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Molecular biology and evolution [journal]
- Epistasis constrains mutational pathways of hemoglobin adaptation in high-altitude pikas. [JOURNAL ARTICLE]
- Mol Biol Evol 2014 Nov 18.
A fundamental question in evolutionary genetics concerns the roles of mutational pleiotropy and epistasis in shaping trajectories of protein evolution. This question can be addressed most directly by using site-directed mutagenesis to explore the mutational landscape of protein function in experimentally defined regions of sequence space. Here we evaluate how pleiotropic trade-offs and epistatic interactions influence the accessibility of alternative mutational pathways during the adaptive evolution of hemoglobin (Hb) function in high-altitude pikas (Mammalia: Lagomorpha). By combining ancestral protein resurrection with a combinatorial protein-engineering approach, we examined the functional effects of sequential mutational steps in all possible pathways that produced an increased Hb-O2 affinity. These experiments revealed that the effects of mutations on Hb-O2 affinity are highly dependent on the temporal order in which they occur: each of three β-chain substitutions produced a significant increase in Hb-O2 affinity on the ancestral genetic background, but two of these substitutions produced opposite effects when they occurred as later steps in the pathway. The experiments revealed pervasive epistasis for Hb-O2 affinity, but affinity-altering mutations produced no significant pleiotropic trade-offs. These results provide insights into the properties of adaptive substitutions in naturally evolved proteins and suggest that the accessibility of alternative mutational pathways may be more strongly constrained by sign epistasis for positively selected biochemical phenotypes than by an antagonistic pleiotropy.
- Feather development genes and associated regulatory innovation predate the origin of Dinosauria. [JOURNAL ARTICLE]
- Mol Biol Evol 2014 Nov 18.
The evolution of avian feathers have recently been illuminated by fossils and the identification of genes involved in feather patterning and morphogenesis. However, molecular studies have focused mainly on protein-coding genes. Using comparative genomics and more than 600,000 conserved regulatory elements, we show that patterns of genome evolution in the vicinity of feather genes are consistent with a major role for regulatory innovation in the evolution of feathers. Rates of innovation at feather regulatory elements exhibit an extended period of innovation with peaks in the ancestors of amniotes and archosaurs. We estimate that 86% of such regulatory elements were present prior to the origin of Dinosauria. On the branch leading to modern birds, we detect a strong signal of regulatory innovation near IGFBP2 and IGFBP5, which have roles in body size reduction, and may represent a genomic signature for the miniaturization of dinosaurian body size preceding the origin of flight.
- Functional conservation of both CDS- and 3'UTR- located micro-RNA binding sites between species. [JOURNAL ARTICLE]
- Mol Biol Evol 2014 Nov 19.
MicroRNAs (miRNAs) mediate gene regulation post-transcriptionally through pairing of their seed (2-7nts) to 3' untranslated regions (3'UTRs) or coding regions (CDSs) of their target genes. CDS target sites generally show weaker repression effects than 3'UTR sites. However, little is known about the conservation of the function, i.e. repression effect, for these two groups of target sites. In addition, no systematic analysis of the evolutionary constraint on CDS sites exists to date. To address these questions, we performed RNA-seq to quantify the regulatory effect of miR-15a/miR-16 and miR-92a on their CDS and 3'UTR targets in human and macaque cells. These miRs were knocked down transiently so the repression effect could be tracked immediately. Although on average, CDS targets are less de-repressed than 3'UTR targets in both species, both the 3'UTR targets and the CDS targets are functionally conserved. The evolutionary analysis of miRNA target sites shows that CDS sites are more conserved than non-target control, albeit to a lesser extent than 3'UTR sites. In conclusion, CDS target sites are functional, even though they are subject to less functional constraint than 3'UTR target sites.
- Strong artificial selection in domestic mammals did not result in an increased recombination rate. [JOURNAL ARTICLE]
- Mol Biol Evol 2014 Nov 19.
Recombination rates vary in intensity and location at the species, individual, sex and chromosome levels. Despite the fundamental biological importance of this process, the selective forces that operate to shape recombination rate and patterns are unclear. Domestication offers a unique opportunity to study the interplay between recombination and selection, particularly due to Hill-Robertson interference, which should be important when many linked loci are repeatedly the target of selection. In domesticates, intense selection for particular traits is imposed on small populations over many generations, resulting in organisms that differ, sometimes dramatically, in morphology and physiology from their wild ancestor. Although earlier studies suggested increased recombination rate in domesticates, a formal comparison of recombination rates between domestic mammals and their wild congeners was missing. In order to determine broad-scale recombination rate, we used immunolabeling detection of MLH1 foci as crossover markers in spermatocytes in three pairs of closely related wild and domestic species (dog and wolf, goat and ibex, sheep and mouflon). In the three pairs, and contrary to previous suggestions, our data show that contemporary recombination rate is higher in the wild species. Subsequently, we inferred recombination breakpoints in sequence data for 16 genomic regions in dogs and wolves, each containing a locus associated with a dog phenotype potentially under selection during domestication. No difference in the number and distribution of recombination breakpoints was found between dogs and wolves. We conclude that our data indicate that strong directional selection did not result in changes in recombination in domestic mammals, and that both upper and lower bounds for crossover rates may be tightly regulated.
- Species-specific Exon Loss in Human Transcriptomes. [JOURNAL ARTICLE]
- Mol Biol Evol 2014 Nov 14.
Changes in exon-intron structures and splicing patterns represent an important mechanism for the evolution of gene functions and species-specific regulatory networks. While exon creation is widespread during primate and human evolution and has been studied extensively, much less is known about the scope and potential impact of human-specific exon loss events. Historically, transcriptome data and exon annotations are significantly biased towards humans over nonhuman primates. This ascertainment bias makes it challenging to discover human-specific exon loss events. We carried out a transcriptome-wide search of human-specific exon loss events, by taking advantage of RNA-seq as a powerful and unbiased tool for exon discovery and annotation. Using RNA-seq data of humans, chimpanzees, and other primates, we reconstructed and compared transcript structures across the primate phylogeny. We discovered 33 candidate human-specific exon loss events, among which 6 exons passed stringent experimental filters for the complete loss of splicing activities in diverse human tissues. These events may result from human-specific deletion of genomic DNA, or small-scale sequence changes that inactivated splicing signals. The impact of human-specific exon loss events is predominantly regulatory. Three of the 6 events occurred in the 5'-UTR and affected cis regulatory elements of mRNA translation. In SLC7A6, a gene encoding an amino acid transporter, luciferase reporter assays showed that both a human-specific exon loss event and an independent human-specific single nucleotide substitution in the 5'-UTR increased mRNA translational efficiency. Our study provides novel insights into the molecular mechanisms and evolutionary consequences of exon loss during human evolution.
- How Evolution of Genomes is Reflected in Exact DNA Sequence Match Statistics. [JOURNAL ARTICLE]
- Mol Biol Evol 2014 Nov 13.
Genome evolution is shaped by a multitude of mutational processes, including point mutations, insertions, and deletions of DNA sequences, as well as segmental duplications. These mutational processes can leave distinctive qualitative marks in the statistical features of genomic DNA sequences. One such feature is the match length distribution (MLD) of exactly matching sequence segments within an individual genome, or between the genomes of related species. These have been observed to exhibit characteristic power-law decays in many species. Here we show that simple dynamical models consisting solely of duplication and mutation processes can already explain the characteristic features of MLDs observed in genomic sequences. Surprisingly, we find that these features are largely insensitive to details of the underlying mutational processes and do not necessarily rely on the action of natural selection. Our results demonstrate how analyzing statistical features of DNA sequences can help us reveal and quantify the different mutational processes that underlie genome evolution.
- In search of beneficial coding RNA editing. [JOURNAL ARTICLE]
- Mol Biol Evol 2014 Nov 12.
RNA editing is a post-transcriptional modification that can lead to a change in the encoded protein sequence of a gene. While a few cases of mammalian coding RNA editing are known to be functionally important, the vast majority of over 2000 A-to-I editing sites that have been identified from the coding regions of the human genome are likely nonadaptive, representing tolerable promiscuous targeting of editing enzymes. Finding the potentially tiny fraction of beneficial editing sites from the sea of mostly nearly neutral editing is a difficult but important task. Here we propose and provide evidence that evolutionarily conserved or "hardwired" residues that experience high-level nonsynonymous RNA editing in a species are enriched with beneficial editing. This simple approach allows the prediction of sites where RNA editing is functionally important. We suggest that priority be given to these candidates in future characterizations of the functional and fitness consequences of RNA editing.
- Mutational studies on resurrected ancestral proteins reveal conservation of site-specific amino acid preferences throughout evolutionary history. [JOURNAL ARTICLE]
- Mol Biol Evol 2014 Nov 12.
Local protein interactions ("molecular context" effects) dictate amino acid replacements and can be described in terms of site-specific, energetic preferences for any different amino acid. It has been recently debated whether these preferences remain approximately constant during evolution or whether, due to co-evolution of sites, they change strongly. Such research highlights an unresolved and fundamental issue with far-reaching implications for phylogenetic analysis and molecular evolution modeling. Here, we take advantage of the recent availability of phenotypically supported laboratory resurrections of Precambrian thioredoxins and β-lactamases to experimentally address the change of site-specific amino acid preferences over long geological timescales. Extensive mutational analyses support the notion that evolutionary adjustment to a new amino acid may occur, but to a large extent this is insufficient to erase the primitive preference for amino acid replacements. Generally, site-specific amino acid preferences appear to remain conserved throughout evolutionary history despite local sequence divergence. We show such preference conservation to be readily understandable in molecular terms and we provide crystallographic evidence for an intriguing structural-switch mechanism: energetic preference for an ancestral amino acid in a modern protein can be linked to re-organization upon mutation to the ancestral local structure around the mutated site. Lastly, we point out that site-specific preference conservation naturally leads to one plausible evolutionary explanation for the existence of intragenic global suppressor mutations.
- Mutational signatures indicative of environmental stress in bacteria. [JOURNAL ARTICLE]
- Mol Biol Evol 2014 Nov 11.
Evolutionary innovations are dependent on mutations. Mutation rates are increased by adverse conditions in the laboratory but there is no evidence that stressful environments that do not directly impact on DNA leave a mutational imprint on extant genomes. Mutational spectra in the laboratory are normally determined with unstressed cells but are unavailable with stressed bacteria. To by-pass problems with viability, selection effects and growth rate differences due to stressful environments, in this study we used a set of genetically engineered strains to identify the mutational spectrum associated with nutritional stress. The strain set members each had a fixed level of the master regulator protein, RpoS, which controls the general stress response of Escherichia coli. By assessing mutations in cycA gene from 485 cycloserine resistant mutants collected from as many as independent cultures with three distinct perceived stress (RpoS) levels, we were able establish a dose-dependent relationship between stress and mutational spectra. The altered mutational patterns included base pair substitutions, single base pair indels, longer indels and transpositions of different insertion sequences. The mutational spectrum of low-RpoS cells closely matches the genome-wide spectrum previously generated in laboratory environments, while the spectra of high-RpoS, high perceived stress cells more closely matches spectra found in comparisons of extant genomes. Our results offer an explanation of the uneven mutational profiles such as the transition-transversion biases observed in extant genomes and provide a framework for assessing the contribution of stress-induced mutagenesis to evolutionary transitions and the mutational emergence of antibiotic resistance and disease states.
- Accelerated diversification of non-human primate malarias in Southeast Asia: adaptive radiation or geographic speciation? [JOURNAL ARTICLE]
- Mol Biol Evol 2014 Nov 10.
Although parasitic organisms are found worldwide, the relative importance of host specificity and geographic isolation for parasite speciation has been explored in only a few systems. Here we study Plasmodium parasites known to infect Asian non-human primates, a monophyletic group that includes the lineage leading to the human parasite Plasmodium vivax and several species used as laboratory models in malaria research. We analyze the available data together with new samples from three sympatric primate species from Borneo: the Bornean orangutan and the long-tailed and the pig-tailed macaques. We find several species of malaria parasites, including three putatively new species in this biodiversity hotspot. Among those newly discovered lineages, we report two sympatric parasites in orangutans. We find no differences in the sets of malaria species infecting each macaque species indicating that these species show no host specificity. Finally, phylogenetic analysis of this data suggests that the malaria parasites infecting Southeast Asian macaques and their relatives are speciating three to four times more rapidly than those with other mammalian hosts such as lemurs and African apes. We estimate that these events took place in approximately a 3 to 4 million years period. Based on the genetic and phenotypic diversity of the macaque malarias, we hypothesize that the diversification of this group of parasites has been facilitated by the diversity, geographic distributions, and demographic histories of their primate hosts.