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Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2014

Comparison of the 3D organization of sperm and fibroblast genomes using the Hi-C approach

The 3D organization of the genome is tightly connected to its biological function. The Hi-C approach was recently introduced as a method that can be used to identify higher-order chromatin interactions genome-wide. The aim of this study was to determine genome-wide chromatin interaction frequencies using the Hi-C approach in mouse sperm cells and embryonic fibroblasts. The obtained results demonstrated that the 3D genome organizations of sperm and fibroblast cells show a high degree of similarity both with each other and with the previously described mouse embryonic stem (ES) cells. Both A- and B-compartments and topologically associated domains (TADs) are present in spermatozoa and fibroblasts. Nevertheless, sperm cells and fibroblasts exhibited statistically significant differences between each other in the contact probabilities of defined loci. Tight packaging of the sperm genome resulted in an enrichment of long-range contacts compared with the fibroblasts. However, only 30% of the differences in the number of contacts are based on differences in the densities of their genome packages; the main source of the differences is the gain or loss of contacts that are specific for defined genome regions. An analysis of interchromosomal contacts in both cell types demonstrated that the large chromosomes showed a tendency to interact with each other more than with the small chromosomes and vice versa. We found that the dependence of the contact probability P(s) on genomic distance for sperm is in a good agreement with the fractal globular folding of chromatin. The similarity of the spatial DNA organization in sperm and somatic cell genomes suggests the stability of the 3D structure of genomes through generations.

Developmental Biology↗

bioRxiv2015

A statistical approach to genome size evolution: Observations and explanations

Genome size evolution is a fundamental problem in molecular evolution. Statistical analysis of genome sizes brings new insight into the evolution of genome size. Although the variation of genome sizes is complicated, it is indicated that the genome size evolution can be explained more clearly at taxon level than at species level. I find that the genome size distribution for species in a taxon fits log-normal distribution. And I find a relationship between the phylogeny of life and the statistical features of genome size distributions among taxa. I observed different statistical features of genome size distributions between animal taxa and plant taxa. A log-normal stochastic process model is developed to simulate the genome size evolution. The simulation results on the log-normal distributions of genome sizes and their statistical features agree with the observations.

Evolutionary Biology↗

bioRxiv2016

Identification of physical interactions between genomic regions by enChIP-Seq

Physical interactions between genomic regions play critical roles in the regulation of genome functions, including gene expression. However, the methods for confidently detecting physical interactions between genomic regions remain limited. Here, we demonstrate the feasibility of using engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP) in combination with next-generation sequencing (NGS) (enChIP-Seq) to detect such interactions. In enChIP-Seq, the target genomic region is captured by an engineered DNA-binding complex, such as a CRISPR system consisting of a catalytically inactive form of Cas9 (dCas9) and a single guide RNA (sgRNA). Subsequently, the genomic regions that physically interact with the target genomic region in the captured complex are sequenced by NGS. Using enChIP-Seq, we found that the 5HS5 locus, which regulates expression of the {beta}-globin genes, interacts with multiple genomic regions upon erythroid differentiation in the human erythroleukemia cell line K562. Genes near the genomic regions inducibly associated with the 5HS5 locus were transcriptionally up-regulated in the differentiated state, suggesting the existence of a coordinated transcription mechanism directly or indirectly mediated by physical interactions between these loci. Our data suggest that enChIP-Seq is a potentially useful tool for detecting physical interactions between genomic regions in a non-biased manner, which would facilitate elucidation of the molecular mechanisms underlying regulation of genome functions.

Molecular Biology↗

bioRxiv2016

Genomic epidemiology and global diversity of the emerging bacterial pathogen Elizabethkingia anophelis

Elizabethkingia anophelis is an emerging pathogen. Genomic analysis of strains from clinical, environmental or mosquito sources is needed to understand the epidemiological emergence of E. anophelis and to uncover genetic elements implicated in antimicrobial resistance, pathogenesis, or niche adaptation. Here, the genomic sequences of two nosocomial isolates that caused neonatal meningitis in Bangui, Central African Republic, were determined and compared with Elizabethkingia isolates from other world regions and sources. Average nucleotide identity firmly confirmed that E. anophelis, E. meningoseptica and E. miricola represent distinct genomic species and led to re-identification of several strains. Phylogenetic analysis of E. anophelis strains revealed several sublineages and demonstrated a single evolutionary origin of African clinical isolates, which carry unique antimicrobial resistance genes acquired by horizontal transfer. The Elizabethkingia genus and the species E. anophelis had pan-genomes comprising respectively 7,801 and 6,880 gene families, underlining their genomic heterogeneity. African isolates were capsulated and carried a distinctive capsular polysaccharide synthesis cluster. A core-genome multilocus sequence typing scheme applicable to all Elizabethkingia isolates was developed, made publicly available (http://bigsdb.web.pasteur.fr/elizabethkingia), and shown to provide useful insights into E. anophelis epidemiology. Furthermore, a clustered regularly interspaced short palindromic repeats (CRISPR) locus was uncovered in E. meningoseptica, E. miricola and in a few E. anophelis strains. CRISPR spacer variation was observed between the African isolates, illustrating the value of CRISPR for strain subtyping. This work demonstrates the dynamic evolution of E. anophelis genomes and provides innovative tools for Elizabethkingia identification, population biology and epidemiology.\n\nIMPORTANCEElizabethkingia anophelis is a recently recognized bacterial species involved in human infections and outbreaks in distinct world regions. Using whole-genome sequencing, we showed that the species comprises several sublineages, which differ markedly in their genomic features associated with antibiotic resistance and host-pathogen interactions. Further, we have devised high-resolution strain subtyping strategies and provide an open genomic sequence analysis tool, facilitating the investigation of outbreaks and tracking of strains across time and space. We illustrate the power of these tools by showing that two African healthcare-associated meningitis cases observed 5 years apart were caused by the same strain, providing evidence that E. anophelis can persist in the hospital environment.

Microbiology↗

bioRxiv2016

Allele-Specific Quantification of Structural Variations in Cancer Genomes

One of the hallmarks of cancer genome is aneuploidy, resulting in abnormal copy numbers of alleles. Structural variations (SVs) can further modify the aneuploid cancer genomes into a mixture of rearranged genomic segments with extensive range of somatic copy number alterations (CNAs). Indeed, aneuploid cancer genomes have significantly higher rate of CNAs and SVs. However, although methods have been developed to identify SVs and allele-specific copy number of genome (ASCNG) separately, no existing algorithm can simultaneously analyze SVs and ASCNG. Such integrated approach is particularly important to fully understand the complexity of cancer genomes. Here we introduce a new algorithm called Weaver to provide allele-specific quantification of SVs and CNAs in aneuploid cancer genomes. Weaver uses a probabilistic graphical model by utilizing cancer whole genome sequencing data to simultaneously estimate the digital copy number and inter-connectivity of SVs. Our simulation evaluation, comparison with single-molecule Optical Mapping analysis, and real data applications (including MCF-7, HeLa, and TCGA whole genome sequencing samples) demonstrated that Weaver is highly accurate and can greatly refine the analysis of complex cancer genome structure.

Bioinformatics↗

bioRxiv2016

Coordinates and Intervals in Graph-based Reference Genomes

MotivationIt has been proposed that future reference genomes should be graph structures in order to better represent the sequence diversity present in a species. However, there is currently no standard method to represent genomic intervals, such as positions of genes, on graph-based reference genomes.\n\nResultsWe formalize offset-based coordinate systems on graph-based reference genomes and introduce a method for representing intervals on these reference structures. We show the advantage of our method by representing genes on a graph-based representation of the GRCh38 version of the human genome and its alternative loci for regions that are highly variable.\n\nConclusionMore complex reference genomes, containing alternative loci, require methods to represent genomic data on these structures. Our proposed notation for genomic intervals makes it possible to fully utilize the alternative loci of GRCh38 and potential future graph-based reference genomes. We illustrate our notation for genomic intervals, as well as the offset-based coordinate systems, through a web tool at: https://github.com/uio-cels/gen-graph-coords.

Bioinformatics↗

bioRxiv2017

Re-evaluating inheritance in genome evolution: widespread transfer of LINEs between species

Transposable elements (TEs) are mobile DNA sequences, colloquially known as jumping genes because of their ability to replicate to new genomic locations. Given a vector of transfer (e.g. tick or virus), TEs can jump further: between organisms or species in a process known as horizontal transfer (HT). Here we propose that LINE-1 (L1) and Bovine-B (BovB), the two most abundant TE families in mammals, were initially introduced as foreign DNA via ancient HT events. Using a 503-genome dataset, we identify multiple ancient L1 HT events in eukaryotes and provide evidence that L1s infiltrated the mammalian lineage after the monotreme-therian split. We also extend the BovB paradigm by increasing the number of estimated transfer events compared to previous studies, finding new potential blood-sucking parasite vectors and occurrences in new lineages (e.g. bats, frog). Given that these TEs make up nearly half of the genome sequence in todays mammals, our results provide the first evidence that HT can have drastic and long-term effects on the new host genomes. This revolutionizes our perception of genome evolution to consider external factors, such as the natural introduction of foreign DNA. With the advancement of genome sequencing technologies and bioinformatics tools, we anticipate our study to be the first of many large-scale phylogenomic analyses exploring the role of HT in genome evolution.\n\nSignificance statementLINE-1 (L1) elements occupy about half of most mammalian genomes (1), and they are believed to be strictly vertically inherited (2). Mutagenic L1 insertions are thought to account for approximately 1 of every 1000 random, disease-causing insertions in humans (4-7). Our research indicates that the very presence of L1s in humans, and other therian mammals, is due to an ancient transfer event - which has drastic implications for our perception of genome evolution. Using a machina analyses over 503 genomes, we trace the origins of L1 and BovB retrotransposons across the tree of life, and provide evidence of their long-term impact on eukaryotic evolution.

evolutionary biology↗

bioRxiv2017

Diverse genome organization following 13 independent mesopolyploid events in Brassicaceae contrasts with convergent patterns of gene retention

Hybridization and polyploidy followed by genome-wide diploidization significantly impacted the diversification of land plants. The ancient At- whole-genome duplication (WGD) preceded the diversification of crucifers (Brassicaceae). Some genera and tribes also experienced younger, mesopolyploid WGDs concealed by subsequent genome diploidization. Here we tested if multiple base chromosome numbers originated due to genome diploidization after independent mesopolyploid WGDs and how diploidization impacted post-polyploid gene retention. Sixteen species representing ten Brassicaceae tribes were analyzed by comparative chromosome painting and/or whole-transcriptome analysis of gene age distributions and phylogenetic analyses of gene duplications. Overall, we found evidence for at least 13 independent mesopolyploidies followed by different degrees of diploidization across the Brassicaceae. New mesotetraploid events were uncovered for tribes Anastaticeae, Iberideae and Schizopetaleae, and mesohexaploid WGDs for Cochlearieae and Physarieae. In contrast, we found convergent patterns of gene retention and loss among these independent WGDs. Our combined analyses of Brassicaceae genomic data indicate that the extant chromosome number variation in many plant groups, and especially polybasic but monophyletic taxa, can result from clade-specific genome duplications followed by diploidization. Our observation of parallel gene retention and loss across multiple independent WGDs provides one of the first multi-species tests that post-polyploid genome evolution is predictable.\n\nSignificance statementOur data show that multiple base chromosome numbers in some Brassicaceae clades originated due to genome diploidization following multiple independent whole-genome duplications (WGD). The parallel gene retention/loss across independent WGDs and diploidizations provides one of the first tests that post-polyploid genome evolution is predictable.

evolutionary biology↗

bioRxiv2017

Inherited chromosomally integrated human herpesvirus 6 genomes are ancient, intact and potentially able to reactivate from telomeres

Human herpesviruses 6A and 6B (HHV6-A and HHV-6B; species Human herpesvirus 6A and Human herpesvirus 6B) have the capacity to integrate into telomeres, the essential capping structures of chromosomes that play roles in cancer and ageing. About 1% of people worldwide are carriers of chromosomally integrated HHV-6 (ciHHV-6), which is inherited as a genetic trait. Understanding the consequences of integration for the evolution of the viral genome, for the telomere and for the risk of disease associated with carrier status is hampered by a lack of knowledge about ciHHV-6 genomes. Here, we report an analysis of 28 ciHHV-6 genomes and show that they are significantly divergent from the few modern non-integrated HHV-6 strains for which complete sequences are currently available. In addition ciHHV-6B genomes in Europeans are more closely related to each other than to ciHHV-6B genomes from China and Pakistan, suggesting regional variation of the trait. Remarkably, at least one group of European ciHHV-6B carriers has inherited the same ciHHV-6B genome, integrated in the same telomere allele, from a common ancestor estimated to have existed 24,500 {+/-}10,600 years ago. Despite the antiquity of some, and possibly most, germline HHV-6 integrations, the majority of ciHHV-6B (95%) and ciHHV-6A (72%) genomes contain a full set of intact viral genes and therefore appear to have the capacity for viral gene expression and full reactivation.\n\nIMPORTANCEInheritance of HHV-6A or HHV-6B integrated into a telomere occurs at a low frequency in most populations studied to date but its characteristics are poorly understood. However, stratification of ciHHV-6 carriers in modern populations due to common ancestry is an important consideration for genome-wide association studies that aim to identify disease risks for these people. Here we present full sequence analysis of 28 ciHHV-6 genomes and show that ciHHV-6B in many carriers with European ancestry most likely originated from ancient integration events in a small number of ancestors. We propose that ancient ancestral origins for ciHHV-6A and ciHHV-6B are also likely in other populations. Moreover, despite their antiquity, all of the ciHHV-6 genomes appear to retain the capacity to express viral genes and most are predicted to be capable of full viral reactivation. These discoveries represent potentially important considerations in immune-compromised patients, in particular in organ transplantation and in stem cell therapy.

evolutionary biology↗

bioRxiv2017

A computational framework for detecting signatures of accelerated somatic evolution in cancer genomes

By accumulation of somatic mutations, cancer genomes evolve, diverging away from the genome of the host. It remains unclear to what extent somatic evolutionary divergence is comparable across different regions of the cancer genome versus concentrated in specific genomic elements. We present a novel computational framework, SASE-mapper, to identify genomic regions that show signatures of accelerated somatic evolution (SASE) in a subset of samples in a cohort, marked by accumulation of an excess of somatic mutations compared to that expected based on local, context-aware background mutation rates in the cancer genomes. Analyzing tumor whole genome sequencing data for 365 samples from 5 cohorts we detect recurrent SASE at a genome-wide scale. The SASEs were enriched for genomic elements associated with active chromatin, and regulatory regions of several known cancer genes had SASE in multiple cohorts. Regions with SASE carried specific mutagenic signatures and often co-localized within the 3D nuclear space suggesting their common basis. A subset of SASEs was frequently associated with regulatory changes in key cancer pathways and also poor clinical outcome. While the SASE-associated mutations were not necessarily recurrent at base-pair resolution, the SASEs recurrently targeted same functional regions, with similar consequences. It is likely that regulatory redundancy and plasticity promote prevalence of SASE-like patterns in the cancer genomes.

bioinformatics↗

bioRxiv2017

Superior ab initio Identification, Annotation and Characterisation of TEs and Segmental Duplications from Genome Assemblies.

Transposable Elements (TEs) are mobile DNA sequences that make up significant fractions of amniote genomes. However, they are difficult to detect and annotate ab initio because of their variable features, lengths and clade-specific variants. We have addressed this problem by refining and developing a Comprehensive ab initio Repeat Pipeline (CARP) to identify and cluster TEs and other repetitive sequences in genome assemblies. The pipeline begins with a pairwise alignment using krishna, a custom aligner. Single linkage clustering is then carried out to produce families of repetitive elements. Consensus sequences are then filtered for protein coding genes and then annotated using Repbase and a custom library of retrovirus and reverse transcriptase sequences. This process yields three types of family: fully annotated, partially annotated and unannotated. Fully annotated families reflect recently diverged/young known TEs present in Repbase. The remaining two types of families contain a mixture of novel TEs and segmental duplications. These can be resolved by aligning these consensus sequences back to the genome to assess copy number vs. length distribution. Our pipeline has three significant advantages compared to other methods for ab initio repeat identification: 1) we generate not only consensus sequences, but keep the genomic intervals for the original aligned sequences, allowing straightforward analysis of evolutionary dynamics, 2) consensus sequences represent low-divergence, recently/currently active TE families, 3) segmental duplications are annotated as a useful by-product. We have compared our ab initio repeat annotations for 7 genome assemblies (1 unpublished) to other methods and demonstrate that CARP compares favourably with RepeatModeler, the most widely used repeat annotation package.\n\nAuthor summaryTransposable elements (TEs) are interspersed repetitive DNA sequences, also known as jumping genes, because of their ability to replicate in to new genomic locations. TEs account for a significant proportion of all eukaryotic genomes. Previous studies have found that TE insertions have contributed to new genes, coding sequences and regulatory regions. They also play an important role in genome evolution. Therefore, we developed a novel, ab initio approach for identifying and annotating repetitive elements. The idea is simple: define a \"repeat\" as any sequence that occurs at least twice in the genome. Our ab initio method is able to identify species-specific TEs with high sensitivity and accuracy including both TEs and segmental duplications. Because of the high degree of sequence identity used in our method, the TEs we find are less diverged and may still be active. We also retain all the information that links identified repeat consensus sequences to their genome intervals, permiting direct evolutionary analysis of the TE families we identify.

bioinformatics↗

bioRxiv2017

Idiosyncratic genome degradation in a bacterial endosymbiont of periodical cicadas

When a free-living bacterium transitions to a host-beneficial endosymbiotic lifestyle, it almost invariably loses a large fraction of its genome [1, 2]. The resulting small genomes often become unusually stable in size, structure, and coding capacity [3-5]. Candidatus Hodgkinia cicadicola (Hodgkinia), a bacterial endosymbiont of cicadas, sometimes exemplifies this genomic stability. The Hodgkinia genome has remained completely co-linear in some cicadas diverged by tens of millions of years [6, 7]. But in the long-lived periodical cicada Magicicada tredecim, the Hodgkinia genome has split into dozens of tiny, gene-sparse genomic circles that sometimes reside in distinct Hodgkinia cells [8]. Previous data suggested that other Magicicada species harbor similarly complex Hodgkinia populations, but the timing, number of origins, and outcomes of the splitting process were unknown. Here, by sequencing Hodgkinia metagenomes from the remaining six Magicicada species and two sister species, we show that all Magicicada species harbor Hodgkinia populations of at least twenty genomic circles each. We find little synteny among the 256 Hodgkinia circles analyzed except between the most closely related species. Individual gene phylogenies show that Hodgkinia first split in the common ancestor of Magicicada and its closest known relatives, but that most splitting has occurred within Magicicada and has given rise to highly variable Hodgkinia gene dosages between cicada species. These data show that Hodgkinia genome degradation has proceeded down different paths in different Magicicada species, and support a model of genomic degradation that is stochastic in outcome and likely nonadaptive for the host. These patterns mirror the genomic instability seen in some mitochondria.

evolutionary biology↗

bioRxiv2019

Rapid method for generating designer algal mitochondrial genomes

With synthetic biology, we can turn algae into bio-factories that produce high-value molecules (e.g. medicines or biofuels) or tackle global challenges (e.g. malnutrition and climate change). This realization has provoked rapid progress towards the creation of genetic tools for multiple algal species, notably Phaeodactylum tricornutum. The power of synthetic biology to generate more useful or productive organisms is contingent on the ability to produce diverse DNA molecules and rapidly screen them for beneficial variants. However, it is still relatively expensive to synthesize DNA, and delivering large DNA (>50 kbp) to eukaryotic cellular compartments remains challenging. In this study, we establish a robust system for building algal mitochondrial genomes as a practical alternative to DNA synthesis. Our approach permits an inexpensive and rapid generation of mitochondrial derivatives designed for testing targeted DNA delivery. First, we cloned the mitochondrial genome of P. tricornutum into the eukaryotic host organism S. cerevisiae using two different techniques: transformation-associated recombination; and PCR-based cloning. Next, we analyzed the cloned genomes by multiplex PCR, and correct genomes were transferred to prokaryotic host E. coli. Then these genomes were again analyzed by multiplex PCR, followed by diagnostic digest and complete-plasmid sequencing to evaluate the fidelity of each cloning method. Finally, we assessed the burden on eukaryotic and prokaryotic hosts to propagate the cloned genomes. We conclude that our system can reliably generate variants for genome-level engineering of algal mitochondria. HIGHLIGHTSO_LITAR-cloned mitochondrial genome of P. tricornutum in yeast C_LIO_LIDeveloped PCR-based cloning method to create designer algal mitochondrial genomes C_LIO_LIStably propagated algal mitochondrial genomes in S. cerevisiae and E. coli hosts C_LI

synthetic biology↗

bioRxiv2020

Accurate reconstruction of the pan- and core- genomes of bacteria with PEPPA

Bacterial genomes can contain traces of a complex evolutionary history, including extensive homologous recombination, gene loss, gene duplications and horizontal gene transfer. In order to reconstruct the phylogenetic and population history of a set of multiple bacteria, it is necessary to examine their pan-genome, the composite of all the genes in the set. Here we introduce PEPPAN, a novel pipeline that can reliably construct pan-genomes from thousands of genetically diverse bacterial genomes that represent the diversity of an entire genus. PEPPAN outperforms existing pan-genome methods by providing consistent gene and pseudogene annotations extended by similarity-based gene predictions, and identifying and excluding paralogs by combining tree- and synteny-based approaches. The PEPPAN package additionally includes PEPPAN_parser, which implements additional downstream analyses including the calculation of trees based on accessory gene content or allelic differences between core genes. In order to test the accuracy of PEPPAN, we implemented SimPan, a novel pipeline for simulating the evolution of bacterial pan-genomes. We compared the accuracy and speed of PEPPAN with four state-of-the-art pan-genome pipelines using both empirical and simulated datasets. PEPPAN was more accurate and more specific than any of the other pipelines and was almost as fast as any of them. As a case study, we used PEPPAN to construct a pan-genome of ~40,000 genes from 3052 representative genomes spanning at least 80 species of Streptococcus. The resulting gene and allelic trees provide an unprecedented overview of the genomic diversity of the entire Streptococcus genus.

bioinformatics↗

bioRxiv2020

Repetitive DNA profiles reveal evidence of rapid genome evolution and reflect species boundaries in ground beetles

AO_SCPLOWBSTRACTC_SCPLOWGenome architecture is a complex, multidimensional property of an organism defined by the content and spatial organization of the genomes component parts. Comparative study of entire genome architecture in model organisms is shedding light on mechanisms underlying genome regulation, evolution, and diversification; but such studies require costly analytical approaches which make extensive comparative study impractical for most groups. However, lower-cost methods that measure a single architectural component (e.g., distribution of one class of repeats) have potential as a new data source for evolutionary studies insofar as that measure correlates with more complex biological phenomena, and for which it could serve as part of an explanatory framework. We investigated copy number variation (CNV) profiles in ribosomal DNA (rDNA) as a simple measure reflecting the distribution of rDNA subcomponents across the genome. We find that signatures present in rDNA CNV profiles strongly correlate with species boundaries in the breve species group of Bembidion, and vary across broader taxonomic sampling in Bembidion subgenus Plataphus. Profiles of several species show evidence of re-patterning of rDNA-like sequences throughout the genome, revealing evidence of rapid genome evolution (including among sister pairs) not evident from analysis of traditional data sources such as multi-gene data sets. Major re-patterning of rDNA-like sequences has occurred frequently within the evolutionary history of Plataphus. We confirm that CNV profiles represent an aspect of genomic architecture (i.e., the linear distribution of rDNA components across the genome) via fluorescence in-situ hybridization. In at least one species, novel rDNA-like elements are spread throughout all chromosomes. We discuss the potential of copy number profiles of rDNA, or other repeats, as a low-cost tool for incorporating signal of genomic architecture variation in studies of species delimitation and genome evolution.

evolutionary biology↗

bioRxiv2020

Expanding the utility of sequence comparisons using data from whole genomes

Whole genome comparisons based on Average Nucleotide Identities (ANI), and the Genome-to-genome distance calculator have risen to prominence in rapidly classifying taxa using whole genome sequences. Some implementations have even been proposed as a new standard in species classification and have become a common technique for papers describing newly sequenced genomes. However, attempts to apply whole genome divergence data to delineation of higher taxonomic units, and to phylogenetic inference have had difficulty matching those produced by more complex phylogenetics methods. We present a novel method for generating reliable and statistically supported phylogenies using established ANI techniques. For the test cases to which we applied the developed approach we obtained accurate results up to at least the family level. The developed method uses non-parametric bootstrapping to gauge reliability of inferred groups. This method offers the opportunity make use of whole-genome comparison data that is already being generated to quickly produce accurate phylogenies. Additionally, the developed ANI methodology can assist classification of higher order taxonomic groups. Significance StatementThe average nucleotide identity (ANI) measure and its iterations have come to dominate in-silico species delimitation in the past decade. Yet the problem of gene content has not been fully resolved, and attempts made to do so contain two metrics which makes interpretation difficult at times. We provide a new single based ANI metric created from the combination of genomic content and genomic identity measures. Our results show that this method can handle comparisons of genomes with divergent content or identity. Additionally, the metric can be used to create distance based phylogenetic trees that are comparable to other tree building methods, while also providing a tentative metric for categorizing organisms into higher level taxonomic classifications.

bioinformatics↗

bioRxiv2020

Transformation of single-cell three-dimensional genome structure during postnatal development of the mammalian brain

Both transcription and 3D organization of the mammalian genome play critical roles in neurodevelopment and its disorders. However, 3D genome structures of single brain cells have not been solved; little is known about the dynamics of single-cell transcriptome and 3D genome after birth. Here we generate a transcriptome atlas of 3,517 cells and a 3D genome atlas of 3,646 cells from the developing mouse cortex and hippocampus, using our high-resolution MALBAC-DT and Dip-C methods. In adults, 3D genome "structure types" delineate all major cell types, with high correlation between A/B compartments and gene expression. During development, both transcriptome and 3D genome are extensively transformed in the first postnatal month. In neurons, 3D genome is rewired across multiple scales, correlated with gene expression modules and independent of sensory experience. Finally, we examine allele-specific structure of imprinted genes, revealing local and chromosome-wide differences. These findings uncover a previously unknown dimension of neurodevelopment. HIGHLIGHTSO_LITranscriptomes and 3D genome structures of single brain cells (both neurons and glia) in the developing mouse forebrain C_LIO_LICell type identity encoded in the 3D wiring of the mammalian genome ("structure types") C_LIO_LIMajor transformation of both transcriptome and 3D genome during the first month of life, independent of sensory experience C_LIO_LIAllele-specific 3D structure at 7 imprinted gene loci, including one that spans a whole chromosome C_LI

neuroscience↗

bioRxiv2020

SIGAR: Inferring features of genome architecture and DNA rearrangements by split read mapping

Ciliates are microbial eukaryotes with distinct somatic and germline genomes. Post-zygotic development involves extensive remodeling of the germline genome to form somatic chromosomes. Ciliates therefore offer a valuable model for studying the architecture and evolution of programmed genome rearrangements. Current studies usually focus on a few model species, where rearrangement features are annotated by aligning reference germline and somatic genomes. While many high-quality somatic genomes have been assembled, a high quality germline genome assembly is difficult to obtain due to its smaller DNA content and abundance of repetitive sequences. To overcome these hurdles, we propose a new pipeline SIGAR (Splitread Inference of Genome Architecture and Rearrangements) to infer germline genome architecture and rearrangement features without a germline genome assembly, requiring only short germline DNA sequencing reads. As a proof of principle, 93% of rearrangement junctions identified by SIGAR in the ciliate Oxytricha trifallax were validated by the existing germline assembly. We then applied SIGAR to six diverse ciliate species without germline genome assemblies, including Ichthyophthirius multifilii, a fish pathogen. Despite the high level of somatic DNA contamination in each sample, SIGAR successfully inferred rearrangement junctions, short eliminated sequences and potential scrambled genes in each species. This pipeline enables pilot surveys or exploration of DNA rearrangements in species with limited DNA material access, thereby providing new insights into the evolution of chromosome rearrangements.

evolutionary biology↗