Biology subjects

Grover, S.

Publications and source records attributed to Grover, S..

12 recordsLinked to original sources

bioRxiv2026

Purging of inbreeding depression does not eliminate environmental variation in reproductive onset

Many simultaneous hermaphrodites use selfing for reproductive assurance only when outcrossing opportunities are limited, owing to inbreeding depression in selfed progeny. However, scenarios that enforce substantial selfing (such as during recolonisation) can rapidly select for a high selfing propensity, a shift in mating system that is expected to eliminate both inbreeding depression and the delayed reproductive onset under selfing that is typically associated with it. We tested these predictions in the flatworm Macrostomum hystrix, using a line derived from an outcrossing population that had been subjected to enforced selfing for multiple generations followed by several years of relaxed selection. As predicted, isolated individual forced to self and individuals with constant partner access (i.e. outcrossing opportunities) did not differ in reproductive onset nor in inbreeding depression estimated through offspring survival. However, a third treatment group that provided intermittent partner access (to allow outcrossing but minimise potential competition effects) showed a different pattern: no inbreeding depression in offspring but a substantially accelerated reproductive onset. Whilst our results thus support the effective purging of inbreeding depression and increased selfing propensity under enforced selfing, we suggest that cues of an unstable social or physical environment nevertheless exert a major influence on reproductive timing.

evolutionary biology↗

bioRxiv2025

Meta-analysis reveals the tempo of evolutionary parallelism of local adaptation between native and introduced ranges of plant species

Invasive species are valuable systems for evaluating evolutionary predictability, as populations in native and introduced ranges evolve separately, yet often encounter similar environmental challenges that select for parallel patterns of local adaptation across each range. However, it remains unclear how pervasive and strong such parallelism is and how rapidly it evolves. To address these questions, we first extended cline theory to predict evolutionary patterns of trait cline parallelism between ranges. We then carried out a meta-analysis of clinal divergence in native and introduced populations of the same plant species and evaluated the tempo of trait cline parallelism between ranges. We found that clines in introduced ranges were somewhat shallower than native range clines, and directions of clinal divergence were, on average, partially aligned between ranges, with extensive variation in parallelism among traits and species, including counter-clines between native and introduced ranges. The degree of evolutionary parallelism of clinal divergence strongly increased, and the prevalence of counter-clines decreased, with the time since introduction, where greater parallelism in older introductions was primarily caused by increased alignment in the direction of clinal divergence between ranges rather than changes in their relative magnitudes of divergence. We argue that these observations are consistent with a two-phased process of cline evolution across introduced ranges. In the first phase, misaligned clines between introduced and native ranges can arise during range expansions, often owing to demographic and genetic constraints that initially hinder the evolution of local adaptation within the new range. During the second phase, the evolution of local adaptation eventually resolves early instances of maladaptation across introduced ranges, leading to strong trait cline parallelism between native and introduced ranges.

evolutionary biology↗

bioRxiv2022

Type 2 diabetes susceptibility gene GRK5 regulates physiological pancreatic β-cell proliferation via phosphorylation of HDAC5 in mice

ObjectiveDiabetes onset is accompanied with {beta}-cell deficiency, and thus restoring functional {beta}-cell mass is a promising therapy for those with diabetes. However, the regulatory mechanisms controlling {beta}-cell mass are not fully understood. Previously, we demonstrated that the transcription factor SOX4 is required for {beta}-cell proliferation in the prediabetic state. To elucidate potential mechanisms by which SOX4 regulates {beta}-cell mass, we performed RNA sequencing (RNA-seq) using pancreatic {beta}-cell specific SOX4 knockout mice ({beta}SOX4 KO). The RNA-seq revealed decreased expression of GRK5, a known type 2 diabetes susceptibility gene whose association with diabetes has not been fully elucidated. Therefore, we aimed to clarify the function of GRK5 in pancreatic {beta} cells. MethodsWe generated a novel pancreatic {beta} cell-specific GRK5 knockout mass ({beta}GRK5 KO) and evaluated glucose tolerance and metabolic changes by body weight measurement, oral glucose tolerance test, and insulin tolerance test. The number of pancreatic {beta} cells was quantified by immunohistochemistry. Glucose loading and Ca2+ imaging was performed on isolated islets to evaluate insulin secretory capacity. To elucidate the mechanism of {beta}GRK5 on {beta} cell mass regulation, we performed RNA-seq of isolated islets and identified the signaling pathways that could be regulated by GRK5. Furthermore, in vitro experiments were conducted using human islets and mouse {beta}GRK5 KO islets to clarify the direct effects of GRK5 on these pathways. Results{beta}GRK5 KO islets showed impaired glucose tolerance and insulin secretion, but no change in body weight or insulin resistance, suggesting that the main cause of impaired glucose tolerance is impaired insulin secretion. Isolated islets showed no abnormalities in insulin secretory capacity or changes in calcium influx, but histologically showed a decrease in {beta} cell mass. Consistent with the decreased {beta} cell mass in {beta}GRK5 KO, the cell cycle inhibitor gene Cdkn1a was upregulated in {beta}GRK5 KO islets; this phenocopies the {beta}SOX4 KO. Furthermore, we found that Grk5 positively regulates facultative increases in {beta} cell mass through activity-dependent phosphorylation of HDAC5 and subsequent transcription of immediate early genes (IEGs) such as Nr4a1, Fosb, Junb, Arc, Egr1 and Srf. ConclusionsOur results suggest that GRK5 is associated with type 2 diabetes through regulation of {beta} cell mass. GRK5 could become a potential target of cell therapy to preserve functional {beta} cells during the progression towards frank diabetes.

physiology↗

bioRxiv2022

Development of a novel oral treatment that rescues gait ataxia and retinal degeneration in a phenotypic mouse model of familial dysautonomia.

Familial Dysautonomia (FD) is a rare neurodegenerative disease caused by a splicing mutation in the Elongator complex protein 1 gene (ELP1). This mutation leads to the skipping of exon 20 and a tissue-specific reduction of ELP1 protein, mainly in the central and peripheral nervous systems. FD is a complex neurological disorder accompanied by severe gait ataxia and retinal degeneration. There is currently no effective treatment to restore ELP1 protein expression in individuals with FD, and the disease is ultimately fatal. After identifying kinetin as a small molecule able to correct the ELP1 splicing defect, we worked on its optimization to generate novel splicing modulator compounds (SMCs) that can be used in patients. Here, we optimize the potency, efficacy, and bio-distribution of second-generation kinetin derivatives to develop an oral treatment for FD that can efficiently pass the blood-brain barrier and correct the ELP1 splicing defect in the nervous system. We demonstrate that the novel compound, PTC258, efficiently restores correct ELP1 splicing in mouse tissues, including brain, and most importantly, prevents the progressive neuronal degeneration that is characteristic of FD. Postnatal oral administration of PTC258 to the phenotypic mouse model TgFD9;Elp1{Delta}20/flox increases full-length ELP1 transcript in a dose-dependent manner and leads to a two-fold increase in functional ELP1 protein in the brain. Remarkably, PTC258 treatment improves survival, gait ataxia, and retinal degeneration in the phenotypic FD mice. Our findings highlight the great therapeutic potential of this novel class of small molecules as an oral treatment for FD.

genetics↗

bioRxiv2022

PARNAS: Objectively Selecting the Most Representative Taxa on a Phylogeny

The use of next-generation sequencing technology has enabled phylogenetic studies with hundreds of thousands of taxa. Such large-scale phylogenies have become a critical component in genomic epidemiology in pathogens such as SARS-CoV-2 and influenza A virus. However, detailed phenotypic characterization of pathogens or generating a computationally tractable dataset for detailed phylogenetic analyses requires bias free subsampling of taxa. To address this need, we propose parnas, an objective and flexible algorithm to sample and select taxa that best represent observed diversity by solving a generalized k-medoids problem on a phylogenetic tree. parnas solves this problem efficiently and exactly by novel optimizations and adapting algorithms from operations research. For more nuanced selections, taxa can be weighted with metadata or genetic sequence parameters, and the pool of potential representatives can be user-constrained. Motivated by influenza A virus genomic surveillance and vaccine design, parnas can be applied to identify representative taxa that optimally cover the diversity in a phylogeny within a specified distance radius. We demonstrated that parnas is more efficient and flexible than current approaches, and applied it to select representative influenza A virus in swine genes derived from over 5 years of genomic surveillance data. Our objective selection of 4 to 6 strains selected every two years from the 16 distinct genetic clades were sufficient to cover 80% of diversity circulating in US swine. We suggest that this method, through the objective selection of representatives in a phylogeny, provides criteria for rational multivalent vaccine design and for quantifying diversity. PARNAS is available at https://github.com/flu-crew/parnas.

evolutionary biology↗

bioRxiv2020

A bidirectional Mendelian randomization study of glycemic and anthropometric traits and Parkinsons disease

BackgroundImpaired glucose and obesity are frequently observed in patients with Parkinsons disease (PD), although it is unclear whether the impairment precedes or results from the neurodegeneration. ObjectiveWe aimed to assess whether glycemic and anthropometric traits can influence the risk of PD in 33,674 cases and 449,056 healthy controls using the Mendelian randomization (MR) framework. MethodsWe investigated causality with a two-sample MR approach in the European population to compute effect estimates with summary statistics from available discovery meta-analyses of genome-wide association studies (GWAS) on glycemic and anthropometric traits. ResultsWe considered a threshold of p-value=0.0038 as significant after accounting for multiple testing, and p-value<0.05 was considered to be a suggestive evidence for a potential association. We observed a protective effect of waist-hip ratio (WHR) on PD (Inverse variance-weighted (IVW): OR IVW=0.735; 95%CI= 0.622-0.868; p-value=0.0003; I2 index=22.0%; MR-Egger intercept p-value=0.1508; Cochran Q test p-value=0.0003). The association was further retained after the exclusion of overlapping UK biobank (UKB) samples between the WHR and PD datasets (ORIVW=0.791; 95%CI=0.659-0.950; p-value=0.012; I2 index=13.0%; MR-Egger intercept p-value=0.733; Cochran Q test p-value=0.035). The sensitivity analysis provided suggestive evidence of an increased risk of PD on fasting glucose (FG) ({beta} IVW=0.0188; 95%CI=0.0062-0.0313, p-value=0.0055; I2 index=0.0%; MR-Egger intercept p-value=0.0957; Cochran Q test p-value=0.4555) and protective effect of PD on T2D (Weighted median effect: ORWME=0.946; 95%CI=0.9290.983; p-value=0.0051; Weighted mode effect: ORMBE=0.943; 95%CI=0.904-0.983; p-value=0.0116). ConclusionsOur results showed that central or abdominal obesity may be protective against PD development, independent of glucose levels.

genetics↗

bioRxiv2019

Role of educational attainment, cognitive performance and intelligence in neurodegeneration: a bidirectional Mendelian randomization study

I examined the potential bi-directional causality between educational attainment (EA) (n = 766,345) and age related macular degeneration (AMD) (cases (n) =16144, controls (n) =17832) using the summary GWAS datasets on individuals with European ancestry. I used datasets on other late-onset neurodegenerative diseases including Alzheimers disease (AD) and Parkinsons disease (PD) as controls to validate the findings. A risky effect of EA on AMD was observed (OR=1.318, 95% CI=1.080 -1.610, P=0.0068) after ruling out potential pleiotropy and absence of reverse causality. I further replicated previously observed protective and risky causal associations of EA with AD and PD.

genetics↗

bioRxiv2019

Bidirectional Mendelian randomization analysis of shared genetic signals between coexisting neurodegenerative disorders to decipher underlying causal pathways

OBJECTIVETo investigate whether coexistence of various neurodegenerative disorders is coincidental or biologically connected.\n\nDESIGNTwo sample Mendelian randomization using summary effect estimates\n\nSETTINGGenetic data taken on various neurodegenerative disorders from various cohorts comprising individuals predominantly of European ancestry.\n\nPARTICIPANTSInternational Genomics of Alzheimers patients (IGAP), project MinE, International Age-related Macular Degeneration Consortium (IAMDGC), International Multiple Sclerosis Genetics Consortium (IMSGC), International Parkinsons Disease Genomics Consortium (IPDGC)\n\nMAIN OUTCOME MEASURESAlzheimers disease (AD), Amyotrophic lateral sclerosis (ALS), Age related macular degeneration (AMD), Multiple sclerosis (MS) and Parkinsons disease (PD).\n\nRESULTSA Bonferroni corrected threshold of P=0.005 was considered to be significant, and P<0.05 was considered suggestive of evidence for a potential association. I observed a risky effect of PD on ALS (OR = 1.126, 95% CI = 1.059-1.198, P = 0.005). Using AD as exposure and PD as outcome, I observed a risky effect of AD on PD using all the MR methods with strongest results using MBE method (OR = 2.072, 95% CI = 1.006-4.028, P = 0.0416). Genetic predisposition to AD was further observed to be a risky for AMD (OR = 1.759, 95% CI = 1.040-1.974, P = 0.0363). On the contrary, AMD was observed to be strongly protective towards MS (OR = 0.861, 95% CI = 0.776-0.955, P = 0.0059).\n\nCONCLUSIONSMy findings are consistent with the previously observed relative occurrence of co-existing neurodegenerative diseases or overlapping symptoms among neurodegenerative diseases.

genetics↗

bioRxiv2018

Non-Communicable Diseases and their determinants: A Cross-sectional State-Wide STEPS Survey, Haryana, North India

BackgroundRecent studies have documented high variation in epidemiologic transition levels among Indian states with noncommunicable disease epidemic rising swiftly. However, the estimates suffer from non-availability of reliable data for NCDs from sub populations. In order to fill the knowledge gap, the distribution and determinants of NCD risk factors were studied along with awareness, treatment and control of NCDs among the adult population in Haryana, India.\n\nMethodsNCD risk factors survey was conducted among 5078 residents, aged 18-69 years during 2016-17. Behavioural risk factors were assessed using STEPS instrument, administered through an android software (mSTEPS). This was followed by physical measurements using standard protocols. Finally, biological risk factors were determined through the analysis of serum and urine samples.\n\nResultsMales were found to be consuming tobacco and alcohol at higher rates of 38.9% (95% CI: 35.3-42.4) and 18.8% (95% CI: 15.8-21.8). One-tenth (11%) (95% CI: 8.6-13.4) of the respondents did not meet the specified WHO recommendations for physical activity for health. Around 35.2% (95%CI: 32.6-37.7) were overweight or obese. Hypertension and diabetes were prevalent at 26.2% (95% CI: 24.6-27.8) and 15.5% (95% CI: 11.0-20.0). 91.3% (95% CI: 89.3-93.3) of the population had higher salt intake than recommended 5gms per day.\n\nConclusionThe documentation of strikingly high and uniform distribution of different NCDs and their risk factors in state warrants urgent need for evidence based interventions and advocacy of policy measures.

epidemiology↗

bioRxiv2018

Risky behaviors and Parkinson’s disease: A Mendelian randomization study in up to 1 million study participants

ObjectiveDopaminergic neurotransmission is known to be a potential modulator of risky behaviors including substance abuse, promiscuity, and gambling. Furthermore, observational studies have shown associations between risky behaviors and Parkinsons disease; however, the causal nature of these associations remains unclear. Thus, in this study, we examine causal associations between risky behavior phenotypes on Parkinsons disease using a Mendelian randomization approach.\n\nMethodsWe used two-sample Mendelian randomization to generate unconfounded estimates using summary statistics from two independent, large meta-analyses of genome-wide association studies on risk taking behaviors (n=370,771-939,908) and Parkinsons disease (cases: n=9581, controls: n = 33,245). We used inverse variance weighted as the main method for judging causality.\n\nResultsOur results support a strong protective association between the tendency to smoke and Parkinsons disease (OR=0.714 per log odds of ever smoking; 95% CI=0.568-0.897; p-value=0.0041; Cochran Q test; p-value=0.238; I2 index=6.3%). Furthermore, we observed risk association trends between automobile speed propensity as well as the number of sexual partners and Parkinsons disease after removal of overlapping loci with other risky traits (OR=1.986 for each standard deviation increase in normalized automobile speed propensity; 95% CI=1.215-3.243; p-value=0.0066, OR=1.635 for each standard deviation increase in number of sexual partners; 95% CI=1.165-2.293; p-value=0.0049).\n\nInterpretationThese findings provide support for a causal relationship between general risk tolerance and Parkinsons disease and may provide new insights in the pathogenic mechanisms leading to the development of Parkinsons disease.

genetics↗

bioRxiv2017

Sensory and decisional components of endogenous attention are dissociable.

Endogenously cueing a stimulus for attention enhances sensory processing of the attended stimulus, and efficiently selects information from the attended stimulus for guiding behavioral decisions. Yet, it is unknown if these sensory and decisional components of endogenous attention are under the control of common, overlapping or distinct mechanisms. Here, we tested human observers in a multi-alternative visuospatial attention task with probabilistic spatial cues, whose predictive validity varied across spatial locations. Observers behavioral choices were analyzed with a multidimensional signal detection model, derived from Bayesian decision theory. The model effectively decoupled attentions effects on perceptual sensitivity from those on decisional thresholds (bias), and revealed striking dissociations between them. Sensitivity was highest at the cued location, and not significantly different among uncued locations, suggesting a spotlight-like allocation of sensory resources at the cued location. On the other hand, bias varied systematically with endogenous cue validity, suggesting a graded distribution of decision thresholds across all locations. Cueing-induced modulations of sensitivity and bias were uncorrelated within and across subjects. Finally, bias selectively correlated with key measures of decision-making: reaction times were strongly correlated with bias, cueing-induced benefits in reaction times were correlated with bias changes independently of sensitivity changes, and subjects who exhibited higher bias, rather than higher sensitivity, toward the cued location produced more optimal behavioral decisions. Our model and findings demonstrate that endogenous cueing of attention does not engage a unitary selection mechanism, but rather involves the operation of dissociable sensory enhancement and decisional selection processes.\n\nSignificance statementThe capacity for selective attention allows us to engage efficiently with the most important objects in the world around us. Attention affects the way we perceive important stimuli and also affects how we make behavioral decisions about these stimuli. In this study, we test human observers on a multiple alternative attention task and show that attentions effects on perceptual processing and decision-making can be dissociated. Specifically, attentions sensory effects alone are in line with the conventional notion of an attentional \"spotlight\". These insights are obtained with a novel Bayesian decision model, which we propose as a powerful tool for teasing apart component processes of cognitive phenomena, and could aid the search for the neural correlates of these phenomena.

neuroscience↗

bioRxiv2017

Cis-regulatory evolution integrated the Bric-a-brac transcription factors into a novel fruit fly gene regulatory network

Gene expression evolution through gene regulatory network (GRN) changes has gained appreciation as a driver of morphological evolution. However, understanding how GRNs evolve is hampered by finding relevant cis-regulatory element (CRE) mutations, and interpreting the protein-DNA interactions they alter. We investigated evolutionary changes in the duplicated Bric-a-brac (Bab) transcription factors and a key Bab target gene in a GRN underlying the novel dimorphic pigmentation of D. melanogaster and its relatives. It has remained uncertain how Bab was integrated within the pigmentation GRN. Here we show that Bab gained a role in sculpting sex-specific pigmentation through the evolution of binding sites in a CRE of the pigment-promoting yellow gene and without any noteworthy changes to Bab protein coding sequences. This work demonstrates how a new trait can evolve by incorporating existing transcription factors into a GRN through CRE evolution, an evolutionary path likely to predominate newly evolved functions of transcription factors.

genetics↗