Biology subjects

Faruq, M.

Publications and source records attributed to Faruq, M..

10 recordsLinked to original sources

bioRxiv2025

Layers in the sand: The genetic imprint of migration, culture, and Indus craft in the Thar desert

The Thar Desert of northwest India, despite its harsh ecology, has sustained settlement of ancient crafts and pastoral communities. Their persistence provides a unique opportunity to study how migration, ecology, and culture have shaped genetic diversity. We analyzed genome-wide SNP data from 176 individuals across eight occupational communities along with global, Indian populations and diverse ancient genomes. Population history, ancestral migration, population structure, demography, admixture, and founder effects were elucidated using diverse population genetic statistical methods. The Thar groups occupy an intermediate position on the Indian north-south cline. Pastoralists and artisans (woodcarvers and Persian gold embossers) with West Eurasian lineages, while potters and performers align with southern clines. Uniparental data confirmed heterogeneous Indian lineages. Gene-culture was evident from the lactase persistence allele being higher in pastoralists but lower in gold-embossers despite shared ancestry. Noteworthy, the populations retain a high frequency of the SLC24A5 allele, associated with lighter skin pigmentation in Europeans, despite the desert environment. Demographic analyses indicate admixture of 60-80 GBP and strong founder effects in certain groups, particularly tie-and-dye and Persian migrant artisans [~]500-600 years ago. aDNA comparisons confirmed continuity with Indus-periphery and historical South Asian populations. The genetic landscape of the Thar is a palimpsest shaped by successive layers of settlement, migration, and cultural continuity. By establishing the first genomic baseline of Thars craft and pastoral communities, this study shows how ecology and endogamy with population history shape distinct genetic landscapes. These findings provide essential context for studying genetic risk, adaptation, and human resilience in extreme environments.

genomics↗

bioRxiv2023

Melanocytes Exhibit Distinct Cell States Governed by A Gene Regulatory Network Under Stochastic Influence

Melanocytes serve as a protector of the skin against external stressors such as ultraviolet radiations. While melanocytes remain functional for nearly the entire lifespan of an individual, how they respond efficiently and survive such insults remain elusive. Here, we show the co-existence of multiple distinct states of normal human epidermal melanocytes (NHEMs). Using a progressive pigmentation model, we show that stochasticity in gene expression can lead to the co-existence of multiple melanocyte states. Using active enhancers and gene expression footprint, we identified state-specific transcription factors and constructed a gene regulatory network (GRN). The GRN couples pigmentation and cell cycle regulators and explains the co-existence and transitions of the melanocyte states. Finally, we show that NHEMs respond to external cues by altering the cell state dynamics. These results demonstrate that stochasticity in gene expression followed by epigenetic modification leads to the co-existence of multiple melanocyte states enabling an efficient response to environmental cues.

cell biology↗

bioRxiv2023

Computational and experimental hunt for expansion prone tandem CNG repeats in human genomes

IntroductionSpinocerebellar ataxias (SCA) are a group of clinically and genetically heterogeneous neurodegenerative disorders. Tandem repeat expansion is the pathogenic mutation in most of SCA cases. The pathophysiology of SCAs is still not completely defined due to the lack of genetic mutation in around 50% of cases worldwide. These uncharacterized cases must be genetically diagnosed for a better understanding and future treatment purposes. In this study, we tried a combination of computational and experimental approaches to find out novel CNG repeat loci that may be associated with SCAs. MethodologyWe investigate the human reference genome (hg-37) to find out all the possible CNG repeats present in more than 3 continuous uninterrupted units and annotated their functional locations. For experiment purposes, we targeted 52 loci from exonic and UTR regions and screened them in our 100 control samples through fragment analysis to know their polymorphic status. All the highly polymorphic loci were further investigated in 100 patient samples to know any large repeat expansion. ResultsThere are 15069 CNG repeat loci present in the human genome. After the examination of 52 loci in the control samples, 19 loci showed a highly polymorphic repeat pattern and were screened in patients. The 1000 genome different population data also suggested the polymorphic status in the available 15 loci data. From the GTEx database, 18 loci proposed the expression in the brain, suggesting any variation in these genes may cause neurological disorders. ConclusionWe tried a different kind of approach to find out tandem repeat expansion mutation in a cost-effective manner. Although we were unable to identify any disease-causing mutation in our patient cohort recently, various studies from different populations of the world have vouched for the genetic changes in these genes like GLS, RAI1, GIPC1, and CNKSR2 resulted in neurological disorders. Moreover, publications on the same identified repeats in GIPC1 for OPMD and GLS for ataxia with developmental delay, confirm the hypothesis to evaluate these repeat loci in different populations and other neurological disorders to identify novel targets.

genetics↗

bioRxiv2022

Accurate and simple FXN-GAA repeats (Friedreich ataxia loci) estimation by long read targeted sequencing.

Friedreich ataxia, an autosomal recessive disorder is caused by tandem GAA nucleotide repeats expansion in intron 1 of the FXN (frataxin gene). The GAA repeats above 66 in length are considered as pathogenic and commonly occurring repeats are 600-1200. Clinically the spectrum of the features is confined mainly to the neurological tissue, however, cardiomyopathy and diabetes mellitus has been observed in 60% and 30% of the subjects. The accurate detection of GAA repeats count is of utmost importance for clinical genetic correlation as no study has attempted an approach which is of high throughput nature and defines the sequence of GAA repeats. Largely, the method for detection of GAA repeats so far is either conventional PCR based screening and southern blot which is the gold standard method. We describe for the first time a method of long read sequencing wherein we utilized approach of long range targeted amplification of FXN-GAA repeats and sequencing on oxford MinION platform. We were able to achieve the successful amplification of GAA repeats ranging from 180-1200 at 250x coverage. The total throughput achievable for 96 samples can be less than 24 hours on one flow cell as per our protocol and is scalable and deployable at clinical day to sequencing.

genetics↗

bioRxiv2021

Telomere-Dependent Interleukin-1 Receptor Activation Promotes Immune Suppression in Triple-Negative-Breast Cancer

Telomeres are crucial for cancer progression. Immune signalling in the tumour microenvironment has been shown to be very important in cancer prognosis. However, the mechanisms by which telomeres might affect tumour immune response remain poorly understood. Here, we observed that interleukin-1 signalling is telomere-length dependent in cancer cells. Mechanistically, non-telomeric TRF2 (Telomeric Repeat binding Factor 2) binding at the IL-1-receptor type-1 (IL1R1) promoter was found to be affected by telomere length. Enhanced TRF2 binding at the IL1R1 promoter in cells with short telomeres directly recruited the histone-acetyl-transferase (HAT) p300, and consequent H3K27 acetylation activated IL1R1. This altered NF-kappa B signalling and affected downstream cytokines like IL6, IL8 and TNF. Further, IL1R1 expression was telomere-sensitive in triple-negative breast cancer (TNBC) clinical samples. Infiltration of tumour-associated macrophages (TAM) was also sensitive to the length of tumour cell telomeres and highly correlated with IL1R1 expression. The use of both IL1 Receptor antagonist (IL1RA) and IL1R1 targeting ligands could abrogate M2 macrophage infiltration in TNBC tumour organoids. In summary, using TNBC cancer tissue (>90 patients), tumour-derived organoids, cancer cells and xenograft tumours with either long or short telomeres, we uncovered a heretofore undeciphered function of telomeres in modulating IL1 signalling and tumour immunity.

cancer biology↗

bioRxiv2020

Intra-host variability in global SARS-CoV-2 genomes as signatures of RNA editing: implications in viral and host response outcomes

During the course of the COVID-19 pandemic, large-scale genome sequencing of SARS-CoV-2 has been useful in tracking its spread and in identifying Variants Of Concern (VOC). Besides, viral and host factors could contribute to variability within a host that can be captured in next-generation sequencing reads as intra-host Single Nucleotide Variations (iSNVs). Analysing 1, 347 samples collected till June 2020, we recorded 18, 146 iSNV sites throughout the SARS-CoV-2 genome. Both, mutations in RdRp as well as APOBEC and ADAR mediated RNA editing seem to contribute to the differential prevalence of iSNVs in hosts. Noteworthy, 41% of all unique iSNVs were reported as SNVs by 30th September 2020 in samples submitted to GISAID, which increased to [~]80% by 30th June 2021. Following this, analysis of another set of 1, 798 samples sequenced in India between November 2020 and May 2021 revealed that majority of the Delta (B.1.617.2) and Kappa (B.1.617.1) variations appeared as iSNVs before getting fixed in the population. We also observe hyper-editing events at functionally critical residues in Spike protein that could alter the antigenicity and may contribute to immune escape. Thus, tracking and functional annotation of iSNVs in ongoing genome surveillance programs could be important for early identification of potential variants of concern and actionable interventions. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=177 SRC="FIGDIR/small/417519v3_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@12b6ac2org.highwire.dtl.DTLVardef@16df897org.highwire.dtl.DTLVardef@dbbec2org.highwire.dtl.DTLVardef@c8de14_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2020

High throughput detection and genetic epidemiology of SARS-CoV-2 using COVIDSeq next generation sequencing

The rapid emergence of coronavirus disease 2019 (COVID-19) as a global pandemic affecting millions of individuals globally has necessitated sensitive and high-throughput approaches for the diagnosis, surveillance and for determining the genetic epidemiology of SARS-CoV-2. In the present study, we used the COVIDSeq protocol, which involves multiplex-PCR, barcoding and sequencing of samples for high-throughput detection and deciphering the genetic epidemiology of SARS-CoV-2. We used the approach on 752 clinical samples in duplicates, amounting to a total of 1536 samples which could be sequenced on a single S4 sequencing flow cell on NovaSeq 6000. Our analysis suggests a high concordance between technical duplicates and a high concordance of detection of SARS-CoV-2 between the COVIDSeq as well as RT-PCR approaches. An in-depth analysis revealed a total of six samples in which COVIDSeq detected SARS-CoV-2 in high confidence which were negative in RT-PCR. Additionally, the assay could detect SARS-CoV-2 in 21 samples and 16 samples which were classified inconclusive and pan-sarbeco positive respectively suggesting that COVIDSeq could be used as a confirmatory test. The sequencing approach also enabled insights into the evolution and genetic epidemiology of the SARS-CoV-2 samples. The samples were classified into a total of 3 clades. This study reports two lineages B.1.112 and B.1.99 for the first time in India. This study also revealed 1,143 unique single nucleotide variants and added a total of 73 novel variants identified for the first time. To the best of our knowledge, this is the first report of the COVIDSeq approach for detection and genetic epidemiology of SARS-CoV-2. Our analysis suggests that COVIDSeq could be a potential high sensitivity assay for detection of SARS-CoV-2, with an additional advantage of enabling genetic epidemiology of SARS-CoV-2.

genomics↗

bioRxiv2020

Integrated genomic view of SARS-CoV-2 in India

India first detected SARS-CoV-2, causal agent of COVID-19 in late January-2020, imported from Wuhan, China. March-2020 onwards; importation of cases from rest of the countries followed by seeding of local transmission triggered further outbreaks in India. We used ARTIC protocol based tiling amplicon sequencing of SARS-CoV-2 (n=104) from different states of India using a combination of MinION and MinIT from Oxford Nanopore Technology to understand introduction and local transmission. The analyses revealed multiple introductions of SARS-CoV-2 from Europe and Asia following local transmission. The most prevalent genomes with patterns of variance (confined in a cluster) remain unclassified, here, proposed as A4-clade based on its divergence within A-cluster. The viral haplotypes may link their persistence to geo-climatic conditions and host response. Despite the effectiveness of non-therapeutic interventions in India, multipronged strategies including molecular surveillance based on real-time viral genomic data is of paramount importance for a timely management of the pandemic.

microbiology↗

bioRxiv2019

Anastrozole mediated modulation of mitochondrial activity by inhibition of mitochondrial permeability transition pore opening: An initial perspective

BackgroundMitochondrial permeability transmembrane pore [mPTP] plays a vital role in alteration of the structure and function of mitochondria. Cyclophillin D is a mitochondrial protein that regulates mPTP function and a known drug target for therapeutic studies involving mitochondria. While aromatase inhibitors role on mPTP has been previously studied, the role of anastrazole on mPTP is not completely elucidated.\n\nMethodsThe role of anastrozole in modulating the mPTP was evaluated by docking and molecular dynamics using human cyclophillin D data. Peripheral blood mononuclear cells [PBMCs] of patients with mitochondrial disorders and healthy controls were treated with anastrazole and evaluated for mean fluorescence by flow cytometer. Spectrophotometry was employed for total ATP level estimation.\n\nFindingsAnastrozole - cyclophillin D complex is more stable when compared to cyclosporine A - cyclophillin D. Anastrozole performed better than cyclosporine in inhibiting mPTP pore. Additional effects included reduction in mitochondrial swelling and mitochondrial membrane depolarization, decreased super oxide generations, caspase 3 intrinsic activity and cellular apoptosis levels and increase in ATP levels.\n\nInterpretationThese results highlights the potency of anastrozole as a promising agent in ameliorating the phenotype by inhibiting the opening of mPTP pore. However, larger functional studies are required to validate the efficacy of this molecule as a therapeutic agent in mitochondrial disorders.

molecular biology↗

bioRxiv2017

Transcriptomic Dynamics of a non-coding trinucleotide repeat expansion disorder SCA12 in iPSC derived neuronal cells: signatures of interferon induced response

Spinocerebellar ataxia type-12 (SCA12) is a neurological disorder that exhibits a unique progressive tremor/ataxia syndrome induced by triplet (CAG) repeat expansion in 5 UTR of PPP2R2B. SCA12 is one of the most prominent SCA-subtype in India and till date no appropriate disease models have been described. Our aim was to establish human iPSC derived neuronal cell lines of SCA12 and study transcriptomic level alterations induced by CAG expansion. For translational application, peripheral blood transcriptomics of SCA12 patients was also performed. Lymphoblastoid cell lines of three SCA12 patients were reprogrammed to iPSCs and then re-differentiated into pan-neuronal lineage. RNA-sequencing based comparative transcriptomics was performed for disease and control cell lineages. Microarray based transcriptomic profiling of peripheral blood of SCA12 patients was performed in a case/control (n=15/9) design. We have successfully created human neuronal cell lines of SCA12 patient as exhibited by their molecular profiling. Differential expression analysis of RNA-Seq data has shown enrichment for type-I interferon signaling and other relevant cellular processes in SCA12-neurons. At the splice-isoform level, we observed an upregulation of expanded CAG containing non-coding transcript of PPP2R2B. Peripheral blood transcriptomics analysis and targeted validation of RNA-Seq data has allowed us to identify inflammatory signatures as potential markers of molecular pathology in SCA12. Our study has allowed us to establish first iPSC based neuronal cell lines of SCA12. We have identified pro-inflammatory signatures in SCA12-neurons suggestive of a dsRNA mediated activation of interferon signaling and that corroborates with the emerging evidence of neuronal atrophy due to neuro-inflammation in common neurodegenerative diseases. This study involved development of an iPSCs derived neuronal cells of SCA12 and look through signatures of neurodegeneration by whole RNA sequencing. This model sheds light upon key role of RNA mediated induced response in Interferon signaling for neurodegeneration.

molecular biology↗