal and messenger RNAs. Their presence in both eukaryotes and archaea indicates that snoRNAs are evolutionarily ancient. The location of some snoRNAs within the introns of ribosomal protein genes has been suggested to belie an RNA world origin, with the exons of the earliest protein-coding genes having evolved around snoRNAs after the advent of templated protein synthesis. Alternatively, this intronic location may reflect more recent selection for coexpression of snoRNAs and ribosomal components, ensuring rRNA modification by snoRNAs during ribosome synthesis. To gain insight into the evolutionary origins of this genetic organization, we examined the antiquity of snoRNA families and the stability of their genomic location across 44 eukaryote genomes. Results: We report that dozens of snoRNA families are traceable to the Last Eukaryotic Common Ancestor (LECA), but find only weak similarities between the oldest eukaryotic snoRNAs and archaeal snoRNA-like genes. Moreover, many of these LECA snoRNAs are located within the introns of host genes independently traceable to the LECA. Comparative genomic analyses reveal the intronic location of LECA snoRNAs is not ancestral however, suggesting the pattern we observe is the result of ongoing intragenomic mobility. Analysis of human transcriptome data indicates that the primary requirement for hosting intronic snoRNAs is a broad expression profile. Consistent with ongoing mobility across broadly-expressed genes, we report a case of recent migration of a non-LECA snoRNA from the intron of a ubiquitously expressed non-LECA host gene into the introns of two LECA genes during the evolution of primates. Conclusions: Our analyses show that snoRNAs were a well-established family of RNAs at the time when eukaryotes began to diversify. While many are intronic, this association is not evolutionarily stable across the eukaryote tree; ongoing intragenomic mobility has erased signal of their ancestral gene organization, and neither introns-first nor evolved co-expression adequately explain our results. We therefore present a third model - constrained drift - whereby individual snoRNAs are intragenomically mobile and may occupy any genomic location from which expression satisfies phenotype.
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| 14. |
- Lawrenson, Kate, et al.
(författare)
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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
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| 15. |
- Lundin, Daniel, 1965-, et al.
(författare)
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Ribonucleotide reduction : horizontal transfer of a required function spans all three domains
- 2010
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Ingår i: BMC Evolutionary Biology. - : Springer Science and Business Media LLC. - 1471-2148. ; 10:383
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background Ribonucleotide reduction is the only de novo pathway for synthesis ofdeoxyribonucleotides, the building blocks of DNA. The reaction is catalysed byribonucleotide reductases (RNRs), an ancient enzyme family comprised of threeclasses. Each class has distinct operational constraints, and are broadly distributedacross organisms from all three domains, though few class I RNRs have beenidentified in archaeal genomes, and classes II and III likewise appear rare acrosseukaryotes. In this study, we examine whether this distribution is best explained bypresence of all three classes in the Last Universal Common Ancestor (LUCA), or byhorizontal gene transfer (HGT) of RNR genes. We also examine to what extentenvironmental factors may have impacted the distribution of RNR classes. Results Our phylogenies show that the Last Eukaryotic Common Ancestor (LECA) possesseda class I RNR, but that the eukaryotic class I enzymes are not directly descended fromclass I RNRs in archaea. Instead, our results indicate that archaeal class I RNR geneshave been independently transferred from bacteria on two occasions. While LECApossessed a class I RNR, our trees indicate that this is ultimately bacterial in origin.We also find convincing evidence that eukaryotic class I RNR has been transferred tothe bacteroidetes, providing a stunning example of HGT from eukaryotes back tobacteria. Based on our phylogenies and available genetic and genomic evidence, classII and III RNRs in eukaryotes also appear to have been transferred from bacteria, with subsequent within-domain transfer between distantly-related eukaryotes. Under the three-domains hypothesis the RNR present in the last common ancestor of archaeaand eukaryotes appears, through a process of elimination, to have been a dimeric classII RNR, though limited sampling of eukaryotes precludes a firm conclusion as the data may be equally well accounted for by HGT. Conclusions Horizontal gene transfer has clearly played an important role in the evolution of theRNR repertoire of organisms from all three domains of life. Our results clearly showthat class I RNRs have spread to archaea and eukaryotes via transfers from thebacterial domain, indicating that class I likely evolved in the bacteria. We find noclear evolutionary trace placing either class II or III RNRs in the LUCA, despite thefact that ribonucleotide reduction is an essential cellular reaction and was pivotal tothe transition from RNA to DNA genomes. Instead, a general pattern emerges whereenvironmental and enzyme operational constraints, especially the presence or absenceof oxygen, coupled with horizontal transmission are major determinants of the RNR repertoire of genomes.
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| 16. |
- Lundin, Daniel, 1965-, et al.
(författare)
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RNRdb, a curated database of the universal enzyme family ribonucleotide reductase, reveals a high level of misannotation in sequences deposited to Genbank
- 2009
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Ribonucleotide reductases (RNRs) catalyse the only known de novo pathway for deoxyribonucleotide synthesis, and are therefore essential to DNA-based life. While ribonucleotide reduction has a single evolutionary origin, significant differences between RNRs nevertheless exist, notably in cofactor requirements, subunit composition and allosteric regulation. These differences result in distinct operational constraints (anaerobicity, iron/oxygen dependence and cobalamin dependence), and form the basis for the classification of RNRs into three classes. PMID: 19995434
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| 17. |
- Lundin, Daniel, 1965-
(författare)
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The evolution of ribonucleotide reductases
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Ribonucleotide reductase (RNR) catalyses the transformation of RNA building blocks, ribonucleotides, to DNA building blocks, deoxyribonucleotides. This is the only extant reaction pathway for de novo synthesis of DNA building blocks and the enzyme is thus necessary for life. RNR is found in all but a few organisms. There are three classes of RNR, all evolutionarily related. The classification is built on differences in generation of the radical that is central to the reaction. As a consequence, RNR classes have different operational constraints. Class I requires oxygen, while class III is poisoned by oxygen. Class II is independent of oxygen, but dependent on vitamin B12 and, hence, cobalt. This makes RNR interesting from an evolutionary as well as environmental point of view. RNR must have evolved before the transition from RNA encoded genomes to DNA encoded. The extant radical-based reaction is likely similar to the ancestral reaction, which entails that the ancestral enzyme was a protein and not an RNR. My results are consistent with both class II and III being present in the last universal common ancestor. Class I RNR evolved later, presumably once oxygen levels had risen. From commonalities in extant RNRs we can reconstruct their last common ancestor as an enzyme that 1) used a transient cysteine-radical in the reaction, 2) reduced all four ribonucleotides, 3) regulated which nucleotide was reduced after binding an effector nucleotide in the dimer interface of the enzyme and 4) had activity regulation through binding of a nucleotide to another part of the enzyme. The presence of a specific RNR class is likely to influence the environmental range of organisms, which makes horizontal transfer of RNR particularly interesting. Horizontal transfer of RNR genes is widespread, both between closely related organisms and between domains. For instance, all three classes are present in eukaryotes, but likely all three are results of horizontal transfer.
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| 18. |
- Lundin, Daniel, 1965-, et al.
(författare)
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The functional diversity and evolutionary relationships of ferritin-like proteins
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundThe ferritin-like proteins are evolutionarily related, as evidenced by the topology oftheir signature metal-binding four-helix bundle. They perform diverse functions suchas iron/oxygen detoxification, iron storage, DNA protection and substrate oxidation.Though evolutionarily related, sequence similarity between families and often withinfamilies is low. To analyse the evolutionary relationships between individual familiesand their functional roles systematically, we turned to 3D structural alignment andphylogenetic methods.ResultsOur phylogenetic network recovers all characterised functional groups of ferritin-likeproteins and suggests evolutionary relationships between them. The evolutionaryhypotheses that are suggested by the phylogeny are tested against availableindependent evidence such as dimerisation geometries, qualitative comparison ofstructures and sequence based partial phylogenies. Generally our hypotheses stand upagainst the evidence, but in a few cases verification have to await further data.ConclusionsTwo large evolutionary groups of ferritin-like proteins are identified from structuralphylogeny: ferritins, bacterioferritins and Dps proteins on one hand, and substrateoxidising proteins, bacterial multicomponent monooxygenases, fatty acid desaturasesand class I ribonucleotide reductase radical generating subunits, on the other. Themethod we present provides a robust way of evolutionarily classifying a functionallydiverse group of distantly related proteins, as well as examining the possible functionsof poorly-characterised proteins.
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| 19. |
- Lundin, Daniel, 1965-, et al.
(författare)
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Use of Structural Phylogenetic Networks for Classification of the Ferritin-like Superfamily
- 2012
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 287:24, s. 20565-20575
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Tidskriftsartikel (refereegranskat)abstract
- In the postgenomic era, bioinformatic analysis of sequence similarity is an immensely powerful tool to gain insight into evolution and protein function. Over long evolutionary distances, however, sequence-based methods fail as the similarities become too low for phylogenetic analysis. Macromolecular structure generally appears better conserved than sequence, but clear models for how structure evolves over time are lacking. The exponential growth of three-dimensional structural information may allow novel structure-based methods to drastically extend the evolutionary time scales amenable to phylogenetics and functional classification of proteins. To this end, we analyzed 80 structures from the functionally diverse ferritin-like superfamily. Using evolutionary networks, we demonstrate that structural comparisons can delineate and discover groups of proteins beyond the “twilight zone” where sequence similarity does not allow evolutionary analysis, suggesting that considerable and useful evolutionary signal is preserved in three-dimensional structures.
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| 20. |
- Neumann, Nadja, et al.
(författare)
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Comparative Genomic Evidence for a Complete Nuclear Pore Complex in the Last Eukaryotic Common Ancestor
- 2010
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 5:10
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe Nuclear Pore Complex (NPC) facilitates molecular trafficking between nucleus and cytoplasm and is an integral feature of the eukaryote cell. It exhibits eight-fold rotational symmetry and is comprised of approximately 30 nucleoporins (Nups) in different stoichiometries. Nups are broadly conserved between yeast, vertebrates and plants, but few have been identified among other major eukaryotic groups.Methodology/Principal FindingsWe screened for Nups across 60 eukaryote genomes and report that 19 Nups (spanning all major protein subcomplexes) are found in all eukaryote supergroups represented in our study (Opisthokonts, Amoebozoa, Viridiplantae, Chromalveolates and Excavates). Based on parsimony, between 23 and 26 of 31 Nups can be placed in LECA. Notably, they include central components of the anchoring system (Ndc1 and Gp210) indicating that the anchoring system did not evolve by convergence, as has previously been suggested. These results significantly extend earlier results and, importantly, unambiguously place a fully-fledged NPC in LECA. We also test the proposal that transmembrane Pom proteins in vertebrates and yeasts may account for their variant forms of mitosis (open mitoses in vertebrates, closed among yeasts). The distribution of homologues of vertebrate Pom121 and yeast Pom152 is not consistent with this suggestion, but the distribution of fungal Pom34 fits a scenario wherein it was integral to the evolution of closed mitosis in ascomycetes. We also report an updated screen for vesicle coating complexes, which share a common evolutionary origin with Nups, and can be traced back to LECA. Surprisingly, we find only three supergroup-level differences (one gain and two losses) between the constituents of COPI, COPII and Clathrin complexes.Conclusions/SignificanceOur results indicate that all major protein subcomplexes in the Nuclear Pore Complex are traceable to the Last Eukaryotic Common Ancestor (LECA). In contrast to previous screens, we demonstrate that our conclusions hold regardless of the position of the root of the eukaryote tree.
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| 21. |
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| 22. |
- Neumann, Nadja, et al.
(författare)
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Outsourcing the Nucleus : Nuclear Pore Complex Genes are no Longer Encoded in Nucleomorph Genomes
- 2006
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Ingår i: Evolutionary Bioinformatics. - 1176-9343. ; 2, s. 23-34
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Tidskriftsartikel (refereegranskat)abstract
- The nuclear pore complex (NPC) facilitates transport between nucleus and cytoplasm. The protein constituents of the NPC, termed nucleoporins (Nups), are conserved across a wide diversity of eukaryotes. In apparent exception to this, no nucleoporin genes have been identified in nucleomorph genomes. Nucleomorphs, nuclear remnants of once free-living eukaryotes, took up residence as secondary endosymbionts in cryptomonad and chlorarachniophyte algae. As these genomes are highly reduced, Nup genes may have been lost, or relocated to the host nucleus. However, Nup genes are often poorly conserved between species, so absence may be an artifact of low sequence similarity. We therefore constructed an evolutionary bioinformatic screen to establish whether the apparent absence of Nup genes in nucleomorph genomes is due to genuine absence or the inability of current methods to detect homologues. We searched green plant (Arabidopsis and rice), green alga (Chlamydomonas reinhardtii) and red alga (Cyanidioschyzon merolae) genomes, plus two nucleomorph genomes (Bigelowiella natans and Guillardia theta) with profile hidden Markov models (HMMs) from curated alignments of known vertebrate/yeast Nups. Since the plant, algal and nucleomorph genomes all belong to the kingdom Plantae, and are evolutionarily distant from the outgroup (vertebrate/yeast) training set, we use the plant and algal genomes as internal positive controls for the sensitivity of the searches in nucleomorph genomes. We find numerous Nup homologues in all plant and free-living algal species, but none in either nucleomorph genome. BLAST searches using identified plant and algal Nups also failed to detect nucleomorph homologues. We conclude that nucleomorph Nup genes have either been lost, being replaced by host Nup genes, or, that nucleomorph Nup genes have been transferred to the host nucleus twice independently; once in the evolution of the red algal nucleomorph and once in the green algal nucleomorph.
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| 23. |
- Neumann, Nadja, 1977-
(författare)
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The evolution of the nuclear envelope
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The nucleus is one of the defining features of eukaryotes and the question of its origin is intimately linked to the evolution of the eukaryotic cell. It is delimited by a double lipid bilayer called the nuclear envelope, which separates the nuclear interior from the cytoplasm. The inner and outer membranes of the nucleus are continuous with one another creating a single folded envelope, interrupted by nuclear pore complexes (NPCs), which enable transport of proteins and RNA between nucleoplasm and cytoplasm. A combination of proteomic and bioinformatic analyses has shown that numerous Nups are conserved between yeast and vertebrates. As this only describes a subset of eukaryotic diversity, comparative genomic analyses were used to establish the extent to which the NPC is conserved across the eukaryotic tree. NPCs have been suggested to share a common origin with vesicle coat proteins of the endomembrane system. An additional goal of this work was therefore to establish the distribution of three complexes involved in vesicle transport between organelles of the secretory pathway, called COPI, COPII and Clathrin. Using profile hidden Markov models in combination with BLAST resulted in identification of nucleoporins and coat protein homologs across all five eukaryotic supergroups for which sequence data is available, indicating both were already present in the Last Eukaryotic Common Ancestor (LECA).Nup homologs were shown to be definitively absent from vestigial nucleomorph nuclei, resultant from secondary endosymbioses, suggesting that Nup genes have either been relocated to the host nuclear genome or that the same set of Nups are used for constructing both the NPC of the main nucleus and nucleomorph.´ We also tested the proposal that transmembrane Nups in vertebrates and yeasts may account for their variant forms of mitosis (‘open’ in vertebrates, ‘closed’ among yeasts). Consistent with this suggestion, the distribution of fungal Pom34 fits a scenario wherein it was integral to the evolution of 'closed’ mitosis in ascomycetes.A unique arrangement for the chromosomes occurs during early meiosis, where the telomeres cluster at the nuclear envelope, forming a distinct ‘bouquet’ arrangement. This forms prior to homolog pairing and recombination in meiosis I. Hypotheses concerning the antiquity of the bouquet were tested by examining the extent of conservation of proteins involved in this stage of meiosis. Distribution appeared patchy, so its presence in LECA could not be unequivocally established and is discussed together with a model aimed at explaining the functional role of the bouquet.
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| 24. |
- Parodis, Ioannis, 1981-, et al.
(författare)
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EULAR recommendations for the non-pharmacological management of systemic lupus erythematosus and systemic sclerosis
- 2024
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Ingår i: Annals of the Rheumatic Diseases. - : HighWire Press. - 0003-4967 .- 1468-2060. ; 83, s. 720-729
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To develop evidence-based recommendations for the non-pharmacological management of systemic lupus erythematosus (SLE) and systemic sclerosis (SSc).METHODS: A task force comprising 7 rheumatologists, 15 other healthcare professionals and 3 patients was established. Following a systematic literature review performed to inform the recommendations, statements were formulated, discussed during online meetings and graded based on risk of bias assessment, level of evidence (LoE) and strength of recommendation (SoR; scale A-D, A comprising consistent LoE 1 studies, D comprising LoE 4 or inconsistent studies), following the European Alliance of Associations for Rheumatology standard operating procedure. Level of agreement (LoA; scale 0-10, 0 denoting complete disagreement, 10 denoting complete agreement) was determined for each statement through online voting.RESULTS: Four overarching principles and 12 recommendations were developed. These concerned common and disease-specific aspects of non-pharmacological management. SoR ranged from A to D. The mean LoA with the overarching principles and recommendations ranged from 8.4 to 9.7. Briefly, non-pharmacological management of SLE and SSc should be tailored, person-centred and participatory. It is not intended to preclude but rather complement pharmacotherapy. Patients should be offered education and support for physical exercise, smoking cessation and avoidance of cold exposure. Photoprotection and psychosocial interventions are important for SLE patients, while mouth and hand exercises are important in SSc.CONCLUSIONS: The recommendations will guide healthcare professionals and patients towards a holistic and personalised management of SLE and SSc. Research and educational agendas were developed to address needs towards a higher evidence level, enhancement of clinician-patient communication and improved outcomes.
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| 25. |
- Penny, David, et al.
(författare)
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An Overview of the Introns-First Theory
- 2009
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Ingår i: Journal of Molecular Evolution. - : Springer Science and Business Media LLC. - 0022-2844 .- 1432-1432. ; 69, s. 527-540
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Tidskriftsartikel (refereegranskat)abstract
- We review the introns-first hypothesis a decade after it was first proposed. It is that exons emerged from non-coding regions interspersed between RNA genes in an early RNA world, and is a subcomponent of a more general ‘RNA-continuity’ hypothesis. The latter is that some RNA based systems, especially in RNA processing, are ‘relics’ that can be traced back either to the RNA world that preceded both DNA and encoded protein synthesis or to the later ribonucleoprotein (RNP) world (before DNA took over the main coding role). RNA-continuity is based on independent evidence—in particular, the relative inefficiency of RNA catalysis compared with protein catalysis— and leads to a wide range of predictions, ranging from the origin of the ribosome, the spliceosome, small nucleolar RNAs, RNases P and MRP, and mRNA, and it is consistent with the wide involvement of RNA-processing and regulation of RNA in modern eukaryotes. While there may still be cause to withhold judgement on intron origins, there is strong evidence against introns being uncommon in the last eukaryotic common ancestor (LECA), and expanding only within extant eukaryotic groups—the ‘very-late’ intron invasion model. Similarly, it is clear that there are selective forces on numbers and positions of introns; their existence may not always be neutral. There is still a range of viable alternatives, including introns first, early, and ‘latish’ (i.e. well established in LECA), and regardless of which is ultimately correct, it pays to separate out various questions and to focus on testing the predictions of sub-theories.
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| 26. |
- Peres, Lauren C, et al.
(författare)
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High Levels of C-Reactive Protein Are Associated with an Increased Risk of Ovarian Cancer : Results from the Ovarian Cancer Cohort Consortium
- 2019
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Ingår i: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 79:20, s. 5442-5451
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Tidskriftsartikel (refereegranskat)abstract
- Growing epidemiologic evidence supports chronic inflammation as a mechanism of ovarian carcinogenesis. An association between a circulating marker of inflammation, C-reactive protein (CRP), and ovarian cancer risk has been consistently observed, yet, potential heterogeneity of this association by tumor and patient characteristics has not been adequately explored. In this study, we pooled data from case-control studies nested within six cohorts in the Ovarian Cancer Cohort Consortium (OC3) to examine the association between CRP and epithelial ovarian cancer risk overall, by histologic subtype and by participant characteristics. CRP concentrations were measured from prediagnosis serum or plasma in 1,091 cases and 1,951 controls. Multivariable conditional logistic regression was used to estimate ORs and 95% confidence intervals (CI). When CRP was evaluated using tertiles, no associations with ovarian cancer risk were observed. A 67% increased ovarian cancer risk was found for women with CRP concentrations >10 mg/L compared with <1 mg/L (OR = 1.67; 95% CI = 1.12-2.48). A CRP concentration >10 mg/L was positively associated with risk of mucinous (OR = 9.67; 95% CI = 1.10-84.80) and endometrioid carcinoma (OR = 3.41; 95% CI = 1.07-10.92), and suggestively positive, although not statistically significant, for serous (OR = 1.43; 95% CI = 0.82-2.49) and clear cell carcinoma (OR = 2.05; 95% CI = 0.36-11.57; P heterogeneity = 0.20). Heterogeneity was observed with oral contraceptive use (P interaction = 0.03), where the increased risk was present only among ever users (OR = 3.24; 95% CI = 1.62-6.47). This study adds to the existing evidence that CRP plays a role in ovarian carcinogenesis and suggests that inflammation may be particularly implicated in the etiology of endometrioid and mucinous carcinoma. SIGNIFICANCE: C-reactive protein is involved in ovarian carcinogenesis, and chronic inflammation may be particularly implicated in the etiology of mucinous and endometrioid carcinomas.
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| 27. |
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| 28. |
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| 29. |
- Poole, Anthony, et al.
(författare)
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Engulfed by speculation
- 2007
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Ingår i: Nature. ; 447:913
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 30. |
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| 31. |
- Poole, Anthony M., et al.
(författare)
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Can identification of a fourth domain of life be made from sequence data alone, and could it be done on mars?
- 2007
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Ingår i: Astrobiology. - : Mary Ann Liebert Inc. - 1531-1074 .- 1557-8070. ; 7:5, s. 801-814
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Forskningsöversikt (refereegranskat)abstract
- A central question in astrobiology is whether life exists elsewhere in the universe. If so, is it related to Earth life? Technologies exist that enable identification of DNA- or RNA-based microbial life directly from environmental samples here on Earth. Such technologies could, in principle, be applied to the search for life elsewhere; indeed, efforts are underway to initiate such a search. However, surveying for nucleic acid-based life on other planets, if attempted, must be carried out with caution, owing to the risk of contamination by Earth-based life. Here we argue that the null hypothesis must be that any DNA discovered and sequenced from samples taken elsewhere in the universe are Earth-based contaminants. Experience from studies of low-biomass ancient DNA demonstrates that some results, by their very nature, will not enable complete rejection of the null hypothesis. In terms of eliminating contamination as an explanation of the data, there may be value in identification of sequences that lie outside the known diversity of the three domains of life. We therefore have examined whether a fourth domain could be readily identified from environmental DNA sequence data alone. We concluded that, even on Earth, this would be far from trivial, and we illustrate this point by way of examples drawn from the literature. Overall, our conclusions do not bode well for planned PCR-based surveys for life on Mars, and we argue that other independent biosignatures will be essential in corroborating any claims for the presence of life based on nucleic acid sequences.
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| 32. |
- Poole, Anthony M
(författare)
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Horizontal gene transfer and the earliest stages of the evolution of life
- 2009
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Ingår i: Research in Microbiology. - : Elsevier. - 0923-2508 .- 1769-7123. ; 160:7, s. 473-480
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Tidskriftsartikel (refereegranskat)abstract
- Horizontal gene transfer (HGT) has been suggested to be the dominant hereditary process at the earliest stages of evolution. I examine this suggestion within the context of the problem of genetic parasites and suggest that extreme rates of transfer may in fact negatively impact evolutionary transitions. In regard to the proposal that HGT is Lamarckian, the apparent conflict between HGT and Darwinian evolution is easily avoided by considering HGT at the appropriate level of selection.
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| 33. |
- Poole, Anthony M
(författare)
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How the endosymbiont got its cell
- 2009
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Ingår i: New Zeeland Science Review. ; 66:1, s. 28-33
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Recension (övrigt vetenskapligt/konstnärligt)abstract
- Despite fundamental advances in cellular, molecular and genome biology, there is still surprisingly little consensus concerning the evolutionary origins of the eukaryote cell. While it is clear that the mitochondrion (responsible for generating much of the energy requirements of the eukaryote cell) has evolved from an endosymbiont cell of bacterial origin, the recent literature has borne witness to a tidal wave of speculative theories regarding the nature of the cell in which this bacterium took up residence. David Penny and I recently argued that much of this confusion can be avoided if models are grounded in known biological processes, and if speculation is tempered by formulating testable hypotheses. The most fanciful hypotheses are an inevitable casualty of a pragmatic approach, but what remains is a productive framework wherein biologically plausible alternatives can be evaluated without the need to invoke ad hoc events or processes, such as biological ‘big bangs’ or hitherto unobserved cell biological phenomena.
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| 34. |
- Poole, Anthony M., et al.
(författare)
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Reconciling an archaeal origin of eukaryotes with engulfment : a biologically plausible update of the Eocyte hypothesis
- 2011
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Ingår i: Research in Microbiology. - : Elsevier BV. - 0923-2508 .- 1769-7123. ; 162:1, s. 71-76
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Tidskriftsartikel (refereegranskat)abstract
- An archaeal origin of eukaryotes is often equated with the engulfment of the bacterial ancestor of mitochondria by an archaeon. Such an event is problematic in that it is not supported by archaeal cell biology. We show that placing phylogenetic results within a stem-and-crown framework eliminates such incompatibilities, and that an archaeal origin for eukaryotes (as suggested from recent phylogenies) can be uncontroversially reconciled with phagocytosis as the mechanism for engulfment of the mitochondrial ancestor. This is significant because it eliminates a perceived problem with eukaryote origins: that an archaeal origin of eukaryotes (as under the Eocyte hypothesis) cannot be reconciled with existing cell biological mechanisms through which bacteria may take up residence inside eukaryote cells.
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| 35. |
- Poole, Anthony M., et al.
(författare)
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The evolution of early cellular systems viewed through the lens of biological interactions
- 2015
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Ingår i: Frontiers in Microbiology. - : Frontiers Media SA. - 1664-302X. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- The minimal cell concept represents a pragmatic approach to the question of how few genes are required to run a cell. This is a helpful way to build a parts-list, and has been more successful than attempts to deduce a minimal gene set for life by inferring the gene repertoire of the last universal common ancestor, as few genes trace back to this hypothetical ancestral state. However, the study of minimal cellular systems is the study of biological outliers where, by practical necessity, coevolutionary interactions are minimized or ignored. In this paper, we consider the biological context from which minimal genomes have been removed. For instance, some of the most reduced genomes are from endosymbionts and are the result of coevolutionary interactions with a host; few such organisms are "free-living." As few, if any, biological systems exist in complete isolation, we expect that, as with modern life, early biological systems were part of an ecosystem, replete with organismal interactions. We favor refocusing discussions of the evolution of cellular systems on processes rather than gene counts. We therefore draw a distinction between a pragmatic minimal cell (an interesting engineering problem), a distributed genome (a system resulting from an evolutionary transition involving more than one cell) and the looser coevolutionary interactions that are ubiquitous in ecosystems. Finally, we consider the distributed genome and coevolutionary interactions between genomic entities in the context of early evolution.
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| 36. |
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| 37. |
- Poole, Anthony, et al.
(författare)
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Response to Dagan and Martin
- 2007
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Ingår i: BioEssays. ; 29, s. 611-614
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 38. |
- Poole, Anthony, et al.
(författare)
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The evolution of the ribonucleotide reductases: Much ado about oxygen
- 2002
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Ingår i: Journal of Molecular Evolution. - : Springer Science and Business Media LLC. - 0022-2844 .- 1432-1432. ; 55:2, s. 180-196
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Tidskriftsartikel (refereegranskat)abstract
- Ribonucleotide reduction is the only known biological means for de novo production of deoxyribonucleotides, the building blocks of DNA. These are produced from ribonucleotides, the building blocks of RNA, and the direction of this reaction has been taken to support the idea that, in evolution, RNA preceded DNA as genetic material. However, an understanding of the evolutionary relationships among the three modern-day classes of ribonucleotide reductase and how the first reductase arose early in evolution is still far off. We propose that the diversification of this class of enzymes is inherently tied to microbial colonization of aerobic and anaerobic niches. The work is of broader interest, as it also sheds light on the process of adaptation to oxygenic environments consequent to the evolution of atmospheric oxygen.
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| 39. |
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| 40. |
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| 41. |
- Tamas, Ivica, et al.
(författare)
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Endosymbiont gene functions impaired and rescued by polymerase infidelity at poly(A) tracts
- 2008
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 105:39, s. 14934-14939
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Tidskriftsartikel (refereegranskat)abstract
- Among host-dependent bacteria that have evolved by extreme reductive genome evolution, long-term bacterial endosymbionts of insects have the smallest (160-790 kb) and most A + T-rich (>70%) bacterial genomes known to date. These genomes are riddled with poly(A) tracts, and 5-50% of genes contain tracts of 10 As or more. Here, we demonstrate transcriptional slippage at poly(A) tracts within genes of Buchnera aphidicola associated with aphids and Blochmannia pennsylvanicus associated with ants. Several tracts contain single frameshift deletions; these apparent pseudogenes showed patterns of constraint consistent with purifying selection on the encoded proteins. Transcriptional slippage yielded a heterogeneous population of transcripts with variable numbers of As in the tract. Across several frameshifted genes, including B. aphidicola cell wall biosynthesis genes and a B. pennsylvanicus histidine biosynthesis gene, 12-50% of transcripts contained corrected reading frames that could potentially yield full-length proteins. In situ immunostaining confirmed the production of the cell wall biosynthetic enzyme UDP-N-acetylmuramyl pentapeptide synthase encoded by the frameshifted murF gene. Simulation studies indicated an overrepresentation of poly(A) tracts in endosymbiont genomes relative to other A + T-rich bacterial genomes. Polymerase infidelity at poly(A) tracts rescues the functionality of genes with frameshift mutations and, conversely, reduces the efficiency of expression for in-frame genes carrying poly(A) regions. These features of homopolymeric tracts could be exploited to manipulate gene expression in small synthetic genomes.
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| 42. |
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| 43. |
- Wentzensen, Nicolas, et al.
(författare)
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Ovarian Cancer Risk Factors by Histologic Subtype : An Analysis From the Ovarian Cancer Cohort Consortium
- 2016
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Ingår i: Journal of Clinical Oncology. - : AMER SOC CLINICAL ONCOLOGY. - 0732-183X .- 1527-7755. ; 34:24, s. 2888-2898
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: An understanding of the etiologic heterogeneity of ovarian cancer is important for improving prevention, early detection, and therapeutic approaches. We evaluated 14 hormonal, reproductive, and lifestyle factors by histologic subtype in the Ovarian Cancer Cohort Consortium (OC3).Patients and Methods: Among 1.3 million women from 21 studies, 5,584 invasive epithelial ovarian cancers were identified (3,378 serous, 606 endometrioid, 331 mucinous, 269 clear cell, 1,000 other). By using competing-risks Cox proportional hazards regression stratified by study and birth year and adjusted for age, parity, and oral contraceptive use, we assessed associations for all invasive cancers by histology. Heterogeneity was evaluated by likelihood ratio test.Results: Most risk factors exhibited significant heterogeneity by histology. Higher parity was most strongly associated with endometrioid (relative risk [RR] per birth, 0.78; 95% CI, 0.74 to 0.83) and clear cell (RR, 0.68; 95% CI, 0.61 to 0.76) carcinomas (P value for heterogeneity [P-het] < .001). Similarly, age at menopause, endometriosis, and tubal ligation were only associated with endometrioid and clear cell tumors (P-het ≤ .01). Family history of breast cancer (P-het = .008) had modest heterogeneity. Smoking was associated with an increased risk of mucinous (RR per 20 pack-years, 1.26; 95% CI, 1.08 to 1.46) but a decreased risk of clear cell (RR, 0.72; 95% CI, 0.55 to 0.94) tumors (P-het = .004). Unsupervised clustering by risk factors separated endometrioid, clear cell, and low-grade serous carcinomas from high-grade serous and mucinous carcinomas.Conclusion: The heterogeneous associations of risk factors with ovarian cancer subtypes emphasize the importance of conducting etiologic studies by ovarian cancer subtypes. Most established risk factors were more strongly associated with nonserous carcinomas, which demonstrate challenges for risk prediction of serous cancers, the most fatal subtype.
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