👤 Mohsin Nawaz

Indigenous chickens in tropical regions routinely survive high environmental temperatures (40-45 °C) that cause significant mortality and production loss in commercial breeds, yet the genetic mechanisms of thermotolerance remain poorly understood. This study integrated genome-wide selective scans across 14 geographically and climatically diverse chicken breeds with multi-tissue expression data, gene expression quantitative trait locus (eQTL) analysis, transcriptome-wide association study (TWAS), and cross-species phenome-wide association study (PheWAS) to validate candidate genes. We identified 25 high-confidence genes under selection, with ATP1A1, PLCB4, RYR2 and AKT3 forming a regulatory hub coordinating cardiovascular, calcium and survival signaling. These genes converge on interconnected adrenergic, calcium, and GnRH signaling pathways, with coordinated expression across heart, hypothalamus, and liver forming an integrated thermoregulatory axis. The eQTL integration analysis using ChickenGTEx data identified 359 tissue-specific cis-eQTLs in selected regions. Additionally, TWAS analysis linked ATP1A1 to 145 gene-trait associations across 13 tissues and 14 trait categories (hepatic regulation, β = -2.13, p = 4.21 × 10⁻¹²), and cross-species PheWAS validated conserved roles in cardiovascular function (RYR2, resting heart rate p = 4.9 × 10⁻¹²), and ionic homeostasis (ATP1A1, chloride p = 1.18 × 10⁻³). In parallel, we also identified robust genomic signatures of domestication in classic candidate genes (TSHR, TBC1D1, BDNF), highlighting how initial separation from Red Jungle Fowl and subsequent adaptation to diverse climates have shaped the genetic and physiological diversity of the domesticated chicken. Collectively, our results reveal an integrated cardio-neuroendocrine calcium network driving heat adaptation, providing potential targets for breeding heat-tolerant chickens. Show less

Egg weight is an economically important trait in the chicken, and affects the hatchability and chicks' performance in broiler breeding programs. Our comprehensive analysis of 22,375 chickens revealed that the hens' egg weight was linked to their body weight, egg production and hatchability, with higher egg weight potentially increasing the body weight and delaying the female sexual maturity. Egg weight is a dynamic trait, however, previous studies usually focused on single time point and overlooked the dynamic changes during egg-laying period. We performed both single and longitudinal genome-wide association studies in 2,350 hens, combining selective sweep analysis, to identify genetic variants. Then, we integrated multi-omics data of 40 chickens to determine key genes and metabolites. A multi-omics analysis identified 22 key candidate genes, such as ATF6, CSPG4, SH3GL3, C4, LMX1B, CDC34, and CCDC171, of which four (BSG, CFD, MAP2K2, and POLRMT) were associated with egg weights in the ChickenGTEx database. In particular, the SNP rs315726522 may regulate MAP2K2 and FSHB gene expression by modulating the binding of transcription factors, and the SNP rs738839430 caused amino acid change that affected function of CFD protein. This, in turn, affected gonadotropin expression within the GnRH signaling pathway, which ultimately influenced egg weights. Metabolomic analysis revealed 13 metabolites associated with oxidative stress and metabolism of fatty acids, which potentially influenced reproductive performance through stress reduction and hormonal regulation. This study comprehensively analyzed the effects of egg weight in broiler breeders and enhanced our understanding of the genetic mechanisms underlying egg weight in chickens. Show less

This study aims to clinically and genetically assess 30 unrelated consanguineous Pakistani families from various ethnic backgrounds, all exhibiting features of neurodevelopmental disorders (NDDs). We conducted clinical, genetic, biochemical, and molecular analyses on 30 consanguineous families with NDDs enrolled from various regions of Pakistan. The likely molecular causes of primary microcephaly and NDDs were identified. Detailed clinical investigations and molecular diagnoses were performed using whole exome sequencing (WES) of the proband, followed by Sanger sequencing for validation and segregation in the available family members of the affected families. WES identified likely disease-causing homozygous variants in 30 unrelated consanguineous families. Six families presented newly described variants in known NDD-related genes: In the present study, we observed a high frequency of Show less

Kashmir cattle, which were kept by local pastoralists for centuries, are exceptionally resilient and adaptive to harsh environments. Despite its significance, the genomic characteristics of this cattle breed remain elusive. This study utilized whole genome sequences of Kashmir cattle (n = 20; newly sequenced) alongside published whole genomes of 32 distinct breeds and seven core cattle populations (n = 135). The analysis identified ~25.87 million biallelic single nucleotide polymorphisms in Kashmir cattle, predominantly in intergenic and intron regions. Population structure analyses revealed distinct clustering patterns of Kashmir cattle with proximity to the South Asian, African and Chinese indicine cattle populations. Genetic diversity analysis of Kashmir cattle demonstrated lower inbreeding and greater nucleotide diversity than analyzed global breeds. Homozygosity runs indicated less consanguineous mating in Kashmir cattle compared with European taurine breeds. Furthermore, six selection sweep detection methods were used within Kashmir cattle and other cattle populations to identify genes associated with vital traits, including immunity (BOLA-DQA5, BOLA-DQB, TNFAIP8L, FCRL4, AOAH, HIF1AN, FBXL3, MPEG1, CDC40, etc.), reproduction (GOLGA4, BRWD1, OSBP2, LEO1 ADCY5, etc.), growth (ADPRHL1, NRG2, TCF12, TMOD4, GBP4, IGF2, RSPO3, SCD, etc.), milk composition (MRPS30 and CSF1) and high-altitude adaptation (EDNRA, ITPR2, AGBL4 and SCG3). These findings provide essential genetic insights into the characteristics and establish the foundation for the scientific conservation and utilization of Kashmir cattle breed. Show less

BACE1 enzyme has been known a potential target involved in Alzheimer's disease (AD). Present research was focused on the principles of virtually screening, chemical synthesis and protease inhibitory effect of BACE1 enzyme via biaryl guanidine derivatives. In-silico based paradigm (ligand binding interaction within active domain of BACE 1 enzyme i.e., aspartate Asp32 and Asp228) a novel compound was synthesized and subsequently subjected to in-vitro and in-vivo evaluation. 1,3-di(isoquinolin-6-yl) guanidine was synthesized and found potent (IC Show less

Tannic acid (TA) is a natural compound present abundantly in fruit such as grapes and green tea. In this study, we have evaluated the therapeutic efficacy of TA against Lipopolysaccharide (LPS)-induced oxidative stress-mediated memory impairment, neuroinflammation, insulin signaling impairment, and Amyloid Beta (Aβ) deposition in adult male mice. The LPS was administered once per week and TA twice a week to adult male mice for three months consecutively. Behavioral studies were performed using different behavioral models such as balance beam, novel object recognition (NOR), Morris water maze (MWM), and Y-maze tests. The protein expression of different mediators such as TNF-α, p-JNK, pIRS636, BACE1, APP, and Aβ was evaluated through western blot and immunofluorescence staining techniques. Biochemical assays were carried out to assess the antioxidant activities of TA. The computational study was conducted to predict the binding mode of TA with target sites of TNF-α. Behavioral studies showed that the TA-treated mice exhibited gradual memory improvement. TA significantly inhibited BACE1 activity and reduced production and accumulation of Aβ in the hippocampus of mice brains. Moreover, the TA significantly inhibited LPS-induced ROS production and enhanced the glutathione levels. Furthermore, we have shown via the computational method for the first time that TA inhibits LPS-triggered TNF-ὰ and its downstream signaling to reduce AD pathology including memory impairment, neuroinflammation, insulin signaling impairment, and Aβ deposition in adult mice. Taken together our current study demonstrates that TA is a potential candidate for the abrogation of LPS-induced neurotoxicity and AD pathology in rodent's models. Show less

Obesity is highly polygenic disease where several genetic variants have been reportedly associated with obesity in different ethnicities of the world. In the current study, we identified the obesity risk or protective association and BMI raising effect of the minor allele of adiponectin, C1Q and collagen domain containing (ADIPOQ), cholesteryl ester transfer protein (CEPT), FTO alpha-ketoglutarate dependent dioxygenase (FTO), leptin (LEP), and leptin receptor (LEPR) genes in a large cohort stratified into four BMI-based body weight categories i.e., normal weight, lean, over-weight, and obese. Based on selected candidate genetic markers, the genotyping of all study subjects was performed by PCR assays, and genotypes and allele frequencies were calculated. The minor allele frequencies (MAFs) of all genetic markers were computed for total and BMI-based body weight categories and compared with MAFs of global and South Asian (SAS) populations. Genetic associations of variants with obesity risk were calculated and BMI raising effect per copy of the minor allele were estimated. The genetic variants with higher MAFs in obese BMI group were; rs2241766 (G = 0.43), rs17817449 (G = 0.54), rs9939609 (A = 0.51), rs1421085 (C = 0.53), rs1558902 (A = 0.63), and rs1137101 (G = 0.64) respectively. All these variants were significantly associated with obesity (OR = 1.03-4.42) and showed a high BMI raising effect (β = 0.239-0.31 Kg/m2) per copy of the risk allele. In contrast, the MAFs of three variants were higher in lean-normal BMI groups; rs3764261 A = 0.38, rs9941349 T = 0.43, and rs7799039 G = 0.40-0.43). These variants showed obesity protective associations (OR = 0.68-0.76), and a BMI lowering effect per copy of the protective allele (β = -0.103-0.155 Kg/m2). The rs3764261 variant also showed significant and positive association with lean body mass (OR = 2.38, CI = 1.30-4.34). Overall, we report six genetic variants of ADIPOQ, FTO and LEPR genes as obesity-risk markers and a CETP gene variant as lean mass/obesity protective marker in studied Pakistani cohort. Show less

Whilst the prevalence of obesity continues to increase at an alarming rate worldwide, the personal and economic burden of obesity-related complications becomes ever more important. Whilst dietary and lifestyle measures remain the fundamental focus of the patient to counter obesity, more frequently pharmacological and/or surgical interventions are required. Nevertheless, these therapies are often limited by weight loss efficacy, side effects, surgical risks and frequently obesity relapse. Currently, only five drug therapies are approved for the specific treatment of obesity. However, our understanding of the pathophysiology of obesity and of gut hormones has developed precipitously over the last 20-30 years. As a result, there has been a recent movement to create and use analogues that manipulate these gut hormones to support weight loss. In this article we review the efficacy of the currently approved drug therapies and discuss future potential drug mechanisms and early clinical trial results exploring these budding avenues. We discuss the use of glucagon-like peptide-1 (GLP-1) analogues as monotherapy and unimolecular dual or triple agonists that exploit the GLP-1 receptor and/or the gastric inhibitory peptide (GIP) receptor and/or the glucagon receptor. We also explore the use of sodium-glucose co-transporter-2 (SGLT-2) inhibitors, amylin mimetics, leptin analogues, ghrelin antagonists and centrally acting agents to suppress appetite [neuropeptide Y (NPY) antagonists, melanocortin-4 receptor (MC4R) agonists and cannabinoid-1 receptor antagonists]. Whilst further evidence is required to support their clinical use, preclinical and early clinical trial results are encouraging. Show less

Dyggve melchior clausen syndrome (DMC, MIM 223800) is a very rare autosomal recessive form of skeletal dysplasia associated with various degrees of mental retardation. It is characterized by a progressive spondyloepimetaphyseal dysplasia (SEMD) with disproportionate short stature, generalized platyspondyly and lacy iliac crest. Here, we report characterization of large consanguineous family segregating DMC in autosomal recessive manner. Scanning SNP-based human genome identified a 5.3 Mb homozygous region on chromosome 18q21.1-q21.2. Sanger sequencing of the DYM gene, located in the homozygous region, revealed a novel homozygous nonsense variant [c.59 T > A; p.(Leu20*)] in affected members of the family. Analysis of the mRNA, extracted from hair follicles of an affected individual, suggested non-sense mediated decay (NMD) of the truncated transcript. This is the first nonsense and fourth loss of function variant in the DYM gene, causing DMC, reported in the Pakistani population. This study not only extended spectrum of the mutations in the DYM gene but will also facilitate diagnosis of similar other cases in Pakistani population. Show less

Diabetic retinopathy (DR) is one of the most common complications of diabetes mellitus. Vision loss in DR principally occurs due to breakdown of the blood-retinal barrier (BRB), leading to macular edema, retinal detachment and inner retinal and vitreous hemorrhage. Several growth factors have been shown to play crucial role in the development of these vascular changes; however, the cellular and molecular mechanisms of DR are not yet fully revealed. In the current study we investigated the role of bone morphogenetic protein-2 (BMP2) in DR. We examined the changes in the protein levels of BMP2 in human vitreous and retina in addition to the mouse retina of streptozotocin-induced diabetes. To detect the source of BMP2 during diabetes, human retinal endothelial cells (hRECs) were subjected to high glucose (HG) for 5 days and levels of BMP2 protein were analyzed in conditioned media of these cells relative to control. We also evaluated the effect of BMP2 on the levels of VEGF in cultured rat Müller cells (rMC1). In addition, we tested the pro-inflammatory effects of BMP2 by examining its effect on leukocyte adhesion to cultured hRECs, and levels of adhesion molecules and cytokines production. Finally, the effect of different concentrations of BMP2 on permeability of confluent monolayer of hRECs was evaluated using FITC-Dextran flux permeability assay and by measuring Transcellular Electrical Resistance (TER) using Electric Cell-substrate Impedance Sensing (ECIS). Our results show, for the first time, the up-regulation of BMP2 in diabetic human and mouse retinas in addition to its detection in vitreous of patients with proliferative DR (72 ± 7 pg/ml). In vitro, hRECs showed upregulation of BMP2 in HG conditions suggesting that these cells are a potential source of BMP2 in diabetic conditions. Furthermore, BMP2 induced VEGF secretion by Müller cells in-vitro; and showed a dose response in increasing permeability of cultured hRECs. Meanwhile, BMP2 pro-inflammatory effects were recognized by its ability to induce leukocyte adhesion to the hRECs, intercellular adhesion molecule-1 (ICAM-1) and upregulation of interleukin-6 and 8 (IL-6 and IL-8). These results show that BMP2 could be a contributing growth factor to the development of microvascular dysfunction during DR via enhancing both pro-angiogenic and inflammatory pathways. Our findings suggest BMP2 as a potential therapeutic target to prevent/treat DR. Show less

The neuronal ceroid lipofuscinoses (NCLs) are the commonest neurodegenerative disorders of children. The aims of this study were to determine the incidence of NCL in Newfoundland, identify the causative genes, and analyze the relationship between phenotype and genotype. Patients with NCL diagnosed between 1960 and 2005 were ascertained through the provincial genetics and pediatric neurology clinics. Fifty-two patients from 34 families were identified. DNA was obtained from 28/34 (82%) families; 18 families had mutations in the CLN2 gene, comprising five different mutations of which two were novel. One family had a CLN3 mutation, another had a novel mutation in CLN5, and five families shared the same mutation in CLN6. One family was misdiagnosed, and in two, molecular testing was inconclusive. Disease from CLN2 mutations had an earlier presentation (p = 0.003) and seizure onset (p < 0.001) compared with CLN6 mutation. There was a slower clinical course for those with CLN5 mutation compared with CLN2 mutation. NCL in Newfoundland has a high incidence, 1 in 7353 live births, and shows extensive genetic heterogeneity. The incidence of late infantile NCL, 9.0 per 100,000 (or 1 in 11,161) live births, is the highest reported in the world. Show less