Mutations of Different Molecular Origins Exhibit Contrasting Patterns of Regional Substitution Rate Variation

Transitions at CpG dinucleotides, referred to as “CpG substitutions”, are a major mutational input into vertebrate genomes and a leading cause of human genetic disease. The prevalence of CpG substitutions is due to their mutational origin, which is dependent on DNA methylation. In comparison, other single nucleotide substitutions (for example those occurring at GpC dinucleotides) mainly arise from errors during DNA replication. Here we analyzed high quality BAC-based data from human, chimpanzee, and baboon to investigate regional variation of CpG substitution rates

Mutation Patterns in the Human Genome: More Variable Than Expected

Why are some genomic positions more mutable than others? The identification of cryptic mutation hotspots in the human genome indicates that the determinants of mutation rates are more complex than anticipated

The Impact of Linked Selection in Chimpanzees: A Comparative Study

abstract: Levels of nucleotide diversity vary greatly across the genomes of most species owing to multiple factors. These include variation in the underlying mutation rates, as well as the effects of both direct and linked selection. Fundamental to interpreting the relative importance of these forces is the common observation of a strong positive correlation between nucleotide diversity and recombination rate. While indeed observed in humans, the interpretation of this pattern has been difficult in the absence of high-quality polymorphism data and recombination maps in closely related species. Here, we characterize genetic features driving nucleotide diversity in Western chimpanzees using a recently generated whole genome polymorphism data set. Our results suggest that recombination rate is the primary predictor of nucleotide variation with a strongly positive correlation. In addition, telomeric distance, regional GC-content, and regional CpG-island content are strongly negatively correlated with variation. These results are compared with humans, with both similarities and differences interpreted in the light of the estimated effective population sizes of the two species as well as their strongly differing recent demographic histories.The final version of this article, as published in Genome Biology and Evolution, can be viewed online at: https://academic.oup.com/gbe/article/8/10/3202/2939577/The-Impact-of-Linked-Selection-in-Chimpanzees-

Context dependent substitution biases vary within the human genome

Background: Models of sequence evolution typically assume that different nucleotide positions evolve independently. This assumption is widely appreciated to be an over-simplification. The best known violations involve biases due to adjacent nucleotides. There have also been suggestions that biases exist at larger scales, however this possibility has not been systematically explored. Results: To address this we have developed a method which identifies over- and under-represented substitution patterns and assesses their overall impact on the evolution of genome composition. Our method is designed to account for biases at smaller pattern sizes, removing their effects. We used this method to investigate context bias in the human lineage after the divergence from chimpanzee. We examined bias effects in substitution patterns between 2 and 5 bp long and found significant effects at all sizes. This included some individual three and four base pair patterns with relatively large biases. We also found that bias effects vary across the genome, differing between transposons and non-transposons, between different classes of transposons, and also near and far from genes. Conclusions: We found that nucleotides beyond the immediately adjacent one are responsible for substantial context effects, and that these biases vary across the genome

The topography of mutational processes in breast cancer genomes.

Somatic mutations in human cancers show unevenness in genomic distribution that correlate with aspects of genome structure and function. These mutations are, however, generated by multiple mutational processes operating through the cellular lineage between the fertilized egg and the cancer cell, each composed of specific DNA damage and repair components and leaving its own characteristic mutational signature on the genome. Using somatic mutation catalogues from 560 breast cancer whole-genome sequences, here we show that each of 12 base substitution, 2 insertion/deletion (indel) and 6 rearrangement mutational signatures present in breast tissue, exhibit distinct relationships with genomic features relating to transcription, DNA replication and chromatin organization. This signature-based approach permits visualization of the genomic distribution of mutational processes associated with APOBEC enzymes, mismatch repair deficiency and homologous recombinational repair deficiency, as well as mutational processes of unknown aetiology. Furthermore, it highlights mechanistic insights including a putative replication-dependent mechanism of APOBEC-related mutagenesis

Contrasting Demographic History and Phylogeographic Patterns in Two Indo-Pacific Gastropods

Marine species with ranges that span the Indo-Australian Archipelago (IAA) exhibit a range of phylogeographic patterns, most of which are interpreted in the context of vicariance between Indian and Pacific Ocean populations during Pliocene and Pleistocene low sea level stands. However, patterns often vary among ecologically similar taxa, sometimes even within genera. This study compares phylogeographic patterns in two species of highly dispersive Neritid gastropod, Nerita albicilla and Nerita plicata, with nearly sympatric ranges that span the Indo-Pacific. Mitochondrial COI sequences from \u3e 1000 individuals from 97 sites reveal similar phylogenies in both species (two divergent clades differing by 3.2% and 2.3%, for N. albicilla and N. plicata respectively). However, despite ecological similarity and congeneric status, the two species exhibit phylogeographic discordance, with N. albicilla maintaining reciprocal monophyly of Indian and Pacific Ocean populations, while N. plicata is panmictic between oceans, but displays a genetic cline in the Central Pacific. Although this difference might be explained by qualitatively different demographic histories, parameter estimates from three coalescent models indicate that both species have high levels of gene flow between demes (2Ne m \u3e 75), and share a common history of population expansion that is likely associated with cyclical flooding of continental shelves and island lagoons following low sea level stands. Results indicate that ecologically similar co-distributed species may respond very differently to shared environmental processes, suggesting that relatively minor differences in traits such as pelagic larval duration or microhabitat association may profoundly impact phylogeographic structure

Functional Conservation of DNA Methylation in the Pea Aphid and the Honeybee

DNA methylation is a fundamental epigenetic mark known to have wide-ranging effects on gene regulation in a variety of animal taxa. Comparative genomic analyses can help elucidate the function of DNA methylation by identifying conserved features of methylated genes and other genomic regions. In this study, we used computational approaches to distinguish genes marked by heavy methylation from those marked by little or no methylation in the pea aphid, Acyrthosiphon pisum. We investigated if these two classes had distinct evolutionary histories and functional roles by conducting comparative analysis with the honeybee, Apis (Ap.) mellifera. We found that highly methylated orthologs in A. pisum and Ap. mellifera exhibited greater conservation of methylation status, suggesting that highly methylated genes in ancestral species may remain highly methylated over time. We also found that methylated genes tended to show different rates of evolution than unmethylated genes. In addition, genes targeted by methylation were enriched for particular biological processes that differed from those in relatively unmethylated genes. Finally, methylated genes were preferentially ubiquitously expressed among alternate phenotypes in both species, whereas genes lacking signatures of methylation were preferentially associated with condition-specific gene expression. Overall, our analyses support a conserved role for DNA methylation in insects with comparable methylation systems

The evolution of transcription-associated biases of mutations across vertebrates

<p>Abstract</p> <p>Background</p> <p>The interplay between transcription and mutational processes can lead to particular mutation patterns in transcribed regions of the genome. Transcription introduces several biases in mutational patterns; in particular it invokes strand specific mutations. In order to understand the forces that have shaped transcripts during evolution, one has to study mutation patterns associated with transcription across animals.</p> <p>Results</p> <p>Using multiple alignments of related species we estimated the regional single-nucleotide substitution patterns along genes in four vertebrate taxa: primates, rodents, laurasiatheria and bony fishes. Our analysis is focused on intronic and intergenic regions and reveals differences in the patterns of substitution asymmetries between mammals and fishes. In mammals, the levels of asymmetries are stronger for genes starting within CpG islands than in genes lacking this property. In contrast to all other species analyzed, we found a mutational pressure in dog and stickleback, promoting an increase of GC-contents in the proximity to transcriptional start sites.</p> <p>Conclusions</p> <p>We propose that the asymmetric patterns in transcribed regions are results of transcription associated mutagenic processes and transcription coupled repair, which both seem to evolve in a taxon related manner. We also discuss alternative mechanisms that can generate strand biases and involves error prone DNA polymerases and reverse transcription. A localized increase of the GC content near the transcription start site is a signature of biased gene conversion (BGC) that occurs during recombination and heteroduplex formation. Since dog and stickleback are known to be subject to rapid adaptations due to population bottlenecks and breeding, we further hypothesize that an increase in recombination rates near gene starts has been part of an adaptive process.</p

Dung beetle radiations in Madagascar

Speciation on islands is affected by island size and the range of habitats and resources available and often also by limited interactions with other taxa. An ancestral population may evolve into a large number of species via an adaptive radiation. In Madagascar, most groups of animals and plants have radiated on the island, having arrived via oceanic dispersal during the long isolation of Madagascar. Characteristic features of Malagasy biota are exceptionally high level of endemism, high species richness as well as lack of many higher taxa that are dominant on the African mainland. Malagasy dung beetles are dominated by two tribes, Canthonini and Helictopleurina, with more than 250 endemic species. In this thesis I have reconstructed molecular phylogenies for the two tribes using several gene regions and different phylogenetic methods. Evolution of closely related species and among populations of the same species was examined with haplotype networks. The Malagasy Canthonini consists of three large lineages, while Helictopleurina forms a monophyletic group. The ancestors of each of the four clades colonised Madagascar at different times during Cenozoic. The subsequent radiations differ in terms of the number of extant species (from 37 to more than 100) and the level of ecological differentiation. In addition, Onthophagini (6 species) and Scarabaeini (3) have colonised Madagascar several times, but they have not radiated and the few species have not entered forests where Canthonini and Helictopleurina mostly occur. Among the three Canthonini radiations, speciation appears to have been mostly allopatric in the oldest and the youngest clades, while in the Epactoides clade sister species have diverged in their ecologies but have similar geographical distributions, indicating that speciation may have occurred in regional sympatry. The most likely isolating mechanisms have been rivers and forest refugia during dry and cool geological periods. Most species are generalists feeding on both carrion and dung, and competition among ecologically similar species may prevent their coexistence in the same communities. Some species have evolved to forage in the canopy and a few species have shifted to use cattle dung, a new resource in the open habitats following the introduction of cattle 1500 years ago. The latter shift has allowed species to expand their geographical ranges.Madagaskarin eläin- ja kasvilajisto on hyvin rikas, ja suurin osa lajeista on kotoperäisiä, eli ne ovat kehittyneet saarella ja ne esiintyvät vain siellä. Pääosin nykylajiston kantamuodot ovat saapuneet saarelle meriteitse kymmeniä miljoonia vuosia sitten saaren jo ollessa erkaantunut Afrikan mantereesta. Lajit ovat syntyneet saarella ja sopeutuneet sen moniin erilaisiin ympäristöihin. Toisaalta, eristyneisyytensä takia Madagaskarilta puuttuu monia eläinryhmiä, jotka esiintyvät runsaina manner-Afrikassa. Erityispiirteidensä ansiosta Madagaskar on oivallinen alue tutkia lajiutumista ja lajiryhmien kehittymistä. Madagaskarilta tunnetaan yli 250 kotoperäistä lantakuoriaislajia. Suurin osa lajeista kuuluu Canthonini- ja Helictopleurina-sukuryhmiin. Väitöskirjatutkimuksessani olen selvittänyt madagaskarilaisten lantakuoriaisten evoluutiota rakentamalla useaan geenialueeseen perustuvia sukupuita. Lajistoltaan suurempi sukuryhmistä, Canthonini, koostuu kolmesta erillisestä kehityslinjasta Kunkin linjan kantamuoto on saapunut saarelle viimeisen 65 miljoonan vuoden aikana. Helictopleurina-ryhmällä on vain yksi kantamuoto, joka saapui saarelle noin 30 miljoonaa vuotta sitten. Nämä neljä lantakuoriaislinjaa eroavat toisistaan lajimääriltään (37 yli 100 lajiin) sekä monilta ekologisilta piirteiltään. Suurin osa lajeista ei ole erikoistunut eri ravintoihin, mutta kahdella vanhimmalla linjalla on monipuolisempi ravinto kuin nuoremmilla ryhmillä. Kaikki neljä linjaa esiintyvät useissa metsätyypeissä, mutta erityisesti sademetsäalueella, jossa niille on parhaiten tarjolla ravintoa. Jotkin lajeista ovat kehittyneet asumaan puiden latvustossa, kun taas muutama laji on siirtynyt käyttämään lehmänlantaa avoimilla alueilla. Kumpikin näistä muutoksista on tapahtunut useaan kertaan. Lehmänlannan käyttö on mahdollistanut näiden lajien levittäytymisen koko saarelle, sillä karjaa kasvatetaan ympäri saarta. Saarella esiintyy myös Onthophagini- ja Scarabaeini-sukuryhmien lantakuoriaislajeja, mutta nämä ryhmät eivät ole pystyneet lajiutumaan saarella lähes lainkaan eivätkä leviämään sademetsiin. Todennäköisesti ne ovat saapuneet saarelle myöhemmin kuin Canthonini- ja Helictopleurina-ryhmät, ja kilpailu näiden aiemmin kehittyneiden ja siten saarelle paremmin sopeutuneiden lajien kanssa on estänyt uudempien ryhmien levittäytymisen