Biology subjects

Modi, A.

Publications and source records attributed to Modi, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Developmental Convergence Across Diverse Genetic Architectures in Childhood Apraxia of Speech

Childhood apraxia of speech (CAS) is a neurodevelopmental disorder of speech-motor planning and programming, associated with literacy, academic, and psychosocial difficulties. We performed whole-exome sequencing in 11 families comprising 21 affected and 15 unaffected individuals with phenotyping spanning speech, language, cognition, literacy, and motor function. We identified 60 prioritized variant observations representing 22 unique variants across 20 genes with family-based segregation analysis assessed in informative relatives; 5 arose de novo. Our cohort included multiple affected siblings and extended relatives, with several families carrying multiple prioritized variants, suggesting cumulative or oligogenic susceptibility. Speech and literacy impairment co-occurred with oral-motor, feeding, and fine-motor difficulties. BrainSpan co-expression analysis identified MECP2 and ANK2 as the genes with the highest observed connectivity in the sampled postnatal network. Exploratory analysis of the KOLF2.1J perturbation atlas in undifferentiated human induced pluripotent stem cells identified a positive LMO3 expression-response score following NIPBL repression and opposing LMO3 and ANK2 response directions within a cohesin-associated perturbation cluster. These observations motivate testing in human neural cells. Functional enrichment, protein-association, and developmental-expression analyses supported shared biological themes involving chromatin regulation, neuronal signaling, and extracellular-matrix organization. Among six families, multiple affected relatives shared prioritized variants across a unique set of several genes, demonstrating multilocus candidate profiles whose individual and combined effects may contribute to CAS susceptibility. We propose four novel CAS candidate genes: LMO3 and PCDH10, previously linked to human accelerated regions, as well as MYCBP2 and PTPRS. Our work provides multiple testable hypotheses for future variant-specific functional validation in speech-motor development.

genetics↗

bioRxiv2026

Stereoselective Covalent Inhibitor of the Ovarian Cancer-Driving Transcription Factor PAX8

Transcription factors remain among the most challenging therapeutic targets in part because they lack well-defined ligandable binding pockets. We recently showed that aberrantly reactive cysteines in transcription factors can be directly targeted with electrophilic small molecules to induce selective transcription factor destabilization and degradation. Here, we extend this strategy to the lineage-defining oncogenic transcription factor PAX8, a critical driver of ovarian cancer. Screening of a chemically diverse library of more than 3,000 cysteine-reactive compounds against an endogenously HiBiT-tagged PAX8 reporter identified a sulfinyl aziridine chemotype that selectively reduced PAX8 abundance. Structure-activity and stereochemical analyses revealed highly enantio- and diastereoselective activity, identifying KL6-159A as the lead compound. Quantitative proteomics demonstrated selective loss of PAX8, while cellular thermal shift analysis and chemoproteomic profiling established direct covalent engagement of PAX8 at cysteine C57. Mutation of C57 completely abolished KL6-159A-induced PAX8 depletion, demonstrating that this residue is essential for compound activity. Transcriptomic profiling revealed broad suppression of the PAX8 transcriptional program, with FOXM1 emerging as the most significantly downregulated regulatory network together with numerous established PAX8 target genes. Collectively, these studies establish direct covalent engagement, transcriptional inhibition, and destabilization of PAX8 and further demonstrate the generality of covalent chemoproteomic approaches for drugging previously intractable transcription factors.

biochemistry↗

bioRxiv2026

Distinct functions of PBRM1 and BAP1 reconcile the course of kidney cancer evolution and disease progression

Clear cell renal cell carcinoma (ccRCC) progresses along two predominant evolutionary trajectories, defined by PBRM1 ([~]40%) or BAP1 ([~]15%) mutations on a VHL-inactivated background. They have distinct patterns of evolutionary tempo and mode, and vastly different clinical outcomes, yet the underlying genotype-specific molecular phenotypic programmes are unknown. We established a patient-derived preclinical model biobank that captures the genetic diversity of ccRCC. Through integrative analyses of preclinical models and tumour bulk and single cell profiling, we identified transcriptional and epigenetic changes specific to PBRM1- and BAP1-driven ccRCC. Modelling PBRM1 loss in vitro demonstrates that it reinforces renal lineage identity and maintains progenitor-like cell state. In contrast, BAP1 loss drives inflammatory signalling and chromosomal instability. These insights reconcile the distinct evolutionary modes (branched versus punctuated), tempo (slow versus fast) and clinical outcomes associated with PBRM1 and BAP1 mutations, respectively, establishing a framework for patient stratification and genotype-directed therapeutic development.

cancer biology↗

bioRxiv2026

An Optimized RNF126-Targeting Covalent Handle for Molecular Glue Degraders

Molecular glue degraders represent a powerful modality for targeting proteins that are refractory to traditional inhibition. However, rational design principles for molecular glue degraders remain poorly defined. Previously, we reported a chemistry-centric strategy to identify covalent degradative handles that, when appended to established ligands, convert non-degradative inhibitors into molecular glue degraders by engaging permissive E3 ligases. This effort identified a fumarate-based electrophilic handle that covalently modified the E3 ligase RNF126, enabling degradation of multiple protein targets when transplanted across diverse ligands. Despite its conceptual impact, the high intrinsic reactivity and cytotoxicity of the fumarate handle limited its translational utility. Here, we report the development of an optimized and metabolically stabilized RNF126-targeting covalent handle incorporating a trans-cyclobutane linker that exhibits reduced glutathione reactivity and diminished cytotoxicity while retaining robust degradative activity. When appended to the BET bromodomain inhibitor JQ1, this optimized handle yielded a potent and selective BRD4 degrader whose activity was dependent on RNF126. Importantly, transplantation of this handle onto a previously non-inhibitory ligand targeting the androgen receptor (AR) and its truncation variant, AR-V7, enabled selective degradation of both AR and AR-V7 in androgen-independent prostate cancer cells, thereby robustly inhibiting AR transcriptional activity beyond the established AR antagonist enzalutamide. Collectively, these findings demonstrate an optimized RNF126-based covalent handle for the rational development of molecular glue degraders against transcriptional regulators, including undruggable variants such as AR-V7.

biochemistry↗

bioRxiv2025

The shifting dynamics of ancestry and culture at a post-Roman crossroads

The collapse of the western Roman Empire in the 5th century created a period of geopolitical upheaval, driven by Barbarians dispersing into the former Empire and reshaping post-Roman communities. While there is now evidence for a major genetic impact of these migrations into specific regions of Europe, it is unknown whether these changes in ancestry were uniform across the continent. We investigate present-day Slovenia, a crucial crossroad connecting the Roman East and West and the gate to Italy during the Langobard invasion. We conducted paleogenomic and isotopic analyses of 410 individuals from 21 sites across Slovenia and Cividale (Italy), establishing a longitudinal transect, spanning eight centuries. During Late Antiquity, despite changes in burial artifacts, kinship practices, and settlement structures reflecting a shift in culture, we find high levels of genetic continuity with the local Late Roman population and reduced mobility. However, demographic turnover began during the 8th century, when communities with northeastern European ancestry and distinct cultural practices entered the region, gradually advancing westward over the span of three centuries, replacing the local populations. This shows that cultural change in post-Roman Europe could be decoupled from genetic change in transit zones, demonstrating a dynamic spatiotemporal process across the continent.

genetics↗

bioRxiv2025

Biophysically relevant network model of the piriform cortex predicts odor frequency encoding using network mechanisms

Olfactory-guided animals utilize fast concentration fluctuations in turbulent odor plumes to perceive olfactory landscapes. Recent studies have demonstrated that the olfactory bulb (OB) encodes such temporal features present in natural odor stimuli. However, whether this temporal information is encoded in the piriform cortex (PCx) remains unknown. Hence, we developed a biophysically relevant PCx network model and simulated it using previously recorded in vivo activities of mitral and tufted cells in response to 2Hz and 20Hz odor frequencies for three stimulus mixtures. Analysis of single-cell activity across trials revealed that individual pyramidal neurons (PYRs) were largely ineffective at discriminating between 2Hz and 20Hz. However, the trial-averaged activity of the PYR population could discriminate between the two frequencies significantly. Moreover, using log-likelihood scores we further discovered that odor frequency discrimination happened through a highly distributed mechanism among the PYRs. One-dimensional convolutional neural network models trained and tested on PYRs activities achieved discrimination accuracies up to 95%. Using virtual synaptic knockout models, we found that eliminating either feedback or feedforward inhibition onto PYRs improved the decoding accuracy across all odor conditions. Conversely, eliminating recurrent excitation among PYRs or simultaneously eliminating recurrent inhibition within both interneuron populations degraded decoding performance. Removing recurrent connections within individual interneuron populations had minimal effects on the performance. Overall, our PCx model demonstrates that it can discriminate between 2Hz and 20Hz odor stimuli, with a bidirectional capability of performance modulation by specific circuit motifs. These findings predict that the piriform cortex encodes and processes temporal features of odor stimuli. New & NoteworthyWe simulated the first biophysically relevant network model of the piriform cortex (PCx) to show differential encoding of odor frequencies at 2Hz and 20Hz. 1D convolutional neural networks demonstrated a distributed role of pyramidal neurons in the encoding. Surprisingly, eliminating feedforward or feedback inhibition improves frequency discrimination, while eliminating recurrency impairs it. Specific circuit motifs, not just baseline activity levels, determine odor frequency representation. Overall, our results predict the PCxs capacity for temporal odor processing.

neuroscience↗

bioRxiv2025

Optimization of Genome-wide CRISPR Screens using dual-guide RNA Infection with Cas9 Electroporation (DICE)

Single-guide RNA lentiviral infection with Cas9 protein electroporation (SLICE) enables CRISPR screening in primary cell types that require transient Cas9 expression yet is limited by scalability and robustness. Here, we introduce dual-guide RNA infection with Cas9 electroporation (DICE), which expresses two guides from the same lentiviral construct that target the same gene. In genome-wide screens, DICE outperformed SLICE in defining essential genes and modulators of PD-L1 expression in IFN gamma activated THP1 cells. Collectively, these data demonstrate that DICE can be utilized for reduced-scale CRISPR screens in cell types with transient Cas9 protein expression without sacrificing screening quality.

genomics↗

bioRxiv2024

Field monitoring and hydraulic modelling quantify untreated wastewater as dominant source of AMR in a small river running through a big city

Quantifying sources of antimicrobial resistance (AMR) in rivers receiving various waste streams is essential for targeting mitigation strategies yet rarely performed. This study combined field monitoring with hydraulic modelling and mass balance calculations to attribute sources of AMR in the Musi River running through Hyderabad, India, a city renowned for pharmaceutical manufacturing. We quantified antibiotic resistance genes (ARGs), resistant bacteria (ARBs), and physicochemical parameters in water and sediment samples in the dry and wet season. Absolute ARG and ARB abundances spiked in the city, declining again downstream. Changes were more gradual in the wet season. Pollution levels were significantly different between upstream, city and downstream stretches and seasons. Hydraulic modelling revealed that 60-80% or 20-40% of the river water in the city derived from untreated sewage during the dry or wet seasons, respectively. This established municipal waste, not pharmaceutical sources, as the dominant driver of AMR in the Musi. Linear discriminant analysis identified dissolved oxygen and total nitrogen as reliable proxies for distinguishing AMR-polluted from less-polluted sites. The Musi, with insufficient wastewater treatment and limited dilution of point-source loadings, is typical for many urban rivers in resource-limited countries highlighting the urgent need for improved wastewater management to reduce AMR exposures.

microbiology↗

bioRxiv2023

A proteogenomic surfaceome study identifies DLK1 as an immunotherapeutic target in neuroblastoma

Cancer immunotherapies have produced remarkable results in B-cell malignancies; however, optimal cell surface targets for many solid cancers remain elusive. Here, we present an integrative proteomic, transcriptomic, and epigenomic analysis of tumor specimens along with normal tissues to identify biologically relevant cell surface proteins that can serve as immunotherapeutic targets for neuroblastoma, an often-fatal childhood cancer of the developing nervous system. We apply this approach to human-derived cell lines (N=9) and cell/patient-derived xenograft (N=12) models of neuroblastoma. Plasma membrane-enriched mass spectrometry identified 1,461 cell surface proteins in cell lines and 1,401 in xenograft models, respectively. Additional proteogenomic analyses revealed 60 high-confidence candidate immunotherapeutic targets and we prioritized Delta-like canonical notch ligand 1 (DLK1) for further study. High expression of DLK1 directly correlated with the presence of a super-enhancer spanning the DLK1 locus. Robust cell surface expression of DLK1 was validated by immunofluorescence, flow cytometry, and immunohistochemistry. Short hairpin RNA mediated silencing of DLK1 in neuroblastoma cells resulted in increased cellular differentiation. ADCT-701, a DLK1-targeting antibody-drug conjugate (ADC), showed potent and specific cytotoxicity in DLK1-expressing neuroblastoma xenograft models. Moreover, DLK1 is highly expressed in several adult cancer types, including adrenocortical carcinoma (ACC), pheochromocytoma/paraganglioma (PCPG), hepatoblastoma, and small cell lung cancer (SCLC), suggesting potential clinical benefit beyond neuroblastoma. Taken together, our study demonstrates the utility of comprehensive cancer surfaceome characterization and credentials DLK1 as an immunotherapeutic target. HighlightsO_LIPlasma membrane enriched proteomics defines surfaceome of neuroblastoma C_LIO_LIMulti-omic data integration prioritizes DLK1 as a candidate immunotherapeutic target in neuroblastoma and other cancers C_LIO_LIDLK1 expression is driven by a super-enhancer C_LIO_LIDLK1 silencing in neuroblastoma cells results in cellular differentiation C_LIO_LIADCT-701, a DLK1-targeting antibody-drug conjugate, shows potent and specific cytotoxicity in DLK1-expressing neuroblastoma preclinical models C_LI

cancer biology↗

bioRxiv2023

A genome-wide CRISPR screen supported by human genetics identifies the TNRC18 gene locus as a novel regulator of inflammatory signaling

Interleukin-1{beta} (IL-1{beta}) is dysregulated in many chronic inflammatory diseases, yet the genetic factors influencing IL-1{beta} production and signaling remain largely unknown. Myeloid-derived cells are the primary producers of IL-1{beta}, prompting a genome-wide CRISPR knockout screen in the human myeloid-derived U937 cell model, treated with lipopolysaccharide (LPS) to mimic inflammatory conditions, and sorted for high and low intracellular IL-1{beta} levels. A total of 295 genes were identified as regulators of IL-1{beta} production, including known mediators, such as TLR4, JAK-STAT, IL-10 receptor, and the Cullin ring finger ligase complex. Notably, 57 out of the 295 genes overlapped with loci associated with human inflammatory diseases, including the TNRC18 gene on chromosome 7p22.1 associated with multiple diseases in the Finnish population. U937 cells engineered with the homozygous rs748670681 risk allele associated with inflammatory bowel disease, demonstrated decreased levels of mRNA for TNRC18 and an adjacent gene WIPI2, reduction in LPS-dependent gene activation and cytokine production, but elevation of interferon-responsive gene programs. Transcriptomic profiles for individual knockouts of TNRC18 and WIPI2 attributed the loss of LPS-dependent signaling primarily to TNRC18 while the exacerbation of interferon signaling is a hallmark of loss of WIPI2. Collectively, these findings delineate the global regulatory mechanisms of IL-1{beta} production and provide molecular insights to the role of the rs748670681 variant as a pleiotropic risk factor for inflammatory diseases.

genomics↗

bioRxiv2022

Optimization of genomewide CRISPR screens using AsCas12a and multi-guide arrays

Genomewide loss-of-function (LOF) screening using CRISPR (clustered regularly interspaced short palindromic repeats) has facilitated the discovery of novel gene functions across diverse physiological and pathophysiological systems. A challenge with conventional genomewide CRISPR/Cas9 libraries is the unwieldy size (60,000 to 120,000 constructs), which is resource intensive and prohibitive in some experimental contexts. One solution to streamlining CRISPR screening is by multiplexing two or more guides per gene on a single construct, which enables functional redundancy to compensate for suboptimal gene knockout by individual guides. In this regard, AsCas12a (Cpf1) and its derivatives, e.g., enhanced AsCas12a (enAsCas12a), have enabled multiplexed guide arrays to be specifically and efficiently processed for genome editing. Prior studies have established that multiplexed CRISPR/Cas12a libraries perform comparably to the larger equivalent CRISPR/Cas9 libraries, yet the most efficient CRISPR/Cas12a library design remains unresolved. Here, we demonstrate that CRISPR/Cas12a genomewide LOF screening performed optimally with three guides arrayed per gene construct and could be adapted to robotic cell culture without noticeable differences in screen performance. Thus, the conclusions from this study provide novel insight to streamlining genomewide LOF screening using CRISPR/Cas12a and robotic cell culture.

genetics↗

bioRxiv2022

Investigating community formation through dense spatial and temporal sampling of 5-6th century cemeteries in Pannonia

As the collapse of the Western Roman Empire accelerated during the 4th and 5th centuries, arriving "barbarian" groups began to establish new communities in the border provinces of the declining (and eventually former) empire. This was a time of significant cultural and political change throughout not only these border regions but Europe as a whole.1,2 To better understand post-Roman community formation in one of these key frontier zones after the collapse of the Hunnic movement, we generated new paleogenomic data for a set of 38 burials from a time series of three 5th century cemeteries3-5 at Lake Balaton, Hungary. We utilized a comprehensive sampling approach to characterize these cemeteries along with data from 38 additional burials from a previously published mid-6th century site6 and analyzed them alongside data from over 550 penecontemporaneous individuals7-19. The range of genetic diversity in all four of these local burial communities is extensive and wider ranging than penecontemporaneous Europeans sequenced to date. Despite many commonalities in burial representation and demography, we find that there were substantial differences in genetic ancestry between the sites. We detect evidence of northern European gene flow into the Lake Balaton region. Additionally, we observe a statistically significant association between dress artefacts and genetic ancestry among 5th century genetically female burials. Our analysis shows that the formation of early Medieval communities was a multifarious process even at a local level, consisting of genetically heterogeneous groups.

genetics↗

bioRxiv2022

Screening and Identification of Azo Dye Decolourizers from Mangrove Rhizospheric soil

Removal of synthetic textile dye poses a challenge to the textile industry and a threat to environment flora and fauna. These dyes are marginally degradable and recalcitrant, hence alternatives to physical and chemical techniques like various bioremediation studies involving plants, plant roots, single or consortium of microbes have been used as environment friendly methods for the removal of textile dye. In the present study potent bacteria for dye decolourization were isolated from rhizospheric soil collected from Kamothe, Navi Mumbai, India. Of the 20 isolates obtained after enrichment, seven isolates were used for further screening of efficient decolourization ability in MBM media containing 10% glucose, 2.5 % trace metal solution and 0.1% of MO dye concentration. Physiological parameters to optimize the decolourization of dye at optimum pH, temperature and incubation time was studied for all the seven isolates. UV-vis and Fourier Transform Infrared spectroscopy were used to investigate dye decolorization. The seven isolates were characterized morphologically, biochemically, and molecular identification of these strains were performed by 16S rRNA sequence analysis. The isolates were identified as Bacillus paramycoides, Pseudomonas taiwanensis, Citrobacter murliniae, Acinetobacter pitti, Exiguobacterium acetylicum, Psychrobacter celer, and Aeromonas taiwanensis. Out of these Aeromonas taiwanensis has shown exceptional capacity by 100% decolorization of azo dye in minimum time. 1. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=160 SRC="FIGDIR/small/481723v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@e54071org.highwire.dtl.DTLVardef@e9d6dforg.highwire.dtl.DTLVardef@19ccfeorg.highwire.dtl.DTLVardef@1e14201_HPS_FORMAT_FIGEXP M_FIG C_FIG Highlights of the studyO_LICollection of soil samples from rhizospheric and non-rhizospheric region of the mangroves plant. C_LIO_LIEnrichment of soil sample in media containing azo dye for dye decolourization. C_LIO_LIScreening and isolation of potential dye decolourizers. C_LIO_LIOptimize the condition for dye decolourization. C_LIO_LIFTIR analysis and application based studies. C_LIO_LIIdentification of microbes using 16SrRNA. C_LI

microbiology↗

bioRxiv2020

Integrative genomics identifies lncRNA regulatory networks across 1,044 pediatric leukemias and solid tumors

Long non-coding RNAs (lncRNAs) play an important role in gene regulation and contribute to tumorigenesis. While pan-cancer studies of lncRNA expression have been performed for adult malignancies, the lncRNA landscape across pediatric cancers remains largely uncharted. Here, we curate RNA sequencing data for 1,044 pediatric leukemia and solid tumors and integrate paired tumor whole genome sequencing and epigenetic data in relevant cell line models to explore lncRNA expression, regulation, and association with cancer. We report a total of 2,657 robustly expressed lncRNAs across six pediatric cancers, including 1,142 exhibiting histotype-specific expression. DNA copy number alterations contributed to lncRNA dysregulation at a proportion comparable to protein coding genes. Application of a multi-dimensional framework to identify and prioritize lncRNAs impacting gene networks revealed that lncRNAs dysregulated in pediatric cancer are associated with proliferation, metabolism, and DNA damage hallmarks. Analysis of upstream regulation via cell-type specific transcription factors further implicated distinct histotype-specific and developmental lncRNAs. We integrated our analyses to prioritize lncRNAs for experimental validation and showed that silencing of TBX2-AS1, our top-prioritized neuroblastoma-specific lncRNA, resulted in significant growth inhibition of neuroblastoma cells, confirming our computational predictions. Taken together, these data provide a comprehensive characterization of lncRNA regulation and function in pediatric cancers and pave the way for future mechanistic studies.

cancer biology↗

bioRxiv2020

Archaeogenomic Distinctiveness of the Isthmo-Colombian Area

The recently enriched genomic history of Indigenous groups in the Americas is still meagre concerning continental Central America. Here, we report ten pre-Hispanic (plus two early colonial) genomes and 84 genome-wide profiles from seven groups presently living in Panama. Our analyses reveal that pre-Hispanic demographic changes and isolation events contributed to create the extensive genetic structure currently seen in the area, which is also characterized by a distinctive Isthmo-Colombian Indigenous component. This component drives these populations on a specific variability axis and derives from the local admixture of different ancestries of northern North American origin(s). Two of these ancestries were differentially associated to Pleistocene Indigenous groups that also moved into South America leaving heterogenous footprints. An additional Pleistocene ancestry was brought by UPopI, a still unsampled population that remained restricted to the Isthmian area, expanded locally during the early Holocene, and left genomic traces up to the present.

genomics↗

bioRxiv2019

Epigenomic profiling of neuroblastoma cell lines

Understanding the aberrant transcriptional landscape of neuroblastoma is necessary to provide insight to the underlying influences of the initiation, progression and persistence of this developmental cancer. Here, we present chromatin immunoprecipitation sequencing (ChIP-Seq) data for the oncogenic transcription factors, MYCN and MYC, as well as regulatory histone marks H3K4me1, H3K4me3, H3K27Ac, and H3K27me3 in ten commonly used human neuroblastoma-derived cell line models. In addition, for all of the profiled cell lines we provide ATAC-Seq as a measure of open chromatin. We validate specificity of global MYCN occupancy in MYCN amplified cell lines and functional redundancy of MYC occupancy in MYCN non-amplified cell lines. Finally, we show with H3K27Ac ChIP-Seq that these cell lines retain expression of key neuroblastoma super-enhancers (SE). We anticipate this dataset, coupled with available transcriptomic profiling on the same cell lines, will enable the discovery of novel gene regulatory mechanisms in neuroblastoma.

bioinformatics↗

bioRxiv2019

The Arrival of Steppe and Iranian Related Ancestry in the Islands of the Western Mediterranean

A series of studies have documented how Steppe pastoralist-related ancestry reached central Europe by at least 2500 BCE, while Iranian farmer-related ancestry was present in Aegean Europe by at least 1900 BCE. However, the spread of these ancestries into the western Mediterranean where they have contributed to many populations living today remains poorly understood. We generated genome-wide ancient DNA from the Balearic Islands, Sicily, and Sardinia, increasing the number of individuals with reported data from these islands from 3 to 52. We obtained data from the oldest skeleton excavated from the Balearic islands (dating to [~]2400 BCE), and show that this individual had substantial Steppe pastoralist-derived ancestry; however, later Balearic individuals had less Steppe heritage reflecting geographic heterogeneity or immigration from groups with more European first farmer-related ancestry. In Sicily, Steppe pastoralist ancestry arrived by [~]2200 BCE and likely came at least in part from Spain as it was associated with Iberian-specific Y chromosomes. In Sicily, Iranian-related ancestry also arrived by the Middle Bronze Age, thus revealing that this ancestry type, which was ubiquitous in the Aegean by this time, also spread further west prior to the classical period of Greek expansion. In Sardinia, we find no evidence of either eastern ancestry type in the Nuragic Bronze Age, but show that Iranian-related ancestry arrived by at least [~]300 BCE and Steppe ancestry arrived by [~]300 CE, joined at that time or later by North African ancestry. These results falsify the view that the people of Sardinia are isolated descendants of Europes first farmers. Instead, our results show that the islands admixture history since the Bronze Age is as complex as that in many other parts of Europe.

genomics↗

bioRxiv2019

Structural variation targets neurodevelopmental genes and identifies SHANK2 as a tumor suppressor in neuroblastoma

Neuroblastoma is a malignancy of the developing sympathetic nervous system that accounts for 12% of childhood cancer deaths. Like many childhood cancers, neuroblastoma exhibits a relative paucity of somatic single nucleotide variants (SNVs) and small insertions and deletions (indels) compared to adult cancers. Here, we assessed the contribution of somatic structural variation (SV) in neuroblastoma using a combination of whole genome sequencing (WGS; n=135) and single nucleotide polymorphism (SNP) genotyping (n=914) of matched tumor-normal pairs. Our study design allowed for orthogonal validation and replication across platforms. SV frequency, type, and localization varied significantly among high-risk tumors. MYCN non-amplified high-risk tumors harbored an increased SV burden overall, including a substantial excess of tandem-duplication events across the genome. Genes disrupted by SV breakpoints were enriched in neuronal lineages and autism spectrum disorder (ASD). The postsynaptic adapter protein-coding gene SHANK2, located on chromosome 11q13, was disrupted by SVs in 14% of MYCN non-amplified high-risk tumors based on WGS and 10% in the SNP array cohort. Expression of SHANK2 was low across human-derived neuroblastoma cell lines and high-risk neuroblastoma tumors. Forced expression of SHANK2 in neuroblastoma cell models resulted in significant growth inhibition (P=2.62x10-2 to 3.4x10-5) and accelerated neuronal differentiation following treatment with all-trans retinoic acid (P=3.08x10-13 to 2.38x10-30). These data further define the complex landscape of structural variation in neuroblastoma and suggest that events leading to deregulation of neurodevelopmental processes, such as inactivation of SHANK2, are key mediators of tumorigenesis in this childhood cancer.

cancer biology↗