| 1. |
|
|
| 2. |
- Hudson, Lawrence N, et al.
(författare)
-
The database of the PREDICTS (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems) project
- 2017
-
Ingår i: Ecology and Evolution. - : John Wiley & Sons. - 2045-7758. ; 7:1, s. 145-188
-
Tidskriftsartikel (refereegranskat)abstract
- The PREDICTS project-Projecting Responses of Ecological Diversity In Changing Terrestrial Systems (www.predicts.org.uk)-has collated from published studies a large, reasonably representative database of comparable samples of biodiversity from multiple sites that differ in the nature or intensity of human impacts relating to land use. We have used this evidence base to develop global and regional statistical models of how local biodiversity responds to these measures. We describe and make freely available this 2016 release of the database, containing more than 3.2 million records sampled at over 26,000 locations and representing over 47,000 species. We outline how the database can help in answering a range of questions in ecology and conservation biology. To our knowledge, this is the largest and most geographically and taxonomically representative database of spatial comparisons of biodiversity that has been collated to date; it will be useful to researchers and international efforts wishing to model and understand the global status of biodiversity.
|
|
| 3. |
- Kugelberg, Elisabeth, et al.
(författare)
-
The Tandem Inversion Duplication in Salmonella enterica : Selection Drives Unstable Precursors to Final Mutation Types
- 2010
-
Ingår i: Genetics. - : Oxford University Press (OUP). - 0016-6731 .- 1943-2631. ; 185:1, s. 65-80
-
Tidskriftsartikel (refereegranskat)abstract
- During growth under selection, mutant types appear that are rare in unselected populations. Stress-induced mechanisms may cause these structures or selection may favor a series of standard events that modify common preexisting structures. One such mutation is the short junction (SJ) duplication with long repeats separated by short sequence elements: AB*(CD)*(CD)*E (* = a few bases). Another mutation type, described here, is the tandem inversion duplication (TID), where two copies of a parent sequence flank an inverse-order segment: AB(CD)(E'D'C'B')(CD) E. Both duplication types can amplify by unequal exchanges between direct repeats (CD), and both are rare in unselected cultures but common after prolonged selection for amplification. The observed TID junctions are asymmetric (aTIDs) and may arise from a symmetrical precursor (sTID)-ABCDE(E'D'C'B'A')ABCDE-when sequential deletions remove each palindromic junction. Alternatively, one deletion can remove both sTID junctions to generate an SJ duplication. It is proposed that sTID structures form frequently under all growth conditions, but are usually lost due to their instability and fitness cost. Selection for increased copy number helps retain the sTID and favors deletions that remodel junctions, improve fitness, and allow higher amplification. Growth improves with each step in formation of an SJ or aTID amplification, allowing selection to favor completion of the mutation process.
|
|
| 4. |
- Hart, Traver, et al.
(författare)
-
High-Resolution CRISPR Screens Reveal Fitness Genes and Genotype-Specific Cancer Liabilities
- 2015
-
Ingår i: Cell. - : Elsevier BV. - 0092-8674 .- 1097-4172. ; 163:6
-
Tidskriftsartikel (refereegranskat)abstract
- The ability to perturb genes in human cells is crucial for elucidating gene function and holds great potential for finding therapeutic targets for diseases such as cancer. To extend the catalog of human core and context-dependent fitness genes, we have developed a high-complexity second-generation genome-scale CRISPR-Cas9 gRNA library and applied it to fitness screens in five human cell lines. Using an improved Bayesian analytical approach, we consistently discover 5-fold more fitness genes than were previously observed. We present a list of 1,580 human core fitness genes and describe their general properties. Moreover, we demonstrate that context-dependent fitness genes accurately recapitulate pathway-specific genetic vulnerabilities induced by known oncogenes and reveal cell-type-specific dependencies for specific receptor tyrosine kinases, even in oncogenic KRAS backgrounds. Thus, rigorous identification of human cell line fitness genes using a high-complexity CRISPR-Cas9 library affords a high-resolution view of the genetic vulnerabilities of a cell.
|
|
| 5. |
- Sun, Song, 1982-, et al.
(författare)
-
A proactive genotype-to-patient-phenotype map for cystathionine beta-synthase
- 2020
-
Ingår i: Genome Medicine. - : BMC. - 1756-994X .- 1756-994X. ; 12:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background For the majority of rare clinical missense variants, pathogenicity status cannot currently be classified. Classical homocystinuria, characterized by elevated homocysteine in plasma and urine, is caused by variants in the cystathionine beta-synthase (CBS) gene, most of which are rare. With early detection, existing therapies are highly effective. Methods Damaging CBS variants can be detected based on their failure to restore growth in yeast cells lacking the yeast ortholog CYS4. This assay has only been applied reactively, after first observing a variant in patients. Using saturation codon-mutagenesis, en masse growth selection, and sequencing, we generated a comprehensive, proactive map of CBS missense variant function. Results Our CBS variant effect map far exceeds the performance of computational predictors of disease variants. Map scores correlated strongly with both disease severity (Spearman's rho = 0.9) and human clinical response to vitamin B-6 (rho = 0.93). Conclusions We demonstrate that highly multiplexed cell-based assays can yield proactive maps of variant function and patient response to therapy, even for rare variants not previously seen in the clinic.
|
|
| 6. |
- Sun, Song, et al.
(författare)
-
An extended set of yeast-based functional assays accurately identifies human disease mutations
- 2016
-
Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 26:5, s. 670-680
-
Tidskriftsartikel (refereegranskat)abstract
- We can now routinely identify coding variants within individual human genomes. A pressing challenge is to determine which variants disrupt the function of disease-associated genes. Both experimental and computational methods exist to predict pathogenicity of human genetic variation. However, a systematic performance comparison between them has been lacking. Therefore, we developed and exploited a panel of 26 yeast-based functional complementation assays to measure the impact of 179 variants (101 disease-and 78 non-disease-associated variants) from 22 human disease genes. Using the resulting reference standard, we show that experimental functional assays in a 1-billion-year diverged model organism can identify pathogenic alleles with significantly higher precision and specificity than current computational methods.
|
|
| 7. |
- Weile, Jochen, et al.
(författare)
-
A framework for exhaustively mapping functional missense variants
- 2017
-
Ingår i: Molecular Systems Biology. - : WILEY. - 1744-4292 .- 1744-4292. ; 13:12
-
Tidskriftsartikel (refereegranskat)abstract
- Although we now routinely sequence human genomes, we can confidently identify only a fraction of the sequence variants that have a functional impact. Here, we developed a deep mutational scanning framework that produces exhaustive maps for human missense variants by combining random codon mutagenesis and multiplexed functional variation assays with computational imputation and refinement. We applied this framework to four proteins corresponding to six human genes: UBE2I (encoding SUMO E2 conjugase), SUMO1 (small ubiquitin-like modifier), TPK1 (thiamin pyrophosphokinase), and CALM1/2/3 (three genes encoding the protein calmodulin). The resulting maps recapitulate known protein features and confidently identify pathogenic variation. Assays potentially amenable to deep mutational scanning are already available for 57% of human disease genes, suggesting that DMS could ultimately map functional variation for all human disease genes.
|
|
| 8. |
- Yang, Fan, et al.
(författare)
-
Identifying pathogenicity of human variants via paralog-based yeast complementation
- 2017
-
Ingår i: PLOS Genetics. - : PUBLIC LIBRARY SCIENCE. - 1553-7390 .- 1553-7404. ; 13:5
-
Tidskriftsartikel (refereegranskat)abstract
- To better understand the health implications of personal genomes, we now face a largely unmet challenge to identify functional variants within disease-associated genes. Functional variants can be identified by trans-species complementation, e.g., by failure to rescue a yeast strain bearing a mutation in an orthologous human gene. Although orthologous complementation assays are powerful predictors of pathogenic variation, they are available for only a few percent of human disease genes. Here we systematically examine the question of whether complementation assays based on paralogy relationships can expand the number of human disease genes with functional variant detection assays. We tested over 1,000 paralogous human-yeast gene pairs for complementation, yielding 34 complementation relationships, of which 33 (97%) were novel. We found that paralog-based assays identified disease variants with success on par with that of orthology-based assays. Combining all homology-based assay results, we found that complementation can often identify pathogenic variants outside the homologous sequence region, presumably because of global effects on protein folding or stability. Within our search space, paralogy-based complementation more than doubled the number of human disease genes with a yeast-based complementation assay for disease variation.
|
|
| 9. |
- Yang, Xinping, et al.
(författare)
-
Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing
- 2016
-
Ingår i: Cell. - : Elsevier BV. - 0092-8674 .- 1097-4172. ; 164:4, s. 805-817
-
Tidskriftsartikel (refereegranskat)abstract
- While alternative splicing is known to diversify the functional characteristics of some genes, the extent to which protein isoforms globally contribute to functional complexity on a proteomic scale remains unknown. To address this systematically, we cloned full-length open reading frames of alternatively spliced transcripts for a large number of human genes and used protein-protein interaction profiling to functionally compare hundreds of protein isoform pairs. The majority of isoform pairs share less than 50% of their interactions. In the global context of interactome network maps, alternative isoforms tend to behave like distinct proteins rather than minor variants of each other. Interaction partners specific to alternative isoforms tend to be expressed in a highly tissue-specific manner and belong to distinct functional modules. Our strategy, applicable to other functional characteristics, reveals a widespread expansion of protein interaction capabilities through alternative splicing and suggests that many alternative "isoforms'' are functionally divergent (i.e., "functional alloforms'').
|
|
