Molecular dating of caprines using ancient DNA sequences of Myotragus balearicus, an extinct endemic Balearic mammal

Background: Myotragus balearicus was an endemic bovid from the Balearic Islands (Western Mediterranean) that became extinct around 6,000-4,000 years ago. The Myotragus evolutionary lineage became isolated in the islands most probably at the end of the Messinian crisis, when the desiccation of the Mediterranean ended, in a geological date established at 5.35 Mya. Thus, the sequences of Myotragus could be very valuable for calibrating the mammalian mitochondrial DNA clock and, in particular, the tree of the Caprinae subfamily, to which Myotragus belongs. Results: We have retrieved the complete mitochondrial cytochrome b gene (1,143 base pairs), plus fragments of the mitochondrial 12S gene and the nuclear 28S rDNA multi-copy gene from a well preserved Myotragus subfossil bone. The best resolved phylogenetic trees, obtained with the cytochrome b gene, placed Myotragus in a position basal to the Ovis group. Using the calibration provided by the isolation of Balearic Islands, we calculated that the initial radiation of caprines can be dated at 6.2 ± 0.4 Mya. In addition, alpine and southern chamois, considered until recently the same species, split around 1.6 ± 0.3 Mya, indicating that the two chamois species have been separated much longer than previously thought. Conclusion: Since there are almost no extant endemic mammals in Mediterranean islands, the sequence of the extinct Balearic endemic Myotragus has been crucial for allowing us to use the Messinian crisis calibration point for dating the caprines phylogenetic tree

Genetic diagnosis of autoinflammatory disease patients using clinical exome sequencing

Autoinflammatory diseases comprise a wide range of syndromes caused by dysregulation of the innate immune response. They are difficult to diagnose due to their phenotypic heterogeneity and variable expressivity. Thus, the genetic origin of the disease remains undetermined for an important proportion of patients. We aim to identify causal genetic variants in patients with suspected autoinflammatory disease and to test the advantages and limitations of the clinical exome gene panels for molecular diagnosis. Twenty-two unrelated patients with clinical features of autoinflammatory diseases were analyzed using clinical exome sequencing (~4800 genes), followed by bioinformatic analyses to detect likely pathogenic variants. By integrating genetic and clinical information, we found a likely causative heterozygous genetic variant in NFKBIA (p.D31N) in a North-African patient with a clinical picture resembling the deficiency of interleukin-1 receptor antagonist, and a heterozygous variant in DNASE2 (p.G322D) in a Spanish patient with a suspected lupus-like monogenic disorder. We also found variants likely to increase the susceptibility to autoinflammatory diseases in three additional Spanish patients: one with an initial diagnosis of juvenile idiopathic arthritis who carries two heterozygous UNC13D variants (p.R727Q and p.A59T), and two with early-onset inflammatory bowel disease harbouring NOD2 variants (p.L221R and p.A728V respectively). Our results show a similar proportion of molecular diagnosis to other studies using whole exome or targeted resequencing in primary immunodeficiencies. Thus, despite its main limitation of not including all candidate genes, clinical exome targeted sequencing can be an appropriate approach to detect likely causative variants in autoinflammatory diseases

Human Oocyte-derived Methylation Differences Persist In The Placenta Revealing Widespread Transient Imprinting

Thousands of regions in gametes have opposing methylation profiles that are largely resolved during the post-fertilization epigenetic reprogramming. However some specific sequences associated with imprinted loci survive this demethylation process. Here we present the data describing the fate of germline-derived methylation in humans. With the exception of a few known paternally methylated germline differentially methylated regions (DMRs) associated with known imprinted domains, we demonstrate that sperm-derived methylation is reprogrammed by the blastocyst stage of development. In contrast a large number of oocyte-derived methylation differences survive to the blastocyst stage and uniquely persist as transiently methylated DMRs only in the placenta. Furthermore, we demonstrate that this phenomenon is exclusive to primates, since no placenta-specific maternal methylation was observed in mouse. Utilizing single cell RNA-seq datasets from human preimplantation embryos we show that following embryonic genome activation the maternally methylated transient DMRs can orchestrate imprinted expression. However despite showing widespread imprinted expression of genes in placenta, allele-specific transcriptional profiling revealed that not all placenta-specific DMRs coordinate imprinted expression and that this maternal methylation may be absent in a minority of samples, suggestive of polymorphic imprinted methylation

The era of reference genomes in conservation genomics

Progress in genome sequencing now enables the large-scale generation of reference genomes. Various international initiatives aim to generate reference genomes representing global biodiversity. These genomes provide unique insights into genomic diversity and architecture, thereby enabling comprehensive analyses of population and functional genomics, and are expected to revolutionize conservation genomics

On the association between chromosomal rearragements and genic evolution in mammals

The main objectives of this work are:a) To test the predictions of suppressed-recombination chromosomal speciation models on two different lineages of mammals: rodents and rimates. Suppressed-recombination chromosomal speciation is still quite elusive as a mode of speciation in mammals. Experimental results are scarce and the first objective of this work is to analyze whole-genome data looking for traces of events of chromosomal speciation. Rodent and primate lineages were chosen for this search, not just because of their particular biological and cytological characteristics, which make them good candidates to have speciated by this mechanism, but also because they were the first mammalian organisms to be fully sequenced. b) To study the effects of chromosomal rearrangements on genic evolutionary rates. As have been seen in the introduction, there are many of potential interactions among chromosomal rearrangements and evolutionary rates, so the second goal of this work was to try to understand the impact of chromosomal rearrangements over substitution rates by means of other mechanisms not related with speciation. c) To distinguish individual contributions of different genomic factors in the potential association among chromosomal rearrangements and evolutionary rates.The third main goal of this thesis was to discern among the different factors that could be explaining the many associations between chromosomal and genic evolution that were detected in different studies

The molecular evolution of spermatogenesis across mammals

The testis produces gametes through spermatogenesis and evolves rapidly at both the morphological and molecular level in mammals1-6, probably owing to the evolutionary pressure on males to be reproductively successful7. However, the molecular evolution of individual spermatogenic cell types across mammals remains largely uncharacterized. Here we report evolutionary analyses of single-nucleus transcriptome data for testes from 11 species that cover the three main mammalian lineages (eutherians, marsupials and monotremes) and birds (the evolutionary outgroup), and include seven primates. We find that the rapid evolution of the testis was driven by accelerated fixation rates of gene expression changes, amino acid substitutions and new genes in late spermatogenic stages, probably facilitated by reduced pleiotropic constraints, haploid selection and transcriptionally permissive chromatin. We identify temporal expression changes of individual genes across species and conserved expression programs controlling ancestral spermatogenic processes. Genes predominantly expressed in spermatogonia (germ cells fuelling spermatogenesis) and Sertoli (somatic support) cells accumulated on X chromosomes during evolution, presumably owing to male-beneficial selective forces. Further work identified transcriptomal differences between X- and Y-bearing spermatids and uncovered that meiotic sex-chromosome inactivation (MSCI) also occurs in monotremes and hence is common to mammalian sex-chromosome systems. Thus, the mechanism of meiotic silencing of unsynapsed chromatin, which underlies MSCI, is an ancestral mammalian feature. Our study illuminates the molecular evolution of spermatogenesis and associated selective forces, and provides a resource for investigating the biology of the testis across mammals.We thank all members of the Kaessmann group, S. Tirier for discussions and N. Trost for the administration of the Kaessmann laboratory server. Computations were performed on the Kaessmann laboratory server and the bwForCluster from the Heidelberg University Computational Center (supported by the state of Baden-Württemberg through bwHPC and the German Research Foundation grant no. INST 35/1134-1 FUGG). This research was supported by grants from the ERC (grant no. 615253, OntoTransEvol) and German Research Council (DFG, grant nos. SFB 873 and KA 1710/4-1) to H.K., by the CellNetworks Postdoc Fellowship and EMBO Long-Term Fellowship to F.M. (grant no. ALTF 591-2017), and by the Australian Research Council (grant no. FT160100267) to F.G. and by the Novo Nordisk Foundation (grant no. NNF21OC0069913) to K.A. and (grant no. NNF18OC0031004) to M.H.S. The use of all other mammalian samples for the type of work described in this study was approved by ERC ethics screening panels (ERC starting grant no. 242597, SexGenTransEvolution and ERC consolidator grant no. 615253, OntoTransEvol)

Ghost admixture in eastern gorillas

Archaic admixture has had a substantial impact on human evolution with multiple events across different clades, including from extinct hominins such as Neanderthals and Denisovans into modern humans. In great apes, archaic admixture has been identified in chimpanzees and bonobos but the possibility of such events has not been explored in other species. Here, we address this question using high-coverage whole-genome sequences from all four extant gorilla subspecies, including six newly sequenced eastern gorillas from previously unsampled geographic regions. Using approximate Bayesian computation with neural networks to model the demographic history of gorillas, we find a signature of admixture from an archaic 'ghost' lineage into the common ancestor of eastern gorillas but not western gorillas. We infer that up to 3% of the genome of these individuals is introgressed from an archaic lineage that diverged more than 3 million years ago from the common ancestor of all extant gorillas. This introgression event took place before the split of mountain and eastern lowland gorillas, probably more than 40 thousand years ago and may have influenced perception of bitter taste in eastern gorillas. When comparing the introgression landscapes of gorillas, humans and bonobos, we find a consistent depletion of introgressed fragments on the X chromosome across these species. However, depletion in protein-coding content is not detectable in eastern gorillas, possibly as a consequence of stronger genetic drift in this species.This project has been funded by the Vienna Science and Technology Fund (WWTF) (grant no. 10.47379/VRG20001) to M.K. and the European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant no. 864203), PID2021-126004NB-100 (MINECO/FEDER, UE), Secretaria d’Universitats i Recerca and CERCA Program del Departament d’Economia i Coneixement de la Generalitat de Catalunya (GRC 2021 SGR 00177) to T.M.-B. H.P. was supported by a Formació de Personal Investigador fellowship from Generalitat de Catalunya (FI_B100131). M.A.-E. was supported by a Formación de Personal Investigador PRE2018-083966 from Ministerio de Ciencia, Universidades e Investigación. C.T.-S., Y.X. and J.P.-M. were funded by Wellcome grant no. 098051. K.G. was supported by Swedish Research Council grant no. 2020-03398. J.L.K. received the María de Maeztu Mobility Fellowship. O.D. was supported by a John Templeton Foundation grant no. ID 62178. A.M.A. received funding from UCL’s Wellcome Trust ISSF3 award no. 204841/Z/16/Z. Q.A. is supported by strategic funding from Monash University (STG-000114)

Genetic history of an archaic hominin group from Denisova Cave in Siberia

Using DNA extracted from a finger bone found in Denisova Cave in southern Siberia, we have sequenced the genome of an archaic hominin to about 1.9-fold coverage. This individual is from a group that shares a common origin with Neanderthals. This population was not involved in the putative gene flow from Neanderthals into Eurasians; however, the data suggest that it contributed 4-6% of its genetic material to the genomes of present-day Melanesians. We designate this hominin population 'Denisovans' and suggest that it may have been widespread in Asia during the Late Pleistocene epoch. A tooth found in Denisova Cave carries a mitochondrial genome highly similar to that of the finger bone. This tooth shares no derived morphological features with Neanderthals or modern humans, further indicating that Denisovans have an evolutionary history distinct from Neanderthals and modern humans.The Presidential Innovation Fund of the Max Planck Society and the Krekeler Foundation provided financial support. M.S. was supported by a US National Institutes of Health grant (R01-GM40282). The National Science Foundation provided an International Postdoctoral Fellowship (OISE-0754461) to J.M.G., a Fellowship in Biological Informatics to P.L.F.J. and a HOMINID grant (1032255) to D.R

Geometric morphometrics and paleoproteomics enlighten the paleodiversity of Pongo

Pleistocene Pongo teeth show substantial variation in size and morphology, fueling taxonomic debates about the paleodiversity of the genus. We investigated prominent features of the enamel-dentine-junction junction (EDJ)-phylogenetically informative internal structures-of 71 fossil Pongo lower molars from various sites by applying geometric morphometrics and conducted paleoproteomic analyses from enamel proteins to attempt to identify extinct orangutan species. Forty-three orangutan lower molars representing Pongo pygmaeus and Pongo abelii were included for comparison. The shape of the EDJ was analyzed by placing five landmarks on the tip of the main dentine horns, and 142 semilandmarks along the marginal ridges connecting the dentine horns. Paleoproteomic analyses were conducted on 15 teeth of Late Pleistocene Pongo using high-resolution tandem mass spectrometry. The geometric morphometric results show variations in EDJ shape regarding aspects of the height and position of the dentine horns and connecting ridges. Despite the issue of molar position and sample size, modern molars are distinguished from fossil counterparts by their elongated tooth outline and narrowly positioned dentine horns. Proteomic results show that neither a distinction of P. pygmaeus and P. abelii, nor a consistent allocation of fossil specimens to extant species is feasible. Based on the EDJ shape, the (late) Middle to Late Pleistocene Pongo samples from Vietnam share the same morphospace, supporting the previous allocation to P. devosi, although substantial overlap with Chinese fossils could also indicate close affinities with P. weidenreichi. The hypothesis that both species represent one chronospecies cannot be ruled out. Two fossil specimens, one from Tam Hay Marklot (Laos, Late Pleistocene), and another from Sangiran (Java, Early to Middle Pleistocene), along with some specimens within the Punung sample (Java), exhibit affinities with Pongo abelii. The Punung fossils might represent a mix of early Late Pleistocene and later specimens (terminal Pleistocene to Holocene) related to modern Pongo. The taxonomy and phylogeny of the complete Punung sample needs to be further investigated.Funded by the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie (https://marie-sklodowska-curieactions.ec.europa.eu/) grant agreement No. 861389 (JK, RP, IP,TMB,EC,FD,CZ,AMB). EC, FD, MM, CZ and AMB are supported by the European Union's Horizon 2020 research and innovation programme under grant agreement No. 101021361. Scanning of Vietnamese fossil specimens was funded by the CNRS (https://www.cnrs.fr/fr) grant PICS n°5712 (AMB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript