36 research outputs found
Rearrangement processes and structural variations show evidence of selection in oesophageal adenocarcinomas
Oesophageal adenocarcinoma (OAC) provides an ideal case study to characterize large-scale rearrangements. Using whole genome short-read sequencing of 383 cases, for which 214 had matched whole transcriptomes, we observed structural variations (SV) with a predominance of deletions, tandem duplications and inter-chromosome junctions that could be identified as LINE-1 mobile element (ME) insertions. Complex clusters of rearrangements resembling breakage-fusion-bridge cycles or extrachromosomal circular DNA accounted for 22% of complex SVs affecting known oncogenes. Counting SV events affecting known driver genes substantially increased the recurrence rates of these drivers. After excluding fragile sites, we identified 51 candidate new drivers in genomic regions disrupted by SVs, including ETV5, KAT6B and CLTC. RUNX1 was the most recurrently altered gene (24%), with many deletions inactivating the RUNT domain but preserved the reading frame, suggesting an altered protein product. These findings underscore the importance of identification of SV events in OAC with implications for targeted therapies
Integrating evolution into ecological modelling: accommodating phenotypic changes in agent based models.
PMCID: PMC3733718This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Evolutionary change is a characteristic of living organisms and forms one of the ways in which species adapt to changed conditions. However, most ecological models do not incorporate this ubiquitous phenomenon. We have developed a model that takes a 'phenotypic gambit' approach and focuses on changes in the frequency of phenotypes (which differ in timing of breeding and fecundity) within a population, using, as an example, seasonal breeding. Fitness per phenotype calculated as the individual's contribution to population growth on an annual basis coincide with the population dynamics per phenotype. Simplified model variants were explored to examine whether the complexity included in the model is justified. Outputs from the spatially implicit model underestimated the number of individuals across all phenotypes. When no phenotype transitions are included (i.e. offspring always inherit their parent's phenotype) numbers of all individuals are always underestimated. We conclude that by using a phenotypic gambit approach evolutionary dynamics can be incorporated into individual based models, and that all that is required is an understanding of the probability of offspring inheriting the parental phenotype
The rate of beneficial mutations surfing on the wave of a range expansion
Many theoretical and experimental studies suggest that range expansions can
have severe consequences for the gene pool of the expanding population. Due to
strongly enhanced genetic drift at the advancing frontier, neutral and weakly
deleterious mutations can reach large frequencies in the newly colonized
regions, as if they were surfing the front of the range expansion. These
findings raise the question of how frequently beneficial mutations successfully
surf at shifting range margins, thereby promoting adaptation towards a
range-expansion phenotype. Here, we use individual-based simulations to study
the surfing statistics of recurrent beneficial mutations on wave-like range
expansions in linear habitats. We show that the rate of surfing depends on two
strongly antagonistic factors, the probability of surfing given the spatial
location of a novel mutation and the rate of occurrence of mutations at that
location. The surfing probability strongly increases towards the tip of the
wave. Novel mutations are unlikely to surf unless they enjoy a spatial head
start compared to the bulk of the population. The needed head start is shown to
be proportional to the inverse fitness of the mutant type, and only weakly
dependent on the carrying capacity. The second factor is the mutation
occurrence which strongly decreases towards the tip of the wave. Thus, most
successful mutations arise at an intermediate position in the front of the
wave. We present an analytic theory for the tradeoff between these factors that
allows to predict how frequently substitutions by beneficial mutations occur at
invasion fronts. We find that small amounts of genetic drift increase the
fixation rate of beneficial mutations at the advancing front, and thus could be
important for adaptation during species invasions.Comment: 21 pages, 7 figures; to appear in PLoS Computational Biolog
Rearrangement processes and structural variations show evidence of selection in oesophageal adenocarcinomas
Oesophageal adenocarcinoma (OAC) provides an ideal case study to characterize large-scale rearrangements. Using whole genome short-read sequencing of 383 cases, for which 214 had matched whole transcriptomes, we observed structural variations (SV) with a predominance of deletions, tandem duplications and inter-chromosome junctions that could be identified as LINE-1 mobile element (ME) insertions. Complex clusters of rearrangements resembling breakage-fusion-bridge cycles or extrachromosomal circular DNA accounted for 22% of complex SVs affecting known oncogenes. Counting SV events affecting known driver genes substantially increased the recurrence rates of these drivers. After excluding fragile sites, we identified 51 candidate new drivers in genomic regions disrupted by SVs, including ETV5, KAT6B and CLTC. RUNX1 was the most recurrently altered gene (24%), with many deletions inactivating the RUNT domain but preserved the reading frame, suggesting an altered protein product. These findings underscore the importance of identification of SV events in OAC with implications for targeted therapies
Comparative evolutionary genetics of deleterious load in sorghum and maize
Sorghum and maize share a close evolutionary history that can be explored through comparative genomics1,2. To perform a large-scale comparison of the genomic variation between these two species, we analysed ~13 million variants identi- fied from whole-genome resequencing of 499 sorghum lines together with 25 million variants previously identified in 1,218 maize lines. Deleterious mutations in both species were prev- alent in pericentromeric regions, enriched in non-syntenic genes and present at low allele frequencies. A comparison of deleterious burden between sorghum and maize revealed that sorghum, in contrast to maize, departed from the domestication-cost hypothesis that predicts a higher deleterious burden among domesticates compared with wild lines. Additionally, sorghum and maize population genetic summary statistics were used to predict a gene deleterious index with an accuracy greater than 0.5. This research represents a key step towards understanding the evolutionary dynamics of deleterious variants in sorghum and provides a comparative genomics framework to start prioritizing these variants for removal through genome editing and breeding
Mobile element insertions are frequent in oesophageal adenocarcinomas and can mislead paired-end sequencing analysis
Preparation and characterization of hyperbranched polyester conjugate of ciprofloxacin and its in vitro drug release studies
Rearrangement processes and structural variations show evidence of selection in oesophageal adenocarcinomas.
Oesophageal adenocarcinoma (OAC) provides an ideal case study to characterize large-scale rearrangements. Using whole genome short-read sequencing of 383 cases, for which 214 had matched whole transcriptomes, we observed structural variations (SV) with a predominance of deletions, tandem duplications and inter-chromosome junctions that could be identified as LINE-1 mobile element (ME) insertions. Complex clusters of rearrangements resembling breakage-fusion-bridge cycles or extrachromosomal circular DNA accounted for 22% of complex SVs affecting known oncogenes. Counting SV events affecting known driver genes substantially increased the recurrence rates of these drivers. After excluding fragile sites, we identified 51 candidate new drivers in genomic regions disrupted by SVs, including ETV5, KAT6B and CLTC. RUNX1 was the most recurrently altered gene (24%), with many deletions inactivating the RUNT domain but preserved the reading frame, suggesting an altered protein product. These findings underscore the importance of identification of SV events in OAC with implications for targeted therapies