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bioRxiv2018

Linking the International Wheat Genome Sequencing Consortium bread wheat reference genome sequence to wheat genetic and phenomic data

The Wheat@URGI portal (https://wheat-urgi.versailles.inra.fr) has been developed to provide the international community of researchers and breeders with access to the bread wheat reference genome sequence produced by the International Wheat Genome Sequencing Consortium. Genome browsers, BLAST, and InterMine tools have been established for in depth exploration of the genome sequence together with additional linked datasets including physical maps, sequence variations, gene expression, and genetic and phenomic data from other international collaborative projects already stored in the GnpIS information system. The portal provides enhanced search and browser features that will facilitate the deployment of the latest genomics resources in wheat improvement.

bioinformatics↗

bioRxiv2018

Phenogenon: Gene to Phenotype Associations for Rare Genetic Diseases

As genome sequencing is increasingly applied to molecular diagnosis of rare Mendelian disorders, large number of patients with diverse phenotypes have their genomic and phenotypic data pooled together to uncover new genotype - phenotype relations. We introduce Phenogenon, a method that combines: the power of Human Phenotype Ontology for describing patient phenotypes, gnomAD for estimating rare variant population frequency, and CADD for variant pathogenicity prediction. By using a divide and conquer approach, we demonstrate here that Phenogenon is able to uncover true gene to phenotype relations, such as \"ABCA4 - Macular dystrophy\" and \"SCN1A - Seizures\". Additionally, it accurately infers mode of inheritance, such as a recessive mode of inheritance in the case of the \"ABCA4 - Macular dystrophy\" relationship and a dominant mode of inheritance with the \"SCN1A - Seizures\" relationship. We also found that CADD has more power to detect early-onset rare genetic diseases than late-onset diseases. In this study, we ran Phenogenon against a diverse cohort of 3288 patients. Among the top 13 gene-phenotype relations, seven were previously known. We also highlight four potentially novel gene - phenotype relations such as \"SIPA1L3 - Abnormal electroretinogram\".

bioinformatics↗

bioRxiv2018

Skull base invasive low-grade meningiomas, a distinct genetic subgroup: A microarray gene expression profile analysis.

IntroductionMeningioma is the most common adult primary brain tumor originating from meningeal coverings of the brain and spinal cord. Commonly, World Health Organization (WHO) grade-I meningiomas are slowly growing and surgically curative, some present with clinically aggressive behavior, invading the skull base bone and soft tissues by extending into the extracranial spaces.\n\nMethodsTo detect the genetic background of the Skull Base Invasive Low-grade Meningioma (SBILM), we conducted a comprehensive analysis of gene expression was conducted on 32 meningioma samples.\n\nResultsThe cluster analysis of the gene expression profile demonstrated a distinctive clustering pattern of the SBILM. Based on the clinical behavior and the microarray findings, they might be a distinct subgroup of meningiomas.\n\nConclusionFurther studies on characterization of genes specifically expressed by the SBILM could lead to the development of diagnostic tools, differentiating it from other WHO grade-I meningiomas and assist in the appropriate management and follow-up strategy, and open the door for development of pharmacological therapies.

genomics↗

bioRxiv2018

Structural determinants and genetic modifications enhance BMP2 stability and extracellular secretion

The short half-life and use of recombinant bone morphogentic protein (BMP)-2 in large doses poses major limitations in the clinic. Events regulating post-translational processing and degradation of BMP2 in situ, linked to its secretion, have not been understood. Towards identifying mechanisms regulating intracellular BMP2 stability, we first discovered that inhibiting proteasomal degradation enhances both intracellular BMP2 level and its extracellular secretion. Next, we identified BMP2 degradation occurs through an ubiquitin-mediated mechanism. Since ubiquitination precedes proteasomal turnover and mainly occurs on lysine residues of nascent proteins, we systematically mutated individual lysine residues within BMP2 and tested them for enhanced stability. Results revealed that substitutions on four lysine residues within the pro-BMP2 region and three in the mature region increased both BMP2 turnover and extracellular secretion. Structural modeling revealed key lysine residues involved in proteasomal degradation occupy a lysine cluster near proprotein convertase cleavage site. Interestingly, mutations within these residues did not affect biological activity of BMP2. These data suggest preventing intracellular proteasomal loss of BMP2 through genetic modifications can overcome limitations related to its short half-life.

cell biology↗

bioRxiv2018

Extreme genetic structure and dynamic range evolution in a montane passerine bird: implications for tropical diversification

AimEmploy phylogeographic analyses of a widespread species complex to examine the role of historical and evolutionary processes in the origin and maintenance of high species diversity in the Neotropical montane region.\n\nLocationNeotropical highlands.\n\nTaxonHenicorhina wood-wrens (Aves, Troglodytidae).\n\nMethodsWe collected mtDNA sequence data for 288 individuals thoroughly covering the range of the Henicorhina leucophrys complex from Mexico to Bolivia. Sequences were employed to characterize population structure, infer phylogenetic relationships among populations and their divergence times, examine lineage accumulation through time, and identify presumptive species using coalescent methods. We also explored the origin of elevational and latitudinal replacements involved in spatial changes in species assemblages in the Andes.\n\nResultsWe found remarkable genetic structure within the complex, which consists of numerous lineages reaching >12% sequence divergence; most divergent populations occur in areas separated by topographic barriers but several of them, typically not sister to each other, co-occur with elevational segregation on mountain slopes or replace each other with latitude along the Andes. Some close relatives occur in areas separated by thousands of kilometers, with more distant relatives occupying intervening areas. The complex likely originated in the Mexican highlands and expanded extensively in South America while diverging rapidly at a constant rate into many different lineages which have persisted for millions of years. Coalescent analyses consistently revealed that the complex may comprise more than 30 species; while we do not suggest these presumptive species should be recognized by taxonomists in the absence of additional data, H. leucophrys is a distant outlier among New World birds in terms of high lineage diversity within a single recognized species.\n\nMain ConclusionsOur study captured wood-wren lineages in the act of building up diversity via divergence and persistence in allopatry, achievement of secondary sympatry, and coexistence at the landscape scale mediated by ecological and evolutionary divergence. Although dispersal by wood-wrens is restricted at present and this likely accounts for strong population structure across topographic barriers, their ranges have been dynamic, managing to disperse over much of the montane Neotropics. Phases of expansion and contraction of ranges and localized extinctions of populations likely account for phylogeographic patterns which are precursors to the origin of new species and the accumulation of diversity in tropical mountains.

evolutionary biology↗

bioRxiv2018

Tbx1 and Foxi3 genetically interact in the third pharyngeal pouch endoderm required for thymus and parathyroid development

The mechanisms required for segmentation of the pharyngeal apparatus to individual arches are not precisely delineated in mammalian species. Here, using conditional mutagenesis, we found that two transcription factor genes, Tbx1, the gene for 22q11.2 deletion syndrome and Foxi3, genetically interact in the third pharyngeal pouch endoderm for thymus and parathyroid gland development. We found that Tbx1 is autonomously required for the endoderm to form a temporary multilayered epithelium while invaginating. E-cadherin for adherens junctions remains expressed and cells in the apical boundary express ZO-1. Foxi3 is required autonomously to modulate proliferation and promote later restoration of the endoderm to a monolayer once the epithelia meet after invagination. Completion of this process cooccurs with expression of Alcam needed to stabilize adherens junctions and extracellular, Fibronectin. These processes are required in the third pharyngeal pouch to form the thymus and parathyroid glands, disrupted in 22q11.2 deletion syndrome patients.

developmental biology↗

bioRxiv2018

Monarch butterfly and milkweed declines substantially predate the use of genetically modified crops

Monarch butterfly (Danaus plexippus) decline over the past 25 years has received considerable public and scientific attention, in large part because its decline, and that of its milkweed (Asclepias spp.) host plant, have been linked to genetically modified (GM) crops and the associated herbicide use. Therefore, the monarch has emerged as a poster child for the anti-GM movement. Here we use museum and herbaria specimens to extend our knowledge of the dynamics of both monarchs and milkweeds in the United States to more than a century, from 1900-2016. We show that monarch population trends closely follow those of their milkweed hosts; that both monarchs and milkweeds increased during the early 20th century, and that recent declines are actually part of a much longer term decline in both monarchs and milkweed beginning around 1950. Herbicide resistant crops, therefore, are clearly not the only culprit, and likely not even the primary culprit, as these declines began decades before GM crops were introduced.

ecology↗

bioRxiv2018

Need for high-resolution Genetic Analysis in iPSC: Results and Lessons from the ForIPS Consortium

Genetic integrity of induced pluripotent stem cells (iPSCs) is essential for their validity as disease models and for potential therapeutic use. We describe the comprehensive analysis in the ForIPS consortium: an iPSC collection from donors with neurological diseases and healthy controls. Characterization included pluripotency confirmation, fingerprinting, conventional and molecular karyotyping in all lines. In the majority, somatic copy number variants (CNVs) were identified. A subset with available matched donor DNA was selected for comparative exome sequencing. We identified single nucleotide variants (SNVs) at different allelic frequencies in each clone with high variability in mutational load. Low frequencies of variants in parental fibroblasts highlight the importance of germline samples. Somatic variant number was independent from reprogramming, cell type and passage. Comparison with disease genes and prediction scores suggest biological relevance for some variants. We show that high-throughput sequencing has value beyond SNV detection and the requirement to individually evaluate each clone.

genomics↗

bioRxiv2018

Clownfishes are a genetic model of exceptional longevity and reveal molecular convergence in the evolution of lifespan

Standard evolutionary theories of aging postulate that reduced extrinsic mortality leads to evolution of longevity. Clownfishes of the genus Amphiprion live in a symbiotic relationship with sea anemones that provide protection from predation. We performed a survey and identified at least two species with lifespan of over 20 years. Given their small size and ease of captive reproduction, clownfishes lend themselves as experimental models of exceptional longevity.\n\nTo identify genetic correlates of exceptional longevity, we sequenced the transcriptomes of Amphiprion percula and A. clarkii and performed a scan for positively-selected genes (PSGs). These were compared with PSGs detected in long-lived mole rats and short-lived killifishes revealing convergent evolution in processes such as mitochondrial biogenesis. Among individual genes, the Mitochondrial Transcription Termination Factor 1 (MTERF1), was positively-selected in all three clades, whereas the Glutathione S-Transferase Kappa 1 (GSTK1) was under positive selection in two independent clades. For the latter, homology modelling strongly suggested that positive selection targeted enzymatically important residues.\n\nThese results indicate that specific pathways were recruited in independent lineages evolving an exceptionally extended or shortened lifespan and point to mito-nuclear balance as a key factor.

evolutionary biology↗

bioRxiv2018

Competition between mobile genetic elements drives optimization of a phage-encoded CRISPR-Cas system: Insights from a natural arms-race

CRISPR-Cas systems function as adaptive immune systems by acquiring nucleotide sequences called spacers that mediate sequence-specific defense against competitors. Uniquely, the phage ICP1 encodes a Type I-F CRISPR-Cas system that is deployed to target and overcome PLE, a mobile genetic element with anti-phage activity in Vibrio cholerae. Here, we exploit the arms race between ICP1 and PLE to examine spacer acquisition and interference under laboratory conditions to reconcile findings from wild populations. Natural ICP1 isolates encode multiple spacers directed against PLE, but we find that single spacers do not equally interfere with PLE mobilization. High-throughput sequencing to assay spacer acquisition reveals that ICP1 can also acquire spacers that target the V. cholerae chromosome. We find that targeting the V. cholerae chromosome proximal to PLE is sufficient to block PLE and propose a model in which indirect chromosomal spacers are able to circumvent PLE by Cas2-3-mediated processive degradation of the V. cholerae chromosome before PLE mobilization. Generally, laboratory acquired spacers are much more diverse than the subset of spacers maintained by ICP1 in nature, showing how evolutionary pressures can constrain CRISPR-Cas targeting in ways that are often not appreciated through in vitro analyses.

microbiology↗

bioRxiv2018

The fitness consequences of genetic variation in wild populations of mice

Adaptive evolution can occur when genetic change affects traits subject to natural selection. Although selection is a deterministic process, adaptation can be difficult to predict in finite populations because the functional connections between genotype, phenotype, and fitness are complex. Here, we make these connections using a combination of field and laboratory experiments. We conduct a large-scale manipulative field experiment with wild populations of deer mice in distinct habitats to directly estimate natural selection on pigmentation traits and next test whether this selection drives changes in allele frequency at an underlying pigment locus. We find that divergent cryptic phenotypes are repeatedly favoured in each habitat, leaving footprints of selection in the Agouti gene. Next, using transgenic experiments in Mus, we functionally test one of the Agouti mutations associated with survival, a Serine deletion in exon 2, and find that it causes lighter coat colour via changes in its protein binding properties. Finally, we show significant change in the frequency of this mutation in our field experiment. Together, our findings demonstrate how a sequence variant alters phenotype and show the ensuing ecological consequences that drive changes in population allele frequency, thereby revealing the full process of evolution by natural selection.

evolutionary biology↗

bioRxiv2018

Genetic draft and valley crossing

Living systems are characterized by complex adaptations which require multiple coordinated mutations in order to function. Empirical studies of fitness landscapes that result from the many possible mutations in a gene region reveal many fitness peaks and valleys that connect them. Thus, it is possible that some complex adaptations have arisen by evolutionary paths whose intermediate states are neutral or even deleterious. When intermediates are deleterious, traversing such an evolutionary path is known as \"crossing a fitness valley\". Previous efforts at studying this problem have rigorously characterized the rate at which such complex adaptations evolve in populations of roughly equally fit individuals. However, populations that are very large or have broad fitness distributions, such as many microbial populations, adapt quickly, which substantially alters the fate and dynamics of individual mutations due to the action of genetic draft. We investigate the rate at which complex adaptations evolve in these rapidly adapting populations in regions without recombination. We confirm that rapid adaptation overall increases the time required to cross a valley; however, rapid adaptation can make it easier for deeper valleys to be crossed relative to the time required for single beneficial mutations to sweep to fixation.

evolutionary biology↗

bioRxiv2018

Genetic deletion of genes in the cerebellar rhombic lip lineage can stimulate compensation through adaptive reprogramming of ventricular zone-derived progenitors

BackgroundThe cerebellum is a foliated posterior brain structure involved in coordination of motor movements and cognition. The cerebellum undergoes rapid growth postnataly due to Sonic Hedgehog (SHH) signaling-dependent proliferation of ATOH1+ granule cell precursors (GCPs) in the external granule cell layer (EGL), a key step for generating cerebellar foliation and the correct number of granule cells. Due to its late development, the cerebellum is particularly vulnerable to injury from preterm birth and stress around birth. We recently uncovered an intrinsic capacity of the developing cerebellum to replenish ablated GCPs via adaptive reprogramming of Nestin-expressing progenitors (NEPs). However, whether this compensation mechanism occurs in mouse mutants affecting the developing cerebellum and could lead to mis-interpretation of phenotypes was not known.\n\nMethodsWe used two different approaches to remove the main SHH signaling activator GLI2 in GCPs: 1) our mosaic mutant analysis with spatial and temporal control of recombination (MASTR) technique to delete Gli2 in a small subset of GCPs; 2) An Atohl-Cre transgene to delete Gli2 in most of the EGL. Genetic Inducible Fate Mapping (GIFM) and live imaging were used to analyze the behavior of NEPs after Gli2 deletion.\n\nResultsMosaic analysis demonstrated that SHH-GLI2 signaling is critical for generating the correct pool of granule cells by maintaining GCPs in an undifferentiated proliferative state and promoting their survival. Despite this, inactivation of GLI2 in a large proportion of GCPs in the embryo did not lead to the expected dramatic reduction in the size of the adult cerebellum. GIFM uncovered that NEPs do indeed replenish GCPs in Gli2 conditional mutants, and then expand and partially restore the production of granule cells. Furthermore, the SHH signaling-dependent NEP compensation requires Gli2, demonstrating that the activator side of the pathway is involved.\n\nConclusionWe demonstrate that a mouse conditional mutation that results in loss of SHH signaling in GCPs is not sufficient to induce long term severe cerebellum hypoplasia. The ability of the neonatal cerebellum to regenerate after loss of cells via a response by NEPs must therefore be considered when interpreting the phenotypes of conditional mutants affecting GCPs.

developmental biology↗

bioRxiv2018

Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis

Streptococcus pneumoniae is a common nasopharyngeal colonizer, but can also cause life-threatening invasive diseases such as empyema, bacteremia and meningitis. Genetic variation of host and pathogen is known to play a role in invasive pneumococcal disease, though to what extent is unknown. In a genome-wide association study of human and pathogen we show that human variation explains almost half of variation in susceptibility to pneumococcal meningitis and one-third of variation in severity, and identified variants in CCDC33 associated with susceptibility. Pneumococcal variation explained a large amount of invasive potential, but serotype explained only half of this variation. Newly developed methods identified pneumococcal genes involved in invasiveness including pspC and zmpD, and allowed a human-bacteria interaction analysis, finding associations between pneumococcal lineage and STK32C.

genomics↗

bioRxiv2018

The genetics and genome-wide screening of perennialism loci in Zea diploperennis

Perennialism is common among the higher plants, yet we know little about its inheritance. To address this, six hybrids were made by reciprocally crossing perennial Zea diploperennis Iltis, Doebley & R. Guzman with three varieties/inbred lines of annual maize (Z. mays L. spp. mays). We specifically focused on the plants ability to regrow after flowering and senescence. All the F1 plants demonstrated senescence and regrowth for several cycles, indicating a dominant effect of the Z. diploperennis alleles. The regrowth ability was stably transmitted to progeny of the hybrids in segregation ratios that suggested the trait was controlled by two dominant, complementary loci. Genome-wide screening with genotyping-by-sequencing (GBS) identified two major regrowth loci reg1 and reg2 on chromosomes 2 and 7, respectively. GBS results were validated using a larger F2 population and PCR markers derived from the single nucleotide polymorphisms within the locus intervals. These markers will be employed to select near-isogenic lines for the two loci and to identify candidate genes in the loci in Z. diploperennis.\n\nSignificance StatementOur study contributes to our general understanding of inheritance of perennialism in the higher plants. Previous genetic studies of the perennialism in Zea have yielded contradictory results. We take a reductionist approach by specifically focusing on the plants ability to regenerate new shoots after senescence without regard to associated traits, such as rhizome formation, tillering or environmental impacts. Using this criterion, inheritance of perennialism in Zea appears to be dominantly and qualitatively inherited. Importantly, our data indicate that there is no major barrier to transferring this trait into maize or other grass crops for perennial crop development, which enhances sustainability of grain crop production in an environmentally friendly way.

plant biology↗

bioRxiv2018

Functional Interpretation of Genetic Variants Using Deep Learning Predicts Impact on Epigenome

Identifying causal variants underling disease risk and adoption of personalized medicine are currently limited by the challenge of interpreting the functional consequences of genetic variants. Predicting the functional effects of disease-associated protein-coding variants is increasingly routine. Yet the vast majority of risk variants are non-coding, and predicting the functional consequence and prioritizing variants for functional validation remains a major challenge. Here we develop a deep learning model to accurately predict locus-specific signals from four epigenetic assays using only DNA sequence as input. Given the predicted epigenetic signal from DNA sequence for the reference and alternative alleles at a given locus, we generate a score of the predicted epigenetic consequences for 438 million variants. These impact scores are assay-specific, are predictive of allele-specific transcription factor binding and are enriched for variants associated with gene expression and disease risk. Nucleotide-level functional consequence scores for non-coding variants can refine the mechanism of known causal variants, identify novel risk variants and prioritize downstream experiments.

genomics↗

bioRxiv2018

Complex genetic and epigenetic regulation deviates gene expression from a global transcriptional program

Environmental or genetic perturbations lead to gene expression changes. While most analyses of these changes emphasize the presence of qualitative differences on just a few genes, we now know that changes are widespread. This large-scale variation has been linked to the exclusive influence of a global transcriptional program determined by the new physiological state of the cell. However, given the sophistication of eukaryotic regulation, we expect to have a complex architecture of specific control affecting this program. Here, we examine this architecture. Using data of Saccharomyces cerevisiae expression in different nutrient conditions, we first propose a five-sector genome partition, which integrates earlier models of resource allocation, as a framework to examine the deviations from the global control. In this scheme, we recognize invariant genes, whose regulation is dominated by physiology, specific genes, which substantially depart from it, and two additional classes that contain the frequently assumed growth-dependent genes. Whereas the invariant class shows a considerable absence of specific regulation, the rest is enriched by regulation at the level of transcription factors (TFs) and epigenetic modulators. We nevertheless find markedly different strategies in how these classes deviate. On the one hand, there are TFs that act in a unique way between partition constituents, and on the other, the action of chromatin modifiers is significantly diverse. The balance between regulatory strategies ultimately modulates the action of the general transcription machinery and therefore limits the possibility of establishing a unifying program of expression change at a genomic scale.

systems biology↗

bioRxiv2018

Genetic control of cellular morphogenesis in Müller glia

Of all the cells in the body, those with the greatest variety of shapes reside in the central nervous system yet they all start their postmitotic lives as simple elongated cells of the neuroepithelium1.The molecular processes by which these, or indeed any, cells gain their particular cell-specific anatomies remain largely unexplored.We, therefore, developed a strategy to identify the genes involved in cellular morphogenesis using Muller glial (MG) cells in the vertebrate retina as a model system.These radially oriented cells, discovered by Heinrich Muller in 1851 and named in his honour2, are astonishingly complex yet, as the great neurohistologist Ramon y Cajal first noted, they share a conserved set of key anatomical features3.Using genomic and CRISPR based strategies in zebrafish, combined with a temporal dissection of the process, we found more than 40 genes involved in MG cell morphogenesis.Strikingly, the sequential steps of anatomical feature addition are regulated by successive expression of cohorts of interrelated genes, revealing unprecedented insights into the developmental genetics of cellular morphogenesis.

cell biology↗