The mitochondrial ratchet: Examples from non-bilaterian animals

The origin of eukaryotes is intrinsically linked with mitochondria. Mitochondrial evolution is characterized by a gradual process of gene loss and transfer to the nucleus, and thus eukaryotic genome evolution is intimately tied to mitochondrial DNA. Among animals, the widest variation in mitochondrial genome structure occurs in the non-bilaterian phyla (Porifera, Cnidaria, Ctenophora, Placozoa), where one can find one of the largest, most gene-rich animal mitochondrial genomes, as well as the smallest and most gene-impoverished. This variation in gene content is predicted to have consequences for the evolution of protein-coding genes that remain trapped in mitochondrial DNA, which are mediated primarily by two non-adaptive forces: mutation and random genetic drift. In particular, increased mutation rates lead to the loss of mitochondrial genes, which in turn can lead to elevated mutation rates through drift. This positive feedback mechanism, or mitochondrial ratchet, can manifest itself in different ways depending on the population genetic environment in which mitochondrial DNA is evolving. I will highlight key examples from non-bilaterian animals that illustrate the link between mutation, selection and drift in animal mitochondrial DNA, and represent some of the more extreme ends of the mitochondrial ratchet spectrum. Furthermore, my results show how the mitochondrial ratchet can extend its reach into the nuclear genome, influencing the evolution of nuclear-encoded mitochondrial genes

The Role of Homology and Orthology in the Phylogenomic Analysis of Metazoan Gene Content

Resolving the relationships of animals (Metazoa) is crucial to our understanding of the origin of key traits such as muscles, guts, and nerves. However, a broadly accepted metazoan consensus phylogeny has yet to emerge. In part, this is because the genomes of deeply diverging and fast-evolving lineages may undergo significant gene turnover, reducing the number of orthologs shared with related phyla. This can limit the usefulness of traditional phylogenetic methods that rely on alignments of orthologous sequences. Phylogenetic analysis of gene content has the potential to circumvent this orthology requirement, with binary presence/absence of homologous gene families representing a source of phylogenetically informative characters. Applying binary substitution models to the gene content of 26 complete animal genomes, we demonstrate that patterns of gene conservation differ markedly depending on whether gene families are defined by orthology or homology, that is, whether paralogs are excluded or included. We conclude that the placement of some deeply diverging lineages may exceed the limit of resolution afforded by the current methods based on comparisons of orthologous protein sequences, and novel approaches are required to fully capture the evolutionary signal from genes within genomes.W.P. was supported by the French National Research Agency (ANR) grant Ancestrome (ANR-10-BINF-01-01), and by grants from the National Science Foundation (DEB1556615, DEB-1256993). D.P. was supported by a NERC BETR (NE/P013643/1) grant. G.W. was supported by LMU Munich’s Institutional Strategy LMUexcellent within the framework of the German Excellence Initiative, and the German Research Foundation (DFG) grant Wo896/19-1, and from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no. 764840 (ITN IGNITE

Genomic data do not support comb jellies as the sister group to all other animals

Understanding how complex traits, such as epithelia, nervous systems, muscles, or guts, originated depends on a well-supported hypothesis about the phylogenetic relationships among major animal lineages. Traditionally, sponges (Porifera) have been interpreted as the sister group to the remaining animals, a hypothesis consistent with the conventional view that the last common animal ancestor was relatively simple and more complex body plans arose later in evolution. However, this premise has recently been challenged by analyses of the genomes of comb jellies (Ctenophora), which, instead, found ctenophores as the sister group to the remaining animals (the “Ctenophora-sister” hypothesis). Because ctenophores are morphologically complex predators with true epithelia, nervous systems, muscles, and guts, this scenario implies these traits were either present in the last common ancestor of all animals and were lost secondarily in sponges and placozoans (Trichoplax) or, alternatively, evolved convergently in comb jellies. Here, we analyze representative datasets from recent studies supporting Ctenophora-sister, including genome-scale alignments of concatenated protein sequences, as well as a genomic gene content dataset. We found no support for Ctenophora-sister and conclude it is an artifact resulting from inadequate methodology, especially the use of simplistic evolutionary models and inappropriate choice of species to root the metazoan tree. Our results reinforce a traditional scenario for the evolution of complexity in animals, and indicate that inferences about the evolution of Metazoa based on the Ctenophora-sister hypothesis are not supported by the currently available data

Reply to Halanych et al.: Ctenophore misplacement is corroborated by independent datasets

In their letter, Halanych et al. (1) criticize our recent assertion (2) that the phylogenetic placement of ctenophores as the sister group to all other animals (the Ctenophora-sister hypothesis) in three previous studies (3–5) was an artifact caused by undetected systematic error. Halanych et al. (1) claim we used no “objective approaches” to identify sources of systematic error. In fact, we used an objective comparison of Bayesian cross-validation scores to select the best-fitting substitution model, because poorly fitting models are a frequent source of systematic error. Halanych et al. point out that this comparison did not include partitioned site-homogeneous models. However, they do not mention that only one of the studies we address (3) used this approach, and that multiple site-homogeneous partitions still do not account for within-partition site-heterogeneous biochemical constraints, which our results show had a major impact on model fit and the tree topology

FossilSim:An r package for simulating fossil occurrence data under mechanistic models of preservation and recovery

1.Key features of the fossil record that present challenges for integrating palaeontological and phylogenetic datasets include (i) non‐uniform fossil recovery, (ii) stratigraphic age uncertainty and (iii) inconsistencies in the definition of species origination and taxonomy. 2.We present an r package FossilSim that can be used to simulate and visualise fossil data for phylogenetic analysis under a range of flexible models. The package includes interval‐, environment‐ and lineage‐dependent models of fossil recovery that can be combined with models of stratigraphic age uncertainty and species evolution. 3.The package input and output can be used in combination with the wide range of existing phylogenetic and palaeontological r packages. We also provide functions for converting between FossilSim and paleotree objects. 4. Simulated datasets provide enormous potential to assess the performance of phylogenetic methods and to explore the impact of using fossil occurrence databases on parameter estimation in macroevolution.ISSN:2041-210XISSN:2041-209

Utility of a buccal swab point-of-care test for the IFNL4 genotype in the era of direct acting antivirals for hepatitis C virus.

BACKGROUND: The CC genotype of the IFNL4 gene is known to be associated with increased Hepatitis C (HCV) cure rates with interferon-based therapy and may contribute to cure with direct acting antivirals. The Genedrive® IFNL4 is a CE marked Point of Care (PoC) molecular diagnostic test, designed for in vitro diagnostic use to provide rapid, real-time detection of IFNL4 genotype status for SNP rs12979860. METHODS: 120 Participants were consented to a substudy comparing IFNL4 genotyping results from a buccal swab analysed on the Genedrive® platform with results generated using the Affymetix UK Biobank array considered to be the gold standard. RESULTS: Buccal swabs were taken from 120 participants for PoC IFNL4 testing and a whole blood sample for genetic sequencing. Whole blood genotyping vs. buccal swab PoC testing identified 40 (33%), 65 (54%), and 15 (13%) had CC, CT and TT IFNL4 genotype respectively. The Buccal swab PoC identified 38 (32%) CC, 64 (53%) CT and 18 (15%) TT IFNL4 genotype respectively. The sensitivity and specificity of the buccal swab test to detect CC vs non-CC was 90% (95% CI 76-97%) and 98% (95% CI 91-100%) respectively. CONCLUSIONS: The buccal swab test was better at correctly identifying non-CC genotypes than CC genotypes. The high specificity of the Genedrive® assay prevents CT/TT genotypes being mistaken for CC, and could avoid patients being identified as potentially 'good responders' to interferon-based therapy

Causes and Timing of Mortality and Morbidity Among Late Presenters Starting Antiretroviral Therapy in the REALITY Trial.

BACKGROUND: In sub-Saharan Africa, 20%-25% of people starting antiretroviral therapy (ART) have severe immunosuppression; approximately 10% die within 3 months. In the Reduction of EArly mortaLITY (REALITY) randomized trial, a broad enhanced anti-infection prophylaxis bundle reduced mortality vs cotrimoxazole. We investigate the contribution and timing of different causes of mortality/morbidity. METHODS: Participants started ART with a CD4 count .3); and reduced nonfatal/fatal tuberculosis and cryptococcosis (P .2). CONCLUSIONS: Enhanced prophylaxis reduced mortality from cryptococcosis and unknown causes and nonfatal tuberculosis and cryptococcosis. High early incidence of fatal/nonfatal events highlights the need for starting enhanced-prophylaxis with ART in advanced disease. CLINICAL TRIALS REGISTRATION: ISRCTN43622374

Strategic treatment optimization for HCV (STOPHCV1): a randomised controlled trial of ultrashort duration therapy for chronic hepatitis C [version 1; peer review: awaiting peer review]

Background: The world health organization (WHO) has identified the need for a better understanding of which patients with hepatitis C virus (HCV) can be cured with ultrashort course HCV therapy. Methods: A total of 202 individuals with chronic HCV were randomised to fixed-duration shortened therapy (8 weeks) vs variable duration ultrashort strategies (VUS1/2). Participants not cured following first-line treatment were retreated with 12 weeks’ sofosbuvir/ledipasvir/ribavirin. The primary outcome was sustained virological response 12 weeks (SVR12) after first-line treatment and retreatment. Participants were factorially randomised to receive ribavirin with first-line treatment. Results: All evaluable participants achieved SVR12 overall (197/197, 100% [95% CI 98-100]) demonstrating non-inferiority between fixedduration and variable-duration strategies (difference 0% [95% CI - 3.8%, +3.7%], 4% pre-specified non-inferiority margin). First-line SVR12 was 91% [86%-97%] (92/101) for fixed-duration vs 48% [39%-57%] (47/98) for variable-duration, but was significantly higher for VUS2 (72% [56%-87%] (23/32)) than VUS1 (36% [25%-48%] (24/66)). Overall, first-line SVR12 was 72% [65%-78%] (70/101) without ribavirin and 68% [61%-76%] (69/98) with ribavirin (p=0.48). At treatment failure, the emergence of viral resistance was lower with ribavirin (12% [2%-30%] (3/26)) than without (38% [21%-58%] (11/29), p=0.01). Conclusions: Unsuccessful first-line short-course therapy did not compromise retreatment with sofosbuvir/ledipasvir/ribavirin (100% SVR12). SVR12 rates were significantly increased when ultrashort treatment varied between 4-7 weeks rather than 4-6 weeks. Ribavirin significantly reduced resistance emergence in those failing first-line therapy. ISRCTN Registration: 37915093 (11/04/2016)

Lessons learned from organizing and teaching virtual phylogenetics workshops

No abstract available