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- Adaptive sequence evolution (1)
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T lymphocytes against tumor-specific mutated neoantigens can induce tumor regression. Also, the size of the immunogenic cancer mutanome is supposed to correlate with the clinical efficacy of checkpoint inhibition. Herein, we studied the susceptibility of tumor cell lines from lymph node metastases occurring in a melanoma patient over several years towards blood-derived, neoantigen-specific CD8+ T cells. In contrast to a cell line established during early stage III disease, all cell lines generated at later time points from stage IV metastases exhibited partial or complete loss of HLA class I expression. Whole exome and transcriptome sequencing of the four tumor lines and a germline control were applied to identify expressed somatic single nucleotide substitutions (SNS), insertions and deletions (indels). Candidate peptides encoded by these variants and predicted to bind to the patient’s HLA class I alleles were synthesized and tested for recognition by autologous mixed lymphocyte-tumor cell cultures (MLTCs). Peptides from four mutated proteins, HERPUD1G161S, INSIG1S238F, MMS22LS437F and PRDM10S1050F, were recognized by MLTC responders and MLTC-derived T cell clones restricted by HLA-A*24:02 or HLA-B*15:01. Intracellular peptide processing was verified with transfectants. All four neoantigens could only be targeted on the cell line generated during early stage III disease. HLA loss variants of any kind were uniformly resistant. These findings corroborate that, although neoantigens represent attractive therapeutic targets, they also contribute to the process of cancer immunoediting as a serious limitation to specific T cell immunotherapy.
Background: Within the complex metazoan phylogeny, the relationships of the three lophophorate lineages, ectoprocts, brachiopods and phoronids, are particularly elusive. To shed further light on this issue, we present phylogenomic analyses of 196 genes from 58 bilaterian taxa, paying particular attention to the influence of compositional heterogeneity.
Results: The phylogenetic analyses strongly support the monophyly of Lophophorata and a sister-group relationship between Ectoprocta and Phoronida. Our results contrast previous findings based on rDNA sequences and phylogenomic datasets which supported monophyletic Polyzoa (= Bryozoa sensu lato) including Ectoprocta, Entoprocta and Cycliophora, Brachiozoa including Brachiopoda and Phoronida as well as Kryptrochozoa including Brachiopoda, Phoronida and Nemertea, thus rendering Lophophorata polyphyletic. Our attempts to identify the causes for the conflicting results revealed that Polyzoa, Brachiozoa and Kryptrochozoa are supported by character subsets with deviating amino acid compositions, whereas there is no indication for compositional heterogeneity in the character subsets supporting the monophyly of Lophophorata.
Conclusion: Our results indicate that the support for Polyzoa, Brachiozoa and Kryptrochozoa gathered so far is likely an artifact caused by compositional bias. The monophyly of Lophophorata implies that the horseshoe-shaped mesosomal lophophore, the tentacular feeding apparatus of ectoprocts, phoronids and brachiopods is, indeed, a synapomorphy of the lophophorate lineages. The same may apply to radial cleavage. However, among phoronids also spiral cleavage is known. This suggests that the cleavage pattern is highly plastic and has changed several times within lophophorates. The sister group relationship of ectoprocts and phoronids is in accordance with the interpretation of the eversion of a ventral invagination at the beginning of metamorphosis as a common derived feature of these taxa.
The taxon Syndermata comprises the biologically interesting wheel animals (“Rotifera”: Bdelloidea + Monogononta + Seisonidea) and thorny-headed worms (Acanthocephala), and is central for testing superordinate phylogenetic hypotheses (Platyzoa, Gnathifera) in the metazoan tree of life. Recent analyses of syndermatan phylogeny suggested paraphyly of Eurotatoria (free-living bdelloids and monogononts) with respect to endoparasitic acanthocephalans. Data of epizoic seisonids, however, were absent, which may have affected the branching order within the syndermatan clade. Moreover, the position of Seisonidea within Syndermata should help in understanding the evolution of acanthocephalan endoparasitism. Here, we report the first phylogenomic analysis that includes all four higher-ranked groups of Syndermata. The analyzed data sets comprise new transcriptome data for Seison spec. (Seisonidea), Brachionus manjavacas (Monogononta), Adineta vaga (Bdelloidea), and Paratenuisentis ambiguus (Acanthocephala). Maximum likelihood and Bayesian trees for a total of 19 metazoan species were reconstructed from up to 410 functionally diverse proteins. The results unanimously place Monogononta basally within Syndermata, and Bdelloidea appear as the sister group to a clade comprising epizoic Seisonidea and endoparasitic Acanthocephala. Our results support monophyly of Syndermata, Hemirotifera (Bdelloidea + Seisonidea + Acanthocephala), and Pararotatoria (Seisonidea + Acanthocephala), rejecting monophyly of traditional Rotifera and Eurotatoria. This serves as an indication that early acanthocephalans lived epizoically or as ectoparasites on arthropods, before their complex lifecycle with arthropod intermediate and vertebrate definite hosts evolved.
Genomic basis of ecological niche divergence among cryptic sister species of non-biting midges
(2013)
Background: There is a lack of understanding the evolutionary forces driving niche segregation of closely related organisms. In addition, pinpointing the genes driving ecological divergence is a key goal in molecular ecology. Here, larval transcriptome sequences obtained by next-generation-sequencing are used to address these issues in a morphologically cryptic sister species pair of non-biting midges (Chironomus riparius and C. piger).
Results: More than eight thousand orthologous open reading frames were screened for interspecific divergence and intraspecific polymorphisms. Despite a small mean sequence divergence of 1.53% between the sister species, 25.1% of 18,115 observed amino acid substitutions were inferred by α statistics to be driven by positive selection. Applying McDonald-Kreitman tests to 715 alignments of gene orthologues identified eleven (1.5%) genes driven by positive selection.
Conclusions: Three candidate genes were identified as potentially responsible for the observed niche segregation concerning nitrite concentration, habitat temperature and water conductivity. Additionally, signs of positive selection in the hydrogen sulfide detoxification pathway were detected, providing a new plausible hypothesis for the species’ ecological differentiation. Finally, a divergently selected, nuclear encoded mitochondrial ribosomal protein may contribute to reproductive isolation due to cytonuclear coevolution.
What is in Umbilicaria pustulata? A metagenomic approach to reconstruct the holo-genome of a lichen
(2020)
Lichens are valuable models in symbiosis research and promising sources of biosynthetic genes for biotechnological applications. Most lichenized fungi grow slowly, resist aposymbiotic cultivation, and are poor candidates for experimentation. Obtaining contiguous, high-quality genomes for such symbiotic communities is technically challenging. Here, we present the first assembly of a lichen holo-genome from metagenomic whole-genome shotgun data comprising both PacBio long reads and Illumina short reads. The nuclear genomes of the two primary components of the lichen symbiosis—the fungus Umbilicaria pustulata (33 Mb) and the green alga Trebouxia sp. (53 Mb)—were assembled at contiguities comparable to single-species assemblies. The analysis of the read coverage pattern revealed a relative abundance of fungal to algal nuclei of ∼20:1. Gap-free, circular sequences for all organellar genomes were obtained. The bacterial community is dominated by Acidobacteriaceae and encompasses strains closely related to bacteria isolated from other lichens. Gene set analyses showed no evidence of horizontal gene transfer from algae or bacteria into the fungal genome. Our data suggest a lineage-specific loss of a putative gibberellin-20-oxidase in the fungus, a gene fusion in the fungal mitochondrion, and a relocation of an algal chloroplast gene to the algal nucleus. Major technical obstacles during reconstruction of the holo-genome were coverage differences among individual genomes surpassing three orders of magnitude. Moreover, we show that GC-rich inverted repeats paired with nonrandom sequencing error in PacBio data can result in missing gene predictions. This likely poses a general problem for genome assemblies based on long reads.
The gradual heterogeneity of climatic factors pose varying selection pressures across geographic distances that leave signatures of clinal variation in the genome. Separating signatures of clinal adaptation from signatures of other evolutionary forces, such as demographic processes, genetic drift, and adaptation to non-clinal conditions of the immediate local environment is a major challenge. Here, we examine climate adaptation in five natural populations of the harlequin fly Chironomus riparius sampled along a climatic gradient across Europe. Our study integrates experimental data, individual genome resequencing, Pool-Seq data, and population genetic modelling. Common-garden experiments revealed a positive correlation of population growth rates corresponding to the population origin along the climate gradient, suggesting thermal adaptation on the phenotypic level. Based on a population genomic analysis, we derived empirical estimates of historical demography and migration. We used an FST outlier approach to infer positive selection across the climate gradient, in combination with an environmental association analysis. In total we identified 162 candidate genes as genomic basis of climate adaptation. Enriched functions among these candidate genes involved the apoptotic process and molecular response to heat, as well as functions identified in other studies of climate adaptation in other insects. Our results show that local climate conditions impose strong selection pressures and lead to genomic adaptation despite strong gene flow. Moreover, these results imply that selection to different climatic conditions seems to converge on a functional level, at least between different insect species.
Active transposable elements (TEs) may result in divergent genomic insertion and abundance patterns among conspecific populations. Upon secondary contact, such divergent genetic backgrounds can theoretically give rise to classical Dobzhansky-Muller incompatibilities (DMI), a way how TEs can contribute to the evolution of endogenous genetic barriers and eventually population divergence. We investigated whether differential TE activity created endogenous selection pressures among conspecific populations of the non-biting midge Chironomus riparius, focussing on a Chironomus-specific TE, the minisatellite-like Cla-element, whose activity is associated with speciation in the genus. Using an improved and annotated draft genome for a genomic study with five natural C. riparius populations, we found highly population-specific TE insertion patterns with many private insertions. A highly significant correlation of pairwise population FST from genome-wide SNPs with the FST estimated from TEs suggests drift as the major force driving TE population differentiation. However, the significantly higher Cla-element FST level due to a high proportion of differentially fixed Cla-element insertions indicates that segregating, i.e. heterozygous insertions are selected against. With reciprocal crossing experiments and fluorescent in-situ hybridisation of Cla-elements to polytene chromosomes, we documented phenotypic effects on female fertility and chromosomal mispairings that might be linked to DMI in hybrids. We propose that the inferred negative selection on heterozygous Cla-element insertions causes endogenous genetic barriers and therefore acts as DMI among C. riparius populations. The intrinsic genomic turnover exerted by TEs, thus, may have a direct impact on population divergence that is operationally different from drift and local adaptation.