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PubMed2024

Critically unwell infants and children with mitochondrial disorders diagnosed by ultrarapid genomic sequencing.

PURPOSE: To characterize the diagnostic and clinical outcomes of a cohort of critically ill infants and children with suspected mitochondrial disorders (MD) undergoing ultrarapid genomic testing as part of a national program. METHODS: Ultrarapid genomic sequencing was performed in 454 families (genome sequencing: n = 290, exome sequencing +/- mitochondrial DNA sequencing: n = 164). In 91 individuals, MD was considered, prompting analysis using an MD virtual gene panel. These individuals were reviewed retrospectively and scored according to modified Nijmegen Mitochondrial Disease Criteria. RESULTS: A diagnosis was achieved in 47% (43/91) of individuals, 40% (17/43) of whom had an MD. Seven additional individuals in whom an MD was not suspected were diagnosed with an MD after broader analysis. Gene-agnostic analysis led to the discovery of 2 novel disease genes, with pathogenicity validated through targeted functional studies (CRLS1 and MRPL39). Functional studies enabled diagnosis in another 4 individuals. Of the 24 individuals ultimately diagnosed with an MD, 79% had a change in management, which included 53% whose care was redirected to palliation. CONCLUSION: Ultrarapid genetic diagnosis of MD in acutely unwell infants and children is critical for guiding decisions about the need for additional investigations and clinical management.

Humans↗

PubMed2026

Haplotype Blocks Are Associated With Rapid Local Adaptation to Environmental Shifts in Wild Barley.

Genomic mechanisms of local adaptation must be highly responsive in geographic regions where climate is changing rapidly. The Levant region is a critical biodiversity hotspot and the distribution edge for many species, including the wild ancestor of domesticated barley. This region is under an accelerated desertification process, thus enforcing a rapid genomic response to the projected environmental changes. To elucidate the genomic basis of rapid local adaptation, we studied wild barley populations using an ecological-genetic sampling design that decouples environmental variation from demographic background. We collected and sequenced 300 wild barley individuals and evaluated the phenotypes of 3600 progeny plants over 3 years. Our genomic analyses revealed that local adaptation is associated with clusters of candidate genes forming haplotype blocks. These clusters are enriched with environment and stress responsive genes, including flowering time regulators, drought and heat responsive genes. We identified six candidate adaptive haplotype blocks which span 1-8 Mbp and are distributed across chromosomes 1H, 2H, 4H and 5H, each segregating as two major haplotypes. Additionally, we integrated over 2600 occurrence records into ecological and evolutionary modelling to assess the genomic vulnerability of populations to projected future climates. Our study identifies candidate genomic regions and environmental drivers of local adaptation in wild barley and highlights the advantage of haplotype blocks architecture in orchestrating an efficient response to rapid environmental change. We highlight the ecological factors most strongly associated with the observed evolutionary responses and provide insights and guidelines for biodiversity conservation and implementation of crop wild relatives in breeding.

Hordeum↗

PubMed1979

Conservation and variation in Orthopoxvirus genome structure.

Orthopoxvirus DNA from representative strains of rabbitpox, vaccinia, monkeypox, variola, cowpox and ectromelia viruses was analysed by cleavage with restriction endonucleases HindIII, XhoI or SmaI. Genome mol. wt. vary from about 120 x 10(6) for rabbitpox to about 145 x 10(6) for cowpox. Physical maps of cleavage sites are similar and characteristic for strains of the same Orthopoxvirus type. The distribution of HindIII sites suggests that an internal region of mol. wt. about 30 x 10(6) is highly conserved between Orthopoxvirus genomes although some type-specific differences occur within this region, especially with strains of ectromelia virus. Conservation of internal sequences is less marked following analysis with XhoI although cleavages within this central region of particular genomes appear to represent a subset of preferred sites. Endonuclease SmaI cleaves exceptionally infrequently and distinguishes variola, monkeypox, vaccinia, cowpox or ectromelia viruses. Type specific differences result largely from extensive, near terminal variations in length and sequence. Representative Orthopoxvirus genomes have rapidly renaturing terminal restriction fragments confirming the presence of near terminal, covalent cross-links. Terminal restriction fragments from the same or different genomes generally cross hybridize indicating the presence of near terminal repetitions of mol. wt. up to 6 x 10(6) and which share at least a subset of common sequences. Variola strains however, appear to lack such sequences from one specific terminus which maps shorter than that of related viruses.

Base Sequence↗

PubMed2022

Effectiveness of rapid SARS-CoV-2 genome sequencing in supporting infection control for hospital-onset COVID-19 infection: Multicentre, prospective study.

BACKGROUND: Viral sequencing of SARS-CoV-2 has been used for outbreak investigation, but there is limited evidence supporting routine use for infection prevention and control (IPC) within hospital settings. METHODS: We conducted a prospective non-randomised trial of sequencing at 14 acute UK hospital trusts. Sites each had a 4-week baseline data collection period, followed by intervention periods comprising 8 weeks of 'rapid' (<48 hr) and 4 weeks of 'longer-turnaround' (5-10 days) sequencing using a sequence reporting tool (SRT). Data were collected on all hospital-onset COVID-19 infections (HOCIs; detected ≥48 hr from admission). The impact of the sequencing intervention on IPC knowledge and actions, and on the incidence of probable/definite hospital-acquired infections (HAIs), was evaluated. RESULTS: A total of 2170 HOCI cases were recorded from October 2020 to April 2021, corresponding to a period of extreme strain on the health service, with sequence reports returned for 650/1320 (49.2%) during intervention phases. We did not detect a statistically significant change in weekly incidence of HAIs in longer-turnaround (incidence rate ratio 1.60, 95% CI 0.85-3.01; p=0.14) or rapid (0.85, 0.48-1.50; p=0.54) intervention phases compared to baseline phase. However, IPC practice was changed in 7.8 and 7.4% of all HOCI cases in rapid and longer-turnaround phases, respectively, and 17.2 and 11.6% of cases where the report was returned. In a 'per-protocol' sensitivity analysis, there was an impact on IPC actions in 20.7% of HOCI cases when the SRT report was returned within 5 days. Capacity to respond effectively to insights from sequencing was breached in most sites by the volume of cases and limited resources. CONCLUSIONS: While we did not demonstrate a direct impact of sequencing on the incidence of nosocomial transmission, our results suggest that sequencing can inform IPC response to HOCIs, particularly when returned within 5 days. FUNDING: COG-UK is supported by funding from the Medical Research Council (MRC) part of UK Research & Innovation (UKRI), the National Institute of Health Research (NIHR) (grant code: MC_PC_19027), and Genome Research Limited, operating as the Wellcome Sanger Institute. CLINICAL TRIAL NUMBER: NCT04405934.

Humans↗

PubMed2026

Nosocomial Outbreak of Lassa Fever in Conakry, Guinea, 2022.

BACKGROUND: Lassa fever is endemic in Guinea, with high seroprevalence in the forest region. However, clinical cases have been only anecdotally reported. In August 2022, a nosocomial outbreak occurred at a private clinic in the capital, Conakry, an area previously considered low risk. METHODS: Suspected cases were confirmed by real-time reverse-transcription polymerase chain reaction within 24 hours. Viremia was monitored during hospitalization, and whole-genome sequencing was performed in-country within 13 days of outbreak detection. Outbreak investigation involved rodent testing in the home village of the suspected primary case. RESULTS: Six cases were laboratory-confirmed, 5 of which were healthcare workers of the clinic. The case fatality rate was 16.7%. Viral RNA remained detectable in blood of survivors for a median of 26 days (interquartile range, 24-41 days) post-disease onset. Epidemiological investigations identified a suspected primary case, who had died of a febrile disease compatible with Lassa fever, had contact with all secondary cases, and had a travel history from Kissidougou area. Three near-complete and 1 partial Lassa virus genomes were recovered from the secondary cases, which phylogenetically clustered with genomes from central Guinea. Consistent with a common transmission source, the 4 genomes were almost identical. Rodent testing revealed a new reservoir area in eastern-central Guinea. CONCLUSIONS: This outbreak highlights the vulnerability of healthcare settings in low-prevalence areas of West Africa to nosocomial Lassa virus transmission due to human mobility. Facilitated by capacity-building programs for viral hemorrhagic fevers, rapid diagnosis, genomic analysis, and ecological assessment enabled an efficient outbreak response and control.

Lassa Fever↗

PubMed2025

Annotation matters: the effect of structural gene annotation on orthology inference.

MOTIVATION: In silico gene annotation, the process of identifying the genes present in a genome, remains a challenging task. As genome assemblies rapidly increase, the corresponding gene models and repertoires often fall short in quality. Despite advances in annotation methods, a lack of community standards means that most published gene annotations result from ad hoc pipelines. As a result, only a few species have nearly complete and accurate gene models. This annotation quality is thought to affect downstream analyses, including orthology inference, often the first step of comparative genomics studies. RESULTS: We show that different annotation methods yield markedly distinct orthology inferences. We compared orthology assignments of gene models obtained by four prominent protein-coding gene model sources: the NCBI Eukaryotic Genome Annotation Pipeline, the Ensembl Gene Annotation System, the UniProt Reference Proteomes, and Augustus 3.4 (an ab initio pipeline). We observe significant discrepancies between sources, namely in the proportion of orthologous genes per genome, the completeness of Hierarchical Orthologous Groups, and the accuracy and recall of the predicted orthologs on a standard orthology benchmark.

Molecular Sequence Annotation↗

PubMed2025

Comparative Analysis of Mammalian Adaptive Immune Loci Revealed Spectacular Divergence and Common Genetic Patterns.

Adaptive immune responses are mediated by the production of adaptive immune receptors, antibodies, and T-cell receptors, which bind antigens, thus causing their neutralization. Unlike other proteins, adaptive immune receptors are not fully encoded in the germline genome and result from a complex of somatic processes collectively called V(D)J recombination affecting germline immunoglobulin (IG) and T-cell receptor (TR) loci consisting of template genes. While various existing studies report extreme diversity of antibodies and T-cell receptors, little is known about the diversity of germline IG and TR loci. To overcome this gap, the first comparative analysis of full-length sequences of IG/TR loci across 46 mammalian species from 13 taxonomic orders was performed. First, germline gene counts were shown to correlate in immunoglobulin heavy chain immunoglobulin heavy chain (IGH)/immunoglobulin lambda (IGL) loci and T-cell receptor alpha (TRA)/T-cell receptor beta (TRB) and anticorrelate in immunoglobulin kappa (IGK)/IGL, possibly indicating coevolution between corresponding chains. Second, structures of IG/TR loci were analyzed, and it was shown that IG/TR loci formed by long arrays of high multiplicity repeats are more common for species that have experienced population bottlenecks. Finally, haplotypes of IG/TR loci with little or no sequence similarity within a species were found, suggesting that they may have a limited potential for homologous recombination. These results demonstrate that IG/TR loci are rapidly evolving genomic regions whose structural variation is shaped by the population history of the species and open new perspectives for immunogenomics studies.

Animals↗

PubMed2026

Clinical and Functional Characterization of Gain-of-Function ABL1 Variants Expands the Phenotypic Spectrum of CHDSKM.

Germline gain-of-function (GOF) variants in ABL1 cause congenital heart defects and skeletal malformations syndrome (CHDSKM), a multisystem developmental disorder characterized by congenital heart disease, skeletal abnormalities, dysmorphic features, and variable developmental delay. More recently, biallelic loss-of-function variants and ABL haploinsufficiency have been associated with distinct phenotypes, expanding the allelic spectrum of ABL1-related disorders. We report three individuals with ABL1 variants. A female infant with tetralogy of Fallot, critical pulmonary stenosis, covered omphalocele, and a lethal outcome was found by rapid trio genome sequencing to harbor a de novo likely pathogenic ABL1 variant, NM_007313.2:c.354G>T p.(Trp118Cys). We also provide updated clinical follow-up of a previously reported individual and describe a third individual, both carrying the recurrent p.(Tyr245Cys) variant. Functional studies were performed and support a GOF mechanism. Similar activation was observed for Tyr245Cys despite the differences in clinical severity. Our findings expand the phenotypic spectrum of ABL1-related CHDSKM to include severe conotruncal heart disease and covered omphalocele. The comparison of two biochemically activating ABL1 variants demonstrates substantial clinical variability despite a shared molecular mechanism. Furthermore, the overlap between ventral body wall abnormalities in GOF disease and omphalocele associated with ABL1 haploinsufficiency suggests that precise regulation of ABL1 signaling is critical for normal ventral body wall formation.

ABL1↗

PubMed2022

The evolutionary dynamics of extrachromosomal DNA in human cancers.

Oncogene amplification on extrachromosomal DNA (ecDNA) is a common event, driving aggressive tumor growth, drug resistance and shorter survival. Currently, the impact of nonchromosomal oncogene inheritance-random identity by descent-is poorly understood. Also unclear is the impact of ecDNA on somatic variation and selection. Here integrating theoretical models of random segregation, unbiased image analysis, CRISPR-based ecDNA tagging with live-cell imaging and CRISPR-C, we demonstrate that random ecDNA inheritance results in extensive intratumoral ecDNA copy number heterogeneity and rapid adaptation to metabolic stress and targeted treatment. Observed ecDNAs benefit host cell survival or growth and can change within a single cell cycle. ecDNA inheritance can predict, a priori, some of the aggressive features of ecDNA-containing cancers. These properties are facilitated by the ability of ecDNA to rapidly adapt genomes in a way that is not possible through chromosomal oncogene amplification. These results show how the nonchromosomal random inheritance pattern of ecDNA contributes to poor outcomes for patients with cancer.

Biological Evolution↗

PubMed2025

tidk: a toolkit to rapidly identify telomeric repeats from genomic datasets.

SUMMARY: "tidk" (short for telomere identification toolkit) uses a simple, fast algorithm to scan long DNA reads for the presence of short tandemly repeated DNA in runs, and to aggregate them based on canonical DNA string representation. These are telomeric repeat candidates. Our algorithm is shown to be accurate in genomes for which the telomeric repeat unit is known and is tested across a wide variety of newly assembled genomes to uncover new telomeric repeat units. Tools are provided to identify telomeric repeats de novo, scan genomes for known telomeric repeats, and to visualize telomeric repeats on the assembly. "tidk" is implemented in Rust and is available as a command line tool which can be compiled using the Rust toolchain or downloaded as a binary from bioconda. AVAILABILITY AND IMPLEMENTATION: The "tidk" Rust crate is freely available under the MIT license (https://crates.io/crates/tidk), and the source code is available at https://github.com/tolkit/telomeric-identifier.

Telomere↗

PubMed2025

Orthrus: Towards Evolutionary and Functional RNA Foundation Models.

In the face of rapidly accumulating genomic data, our ability to accurately predict key mature RNA properties that underlie transcript function and regulation remains limited. Pre-trained genomic foundation models offer an avenue to adapt learned RNA representations to biological prediction tasks. However, existing genomic foundation models are trained using strategies borrowed from textual domains that do not leverage biological domain knowledge. Here, we introduce Orthrus, a Mamba-based mature RNA foundation model pre-trained using a novel self-supervised contrastive learning objective with biological augmentations. Orthrus is trained by maximizing embedding similarity between curated pairs of RNA transcripts, where pairs are formed from splice isoforms of 10 model organisms and transcripts from orthologous genes in 400+ mammalian species from the Zoonomia Project. This training objective results in a latent representation that clusters RNA sequences with functional and evolutionary similarities. We find that the generalized mature RNA isoform representations learned by Orthrus significantly outperform genomic foundation models on mRNA property prediction tasks, and requires only a fraction of fine-tuning data to do so. Finally, we show that Orthrus is capable of capturing divergent biological function of individual transcript isoforms.

Journal Article↗

PubMed2025

Biofilms in clinical infection: pathophysiology, diagnosis, and the evolving therapeutic landscape.

Biofilms are structured communities of microorganisms encased in a self-produced polymeric matrix that typically adhere to surfaces. Recent research, however, has revealed that non-attached aggregates share many common traits with the surface-dependent biofilms. This mode of bacterial growth provides enhanced protection against antibiotics and resistance to host immune defenses. Biofilms require higher antibiotic concentrations than those needed to inhibit planktonic bacteria, necessitating prolonged high-dose and combination therapies to achieve effective eradication. This increased resistance is attributed to multiple factors, including the protective extracellular matrix, reduced metabolic activity of bacteria within the biofilm, and also the ability of bacterial genomes to rapidly adjust in response to environmental changes. Diagnostic modalities such as sonication, tissue culture, and polymerase chain reaction-based assays currently dominate clinical diagnostics of biofilm infections due to their practicality, cost-effectiveness, and proven reliability. Recent research has led to innovative treatment strategies that target biofilm structure, enhance drug delivery, and modulate host-pathogen interactions. This review summarizes our current knowledge of biofilm formation, explores the current techniques for detecting microbial biofilms, and discusses future perspectives for advancing diagnostic and therapeutic strategies.

Biofilms↗

PubMed2025

Whole genome sequencing and phylogenetic classification accelerate the implementation of respiratory syncytial virus genomic surveillance in Canada: a pilot study.

UNLABELLED: Whole genome sequencing (WGS) has emerged as a powerful tool to facilitate the study of existing and emerging infectious diseases. WGS-based genomic surveillance provides information on the genetic diversity and tracks the evolution of important viral pathogens, including respiratory syncytial virus (RSV). Multiplex tiling polymerase chain reaction (PCR) assays have been used to facilitate sequencing of a variety of pathogens in support of genomics-based surveillance initiatives. We developed, optimized, and implemented multiplex tiling PCR assays for RSVA and RSVB capable of generating near-complete genomes in the majority of contemporaneous specimens tested. A pilot data set comprising 52 RSVA and 37 RSVB genomes derived from Canadian clinical specimens during the 2022-2023 respiratory virus season was used to perform phylogenetic analyses using both near-complete genome and glycoprotein (G) sequences. Overall, the RSV phylogenetic tree built with whole genomes showed identical lineage clusters as compared to the G gene but was more discriminatory. Moreover, the availability of complete genomes enables the identification of a broader range of mutations. For instance, mutations identified in the fusion protein among Canadian isolates tested here, including S377N, K272M, S276N, S211N, S206I, and S209Q, could affect the efficacy of current vaccines or antiviral-based therapeutics. In conclusion, our work reinforces other recent studies demonstrating the utility of multiplex tiling PCR assays to facilitate high-throughput WGS of RSV, which is capable of supporting enhanced genomic surveillance initiatives, as well as the more comprehensive genomic analyses required to inform public health strategies for the development and usage of vaccines and antiviral drugs. IMPORTANCE: We present assays to efficiently sequence genomes of RSVA and RSVB. This enables researchers and public health agencies to acquire high-quality genomic data using rapid and cost-effective approaches. Genomic data-based comparative analysis can be used to conduct surveillance and monitor circulating isolates for efficacy of vaccines and antiviral therapeutics.

Humans↗

PubMed2024

Congenital hallux valgus occurs in Fibrodysplasia Ossificans Progressiva and BMPR1B-associated dysplasia: an important distinction.

BACKGROUND: Fibrodysplasia Ossificans Progressiva (FOP; OMIM #135100) is an ultrarare genetic disorder characterised by congenital bilateral hallux valgus (CBHV), intermittent soft tissue swellings and progressive heterotopic ossification. We report a three-month-old girl with great toe abnormalities similar to FOP, in whom comprehensive clinical workup and genetic investigations illustrates an alternative diagnosis. CASE PRESENTATION: A three-month-old girl presented with CBHV. The antenatal period was unremarkable, she was born by spontaneous vaginal delivery with an uneventful subsequent course, except for maternal concern of her bent toes which received reassurance from several health professionals. Her mother's persisting concerns were explored via the internet and social media leading her to request referral to an expert bone centre for consideration of FOP. On examination, she was thriving, there was no dysmorphism, subcutaneous lumps, skeletal or extra-skeletal deformity except for shortened great toes with lateral deviation of the proximal and distal phalanges. FOP was a feasible diagnosis, for which CBHV is highlighted as an early sign. A cautionary potential diagnosis of FOP was counselled, including advice to defer intramuscular immunisations until genetic results available. Genetic investigation was undertaken through rapid whole genomic sequencing (WGS), with analysis of data from a skeletal dysplasia gene panel, which demonstrated no ACVR1variants. The only finding was a heterozygous variant of unknown significance in BMPR1B (c1460T>A, p.(Val487Asp)), which encodes a bone morphogenic receptor involved in brachydactyly syndromes A1, A2 and D and acromesomelic dysplasia 3 (only the latter being an autosomal recessive condition). CONCLUSION: This report highlights that CBHV serves as a vital diagnostic indicator of FOP and affected infants should be considered and investigated for FOP, including precautionary management whilst awaiting genetic studies. The second educational aspect is that CBHV may not represent a generalised skeletal disorder, or one much less significant than FOP. Receptor-ligand BMP and Activins mediated interactions are instrumental in the intricate embryology of the great toe. Recognition of non-FOP conditions caused by alterations in different genes are likely to increase with new genomic technology and large gene panels, enhancing understanding of bone signaling pathways.

Humans↗

PubMed2026

The cellular protein TIAR mediates rapid initiation of West Nile virus genome RNA synthesis.

During the intracellular replication cycle of West Nile virus (WNV), genome RNA synthesis is initially inefficient but increases exponentially as viral replication complexes are sequestered in invaginations in the endoplasmic reticulum. In this study, we investigated the functional role of the cellular protein TIAR (T-cell intracellular antigen-related protein) in the transcription of WNV genome RNA. Close colocalization of cytoplasmic TIAR with viral double-stranded RNA was detected by a proximity ligation assay in WNV-infected cells. TIAR binds specifically to the WNV 3'(-) SL but not to the complementary WNV 5'(+) SL in in vitro RNA binding assays. Only the 3' end of the WNV minus-strand RNA was enriched by immunoprecipitation of infected cell lysates with anti-TIAR antibody. Stable overexpression of TIAR in clonal A549 cells increased the ratio of intracellular viral plus-strand to minus-strand RNA in a dose-dependent manner. TIAR contains three RNA recognition motifs (RRMs). Biophysical data indicated that only RRM2 directly contacts RNA and that up to three TIAR molecules can bind cooperatively to the WNV 3'(-) SL RNA. These data provide additional evidence that TIAR functions as a proviral host factor facilitating exponential amplification of WNV genome production in infected cells.IMPORTANCEWest Nile virus (WNV) is a mosquito-borne orthoflavivirus associated with increasing global human disease incidence. The molecular mechanisms underlying viral replication are not fully understood. In early stages of infection, viral genome transcription is inefficient; however, in late stages, viral genome transcription increases exponentially. T-cell intracellular antigen-related (TIAR) protein is a cellular protein that has been shown to interact with the 3' end of the WNV negative-sense antigenomic RNA. We obtained data showing colocalization of cellular TIAR with viral replication complexes in infected cells and an increased ratio of intracellular genomic to antigenomic viral RNA in TIAR-overexpressing cells, and confirmed preferential binding of TIAR to the 3' end of the WNV antigenome both in vitro and in infected cell extracts. We also demonstrated that multiple TIAR proteins can bind cooperatively to the WNV 3'(-) stem-loop RNA. These data provide supporting evidence for a model of TIAR-mediated rapid initiation of nascent genome RNA synthesis in infected cells.

TIAR↗

PubMed2026

Advances in CRISPR multiplex gene editing to map and modify stress-responsive transcription factor networks for crop improvement.

The development of CRISPR multiplex genome-editing (MGE) tools is rapidly transforming plant functional genomics and accelerating crop improvements. By simultaneously targeting two or more DNA loci, it allows scientists to precisely edit multiple genes at the single-nucleotide level, within the target genome. Simultaneous manipulation of multiple targets has revolutionized the functional elucidation studies, particularly the dissection of complex genetic pathways. Due to its superior precision and feasibility, CRISPR-MGE is widely accepted and has largely replaced alternative editing tools such as TALENs and ZFNs. Several CRISPR-MGE strategies, including the use of individual expression cassettes, tRNA-processing enzymes, Csy4 or ribozymes, have been successfully deployed in plants. Recent advancements, such as Cpf1, transgene-free methods, or ultra-multiplexing approaches, have further refined the technology into a powerful, efficient, and robust toolkit. MGE enables complex genome editing, including multiple-gene knockouts, base alterations, transcriptional regulation, metabolic engineering, or their combinations. Consequently, it is ideal for elucidating the function of transcription factors that are key molecular players in regulating diverse plant responses, especially in stress pathways. Several stress-responsive TFs have been functionally characterized via CRISPR-MGE, and more advanced tools are being employed. This review evaluates multiplexing tools, their diverse applications, and the current progress toward developing advanced MGE tools. Ultimately, we provide evidence to encourage the use of advanced MGE tools for functional characterization studies of stress-responsive TFs, thereby highlighting their potential to accelerate crop improvement.

Gene Editing↗

PubMed2026

Lift&Add-rapid and robust addition of new species to alignments of conserved non-coding sequences.

MOTIVATION: Identifying sequence constraint across long evolutionary distances is a powerful method for the discovery of functional genomic sequences, especially putative non-coding elements. Conserved elements have been a mainstay of comparative genomic research, and can be further investigated for species-specific sequence acceleration to dissect the genetic basis of trait evolution. The conclusions of these comparative genomic studies are contingent on the number and range of species included in this phylogenetic analysis. However, while the number of metazoan genomes sequences is increasing rapidly, adding new genomes to existing whole-genome alignments remains computationally expensive. RESULTS: Here, we present a bioinformatic workflow, Lift&Add, that enables conserved elements, coding or non-coding, to be rapidly mapped to new genomes ("Lift") and subsequently be added to pre-existing multiple species alignments ("Add"), thus providing an avenue for easy exploration of these putative functional elements. Focusing here on a group of species that has been largely under-represented in genomic comparisons, the marsupials, we demonstrate the intuition behind this workflow and provide an example comparative genomic analysis that can be performed. IMPLEMENTATION AND AVAILABILITY: Lift&Add is implemented as a series of scripts in Snakemake and bash, which can be downloaded from https://github.com/navyashukladr/Lift_and_Add.

Conserved Sequence↗

PubMed1979

Late replication and recombination in the vegetative pool of T4.

The rates and extents of replication are the same for all members of the vegetative pool, whether already residing (progeny) or newly entered (superinfecting). Thus, no member of the pool is sequestered in a replicative complex. Amber N82 infections of nonpermissive host result in extensive breakdown of phage DNA. The extent of fragmentation observed depends on the multiplicity of infection and whether phage ligase is present. Hence, parental DNA suffers single-strand nicks which can be repaired by ligase only if recombination does not interfere. The physiological role of ligase in compensating for such nicks is reemphasized. Superinfecting genomes recombine very rapidly with progeny molecules whose combined lengths are approximately six times that of the superinfecting genomic fragment. The superinfecting phage does not replicate before recombining. Therefore, the lack of replication poses no barrier to efficient recombination.

DNA Ligases↗