Despite the explosive growth of genomic data, functional annotation of regulatory sequences remains difficult. Here, we introduce “comparative epigenomics”—interspecies comparison of DNA and histone ...modifications—as an approach for annotation of the regulatory genome. We measured in human, mouse, and pig pluripotent stem cells the genomic distributions of cytosine methylation, H2A.Z, H3K4me1/2/3, H3K9me3, H3K27me3, H3K27ac, H3K36me3, transcribed RNAs, and P300, TAF1, OCT4, and NANOG binding. We observed that epigenomic conservation was strong in both rapidly evolving and slowly evolving DNA sequences, but not in neutrally evolving sequences. In contrast, evolutionary changes of the epigenome and the transcriptome exhibited a linear correlation. We suggest that the conserved colocalization of different epigenomic marks can be used to discover regulatory sequences. Indeed, seven pairs of epigenomic marks identified exhibited regulatory functions during differentiation of embryonic stem cells into mesendoderm cells. Thus, comparative epigenomics reveals regulatory features of the genome that cannot be discerned from sequence comparisons alone.
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► Epigenetic patterns of histone and DNA modification are conserved across species ► Epigenomic conservation occurs in both fast- and slow-evolving DNA sequences ► Changes in the epigenome, transcriptome, and protein-DNA binding patterns are correlated ► The conserved colocalization of different epigenetic marks defines regulatory DNA
Interspecies, comparative analysis of DNA methylation and histone modification patterns can be used to identify regulatory DNA sequences and may explain how changes in transcription and protein-DNA interactions arise during evolution.
As the global population and global wealth both continue to increase, so will the demand for livestock products, especially those that are highly nutritious. However, competition with other uses for ...land and water resources will also intensify, necessitating more efficient livestock production. In addition, as climate change escalates, reduced methane emissions from cattle and sheep will be a critical goal. Application of new technologies, including genomic selection and advanced reproductive technologies, will play an important role in meeting these challenges. Genomic selection, which enables prediction of the genetic merit of animals from genome-wide SNP markers, has already been adopted by dairy industries worldwide and is expected to double genetic gains for milk production and other traits. Here, we review these gains. We also discuss how the use of whole-genome sequence data should both accelerate the rate of gain and enable rapid discovery and elimination of genetic defects from livestock populations.
The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of COVID-19. The main receptor of SARS-CoV-2, angiotensin I converting enzyme 2 (ACE2), is now ...undergoing extensive scrutiny to understand the routes of transmission and sensitivity in different species. Here, we utilized a unique dataset of ACE2 sequences from 410 vertebrate species, including 252 mammals, to study the conservation of ACE2 and its potential to be used as a receptor by SARS-CoV-2. We designed a five-category binding score based on the conservation properties of 25 amino acids important for the binding between ACE2 and the SARS-CoV-2 spike protein. Only mammals fell into the medium to very high categories and only catarrhine primates into the very high category, suggesting that they are at high risk for SARS-CoV-2 infection. We employed a protein structural analysis to qualitatively assess whether amino acid changes at variable residues would be likely to disrupt ACE2/SARS-CoV-2 spike protein binding and found the number of predicted unfavorable changes significantly correlated with the binding score. Extending this analysis to human population data, we found only rare (frequency <0.001) variants in 10/25 binding sites. In addition, we found significant signals of selection and accelerated evolution in the ACE2 coding sequence across all mammals, and specific to the bat lineage. Our results, if confirmed by additional experimental data, may lead to the identification of intermediate host species for SARS-CoV-2, guide the selection of animal models of COVID-19, and assist the conservation of animals both in native habitats and in human care.
Earth BioGenome Project Lewin, Harris A.; Robinson, Gene E.; Kress, W. John ...
Proceedings of the National Academy of Sciences - PNAS,
04/2018, Letnik:
115, Številka:
17
Journal Article
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Increasing our understanding of Earth’s biodiversity and responsibly stewarding its resources are among the most crucial scientific and social challenges of the new millennium. These challenges ...require fundamental new knowledge of the organization, evolution, functions, and interactions among millions of the planet’s organisms. Herein, we present a perspective on the Earth BioGenome Project (EBP), a moonshot for biology that aims to sequence, catalog, and characterize the genomes of all of Earth’s eukaryotic biodiversity over a period of 10 years. The outcomes of the EBP will inform a broad range of major issues facing humanity, such as the impact of climate change on biodiversity, the conservation of endangered species and ecosystems, and the preservation and enhancement of ecosystem services. We describe hurdles that the project faces, including data-sharing policies that ensure a permanent, freely available resource for future scientific discovery while respecting access and benefit sharing guidelines of the Nagoya Protocol. We also describe scientific and organizational challenges in executing such an ambitious project, and the structure proposed to achieve the project’s goals. The far-reaching potential benefits of creating an open digital repository of genomic information for life on Earth can be realized only by a coordinated international effort.
Whole-genome assemblies of 19 placental mammals and two outgroup species were used to reconstruct the order and orientation of syntenic fragments in chromosomes of the eutherian ancestor and six ...other descendant ancestors leading to human. For ancestral chromosome reconstructions, we developed an algorithm (DESCHRAMBLER) that probabilistically determines the adjacencies of syntenic fragments using chromosome-scale and fragmented genome assemblies. The reconstructed chromosomes of the eutherian, boreoeutherian, and euarchontoglires ancestor each included >80% of the entire length of the human genome, whereas reconstructed chromosomes of the most recent common ancestor of simians, catarrhini, great apes, and humans and chimpanzees included >90% of human genome sequence. These high-coverage reconstructions permitted reliable identification of chromosomal rearrangements over ∼105 My of eutherian evolution. Orangutan was found to have eight chromosomes that were completely conserved in homologous sequence order and orientation with the eutherian ancestor, the largest number for any species. Ruminant artiodactyls had the highest frequency of intrachromosomal rearrangements, and interchromosomal rearrangements dominated in murid rodents. A total of 162 chromosomal breakpoints in evolution of the eutherian ancestral genome to the human genome were identified; however, the rate of rearrangements was significantly lower (0.80/My) during the first ∼60 My of eutherian evolution, then increased to greater than 2.0/My along the five primate lineages studied. Our results significantly expand knowledge of eutherian genome evolution and will facilitate greater understanding of the role of chromosome rearrangements in adaptation, speciation, and the etiology of inherited and spontaneously occurring diseases.
Chromosome missegregation during mitosis or meiosis is a hallmark of cancer and the main cause of prenatal death in humans. The gain or loss of specific chromosomes is thought to be random, with cell ...viability being essentially determined by selection. Several established pathways including centrosome amplification, sister-chromatid cohesion defects, or a compromised spindle assembly checkpoint can lead to chromosome missegregation. However, how specific intrinsic features of the kinetochore—the critical chromosomal interface with spindle microtubules—impact chromosome segregation remains poorly understood. Here we used the unique cytological attributes of female Indian muntjac, the mammal with the lowest known chromosome number (2n = 6), to characterize and track individual chromosomes with distinct kinetochore size throughout mitosis. We show that centromere and kinetochore functional layers scale proportionally with centromere size. Measurement of intra-kinetochore distances, serial-section electron microscopy, and RNAi against key kinetochore proteins confirmed a standard structural and functional organization of the Indian muntjac kinetochores and revealed that microtubule binding capacity scales with kinetochore size. Surprisingly, we found that chromosome segregation in this species is not random. Chromosomes with larger kinetochores bi-oriented more efficiently and showed a 2-fold bias to congress to the equator in a motor-independent manner. Despite robust correction mechanisms during unperturbed mitosis, chromosomes with larger kinetochores were also strongly biased to establish erroneous merotelic attachments and missegregate during anaphase. This bias was impervious to the experimental attenuation of polar ejection forces on chromosome arms by RNAi against the chromokinesin Kif4a. Thus, kinetochore size is an important determinant of chromosome segregation fidelity.
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•Centromere/kinetochore functional layers scale proportionally with centromere size•Kinetochore microtubule binding capacity scales with kinetochore size•Chromosome congression and bi-orientation are biased by kinetochore size•Error formation leading to chromosome missegregation is biased by kinetochore size
Drpic et al. use fibroblasts from female Indian muntjac, the mammal with the lowest known chromosome number (2n = 6), to show that chromosome congression and bi-orientation are biased by kinetochore size. Chromosomes with larger kinetochores are also biased to establish erroneous merotelic attachments and missegregate during anaphase. Thus, kinetochore size is an important determinant of chromosome segregation fidelity.
The study of chromosome evolution is undergoing a resurgence of interest owing to advances in DNA sequencing technology that facilitate the production of chromosome-scale whole-genome assemblies de ...novo. This review focuses on the history, methods, discoveries, and current challenges facing the field, with an emphasis on vertebrate genomes. A detailed examination of the literature on the biology of chromosome rearrangements is presented, specifically the relationship between chromosome rearrangements and phenotypic evolution, adaptation, and speciation. A critical review of the methods for identifying, characterizing, and visualizing chromosome rearrangements and computationally reconstructing ancestral karyotypes is presented. We conclude by looking to the future, identifying the enormous technical and scientific challenges presented by the accumulation of hundreds and eventually thousands of chromosome-scale assemblies.
Conservation of chromatin conformation in carnivores Corbo, Marco; Damas, Joana; Bursell, Madeline G ...
Proceedings of the National Academy of Sciences - PNAS,
03/2022, Letnik:
119, Številka:
9
Journal Article
Recenzirano
Odprti dostop
High throughput chromatin conformation capture (Hi-C) of leukocyte DNA was used to investigate the evolutionary stability of chromatin conformation at the chromosomal level in 11 species from three ...carnivore families: Felidae, Canidae, and Ursidae. Chromosome-scale scaffolds (C-scaffolds) of each species were initially used for whole-genome alignment to a reference genome within each family. This approach established putative orthologous relationships between C-scaffolds among the different species. Hi-C contact maps for all C-scaffolds were then visually compared and found to be distinct for a given reference chromosome or C-scaffold within a species and indistinguishable for orthologous C-scaffolds having a 1:1 relationship within a family. The visual patterns within families were strongly supported by eigenvectors from the Hi-C contact maps. Analysis of Hi-C contact maps and eigenvectors across the three carnivore families revealed that most cross-family orthologous subchromosomal fragments have a conserved three-dimensional (3D) chromatin structure and thus have been under strong evolutionary constraint for ∼54 My of carnivore evolution. The most pronounced differences in chromatin conformation were observed for the X chromosome and the red fox genome, whose chromosomes have undergone extensive rearrangements relative to other canids. We also demonstrate that Hi-C contact map pattern analysis can be used to accurately identify orthologous relationships between C-scaffolds and chromosomes, a method we termed "3D comparative scaffotyping." This method provides a powerful means for estimating karyotypes in de novo sequenced species that have unknown karyotype and no physical mapping information.
The cow mammary transcriptome was explored at -30, -15, 1, 15, 30, 60, 120, 240, and 300 d relative to parturition. A total of 6,382 differentially expressed genes (DEG) at a false discovery rate ≤ ...0.001 were found throughout lactation. The greatest number of DEG (>3,500 DEG) was observed at 60 and 120 d vs. -30 d with the largest change between consecutive time points observed at -15 vs. 1 d and 120 vs. 240 d. Functional analysis of microarray data was performed using the Dynamic Impact Approach (DIA). The DIA analysis of KEGG pathways uncovered as the most impacted and induced 'Galactose metabolism', 'Glycosylphosphatidylinositol (GPI)-anchor biosynthesis', and 'PPAR signaling'; whereas, 'Antigen processing and presentation' was among the most inhibited. The integrated interpretation of the results suggested an overall increase in metabolism during lactation, particularly synthesis of carbohydrates and lipid. A marked degree of utilization of amino acids as energy source, an increase of protein export, and a decrease of the protein synthesis machinery as well cell cycle also were suggested by the DIA analysis. The DIA analysis of Gene Ontology and other databases uncovered an induction of Golgi apparatus and angiogenesis, and the inhibition of both immune cell activity/migration and chromosome modifications during lactation. All of the highly-impacted and activated functions during lactation were evidently activated at the onset of lactation and inhibited when milk production declined. The overall analysis indicated that the bovine mammary gland relies heavily on a coordinated transcriptional regulation to begin and end lactation. The functional analysis using DIA underscored the importance of genes associated with lactose synthesis, lipid metabolism, protein synthesis, Golgi, transport, cell cycle/death, epigenetic regulation, angiogenesis, and immune function during lactation.
It has long been a quest in ruminants to understand how two very similar mycobacterial species, Mycobacterium avium ssp. paratuberculosis (MAP) and Mycobacterium avium ssp. avium (MAA) lead to either ...a chronic persistent infection or a rapid-transient infection, respectively. Here, we hypothesized that when the host immune response is activated by MAP or MAA, the outcome of the infection depends on the early activation of signaling molecules and host temporal gene expression. To test our hypothesis, ligated jejuno-ileal loops including Peyer's patches in neonatal calves were inoculated with PBS, MAP, or MAA. A temporal analysis of the host transcriptome profile was conducted at several times post-infection (0.5, 1, 2, 4, 8 and 12 hours). When comparing the transcriptional responses of calves infected with the MAA versus MAP, discordant patterns of mucosal expression were clearly evident, and the numbers of unique transcripts altered were moderately less for MAA-infected tissue than were mucosal tissues infected with the MAP. To interpret these complex data, changes in the gene expression were further analyzed by dynamic Bayesian analysis. Bayesian network modeling identified mechanistic genes, gene-to-gene relationships, pathways and Gene Ontologies (GO) biological processes that are involved in specific cell activation during infection. MAP and MAA had significant different pathway perturbation at 0.5 and 12 hours post inoculation. Inverse processes were observed between MAP and MAA response for epithelial cell proliferation, negative regulation of chemotaxis, cell-cell adhesion mediated by integrin and regulation of cytokine-mediated signaling. MAP inoculated tissue had significantly lower expression of phagocytosis receptors such as mannose receptor and complement receptors. This study reveals that perturbation of genes and cellular pathways during MAP infection resulted in host evasion by mucosal membrane barrier weakening to access entry in the ileum, inhibition of Ca signaling associated with decreased phagosome-lysosome fusion as well as phagocytosis inhibition, bias toward Th2 cell immune response accompanied by cell recruitment, cell proliferation and cell differentiation; leading to persistent infection. Contrarily, MAA infection was related to cellular responses associated with activation of molecular pathways that release chemicals and cytokines involved with containment of infection and a strong bias toward Th1 immune response, resulting in a transient infection.
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