ALBERT

Description: When considering the evolution of a gene’s expression profile, we commonly assume that this is unaffected by its genomic neighborhood. This is, however, in contrast to what we know about the lack of autonomy between neighboring genes in gene expression profiles in extant taxa. Indeed, in all eukaryotic genomes genes of similar expression-profile tend to cluster, reflecting chromatin level dynamics. Does it follow that if a gene increases expression in a particular lineage then the genomic neighbors will also increase in their expression or is gene expression evolution autonomous? To address this here we consider evolution of human gene expression since the human-chimp common ancestor, allowing for both variation in estimation of current expression level and error in Bayesian estimation of the ancestral state. We find that in all tissues and both sexes, the change in gene expression of a focal gene on average predicts the change in gene expression of neighbors. The effect is highly pronounced in the immediate vicinity (〈100 kb) but extends much further. Sex-specific expression change is also genomically clustered. As genes increasing their expression in humans tend to avoid nuclear lamina domains and be enriched for the gene activator 5-hydroxymethylcytosine, we conclude that, most probably owing to chromatin level control of gene expression, a change in gene expression of one gene likely affects the expression evolution of neighbors, what we term expression piggybacking, an analog of hitchhiking.

Description: The nearly neutral theory predicts that small effective population size provides the conditions for weakened selection. This is postulated to explain why our genome is more "bloated" than that of, for example, yeast, ours having large introns and large intergene spacer. If a bloated genome is also an error prone genome might it, however, be the case that selection for error-mitigating properties is stronger in our genome? We examine this notion using splicing as an exemplar, not least because large introns can predispose to noisy splicing. We thus ask whether, owing to genomic decay, selection for splice error-control mechanisms is stronger, not weaker, in species with large introns and small populations. In humans much information defining splice sites is in cis- exonic motifs, most notably exonic splice enhancers (ESEs). These act as splice-error control elements. Here then we ask whether within and between-species intron size is a predictor of the commonality of exonic cis- splicing motifs. We show that, as predicted, the proportion of synonymous sites that are ESE-associated and under selection in humans is weakly positively correlated with the size of the flanking intron. In a phylogenetically controlled framework, we observe, also as expected, that mean intron size is both predicted by N e .μ and is a good predictor of cis- motif usage across species, this usage coevolving with splice site definition. Unexpectedly, however, across taxa intron density is a better predictor of cis -motif usage than intron size. We propose that selection for splice-related motifs is driven by a need to avoid decoy splice sites that will be more common in genes with many and large introns. That intron number and density predict ESE usage within human genes is consistent with this, as is the finding of intragenic heterogeneity in ESE density. As intronic content and splice site usage across species is also well predicted by N e .μ , the result also suggests an unusual circumstance in which selection (for cis- modifiers of splicing) might be stronger when population sizes are smaller, as here splicing is noisier, resulting in a greater need to control error-prone splicing.

Description: Although both genotypes with elevated mutation rate (mutators) and mobilization of insertion sequence (IS) elements have substantial impact on genome diversification, their potential interactions are unknown. Moreover, the evolutionary forces driving gradual accumulation of these elements are unclear: Do these elements spread in an initially transposon-free bacterial genome as they enable rapid adaptive evolution? To address these issues, we inserted an active IS 1 element into a reduced Escherichia coli genome devoid of all other mobile DNA. Evolutionary laboratory experiments revealed that IS elements increase mutational supply and occasionally generate variants with especially large phenotypic effects. However, their impact on adaptive evolution is small compared with mismatch repair mutator alleles, and hence, the latter impede the spread of IS-carrying strains. Given their ubiquity in natural populations, such mutator alleles could limit early phase of IS element evolution in a new bacterial host. More generally, our work demonstrates the existence of an evolutionary conflict between mutation-promoting mechanisms.

Description: Mount Telout, situated at the edge of the Murzuq Basin, is a 325 m high conical hill within a circular collapse structure that records 0·5 km 3 of sand intrusion into Silurian shales. Based on a comparison with other similar circular collapse structures around the Murzuq Basin, it is argued that sand injection in the form of pipes occurred during the Devonian. The overpressures triggering the process are inferred to result from a combination of: (i) tectonic uplift at a basin scale that initially focused regional ground water flows; and (ii) igneous intrusion within the sand-rich Cambrian–Ordovician strata. The palaeorelief buried under the regionally extensive Silurian shales may have locally focused overpressures and localized sand injection at the 1 to 10 km scale. The Mount Telout injected sandbody and related features offer exceptional, seismic-scale outcrop analogues for sand injections that are often identified in seismic reflection data. Large-scale sand injections might be essential in petroleum exploration of the North African Lower Palaeozoic basins as they form seal-bypass systems.

Description: Where in genes do pathogenic mutations tend to occur and does this provide clues as to the possible underlying mechanisms by which single nucleotide polymorphisms (SNPs) cause disease? As splice-disrupting mutations tend to occur predominantly at exon ends, known also to be hot spots of cis -exonic splice control elements, we examine the relationship between the relative density of such exonic cis -motifs and pathogenic SNPs. In particular, we focus on the intragene distribution of exonic splicing enhancers (ESE) and the covariance between them and disease-associated SNPs. In addition to showing that disease-causing genes tend to be genes with a high intron density, consistent with missplicing, five factors established as trends in ESE usage, are considered: relative position in exons, relative position in genes, flanking intron size, splice sites usage, and phase. We find that more than 76% of pathogenic SNPs are within 3–69 bp of exon ends where ESEs generally reside, this being 13% more than expected. Overall from enrichment of pathogenic SNPs at exon ends, we estimate that approximately 20–45% of SNPs affect splicing. Importantly, we find that within genes pathogenic SNPs tend to occur in splicing-relevant regions with low ESE density: they are found to occur preferentially in the terminal half of genes, in exons flanked by short introns and at the ends of phase (0,0) exons with 3' non-"AGgt" splice site. We suggest the concept of the "fragile" exon, one home to pathogenic SNPs owing to its vulnerability to splice disruption owing to low ESE density.

Description: Mount Telout, situated at the edge of the Murzuq Basin, is a 325 m high conical hill within a circular collapse structure that records 0.5 km 3 of sand intrusion into Silurian shales. Based on a comparison with other similar circular collapse structures around the Murzuq Basin, it is argued that sand injection in the form of pipes occurred during the Devonian. The overpressures triggering the process are inferred to result from a combination of: (i) tectonic uplift at a basin scale that initially focused regional ground water flows; and (ii) igneous intrusion within the sand-rich Cambrian–Ordovician strata. The palaeorelief buried under the regionally extensive Silurian shales may have locally focused overpressures and localised sand injection at the 1 to 10 km scale. The Mount Telout injected sand body and related features offer exceptional, seismic-scale outcrop analogues for sand injections that are often identified in seismic reflection data. Large-scale sand injections might be essential in petroleum exploration of the North African Lower Palaeozoic basins as they form seal-bypass systems.

Description: Abstract Loessite present in a borehole into the Smith Bank Formation (early Triassic age, Central North Sea) differentiates five coeval source terranes for aerosol dust, three long distance sources and two local sources. All were active immediately following the end Permian mass extinction. Long distance sources are sedimentary, basic magmatic and acid–intermediate volcanic. Although predominantly silt‐sized and dominated by quartz with subordinate feldspars, muscovite and illite, evidence of basic and acid–intermediate magmatic/volcanic sources are pervasive. Baddeleyite is diagnostic of basic magmatism, an origin supported by enrichment of plagioclase relative to potassium feldspar. Deduction of acid–intermediate volcanism comes from the collective occurrence of irregular geometry quartz, volcanic shards, Ti‐mineralization, euhedral biotite, sanidine, the co‐occurrence of apatite and zircon, and the common occurrence of a tosuditic clay mineral. The tosuditic phase occurs as an unusual diagenetic dioctahedral chlorite/smectite formed at low temperature (〈45°C), during very shallow burial by the decomposition of unstable rhyo‐dacitic and andesitic grains in alkaline pore water from an adjacent lake that yielded pore fluids with a high Al:Si ratio. The Siberian Traps large igneous province is the likely source terrane for the magmatic and volcanic silt. Locally sourced clay pellets and kaolinite booklets formed from aeolian erosion of an adjacent, periodically desiccated lake‐floor and a kaolinitic regolith, respectively. Inference of a prolonged harsh, arid climate leaves no evidence of any periods of sustained humidity or climatic fluctuation, such as pedogenesis. The association between the end Permian mass extinction, emplacement and aeolian erosion of the Siberian Traps large igneous province, and location of the Smith Bank Formation in a large lacustrine endorheic basin, combine to preserve a record of prolonged harsh climate in the early Triassic. This article is protected by copyright. All rights reserved.

Description: Inactivating mutations of STAG2 have been reported at low frequency in several cancers. In glioblastoma, the function of STAG2 has been related to maintenance of euploidy via its role in the cohesin complex. In a screen of a large series of bladder tumours and cell lines, we found inactivating mutations (nonsense, frameshift and splicing) in 67 of 307 tumours (21.8%) and 6 of 47 cell lines. Thirteen missense mutations of unknown significance were also identified. Inactivating mutation was associated with low tumour stage ( P = 0.001) and low grade ( P = 0.0002). There was also a relationship with female patient gender ( P = 0.042). Examination of copy number profiles revealed an inverse relationship of mutation with both fraction of genome altered and whole chromosome copy number changes. Immunohistochemistry showed that in the majority of cases with inactivating mutations, STAG2 protein expression was absent. Strikingly, we identified a relatively large subset of tumours (12%) with areas of both positive and negative immunoreactivity, in only four of which a potentially function-altering mutation was detected. Regions of differential expression were contiguous and showed similar morphological phenotype in all cases. Microdissected positive and negative areas from one tumour showed an inactivating mutation to be present only in the negative area, suggesting intra-tumoral sub-clonal genomic evolution. Our findings indicate that loss of STAG2 function plays a more important role in non-invasive than that in muscle-invasive bladder cancer and suggest that cohesin complex-independent functions are likely to be important in these cases.

Description: There are two strong and equally important predictors of rates of human protein evolution: The amount the gene is expressed and the proportion of exonic sequence devoted to control splicing, mediated largely by selection on exonic splice enhancer (ESE) motifs. Is the same true for noncoding RNAs, known to be under very weak purifying selection? Prior evidence suggests that selection at splice sites in long intergenic noncoding RNAs (lincRNAs) is important. We now report multiple lines of evidence indicating that the great majority of purifying selection operating on lincRNAs in humans is splice related. Splice-related parameters explain much of the between-gene variation in evolutionary rate in humans. Expression rate is not a relevant predictor, although expression breadth is weakly so. In contrast to protein-coding RNAs, we observe no relationship between evolutionary rate and lincRNA stability. As in protein-coding genes, ESEs are especially abundant near splice junctions and evolve slower than non-ESE sequence equidistant from boundaries. Nearly all constraint in lincRNAs is at exon ends (N.B. the same is not witnessed in Drosophila ). Although we cannot definitely answer the question as to why splice-related selection is so important, we find no evidence that splicing might enable the nonsense-mediated decay pathway to capture transcripts incorrectly processed by ribosomes. We find evidence consistent with the notion that splicing modifies the underlying chromatin through recruitment of splice-coupled chromatin modifiers, such as CHD1, which in turn might modulate neighbor gene activity. We conclude that most selection on human lincRNAs is splice mediated and suggest that the possibility of splice–chromatin coupling is worthy of further scrutiny.

Description: Genome-wide association studies (GWAS) of urinary bladder cancer (UBC) have yielded common variants at 12 loci that associate with risk of the disease. We report here the results of a GWAS of UBC including 1670 UBC cases and 90 180 controls, followed by replication analysis in additional 5266 UBC cases and 10 456 controls. We tested a dataset containing 34.2 million variants, generated by imputation based on whole-genome sequencing of 2230 Icelanders. Several correlated variants at 20p12, represented by rs62185668, show genome-wide significant association with UBC after combining discovery and replication results (OR = 1.19, P = 1.5 x 10 –11 for rs62185668-A, minor allele frequency = 23.6%). The variants are located in a non-coding region approximately 300 kb upstream from the JAG1 gene, an important component of the Notch signaling pathways that may be oncogenic or tumor suppressive in several forms of cancer. Our results add to the growing number of UBC risk variants discovered through GWAS.