Biology subjects

O'Connell, M. J.

Publications and source records attributed to O'Connell, M. J..

At least 19 recordsLinked to original sources

bioRxiv2026

Processed pseudogenes as dynamic substrates of vertebrate genome evolution

Pseudogenes, gene copies presumed nonfunctional, are widespread products of genome evolution, yet their retention under selection and functional significance across vertebrate diversity remain poorly understood. Here, by analyzing 244 high-quality, chromosome-scale genomes from the Vertebrate Genomes Project spanning seven major vertebrate lineages, we show that the most abundant class of pseudogenes, processed pseudogenes (retrocopies), is a dynamic substrate for evolutionary innovation rather than an inert relic. Retrocopy abundance varies by more than an order of magnitude across lineages, closely tracks autonomous retrotransposon content, and a considerable fraction retains intact open reading frames under purifying selection. We establish a two-stage model in which a conserved formation bias toward highly expressed housekeeping genes is followed by lineage-specific selective filtering that shapes distinct functional repertoires. Testing this model, we show that the mammalian X chromosome exports retrocopies to autosomes at significantly elevated rates enriched for functionally constrained copies, establishing meiotic sex chromosome inactivation as the selective driver. Furthermore, tumor suppressor gene retrocopies accumulate preferentially over oncogene retrocopies in large-bodied and long-lived mammalian lineages, identifying retrocopy-mediated tumor suppressor dosage expansion as a previously unrecognized genomic correlate of Petos paradox. Beyond cancer-related dynamics, retrocopy abundance itself correlates with key mammalian life-history traits, including brain mass, generation length, and reproductive timing, which suggests that retrocopy turnover is broadly coupled to organismal pace-of-life. These findings recast retrocopies as a major axis of vertebrate genome evolution and provide a comprehensive resource for studying gene duplicate innovation.

genomics↗

bioRxiv2026

Constructive neutral evolution explains the emergence of specialised ribosomes in diverse eukaryotes.

Throughout eukaryotic evolution, the structure of the ribosome has been highly conserved, featuring 80 common protein gene families. However, in many eukaryotes, paralogs of these proteins are present. "Specialised ribosomes" have been documented across diverse groups of eukaryotes where they play an important role in the regulation of translation of specific mRNAs. In the case of specialised ribosomes it has been documented that assembled ribosomes that contain specific paralogs can directly affect translational output. This has been proposed to contribute to the regulation of complex responses to environmental change and to coordinate cell-type specific physiology. This poses the question of whether ribosome specialisation principally emerges under an adaptive or neutral model of evolution. Using gene tree-species tree reconciliation, we test competing hypotheses regarding the evolutionary drivers of ribosome specialisation. We determine that examples of specialisation tend to emerge by independent duplication of the same ribosomal proteins in different lineages. We show that pathways to specialisation through paralog formation have arisen independent of: (i) paralog location within the 3D ribosome complex, and (ii) positive selection in these paralogs. We determine that the generalisable model of best fit for the evolution of paralog-mediated eukaryotic ribosomal specialisation is one of constructive neutral evolution. In lineages with small effective population sizes and increased complexity, the emergence and retention of ribosomal protein paralogs has provided the raw material for ratcheting and the emergence of translational regulation at the level of the ribosome.

evolutionary biology↗

bioRxiv2025

Dissecting Phylogenetic Support: Unified Decay Indices, AU Tests, and Branch-Site Specific Visualizations.

Phylogenetic inference relies on robust measures of branch support to assess the reliability of evolutionary relationships. While bootstrap resampling and Bayesian probabilities have become the predominant support metrics in molecular phylogenetics, decay indices (also known as Bremer support) provide an alternative perspective by quantifying the amount of evidence required to collapse specific clades. We present panDecay, a unified software framework that extends the classical parsimony-based decay index concept to maximum likelihood (ML) and Bayesian inference approaches. panDecay automates the calculation of ML-based decay indices using log-likelihood differences, performs Approximately Unbiased (AU) statistical tests, and computes Bayesian decay indices through marginal likelihood comparisons using stepping-stone sampling. The software integrates with established phylogenetic tools (PAUP* and MrBayes) and provides comprehensive output including site-specific support analysis, multiple annotated tree formats, and detailed statistical reports. panDecay supports diverse data types (DNA, protein, and discrete morphological characters), offers flexible model specification, and provides parallel processing capabilities for computationally intensive Bayesian analyses. By unifying decay index calculations across parsimony, likelihood, and Bayesian frameworks within a single command-line interface, panDecay enables researchers to obtain complementary support metrics that provide deeper insights into phylogenetic signal strength and distribution across sequence alignments. The software is implemented in Python 3.8+, distributed via PyPI, and released under the MIT license.

evolutionary biology↗

bioRxiv2025

Mammal placental phenotypes are predictable from microRNA repertoires.

Similar placental morphologies evolved multiple times independently in the history of mammal evolution1,2. Yet the genetic architecture that repeatedly guides distinct mammal lineages towards similar complex placental phenotypes has remained elusive. MicroRNAs (miRNAs), despite their diversity in mammals3-7 and known roles as developmental regulators8-10, remain under-examined as drivers of morphological innovation. We identified presence-absence patterns for 429 miRNA gene families across 398 mammalian genomes and discovered that placental phenotype is highly predictable from genomic miRNA repertoires (classification accuracy 74.5-95.8%). We identified 42 miRNA gene families significantly associated with placentation type, whose gene targets are enriched for developmental processes. Notably, convergent placental morphologies consistently involve identical miRNA families, revealing that evolution of this trait is constrained to predictable genetic pathways. We demonstrate that MIR-11986, uniquely associated with cotyledonary placentation, has tissue-specific expression in key reproductive tissues. MiRNA-mediated regulation therefore constrains placental morphological diversification into reproducible programs, offering insights into how genetic architecture shapes the predictability of convergent evolution. This striking pattern reveals a fundamental principle of evolution: that the miRNA regulatory networks available to control and guide complex placental morphological innovation are constrained and predictable.

genomics↗

bioRxiv2025

A genomic perspective on the origins, evolution and adaptation of Galapagos iguanas

Island taxa provide opportunities to explore the genomic basis of species diversification and trait evolution arising from adaptation to new environmental conditions and ecological niches. Here we generate the first genomic sequences for the four endemic Galapagos iguana species to reconstruct their evolutionary history and to identify genes which may contribute to their unique adaptations. We show that the marine (Amblyrhynchus) and land (Conolophus) lineages evolved in situ on now submerged islands, following a single colonisation event 9 - 12.4 million years ago. Genomic selection scans identified genes linked to traits potentially facilitating adaptation to the Galapagos environment, including specialised pigmentation phenotypes (e.g. ASIP, BCO2 and KITLG), DNA damage and UV irradiation inflammation responses (e.g. MAPK14 and BRAF), which may contribute to increased resilience to elevated UV exposure at equatorial latitudes. A shift from eumelanin (dark) to pheomelanin (yellow-orange) dominated colouration in Conolophus species may be attributable to fixed substitutions in the MC1R gene that influence protein structure and interactions, with the depigmented skin phenotype of the pink iguana additionally linked to positive selection in regulators of MITF activity, melanosome transport and dermal vasculature unique to that lineage. Further genes with signatures of positive selection in marine iguanas have putative functions including hypoxia response, that may be associated with their transition to underwater foraging (e.g. HBA, HMOX2, HIF), as well as their unique ability to repeatedly shrink and grow in body size through tissue and bone remodelling (e.g. AREG, BMP2, CPNE7). Genome-wide patterns of genetic diversity indicate recent inbreeding coincident with the timing of human settlement. Our study provides insights into the origins and diversification of the iguanas and the molecular basis of adaptation to life in the Galapagos, facilitating future conservation genomic management of threatened iguanid populations.

evolutionary biology↗

bioRxiv2025

An evolutionarily conserved microRNA, miR-185, regulates key pathways that may contribute to implantation failure.

Recurrent implantation failure (RIF) is defined after three or more good quality embryo transfers following in vitro fertilisation without a successful pregnancy outcome. Many factors contribute to RIF however, the endometrial contribution remains unclear. Previous work by our group has identified a micro-RNA (miRNA) miR-185-5p as conserved across placental mammal irrespective of implantation strategies. We tested the hypothesis that miR-185-5p and the pathways it regulates, may be disrupted in the endometria of women with RIF. A human endometrial epithelial cells line (Ishikawa cells) was transfected with mimics or inhibitors for miR-185-5p for 24 (for implantation assay) or 48 hr (for proteomic analysis) along with non-targeting controls. There was a significant different in percentage attachment of BeWoW spheroids to cells transfected with miR-185-5p mimic compared to inhibitor (P<0.05). Transfection of epithelial cells with miR-185-5p altered expression of 1450 (mimic alone) and 509 (inhibitor alone) proteins respective of which, 146 were modified by both. Comparison of predicted targets of miR-185-5p, proteins modified by this study, and key endometrial genes from the literature determined genes and proteins associated with CNP family were further investigated in biopsies from individuals with (n=10) and without RIF (n=9) with CSNK1D expression significantly lower (p<0.05) in individuals with RIF. Collectively these data demonstrate that miR-185-5p modifies pathways that are important for successful implantation in humans.

cell biology↗

bioRxiv2024

Autoencoders with shared and specific embeddings formulti-omics data integration

MotivationIn cancer research, different levels of high-dimensional data are often collected for the same subjects. Effective integration of these data by considering the shared and specific information from each data source can help us better understand different types of cancer. ResultsIn this study we propose a novel autoencoder (AE) structure with explicitly defined orthogonal loss between the shared and specific embeddings to integrate different data sources. We compare our model with previously proposed AE structures based on simulated data and real cancer data from The Cancer Genome Atlas. Using simulations with different proportions of differentially expressed genes, we compare the performance of AE methods for subsequent classification tasks. We also compare the model performance with a commonly used dimension reduction method, joint and individual variance explained. In terms of reconstruction loss, our proposed AE models with orthogonal constraints have a slightly better reconstruction loss. All AE models achieve higher classification accuracy than the original features, demonstrating the usefulness of the embeddings extracted by the model. Particularly, we show that the proposed models have consistently high classification accuracy on both training and testing sets. In comparison, the recently proposed MOCSS model that imposes an orthogonality penalty in the post-processing step has lower classification accuracy that is on par with JIVE. Availability and ImplementatioThe relevant datasets and models developed in this study are available in the following GitHub repository: https://github.com/wangc90/AE_Data_Integration.

bioinformatics↗

bioRxiv2024

The Amphibian Genomics Consortium: advancing genomic and genetic resources for amphibian research and conservation

Amphibians represent a diverse group of tetrapods, marked by deep divergence times between their three systematic orders and families. Studying amphibian biology through the genomics lens increases our understanding of the features of this animal class and that of other terrestrial vertebrates. The need for amphibian genomic resources is more urgent than ever due to the increasing threats to this group. Amphibians are one of the most imperiled taxonomic groups, with approximately 41% of species threatened with extinction due to habitat loss, changes in land use patterns, disease, climate change, and their synergistic effects. Amphibian genomic resources have provided a better understanding of ontogenetic diversity, tissue regeneration, diverse life history and reproductive modes, anti-predator strategies, and resilience and adaptive responses. They also serve as essential models for studying broad genomic traits, such as evolutionary genome expansions and contractions, as they exhibit the widest range of genome sizes among all animal taxa and possess multiple mechanisms of genetic sex determination. Despite these features, genome sequencing of amphibians has significantly lagged behind that of other vertebrates, primarily due to the challenges of assembling their large, repeat-rich genomes and the relative lack of societal support. The emergence of long-read sequencing technologies, combined with advanced molecular and computational techniques that improve scaffolding and reduce computational workloads, is now making it possible to address some of these challenges. To promote and accelerate the production and use of amphibian genomics research through international coordination and collaboration, we launched the Amphibian Genomics Consortium (AGC, https://mvs.unimelb.edu.au/amphibian-genomics-consortium) in early 2023. This burgeoning community already has more than 282 members from 41 countries. The AGC aims to leverage the diverse capabilities of its members to advance genomic resources for amphibians and bridge the implementation gap between biologists, bioinformaticians, and conservation practitioners. Here we evaluate the state of the field of amphibian genomics, highlight previous studies, present challenges to overcome, and call on the research and conservation communities to unite as part of the AGC to enable amphibian genomics research to "leap" to the next level.

genomics↗

bioRxiv2024

The embryo-derived protein PDI is highly conserved among placental mammals and alters the function of the endometrium in species with different implantation strategies.

Pregnancy establishment in mammals requires a complex sequence of events, including bi-lateral embryo-maternal communication, leading up to implantation. This is the time when most pregnancy loss occurs in mammals (including humans and food production species) and dysregulation in embryo-maternal communication contributes to pregnancy loss. Embryo-derived factors modify the function of the endometrium for pregnancy success. We hypothesise that these previously unexplored conceptus-derived proteins may be involved in altering the function of the endometrium to facilitate early pregnancy events in mammals with different early pregnancy phenotypes. Here, we show that protein disulphide-isomerase (PDI) is a highly conserved protein among mammals, and provide evidence for a species-specific roles for PDI in endometrial function in mammals with different implantation strategies. We show how PDI alters the endometrial transcriptome in human and bovine in vitro in a species-specific manner, and using a microfluidic approach we demonstrate that it alters the secretome capability of the endometrium. We also provide evidence from in vitro assays using human-derived cells that MNS1, a transcript commonly downregulated in response to PDI in human and bovine endometrial epithelial cells, may be involved in the attachment (but not invasion) phase of implantation. We propose that the trophoblast-derived protein PDI, is involved in supporting the modulation of the uterine luminal fluid secreted by the endometrium to support conceptus nourishment, and also in the process of embryo attachment to the uterine lumen for pregnancy success in mammals. SIGNIFICANCE STATEMENTWe provide evidence that a highly conserved protein (PDI) alters the endometrial transcriptome in a species- and cell-specific manner. Exposure of endometrial epithelia to PDI altered genes belonging to immune modulatory, pro-inflammatory, and adhesion-pathways. One transcript, MNS1, was commonly downregulated in endometrial epithelia from species with superficial (bovine) and invasive (human) implantation morphologies. Knockdown of MNS1 expression in humans epithelia altered the ability of human trophoblast BeWo spheroids to attach suggesting a mechanism by which PDI affects implantation in human and bovine. In addition, using a microfluidics approach we have shown that PDI alters the secretome in a species-specific manner demonstrating PDI alters a key function of the endometrium in mammals.

developmental biology↗

bioRxiv2023

Batch-effect correction in single-cell RNA sequencing data using JIVE

In single-cell RNA sequencing (scRNA-seq) data analysis, addressing batch effects -- technical artifacts stemming from factors such as varying sequencing technologies, equipment, and capture times -- is crucial. These factors cause unwanted variation in the data and often obfuscate the underlying biological signal of interest. The Joint and Individual Variation Explained (JIVE) method can be used to extract shared biological patterns from multi-source sequencing data while adjusting for individual non-biological variations (i.e., batch effect). However, its current implementation is originally designed for bulk sequencing data, making it computationally infeasible for large-scale single-cell sequencing datasets. In this study, we enhance JIVE for large-scale scRNA-seq data by boosting its computational efficiency and tailoring it to the single-cell context. Additionally, we introduce a novel application of JIVE which we use to perform batch-effect correction on multiple scRNA-seq datasets. Our enhanced JIVE method aims to decompose scRNA-seq datasets into a joint structure capturing the true biological variability and individual structures which capture technical variability within each batch. This joint structure is then suitable for use in downstream analyses. We employed four evaluation metrics and benchmarked the results against two other popular tools, Seurat v3 and Harmony, which were developed for this purpose. We found that JIVE performed best in metrics that consider local neighborhoods (kBET and LISI) and in scenarios in which the original data contained distinct differences between batches and cell types.

bioinformatics↗

bioRxiv2023

Differences in binding preferences for XIST partners are observed in mammals with different early pregnancy morphologies

In comparison to protein-coding genes, long non-coding RNAs (lncRNAs) are poorly conserved between species at the sequence level yet they often perform conserved and essential regulatory roles. The lncRNA XIST mediates X chromosome inactivation (XCI) through the interaction of numerous proteins, most of which bind to its repeat regions. Whilst XIST is present across placental mammals, its sequence is divergent. In addition, the timing and mechanistic details of the process of XCI also vary across placental mammals. Here, we sought to determine whether XIST interactor proteins previously identified in a model mammalian species (mouse) also bind in other mammals which exhibit divergent timing of XCI (human and bovine) and differing pre-implantation embryo morphology. We show that XIST and its putative protein partners are coordinately expressed in the endometria of mammals with different pre-implantation embryo morphologies. RNA immunoprecipitations revealed that human WTAP, SPEN, hnRNPK and CIZ1 proteins bind human XIST. CIZ1-XIST binding was also detected in bovine. In both human and cow, we found CIZ1 binds to the repeat E element of XIST. However, human CIZ1 protein is not able to bind bovine repeat E, indicating a species-specific binding interaction. Together these data indicate that several of the key RNA-protein interactions with XIST are common across placental mammals, even though we observe divergence in both the RNA sequence of XIST, and early embryo morphologies. This work sheds light upon the evolution of RNA-protein binding interactions, revealing that the binding events can be conserved even when the precise mechanism of binding has changed. Statements and DeclarationsAuthors have no financial or non-financial interests that are directly or indirectly related to the work submitted for publication.

developmental biology↗

bioRxiv2023

Bursts of novel composite gene families at major nodes in animal evolution

A molecular level perspective on how novel phenotypes evolve is contingent on our understanding of how genomes evolve through time, and of particular interest is how novel elements emerge or are lost. Mechanisms of protein evolution such as gene duplication have been well established. Studies of gene fusion events show they often generate novel functions and adaptive benefits. Identifying gene fusion and fission events on a genome scale allows us to establish the mode and tempo of emergence of composite genes across the animal tree of life, and allows us to test the repeatability of evolution in terms of determining how often composite genes can arise independently. Here we show that [~]5% of all animal gene families are composite, and their phylogenetic distribution suggests an abrupt, rather than gradual, emergence during animal evolution. We find that gene fusion occurs at a higher rate than fission (73.3% vs 25.4%) in animal composite genes, but many gene fusions (79% of the 73.3%) have more complex patterns including subsequent fission or loss. We demonstrate that nodes such as Bilateria, Euteleostomi, and Eutheria, have significantly higher rates of accumulation of composite genes. We observe that in general deuterostomes have a greater amount of composite genes as compared to protostomes. Intriguingly, up to 41% of composite gene families have evolved independently in different clades showing that the same solutions to protein innovation have evolved time and again in animals. Significance statementNew genes emerge and are lost from genomes over time. Mechanisms that can produce new genes include, but are not limited to, gene duplication, retrotransposition, de novo gene genesis, and gene fusion/fission. In this work, we show that new genes formed by fusing distinct homologous gene families together comprise a significant portion of the animal proteome. Their pattern of emergence through time is not gradual throughout the animal phylogeny - it is intensified on nodes of major transition in animal phylogeny. Interestingly, we see that evolution replays the tape frequently in these genes with 41% of gene fusion/fission events occurring independently throughout animal evolution.

evolutionary biology↗

bioRxiv2022

Improving orthologous signal and model fit in datasets addressing the root of the animal phylogeny.

There is conflicting evidence as to whether Porifera (sponges) or Ctenophora (comb jellies) comprise the root of the animal phylogeny. Support for either a Porifera-sister or Ctenophore-sister tree has been extensively examined in the context of model selection, taxon sampling and outgroup selection. The influence of dataset construction is comparatively understudied. We re-examine five animal phylogeny datasets that have supported either root hypothesis using an approach designed to enrich orthologous signal in phylogenomic datasets. We find that many component orthogroups in animal datasets fail to recover major animal lineages as monophyletic with the exception of Ctenophora, regardless of the supported root. Enriching these datasets to retain orthogroups recovering [≥]3 major lineages reduces dataset size by up to 50% while retaining underlying phylogenetic information and taxon sampling. Site- heterogeneous phylogenomic analysis of these enriched datasets recovers both Porifera-sister and Ctenophora-sister positions, even with additional constraints on outgroup sampling. Two datasets which previously supported Ctenophora-sister support Porifera-sister upon enrichment. All enriched datasets display improved model fitness under posterior predictive analysis. While not conclusively rooting animals at either Porifera or Ctenophora, our results indicate that dataset size and construction as well as model fit influence animal root inference.

evolutionary biology↗

bioRxiv2022

Placental mammal derived microRNAs alter pathways in the endometrial epithelia important for endometrial function.

We tested the hypothesis that a panel of placental mammal-specific miRNAs and their targets play important to establish receptivity to implantation and their dysregulated expression may be a feature in women with early pregnancy loss. Relative expression levels of miR-340-5p, -542-3p, and -671-5p all increased following treatment of Ishikawa cells with progesterone (10 g/ml) for 24 hrs (p < 0.05). RNA sequencing of these P4-treated cells identified co-ordinate changes to 6,367 transcripts of which 1713 were predicted targets of miR-340-5p, 670 of miR-542-3p, and 618 of miR-671-5p. Quantitative proteomic analysis of Ishikawa cells transfected with mimic or inhibitor (48 hrs: n=3 biological replicates) for each of the P4-regulated miRNAs was carried out to identify targets of these miRNAs. Excluding off target effects, mir-340-5p mimic altered 1,369 proteins while inhibition changed expression of 376 proteins (p < 0.05) of which, 72 were common to both treatments. A total of 280 proteins were identified between predicted (mirDB) and confirmed (in vitro) targets. In total, 171 proteins predicted to be targets by mirDB were altered in vitro by treatment with miR-340-5p mimic or inhibitor and were also altered by treatment of endometrial epithelial cells with P4. In vitro targets of miR-542-3p identified 1,378 proteins altered by mimic while inhibition altered 975 a core of 200 proteins were changed by both. 100 protein targets were predicted and only 46 proteins were P4 regulated. miR-671-mimic altered 1,252 proteins with inhibition changing 492 proteins of which 97 were common to both, 95 were miDB predicted targets and 46 were also P4-regulated. All miRNAs were detected in endometrial biopsies taken from patients during the luteal phase of their cycle, irrespective of prior or future pregnancy outcomes Expression of mir-340-5p showed an overall increase in patients who had previously suffered a miscarriage and had a subsequent miscarriage, as compared to those who had infertility or previous miscarriage and subsequently went on to have a life birth outcome. The regulation of these miRNAs and their protein targets regulate the function of transport and secretion, and adhesion of the endometrial epithelia required for successful implantation in humans. Dysfunction of these miRNAs (and therefore the targets they regulate) may contribute to endometrial-derived recurrent pregnancy loss in women.

cell biology↗

bioRxiv2022

Caecilian genomes reveal molecular basis of adaptation and convergent evolution of limblessness in snakes and caecilians.

We present genome sequences for the caecilians Geotrypetes seraphini (3.8Gb) and Microcaecilia unicolor (4.7Gb), representatives of a limbless, mostly soil-dwelling amphibian clade with reduced eyes, and unique putatively chemosensory tentacles. More than 69% of both genomes are composed of repeats, with retrotransposons the most abundant. We identify 1,150 orthogroups which are unique to caecilians and enriched for functions in olfaction and detection of chemical signals. There are 379 orthogroups with signatures of positive selection on caecilian lineages with roles in organ development and morphogenesis, sensory perception and immunity amongst others. We discover that caecilian genomes are missing the ZRS enhancer of Sonic Hedgehog which is also mutated in snakes. In vivo deletions have shown ZRS is required for limb development in mice, thus revealing a shared molecular target implicated in the independent evolution of limblessness in snakes and caecilians.

evolutionary biology↗

bioRxiv2021

Enriching for orthologs increases support for Xenacoelomorpha and Ambulacraria sister relationship

Conflicting studies place a group of bilaterian invertebrates containing xenoturbellids and acoelomorphs, the Xenacoelomorpha, as either the primary emerging bilaterian phylum, or within Deuterostomia, sister to Ambulacraria. While their placement as sister to the rest of Bilateria supports relatively simple morphology in the ancestral bilaterian, their alternative placement within Deuterostomia suggests a morphologically complex ancestral Bilaterian along with extensive loss of major phenotypic traits in the Xenacoelomorpha. More recently, further studies have brought into question whether Deuterostomia should be considered monophyletic at all. Hidden paralogy presents a major challenge for reconstructing species phylogenies. Here we assess whether hidden paralogy has contributed to the conflict over the placement of Xenacoelomorpha. Our approach assesses previously published datasets, enriching for orthogroups whose gene trees support well resolved clans elsewhere in the animal tree of life. We find that the majority of constituent genes in previously published datasets violate incontestable clans, suggesting that hidden paralogy is rife at this depth. We demonstrate that enrichment for genes with orthologous signal alters the final topology that is inferred, whilst simultaneously improving fit of the model to the data. We discover increased, but ultimately not conclusive, support for the existence of Xenambulacraria in our orthology enriched set of genes. At a time when we are steadily progressing towards sequencing all of life on the planet, we argue that long-standing contentious issues in the tree of life will be resolved using smaller amounts of better quality data that can be modelled adequately.

evolutionary biology↗

bioRxiv2021

An ancestral burst of regulatory and protein innovation drives divergent implantation in eutherian mammals.

Summary paragraphThe origin of live birth in mammals [~]148 million years ago was a dramatic shift in reproductive strategy, yet the molecular changes that established mammal viviparity are largely unknown. Although progesterone receptor signalling predates the origin of mammals andis highly conserved in, and critical for, successful mammal pregnancy, it alone cannot explain the origin and subsequent diversity of implantation strategies throughout the placental mammal radiation. MiRNAs are known to be flexible and dynamic regulators with a well established role in the pathophysiology of mammal placenta. We propose that a dynamic core microRNA (miRNA) network originated early in placental mammal evolution, responds to conserved mammal pregnancy cues (e.g. progesterone), and facilitates species-specific responses. Here we identify 13 miRNAs that arose at the origin of placental mammals and were subsequently retained in all descendent lineages. The expression of these 13 miRNAs in response to early pregnancy molecules is regulated in a species-specific manner in endometrial epithelia of species with extremes of implantation strategies. Furthermore, these 13 miRNAs preferentially target 84 proteins under positive selective pressure on ancestral eutherian. Discovery of this core "live-birth" toolkit and specifically adapted proteins helps explain the origin and evolution of the placenta in mammals.

evolutionary biology↗

bioRxiv2020

LncRNAs interacting with the translation machinery contribute to human neuronal differentiation.

LncRNAs are less conserved, yet more tissue and developmental-stage specific than mRNAs and are particularly enriched in the nervous system of Drosophila melanogaster, mouse and human. The function of cytoplasmic lncRNAs and their potential translation remains poorly understood. Here we performed Poly-Ribo-Seq to understand the interaction of lncRNAs with the translation machinery and the functional consequences during neuronal differentiation of SH-SH5Y cells. We discovered 237 cytoplasmic lncRNAs upregulated during early neuronal differentiation, most of which are associated with polysome complexes. The majority are cytoplasmically enriched and are intergenic or anti-sense. In addition, we find 45 small ORFs in lncRNAs to be actively translated, 17 specifically upon differentiation. 11 of these smORFs exhibit high sequence conservation across Hominidae suggesting they are under strong selective constraint with putative function in this clade. We discover LINC01116 is induced upon differentiation and contains an 87 codon smORF, which we detect as translated, with increased ribosome profiling signal upon differentiation. The LINC01116 peptide exhibits a cytoplasmic distribution and is detected in neurites. Knockdown of LINC01116 results in significant reduction of neurite length in differentiated cells indicating it contributes to neuronal differentiation. Our findings indicate lncRNAs are a source of non-canonical peptides and contribute to neuronal function.

molecular biology↗