Widespread loss of mammalian lineage and dietary diversity in the early Oligocene of Afro-Arabia

Diverse lines of geological and geochemical evidence indicate that the Eocene-Oligocene transition (EOT) marked the onset of a global cooling phase, rapid growth of the Antarctic ice sheet, and a worldwide drop in sea level. Paleontologists have established that shifts in mammalian community structure in Europe and Asia were broadly coincident with these events, but the potential impact of early Oligocene climate change on the mammalian communities of Afro-Arabia has long been unclear. Here we employ dated phylogenies of multiple endemic Afro-Arabian mammal clades (anomaluroid and hystricognath rodents, anthropoid and strepsirrhine primates, and carnivorous hyaenodonts) to investigate lineage diversification and loss since the early Eocene. These analyses provide evidence for widespread mammalian extinction in the early Oligocene of Afro-Arabia, with almost two-thirds of peak late Eocene diversity lost in these clades by ~30 Ma. Using homology-free dental topographic metrics, we further demonstrate that the loss of Afro-Arabian rodent and primate lineages was associated with a major reduction in molar occlusal topographic disparity, suggesting a correlated loss of dietary diversity. These results raise new questions about the relative importance of global versus local influences in shaping the evolutionary trajectories of Afro-Arabia’s endemic mammals during the Oligocene.

Evolution, Expression and Meiotic Behavior of Genes Involved in Chromosome Segregation of Monotremes

Chromosome segregation at mitosis and meiosis is a highly dynamic and tightly regulated process that involves a large number of components. Due to the fundamental nature of chromosome segregation, many genes involved in this process are evolutionarily highly conserved, but duplications and functional diversification has occurred in various lineages. In order to better understand the evolution of genes involved in chromosome segregation in mammals, we analyzed some of the key components in the basal mammalian lineage of egg-laying mammals. The chromosome passenger complex is a multiprotein complex central to chromosome segregation during both mitosis and meiosis. It consists of survivin, borealin, inner centromere protein, and Aurora kinase B or C. We confirm the absence of Aurora kinase C in marsupials and show its absence in both platypus and echidna, which supports the current model of the evolution of Aurora kinases. High expression of AURKBC, an ancestor of AURKB and AURKC present in monotremes, suggests that this gene is performing all necessary meiotic functions in monotremes. Other genes of the chromosome passenger complex complex are present and conserved in monotremes, suggesting that their function has been preserved in mammals. Cohesins are another family of genes that are of vital importance for chromosome cohesion and segregation at mitosis and meiosis. Previous work has demonstrated an accumulation and differential loading of structural maintenance of chromosomes 3 (SMC3) on the platypus sex chromosome complex at meiotic prophase I. We investigated if a similar accumulation occurs in the echidna during meiosis I. In contrast to platypus, SMC3 was only found on the synaptonemal complex in echidna. This indicates that the specific distribution of SMC3 on the sex chromosome complex may have evolved specifically in platypus.

Patterns and tempo of PCSK9 pseudogenizations suggest an ancient divergence in mammalian cholesterol homeostasis mechanisms

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a central role in cholesterol homeostasis in humans as a major regulator of LDLR levels. PCSK9 is an intriguing protease in that it does not act by proteolysis but by preventing LDLR recirculation from endosomes to the plasma membrane. This, and the inexistence of any other proteolytic substrate but itself could suggest that PCSK9 is an exquisite example of evolutionary fine-tuning. However, the gene has been lost in several mammalian species, and null alleles are present (albeit at low frequencies) in some human populations without apparently deleterious health effects, raising the possibility that the PCSK9 may have become dispensable in the mammalian lineage. To address this issue, we systematically recovered, assembled, corrected, annotated and analysed publicly available PCSK9 sequences for 420 eutherian species to determine the distribution, frequencies, mechanisms and timing of PCSK9 pseudogenization events, as well as the evolutionary pressures underlying the preservation or loss of the gene. We found a dramatic difference in the patterns of PCSK9 retention and loss between Euarchontoglires—where there is strong pressure for gene preservation—and Laurasiatheria, where multiple independent events have led to PCSK9 loss in most species. These results suggest that there is a fundamental difference in the regulation of cholesterol metabolism between Euarchontoglires and Laurasiatheria, which in turn has important implications for the use of Laurasiatheria species (e.g. pigs) as animal models of human cholesterol-related diseases.

HOX13-MEDIATED DBX2 REGULATION IN LIMBS SUGGESTS INTER-TAD SHARING OF ENHANCERS

ABSTRACTBackgroundDuring tetrapod limb development, the HOXA13 and HOXD13 transcription factors are critical for the emergence and organization of the autopod, the most distal aspect where digits will develop. Since previous work had suggested that the Dbx2 gene is a target of these factors, we set up to analyze in detail this potential regulatory interaction.ResultsWe show that HOX13 proteins bind to eutherian-specific sequences at the vicinity of the Dbx2 locus that have enhancer activity in developing digits. However, the functional inactivation of the DBX2 protein did not elicit any particular phenotype related to Hox genes inactivation in digits, suggesting either redundant or compensatory mechanisms. We report that the neighboring Nell2 and Ano6 genes are also expressed in distal limb buds and are, in part, controlled by the same Dbx2 enhancers despite being localized into two different topologically associating domains (TADs) flanking the Dbx2 locus.ConclusionsWe conclude that Hoxa13 and Hoxd genes cooperatively activate Dbx2 expression in developing digits through binding to eutherian specific regulators elements in the Dbx2 neighborhood. Furthermore, these enhancers can overcome TAD boundaries in either direction to co-regulate a set of genes located in distinct chromatin domains.Bullet pointsHoxa13 and Hoxd genes cooperatively regulate Dbx2 expression in developing digits via eutherian specific enhancers.Dbx2 is expressed in different digit joint precursors but its function there is not essential.Dbx2 enhancers also control the expression of the Nell2 and Ano6 genes, which are located in different TADs, thus overcoming the boundary effect.Dbx2 chromatin architecture and enhancers evolved in the mammalian lineage.Grant Sponsor and NumberSwiss National Research Foundation #310030B_138662.European Research Council grants RegulHox #588029

A Pig White Matter Atlas and Common Connectivity Space Provide a Roadmap for the Introduction of a New Animal Model in Translational Neuroscience

The characterization and definition of homology in the cerebral cortex needed for a species to be adopted as a translational model in neuroscience is a unique challenge given the diverse array of cortical morphology present in the mammalian lineage. Using the domestic pig as an example, we provide a roadmap of how leveraging Magnetic Resonance Imaging of the brain and data-driven tractography can overcome these obstacles and facilitate cortical alignment between distantly related species. In doing so, we created a full platform of neuroimaging tools to be used in the pig, including volumetric and surface templates, a structural white matter atlas, and the establishment of a common connectivity space to facilitate pig-human cortical alignment. Releasing our data and code and our pig-human cortical alignment, we permit researchers already working with the pig to accentuate the clinical relevance and translational capacity of their work. By sharing the intermediate outputs and scripts used to construct our pig-human cortical alignment, we also provide a roadmap to expand the current repertoire of animal models used in neuroscience.

Possible changes in fidelity of DNA polymerase δ in ancestral mammals

DNA polymerase δ (polδ) is one of the major DNA polymerases that replicate chromosomal genomes in eukaryotes. Given the essential role of this protein, its phylogenetic tree was expected to reflect the relationship between taxa, like many other essential proteins. However, the tree of the catalytic subunit of polδ showed an unexpectedly strong heterogeneity among vertebrate lineages in evolutionary rate at the amino acid level, suggesting unusual amino acid substitutions specifically in the ancestral mammalian lineage. Structural and phylogenetic analyses were used to pinpoint where and when these amino acid substitutions occurred: around the 3′-5′ exonuclease domain in later mammal ancestry, after the split between monotremes and therians. The 3′-5′ exonuclease domain of this protein is known to have an impact on the fidelity of replication. Based on these observations, we explored the possibility that the amino acid substitutions we identified in polδ affected the mutation rate of entire chromosomal genomes in this time period.

A Pig White Matter Atlas and Common Connectivity Space Provide a Roadmap for the Introduction of a New Animal Model in Translational Neuroscience

The characterization and definition of homology in the cerebral cortex needed for a species to be adopted as a translational model in neuroscience is a unique challenge given the diverse array of cortical morphology present in the mammalian lineage. Using the domestic pig as an example, we provide a roadmap of how leveraging Magnetic Resonance Imaging of the brain and data-driven tractography can overcome these obstacles and facilitate cortical alignment between distantly related species. In doing so, we created a full platform of neuroimaging tools to be used in the pig, including volumetric and surface templates, a structural white matter atlas, and the establishment of a common connectivity space to facilitate pig-human cortical alignment. Releasing our data and code and our pig-human cortical alignment, we permit researchers already working with the pig to accentuate the clinical relevance and translational capacity of their work. By sharing the intermediate outputs and scripts used to construct our pig-human cortical alignment, we also provide a roadmap to expand the current repertoire of animal models used in neuroscience.

A parapithecid stem anthropoid of African origin in the Paleogene of South America

Phylogenetic evidence suggests that platyrrhine (or New World) monkeys and caviomorph rodents of the Western Hemisphere derive from source groups from the Eocene of Afro-Arabia, a landmass that was ~1500 to 2000 kilometers east of South America during the late Paleogene. Here, we report evidence for a third mammalian lineage of African origin in the Paleogene of South America—a newly discovered genus and species of parapithecid anthropoid primate from Santa Rosa in Amazonian Perú. Bayesian clock–based phylogenetic analysis nests this genus (Ucayalipithecus) deep within the otherwise Afro-Arabian clade Parapithecoidea and indicates that transatlantic rafting of the lineage leading to Ucayalipithecus likely took place between ~35 and ~32 million years ago, a dispersal window that includes the major worldwide drop in sea level that occurred near the Eocene-Oligocene boundary.

Inference of Single-Cell Phylogenies from Lineage Tracing Data

The pairing of CRISPR/Cas9-based gene editing with massively parallel single-cell readouts now enables large-scale lineage tracing. However, the rapid growth in complexity of data from these assays has outpaced our ability to accurately infer phylogenetic relationships. To address this, we provide three resources. First, we introduce Cassiopeia - a suite of scalable and theoretically grounded maximum parsimony approaches for tree reconstruction. Second, we provide a simulation framework for evaluating algorithms and exploring lineage tracer design principles. Finally, we generate the most complex experimental lineage tracing dataset to date - consisting of 34,557 human cells continuously traced over 15 generations, 71% of which are uniquely marked - and use it for benchmarking phylogenetic inference approaches. We show that Cassiopeia outperforms traditional methods by several metrics and under a wide variety of parameter regimes, and provide insight into the principles for the design of improved Cas9-enabled recorders. Together these should broadly enable large-scale mammalian lineage tracing efforts. Cassiopeia and its benchmarking resources are publicly available at www.github.com/YosefLab/Cassiopeia.