Biology subjects

Rahman, S.

Publications and source records attributed to Rahman, S..

71 records · Page 4Linked to original sources

bioRxiv2021

From compartments to gene loops: Functions of the 3D genome in the human brain

The 3D genome plays a key role in the regulation of gene expression. However, little is known about the spatiotemporal organization of chromatin during human brain development. We investigated the 3D genome in human fetal cortical plate and in adult prefrontal cortical neurons and glia. We found that neurons have weaker compartments than glia that emerge during fetal development. Furthermore, neurons form loop domains whereas glia form compartment domains. We show through CRISPRi on CNTNAP2 that transcription is coupled to loop domain insulation. Gene regulation during neural development involves increased use of enhancer-promoter and repressor-promoter loops. Finally, transcription is associated with gene loops. Altogether, we provide novel insights into the relationship between gene expression and different scales of chromatin organization in the human brain.

genomics↗

bioRxiv2021

Acetylated Chromatin Domains Link Chromosomal Organization to Cell- and Circuit-level Dysfunction in Schizophrenia and Bipolar Disorder

To explore modular organization of chromosomes in schizophrenia (SCZ) and bipolar disorder (BD), we applied population-scale correlational structuring of 739 histone H3-lysine 27 acetylation and H3-lysine 4 trimethylation profiles, generated from the prefrontal cortex (PFC) of 568 cases and controls. Neuronal histone acetylomes and methylomes assembled as thousands of cis-regulatory domains (CRDs), revealing fine-grained, kilo-to megabase scale chromatin organization at higher resolution but firmly integrated into Hi-C chromosomal conformations. Large clusters of domains that were hyperacetylated in disease shared spatial positioning within the nucleus, predominantly regulating PFC projection neuron function and excitatory neurotransmission. Hypoacetylated domains were linked to inhibitory interneuron- and myelination-relevant genes. Chromosomal modular architecture is affected in SCZ and BD, with hyperacetylated domains showing unexpectedly strong convergences defined by cell type, nuclear topography, genetic risk, and active chromatin state across a wide developmental window.

genomics↗

bioRxiv2021

Transcribed enhancers in the human brain identify novel disease risk mechanisms

Identification of risk variants for neuropsychiatric diseases within enhancers underscores the importance of understanding the population-level variation of enhancers in the human brain. Besides regulating tissue- and cell-type-specific transcription of target genes, enhancers themselves can be transcribed. We expanded the catalog of known human brain transcribed enhancers by an order of magnitude by generating and jointly analyzing large-scale cell-type-specific transcriptome and regulome data. Examination of the transcriptome in 1,382 brain samples in two independent cohorts identified robust expression of transcribed enhancers. We explored gene-enhancer coordination and found that enhancer-linked genes are strongly implicated in neuropsychiatric disease. We identified significant expression quantitative trait loci (eQTL) for 25,958 enhancers which mediate 6.8% of schizophrenia heritability, mostly independent from standard gene eQTL. Inclusion of enhancer eQTL in transcriptome-wide association studies enhanced functional interpretation of disease loci. Overall, our study characterizes the enhancer-gene regulome and genetic mechanisms in the human cortex in both healthy and disease states.

neuroscience↗

bioRxiv2021

Genomic analysis of response to neoadjuvant chemotherapy in esophageal adenocarcinoma

Neoadjuvant therapy followed by surgery is the standard of care for locally advanced esophageal adenocarcinoma (EAC). Unfortunately, response to neoadjuvant chemotherapy (NAC) is poor (<20%), as is the overall survival benefit at 5 years (5%). The EAC genome is complex and heterogeneous between patients, and it is not yet understood whether specific mutational patterns may result in chemotherapy sensitivity or resistance. To identify associations between genomic events and response to NAC in EAC, a comparative genomic analysis was performed in 65 patients with extensive clinical and pathological annotation using whole-genome sequencing (WGS). We defined response using Mandard Tumor Regression Grade (TRG), with responders classified as TRG1-2 (n=27) and non-responders classified as TRG4-5 (n=38). We report a higher non-synonymous mutation burden in responders (median 2.08/Mb vs 1.70/Mb, P=0.036) and elevated copy number variation in non-responders (282 vs 136/patient, P<0.001). We identified copy number variants unique to each group in our cohort, with cell cycle (CDKN2A, CCND1), c-Myc (MYC), RTK/PIK3 (KRAS, EGFR) and gastrointestinal differentiation (GATA6) pathway genes being specifically altered in non-responders. Of note, NAV3 mutations were exclusively present in the non-responder group with a frequency of 22%. Thus, lower mutation burden, higher chromosomal instability and specific copy number alterations are associated with resistance to NAC.

genomics↗

bioRxiv2021

Finding Druggable Sites in Proteins using TACTICS

Structure-based drug discovery efforts require knowledge of where drug-binding sites are located on target proteins. To address the challenge of finding druggable sites, we developed a machine-learning algorithm called TACTICS (Trajectory-based Analysis of Conformations To Identify Cryptic Sites), which uses an ensemble of molecular structures (such as molecular dynamics simulation data) as input. First, TACTICS uses k-means clustering to select a small number of conformations that represent the overall conformational heterogeneity of the data. Then, TACTICS uses a random forest model to identify potentially bindable residues in each selected conformation, based on protein motion and geometry. Lastly, residues in possible binding pockets are scored using fragment docking. As proof-of-principle, TACTICS was applied to the analysis of simulations of the SARS-CoV-2 main protease and methyltransferase and the Yersinia pestis aryl carrier protein. Our approach recapitulates known small-molecule binding sites and predicts the locations of sites not previously observed in experimentally determined structures. The TACTICS code is available at https://github.com/Albert-Lau-Lab/tactics_protein_analysis.

biophysics↗

bioRxiv2021

Neural markers for Musical Creativity in Jazz Improvisation and Classical Interpretation

Two main types of musical creativity in the western canon are improvisation and interpretation. With improvisation, the fundamental structure of the melody, chords, rhythm and tempo of a piece can be modified, while with interpretation, the focus is on the emotional dynamics. Here we characterise electrical brain activity from professional jazz and classical pianists, whilst they were engaged in these different creative tasks with musical excerpts from both genres. Multivariate EEG was recorded during two phases of each task, mental planning and actual performance. Subsequently neuronal activity patterns were source localised with standardised low resolution electromagnetic tomography (sLORETA). For each musical performance, we obtained both subjective (self-rated) and objective (blind, expert-rated) measures of musical creativity. Across both tasks and genre backgrounds, within the first and middle 4 second segments of the performance phase, for musical performances that were judged highly creative objectively by external expert music assessors, we observed an increased activation in the anterior cingulate and medial prefrontal cortex (Brodmann area, BA32), suggesting a maintenance of executive control, and integrating motoric and emotional communication during creativity. Across genre backgrounds, within the performance phase for the interpretation task compared to the improvisation task, there was an increased activity in the insula (BA 13), suggesting a convergent creative task from the linked goal-orientated conscious error-monitoring and audio-visual integration functions. Genre profession also gave rise to differences across phases; jazz pianists presented a decreased parietal (BA7) activity during improvisation tasks suggesting a role for defocussed attention and for classical pianists, both tasks were associated with occipitotemporal (BA 37) activity which is involved in semantic/ metaphorical processing suggesting a close adherence to the visual score. These 3 areas relate the cognitive demands of the creative musical task to the demands of the corresponding genre of music. HighlightsO_LIEEG activity associated to musical creativity types: Improvisation and Interpretation C_LIO_LIIncreased activity in Insula (BA 13) for Interpretation suggest convergent creativity C_LIO_LIDecreased Precuneus (BA7) activity for Improvisation suggest defocussed attention C_LIO_LIIncreased activity in medial prefrontal cortex (BA32) in highly creative performance C_LI

neuroscience↗

bioRxiv2021

The three-dimensional landscape of chromatin accessibility in Alzheimer's disease

Much is still unknown about the neurobiology of Alzheimers disease (AD). To better understand AD, we generated 636 ATAC-seq libraries from cases and controls to construct detailed genomewide chromatin accessibility maps of neurons and non-neurons from two AD-affected brain regions, the entorhinal cortex and superior temporal gyrus. By analyzing a total of 19.6 billion read pairs, we expanded the known repertoire of regulatory sequences in the human brain. Multi-omic data integration associated global patterns of chromatin accessibility with gene expression and identified cell-specific enhancer-promoter interactions. Using inter-individual variation in chromatin accessibility, we define cis-regulatory domains capturing the 3D structure of the genome. Multifaceted analyses uncovered disease associated perturbations impacting chromatin accessibility, transcription factor regulatory networks and the 3D genome, and implicated transcriptional dysregulation in AD. Overall, we applied a systematic approach to understand the role of the 3D genome in AD and to illuminate novel disease biology that can advance diagnosis and therapy.

neuroscience↗

bioRxiv2020

Complete mitochondrial genome sequence of Bos frontalis (Gayal) from Bangladesh

The Gayal is a large-sized endangered semi-domesticated bovine species belonging to the family Bovidae, tribe Bovini, group Bovina, genus Bos, and species Bos frontalis. It is also called the Mithan or Mithun. Mitochondrial genome is considered as an important tool for species identification and monitoring the populations of conservation concern and therefore it becomes an obligation to sequence the mitochondrial genome of Bagladeshi gayal. We want to identify some important genes related to a particular trait such as those associated with adaptation, muscle strength, or prolificacy. The data will help explore evolutionary relationships with closely related species. The mitogenome of Bos frontalis is 16,347 bp in length and nucleotide composition is AT-based (60.21%), contains 37 genes including 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes, and a control region.

bioinformatics↗

bioRxiv2020

Detection of 'relict' western lineage of citrus tristeza virus virulent genotype in declining Arunachal Wakro orange

Eastern Himalayan foothills are known to have optimal agro-climatic conditions for production of quality citrus fruits including oranges. Among the citrus growing regions of eastern Himalayas, Wakro in the far eastern state of Arunachal Pradesh is known for its superior quality oranges, popular as the Wakro orange or the Arunachal orange, which has been included in Geographical Indication Registry by the Government of India. However, during last few years, Arunachal orange orchards have been experiencing severe infestation of aphid associated with rapid decline disease, causing catastrophe to the farmers as well as state economy. Therefore, in 2015, an intensive survey of severely affected orange orchards was carried out to investigate the aetiological factors of citrus decline. RNA samples extracted from leaf and aphid specimens collected from Wakro orchards were subjected to CTV detection through 3-UTR specific RT-PCR. Subsequently, ORF1 and CP genetic regions were amplified and clonal-sequencing was performed. Although, BLAST search showed close homology of the present sequences with other virulent genotype VT sequences, detailed phylogenetic analysis demonstrated affinity and clustering of present sequences with VT sequences belonging to the western lineage. This finding is considerably distinct from CTV sequences reported from citrus growing orchards in India and other neighbouring countries. Additionally, low diversity of CP gene sequences, recombination patterns and presence of sequence segments identical to the present ones in other CTV genotypes was also revealed. Collectively, these observations indicate pristine and primeval nature of present CTV sequences, corroborating well with the proposed origin of CTV in this part of the globe. We here report our finding of western lineage of CTV virulent genotype VT, which is distinct from CTV molecular epidemiology in other parts of India and discuss the implications of these findings.

microbiology↗

bioRxiv2020

Central opioid receptors mediate morphine-induced itch and chronic itch

Opioids, such as morphine are mainstay treatments for clinical pain conditions. Itch is a common side effect of opioids, particularly as a result of epidural or intrathecal (i.t.) administration. Recent progress has advanced our understanding of itch circuits in the spinal cord. However, the mechanisms underlying opioid-induced itch are not fully understood, although an interaction between {micro}-opioid receptor (MOR) and gastrin-releasing peptide receptor (GRPR) in spinal GRPR-expressing neurons has been implicated. In this study we investigated the cellular mechanisms of intrathecal (i.t.) opioid-induced itch by conditional deletion of MOR-encoding Oprm1 in distinct populations of interneurons and sensory neurons. We found that i.t. injection of the MOR agonists morphine or DAMGO elicited dose-dependent scratching, but this pruritus was totally abolished in mice with a specific Oprm1 deletion in Vgat+ neurons (Oprm1-Vgat). Loss of MOR in somatostatin+ interneurons and TRPV1+ sensory neurons did not affect morphine-induced itch but impaired morphine-induced antinociception. In situ hybridization revealed Oprm1 expression in 30% of inhibitory and 20% of excitatory interneurons in the spinal dorsal horn. Whole-cell recordings from spinal cord slices showed that DAMGO induced outward currents in 9 out of 19 Vgat+ interneurons examined. Morphine also inhibited action potentials in Vgat+ interneurons and suppressed evoked IPSCs in postsynaptic Vgat- excitatory neurons, suggesting a mechanism of disinhibition by MOR agonists. Notably, morphine-elicited itch was suppressed by i.t. administration of NPY and abolished by spinal ablation of GRPR+ neurons, whereas i.t. GRP-induced itch response remained intact in mice lacking Oprm1-Vgat. Additionally, chronic itch from DNFB-induced allergic contact dermatitis was decreased by Oprm1-Vgat deletion. Finally, naloxone, but not peripherally restricted naloxone methiodide, inhibited chronic itch in the DNFB model and the cutaneous T-cell lymphoma (CTCL) model, indicating a contribution of central MOR signaling to chronic itch. Our findings demonstrate that i.t. morphine elicits itch via acting on MOR on spinal inhibitory interneurons, leading to disinhibition of the spinal itch circuit. Our data also suggest that chronic itch could be effectively treated with CNS-targeted naloxone.

neuroscience↗

bioRxiv2020

Salt tolerance QTL derived from the Bangladeshi landrace Horkuch

Salinity has a significant negative impact on production of rice. To cope with the increased soil salinity due to climate change, we need to develop salt tolerant rice varieties that can maintain their high yield. Rice landraces indigenous to coastal Bangladesh can be a great resource to study the genetic basis of salt adaptation. In this study, we implemented a QTL analysis framework on a reciprocal mapping population between a salt tolerant landrace Horkuch and a high yieldingrice variety IR29. Our aim was to detect genetic loci that contributes to the salt adaptive responses of the two different developmental stages of rice which are very sensitive to salinity stress. We identified 14 QTL for 9 traits and found that most are unique to the specific developmental stage. In addition, we detected a significant effect of the cytoplasmic genome on the QTL model for some traits such as leaf total potassium and filled grain weight. This underscores the importance of considering cytoplasm-nuclear interaction for breeding programs. Along with this, we identified QTL co-localization for multiple traits that highlights the possible constraint of multiple QTL selection for breeding programs due to different contributions of a donor allele for different traits. HighlightsWe identified genetic loci for the salt tolerance response of two different developmental stages of the rice plant and detected significant contribution of cytoplasm-nuclear genome interaction for a few traits.

plant biology↗

bioRxiv2019

Growth factor-mediated coupling between lineage size and cell fate choice underlies robustness of mammalian development

Precise control and maintenance of the size of cell populations is fundamental for organismal development and homeostasis. The three cell types that comprise the mammalian blastocyst-stage embryo are generated in precise proportions and over a short time, suggesting a size control mechanism ensures a reproducible outcome. Guided by experimental observations, we developed a minimal mathematical model that shows growth factor signaling is sufficient to guarantee this robustness. The model anticipates, without additional parameter fitting, the response of the embryo to perturbations in its lineage composition. We experimentally added lineage-restricted cells to the epiblast both in vivo and in silico, which resulted in a shift of the fate of progenitors away from the supernumerary cell type, while eliminating cells using laser ablation biased the specification of progenitors towards the targeted cell type. Finally, we show that FGF4 couples cell fate decisions to lineage composition through changes in local concentration of the growth factor. Our results provide a basis for the regulative abilities of the mammalian embryo and reveal how, in a self-organizing system, individual cell fate decisions are coordinated at the population level to robustly generate tissues in the right proportions.

developmental biology↗

bioRxiv2019

Genomic characterization of Vibrio parahaemolyticus from Pacific white shrimp and rearing water reveals novel sequence types and multiple introductions of Photorhabdus insect-related (Pir) toxin-like genes into Malaysia

The Malaysian and global shrimp aquaculture production has been significantly impacted by acute hepatopancreatic necrosis disease (AHPND) typically caused by Vibrio parahaemolyticus harboring the pVA plasmid containing the pirAVpand pirBVpgenes which code for Photorhabdus insect-related (Pir) toxin. The limited genomic resource for V. parahaemolyticus strains from Malaysian aquaculture farms precludes an in-depth understanding of their diversity and evolutionary relationships. In this study, we isolated shrimp-associated and environmental (rearing water) V. parahaemolyticus from three aquaculture farms located in Northern and Central Malaysia followed by whole-genome sequencing of 40 randomly selected isolates on the Illumina MiSeq. Phylogenomic analysis and multilocus sequence typing (MLST) reveal distinct lineages of V. parahaemolyticus that harbor the pirABVpgenes. The recovery of pVA plasmid backbone devoid of pirAVp or pirABVp in some V. parahaemolyticus isolates suggests that the toxin genes are prone to deletion. The new insight gained from phylogenomic analysis of Asian V. parahaemolyticus, in addition to the observed genomic instability of pVa plasmid, will have implications for improvements in aquaculture practices to diagnose, treat or limit the impacts of this disease.

microbiology↗

bioRxiv2018

Incremental BLAST: incremental addition of new sequence databases through e-value correction

MotivationSearch results from local alignment search tools use statistical parameters sensitive to the size of the database. NCBI BLAST, for example, reports important matches using similarity scores and expect or e-values calculated against database size. Over the course of an investigation, the database grows and the best matches may change. To update the results of a sequence similarity search to find the most optimal hits, bioinformaticians must rerun the BLAST search against the entire database; this translates into irredeemable spent time, money, and computational resources.\n\nResultsWe develop an efficient way to redeem spent BLAST search effort by introducing the Incremental BLAST. This tool makes use of the previous BLAST search results as it conducts new searches on only the incremental part of the database, recomputes statistical metrics such as e-values and combines these two sets of results to produce updated results. We develop statistics for correcting e-values of any BLAST result against any arbitrary sequence database. The experimental results and accuracy analysis demonstrate that Incremental BLAST can provide search results identical to NCBI BLAST at a significantly reduced computational cost. We apply three case studies to showcase different use cases where Incremental BLAST can make biological discovery more efficiently at a reduced cost. This tool can be used to update sequence blasts during the course of genomic and transcriptomic projects, such as in re-annotation projects, and to conduct incremental addition of taxon-specific sequences to a BLAST database. Incremental BLAST performs (1 +{delta} )/{delta} times faster than NCBI BLAST for{delta} fraction of database growth.\n\nAvailabilityIncremental BLAST is available at https://bitbucket.org/sajal000/incremental-blast.\n\nContactsajal@vt.edu\n\nSupplementary informationSupplementary data are available at https://bitbucket.org/sajal000/incremental-blast

bioinformatics↗

bioRxiv2018

Mutations in ELAC2 associated with hypertrophic cardiomyopathy impair mitochondrial tRNA 3’-end processing

Dysfunction of mitochondrial gene expression, caused by mutations in either the mitochondrial or nuclear genomes, is associated with a diverse group of human disorders characterized by impaired mitochondrial respiration. Within this group, an increasing number of mutations have been identified in nuclear genes involved in mitochondrial RNA metabolism. For instance, pathogenic mutations have been identified in the genes encoding enzymes involved in the precursor transcript processing, including ELAC2. The ELAC2 gene codes for the mitochondrial RNase Z, which is responsible for endonucleolytic cleavage of the 3 ends of mitochondrial pre-tRNAs. Here, we report the identification of sixteen novel ELAC2 variants in individuals presenting with mitochondrial respiratory chain deficiency, hypertrophic cardiomyopathy and lactic acidosis. We provided further evidence for the pathogenicity of the three previously reported variants by studying the RNase Z activity in an in vitro system and applied this recombinant system to investigate all novel missense variants, confirming the pathogenic role of these new ELAC2 mutations. We also modelled the residues affected by missense mutation in solved RNase Z structures, providing insight into enzyme structure and function. Finally, we show that primary fibroblasts from the individuals with novel ELAC2 variants have elevated levels of unprocessed mitochondrial RNA precursors. Our study thus broadly confirms the correlation of ELAC2 variants with severe infantile-onset forms of hypertrophic cardiomyopathy and mitochondrial respiratory chain dysfunction. One rare missense variant associated with the occurrence of prostate cancer (p.Arg781His) impairs the mitochondrial RNase Z activity of ELAC2, possibly indicating a functional link between tumorigenesis and mitochondrial RNA metabolism.

genetics↗

bioRxiv2018

Rapid Paediatric Sequencing (RaPS): Comprehensive real-life workflow for rapid diagnosis of critically ill children

BackgroundRare genetic conditions are frequent risk factors for, or direct causes of, organ failure requiring paediatric intensive care unit (PICU) support. Such conditions are frequently suspected but unidentified at PICU admission. Compassionate and effective care is greatly assisted by definitive diagnostic information. There is therefore a need to provide a rapid genetic diagnosis to inform clinical management.\n\nTo date, Whole Genome Sequencing (WGS) approaches have proved successful in diagnosing a proportion of children with rare diseases, but results may take months to report or require the use of equipment and practices not compatible with a clinical diagnostic setting. We describe an end-to-end workflow for the use of rapid WGS for diagnosis in critically ill children in a UK National Health Service (NHS) diagnostic setting.\n\nMethodsWe sought to establish a multidisciplinary Rapid Paediatric Sequencing (RaPS) team for case selection, trio WGS, a rapid bioinformatics pipeline for sequence analysis and a phased analysis and reporting system to prioritise genes with a high likelihood of being causal. Our workflow was iteratively developed prospectively during the analysis of the first 10 children and applied to the following 14 to assess its utility.\n\nFindingsTrio WGS in 24 critically ill children led to a molecular diagnosis in ten (42%) through the identification of causative genetic variants. In three of these ten individuals (30%) the diagnostic result had an immediate impact on the individuals clinical management. For the last 14 trios, the shortest time taken to reach a provisional diagnosis was four days (median 7 days).\n\nInterpretationRapid WGS can be used to diagnose and inform management of critically ill children using widely available off the shelf products within the constraints of an NHS clinical diagnostic setting. We provide a robust workflow that will inform and facilitate the rollout of rapid genome sequencing in the NHS and other healthcare systems globally.\n\nFundingThe study was funded by NIHR GOSH/UCL BRC: ormbrc-2012-1

genomics↗

bioRxiv2017

Spatial organization of single mRNPs at different stages of the gene expression pathway

mRNAs form ribonucleoprotein complexes (mRNPs) by association with proteins that are crucial for mRNA metabolism. While the mRNP proteome has been well characterized, little is known about mRNP organization. Using a single molecule approach, we show that mRNA conformation changes depending on its cellular localization and translational state. Compared to nuclear mRNPs and lncRNPs, association with ribosomes decompacts individual mRNAs, while their sequestration into stress-granules leads to increased compaction. Moreover, translating mRNAs rarely show co-localizing 5 and 3 ends, indicating that mRNAs are either not translated in a closed-loop configuration, or that mRNA circularization is transient, suggesting that a stable closed-loop conformation is not a universal state for all translating mRNAs.\n\nOne Sentence SummarySingle mRNA studies in cells show RNA compaction changes depending on translational state, but mRNAs are not translated in closed-loop conformation.

molecular biology↗