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: Shallow, subtidal waters of coastal embayments are the primary nursery habitats of juvenile Pacific cod through much of their range. However, the importance of these habitats to the Bering Sea population is poorly understood as the Bering Sea offers relatively little of this habitat. In this study, we examined the use of demersal and pelagic habitats in the southeast Bering Sea by age-0 Pacific cod. In 4 years of demersal beam trawling on the shelf at depths of 20–146 m, fish were most abundant along the Alaska Peninsula (AKP) at depths to 50 m. In addition, 1 year of spatially intensive beam trawl sampling was conducted at depths of 5–30 m in a nearshore focal area along the central AKP. In this survey, age-0 cod were more abundant along the open coastline than they were in two coastal embayments, counter to patterns observed in the Gulf of Alaska. Demersal sampling in 2012 was conducted synoptically with surveys of surface and subsurface waters over the continental shelf. Age-0 cod were captured in pelagic waters over the middle and outer shelf, with maximum catches occurring over depths of 60–80 m. The similar size distributions of fish in coastal-demersal and shelf-surface habitats and the proximity of concentrations in the two habitat types suggests that habitat use in the Bering Sea occurs along a gradient from coastal to pelagic. While capture efficiencies may differ among trawl types, trawl-based estimates of age-0 cod density in demersal waters along the AKP was 10 times that observed in the highest density pelagic-shelf habitats, demonstrating the importance of coastal nursery habitats in this population. Despite representing a much smaller habitat area, the coastal waters along the AKP appear an important nursery area and support a significant fraction of the age-0 Pacific cod in the Bering Sea.

Description: The Bering Sea and Gulf of Alaska support a number of commercially important flatfish fisheries. These high latitude ecosystems are predicted to be most immediately impacted by ongoing ocean acidification, but the range of responses by commercial fishery species has yet to be fully explored. In this study, we examined the growth responses of northern rock sole ( Lepidopsetta polyxystra ) eggs and larvae across a range of CO 2 levels (ambient to 1500 µatm) to evaluate the potential sensitivity to ocean acidification. Laboratory-spawned eggs and larvae were reared at 8°C in a flow-through culture system in which CO 2 levels were maintained via computer-controlled injection of CO 2 into a seawater conditioning tank. Overall, we observed only minor effects of elevated CO 2 level on sizes of northern rock sole larvae. Size at hatch differed among offspring from four different females, but there was no significant effect of CO 2 level on egg survival or size at hatch. In three separate larval growth trials, there was little effect of CO 2 level on growth rates through the first 28 d post-hatch (DPH). However, in the one trial extended to 60 DPH, fish reared at the highest CO 2 level had lower condition factors after 28 DPH, suggesting that larvae undergoing metamorphosis may be more sensitive to environmental hypercapnia than earlier pre-flexion stages. These results suggest that while early life stages of northern rock sole are less sensitive to ocean acidification than previously examined flatfish, they may be more sensitive to elevated CO 2 levels than a previously studied gadid with a similar geographic range.

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: Exonic splice enhancers (ESEs) are short nucleotide motifs, enriched near exon ends, that enhance the recognition of the splice site and thus promote splicing. Are intronless genes under selection to avoid these motifs so as not to attract the splicing machinery to an mRNA that should not be spliced, thereby preventing the production of an aberrant transcript? Consistent with this possibility, we find that ESEs in putative recent retrocopies are at a higher density and evolving faster than those in other intronless genes, suggesting that they are being lost. Moreover, intronless genes are less dense in putative ESEs than intron-containing ones. However, this latter difference is likely due to the skewed base composition of intronless sequences, a skew that is in line with the general GC richness of few exon genes. Indeed, after controlling for such biases, we find that both intronless and intron-containing genes are denser in ESEs than expected by chance. Importantly, nucleotide-controlled analysis of evolutionary rates at synonymous sites in ESEs indicates that the ESEs in intronless genes are under purifying selection in both human and mouse. We conclude that on the loss of introns, some but not all, ESE motifs are lost, the remainder having functions beyond a role in splice promotion. These results have implications for the design of intronless transgenes and for understanding the causes of selection on synonymous sites.

Description: Accurate knowledge of the mutation rate provides a base line for inferring expected rates of evolution, for testing evolutionary hypotheses and for estimation of key parameters. Advances in sequencing technology now permit direct estimates of the mutation rate from sequencing of close relatives. Within insects there have been three prior such estimates, two in nonsocial insects ( Drosophila : 2.8 x 10 – 9 per bp per haploid genome per generation; Heliconius : 2.9 x 10 – 9 ) and one in a social species, the honeybee (3.4 x 10 – 9 ). Might the honeybee’s rate be ~20% higher because it has an exceptionally high recombination rate and recombination may be directly or indirectly mutagenic? To address this possibility, we provide a direct estimate of the mutation rate in the bumblebee ( Bombus terrestris ), this being a close relative of the honeybee but with a much lower recombination rate. We confirm that the crossover rate of the bumblebee is indeed much lower than honeybees (8.7 cM/Mb vs. 37 cM/Mb). Importantly, we find no significant difference in the mutation rates: we estimate for bumblebees a rate of 3.6 x 10 – 9 per haploid genome per generation (95% confidence intervals 2.38 x 10 – 9 and 5.37 x 10 – 9 ) which is just 5% higher than the estimate that of honeybees. Both genomes have approximately one new mutation per haploid genome per generation. While we find evidence for a direct coupling between recombination and mutation (also seen in honeybees), the effect is so weak as to leave almost no footprint on any between-species differences. The similarity in mutation rates suggests an approximate constancy of the mutation rate in insects.