Biology subjects

Mehrotra, A.

Publications and source records attributed to Mehrotra, A..

11 recordsLinked to original sources

bioRxiv2025

Genetic analysis of iris pigmentation in Swiss pig breeds identifies a missense KITLG variant as a potential causal factor for pale and heterochromatic irises

BackgroundIris pigmentation is a heritable trait with a complex genetic architecture. While the genetic basis of iris pigmentation has been extensively studied in humans, little is known about iris pigmentation in pigs. Iris pigmentation in pigs varies from different shades of brown or pale irises to heterochromia manifesting either as different colors between both irises (heterochromia iridum) or multiple colors within a single iris (heterochromia iridis). This study investigates the genetics of iris pigmentation variability in the Swiss Landrace and Swiss Large White pig breeds. ResultsIris pigmentation was phenotyped in 837 Swiss Landrace and 328 Swiss Large White pigs of which the majority also had array-derived genotypes. A high prevalence of heterochromia iridum (18.6%) was observed in the Swiss Landrace breed. Heritability estimates for iris pigmentation were high in both breeds (h{superscript 2} = 56.0-57.2%). Iris pigmentation was not genetically correlated with production traits. Genome-wide association analysis identified several loci associated with iris pigmentation, including regions near functional candidate genes such as TYR, ALX4 and DCT. The strongest association was detected near the KITLG gene, which was identified as a candidate gene for iris pigmentation in a previous study on Italian Large White pigs. Fine-mapping identified a highly significantly associated (P=3.8x10-11) missense variant in KITLG (5_94084790_G>A, rs342599807, p.R124K) as a potential causal variant for pale and heterochromatic iris pigmentation in Swiss pigs. ConclusionsOur findings provide new insights into the genetic architecture of iris pigmentation in pigs and indicate that KITLG plays a key role. The identification of a putative causal missense variant offers a foundation for further functional studies aiming to better understand pigmentation traits in pigs.

genomics↗

bioRxiv2024

Genome-Wide Association Testing for Haemorrhagic Bowel Syndrome in a Swiss Large White Pig Population

BackgroundThe porcine haemorrhagic bowel syndrome (HBS) is a multifactorial disease causing fatal gastrointestinal disturbances and sudden death in fattening pigs. HBS is the leading cause of deaths during fattening in Swiss pigs, with unclear etiology. Environmental and management factors are associated with HBS incidence, but recent findings also suggest a potential genetic predisposition. Pigs sired by a Swiss Large White (SLW) line appear more prone to HBS. Here we conduct genome-wide association studies (GWAS) for HBS between cases and controls to investigate potential genetic factors for the disease in Swiss fattening pigs. ResultsOur study included 1,036 HBS cases and 4,080 controls with available microarray genotypes or whole-genome sequencing data. Variant positions were determined according to the current porcine reference assembly (Sscrofa11.1) or a HiFi-based SLW haplotype assembly which we constructed using trio-binning. GWAS for HBS were conducted using 12.49 to 15.46 million biallelic variants in three mapping cohorts consisting of purebred animals from SLW sire and dam lines, or crosses between these two parental lines. The statistical model applied for the GWAS accounted for animal relatedness, population structure, and an imbalanced case/control ratio. No sequence variants significantly associated with HBS were identified, regardless of the cohort analysed and the reference sequence considered. ConclusionsThe lack of genetic associations despite a relatively large sample size suggests that susceptibility to HBS in the studied SLW population is not due to large effect variants but may be influenced by numerous small effect genetic variants, in addition to environmental and management factors.

genomics↗

bioRxiv2024

Virus-associated Inflammation Imprints an Inflammatory Profile on Long-lived Monocyte-derived Macrophages in the Human Liver

Chronic liver injury triggers the activation and recruitment of immune cells, causing antigen-independent tissue damage and liver disease progression. Tissue inflammation can reshape macrophage composition through monocyte replacement. Replacement of tissue macrophages with monocytes differentiating in an inflammatory environment can potentially imprint a phenotype that switches the liver from an immunotolerant organ to one predisposed to tissue damage. We longitudinally sampled the liver of chronic hepatitis B (CHB) patients with active liver inflammation starting antiviral therapy. Antiviral therapy suppressed viral replication and liver inflammation, which coincided with decreased myeloid activation markers. Single-cell RNA sequencing mapped peripheral inflammatory markers to a monocyte-derived macrophage population, distinct from Kupffer cells, with an inflammatory transcriptional profile. The inflammatory macrophages (iMacs) differentiated from blood monocytes and established a long-lived population. The iMacs retained their core transcriptional signature, consistent with trained immunity, resulting in a population of macrophages primed for inflammation potentially driving progressive liver disease.

immunology↗

bioRxiv2023

Liver-specific Inflammatory Signatures Predict Clinically Significant Liver Damage.

Background and AimsInflammation drives progression of chronic liver disease. However, the triggers of inflammation remain undefined during chronic hepatitis B (CHB) because hepatic flares are spontaneous and difficult to capture. We used nucleoside analogue (NA) withdrawal to investigate early inflammatory events because liver damage after stopping therapy occurs in a predictable time frame. 11 CHB patients underwent 192 weeks of NA therapy before a protocol defined stop. Liver fine-needle aspirates (FNAs) were collected at baseline and 4-weeks post-withdrawal and analyzed using flow cytometry and single-cell RNA sequencing (scRNA-seq). Intrahepatic mononuclear cells (IHMCs) from uninfected livers were used to validate transcriptomic findings. At 4 weeks post NA-withdrawal, HBV DNA rebounded but alanine aminotransferase (ALT) levels remained normal, 7/11 patients developed ALT elevations (>2xULN) at later timepoints. There were no changes in cell frequencies between baseline and viral rebound. ScRNA-seq revealed upregulation of IFN stimulated genes (ISGs) and pro-inflammatory cytokine MIF upon viral rebound. In vitro experiments confirmed the type I IFN-dependent ISG profile whereas MIF was induced primarily by IL-12. MIF exposure further amplified inflammatory cytokine production by myeloid cells. Our data show that innate immune activation is detectable in the liver before clinically-significant liver damage is detectable in the serum.

immunology↗

bioRxiv2022

Comparison of two multi-trait association testing methods and sequence-based fine mapping of six QTL in Swiss Large White pigs

BackgroundGenetic correlations between complex traits suggest that pleiotropic variants contribute to trait variation. Genome-wide association studies (GWAS) aim to uncover the genetic underpinnings of traits. Multivariate association testing and the meta-analysis of summary statistics from single-trait GWAS enable detecting variants associated with multiple phenotypes. In this study, we used array-derived genotypes and phenotypes for 24 reproduction, production, and conformation traits to explore differences between the two methods and used imputed sequence variant genotypes to fine-map six quantitative trait loci (QTL). ResultsWe considered genotypes at 44,733 SNPs for 5,753 pigs from the Swiss Large White breed that had deregressed breeding values for 24 traits. Single-trait association analyses revealed eleven QTL that affected 15 traits. Multi-trait association testing and the meta-analysis of the single-trait GWAS revealed between 3 and 6 QTL, respectively, in three groups of traits. The multi-trait methods revealed three loci that were not detected in the single-trait GWAS. Four QTL that were identified in the single-trait GWAS, remained undetected in the multi-trait analyses. To pinpoint candidate causal variants for the QTL, we imputed the array-derived genotypes to the sequence level using a sequenced reference panel consisting of 421 pigs. This approach provided genotypes at 16 million imputed sequence variants with a mean accuracy of imputation of 0.94. The fine-mapping of six QTL with imputed sequence variant genotypes revealed four previously proposed causal mutations among the top variants. ConclusionsOur findings in a medium-size cohort of pigs suggest that multivariate association testing and the meta-analysis of summary statistics from single-trait GWAS provide very similar results. Although multi-trait association methods provide a useful overview of pleiotropic loci segregating in mapping populations, the investigation of single-trait association studies is still advised, as multi-trait methods may miss QTL that are uncovered in single-trait GWAS.

genomics↗

bioRxiv2022

Penetratin inhibits α-synuclein fibrillation and improves locomotor functions in mice model of Parkinsons disease

Parkinsons disease (PD) is the second most common neurodegenerative disease. The presence of lewy bodies, primarily consisting of -synuclein (-syn) aggregates is one of the common features seen in the substantia nigra region of the brain in PD patients. The disease remains incurable and only symptomatic relief is available. We screened various cell-penetrating peptides and reveal that penetratin is a potent inhibitor of -syn aggregation in-vitro, and significantly improved locomotor coordination in mice models of PD in-vivo. The peptide inhibits -syn aggregation in vitro as well as in yeast, and C.elegans models. We further made a cyclic derivative of penetratin by disulfide coupling of N- and C-terminal cysteine residues. Both penetratin and its cyclized derivative interact with -syn. NMR studies show that both linear as well as cyclic derivative interact at the acidic C-terminal tail of the protein. Similar to penetratin, its cyclic derivative inhibited -syn aggregation in the C.elegans model of Parkinsons disease, and also improved worm motility. Molecular Dynamics studies show that penetratin interacts with -synuclein and prevents its conformational transition from disordered into {beta}-sheet rich structure. The therapeutic efficacy of penetratin was further confirmed in a transgenic mice model of the disease, wherein penetratin treatment over a period of 90 days improved locomotor coordination, and halted disease progression. Overall, the present work provides a potent therapeutic agent that could be further explored in the management of PD.

neuroscience↗

bioRxiv2021

Clinical implementation of single-cell RNA sequencing using liver fine needle aspirate tissue sampling and centralized processing captures compartment specific immuno-diversity

Blood samples are frequently collected in human studies of the immune system but poorly represent tissue-resident immunity. Understanding the immunopathogenesis of tissue-restricted diseases, such as chronic hepatitis B, necessitates direct investigation of local immune responses. We developed a workflow that enables frequent, minimally invasive collection of liver fine-needle aspirates in multi-site international studies and centralized single-cell RNA sequencing data generation using the Seq-Well S3 picowell-based technology. All immunological cell types were captured, including liver macrophages, and showed distinct compartmentalization and transcriptional profiles, providing a systematic assessment of the capabilities and limitations of peripheral blood samples when investigating tissue-restricted diseases. The ability to electively sample the liver of chronic viral hepatitis patients and generate high-resolution data will enable multi-site clinical studies to power fundamental and therapeutic discovery.

immunology↗

bioRxiv2020

Analysis of selection signatures reveals important insights into the adaptability of high-altitude Indian sheep breed Changthangi

Changthangi is a high-altitude sheep breed of India that is adapted to cold and hypoxic climate of Himalayas. In the present study, we analysed population structure of Changthangi and contrasted it with selected Indian and European commercial sheep breeds to detect genomic regions under positive selection. The studied domesticated sheep breeds included Changthangi, Indian Garole, Deccani, Tibetan, Rambouillet and Australian Merino. While the PCA results revealed Changthangi clustered with Tibetan sheep; TREEMIX and ADMIXTURE results also detected the introgression of lowland Indian sheep inheritance in Changthangi. Cross-population comparisons of Changthangi using XP-EHH showed multiple functional regions present on OAR 7, 15 and 16, to be under selection in Changthangi sheep. These regions are related to adaptation to climatic and hypoxic stressors, nervous system and mitochondrial functioning. The genes present in these regions are suitable candidates for future studies on the genetic mechanisms underlying high-altitude adaptation.

genomics↗

bioRxiv2020

Signature of selection in composite Vrindavani cattle of India

Vrindavani is an Indian composite cattle breed developed by crossbreeding taurine dairy breeds with native indicine cattle in the 1960s. About 190,000 semen doses of Vrindavani bulls have been distributed to the farmers till date. The animals are under artificial and natural selection for higher milk production and adaptation to the tropical climate, respectively. However, the selection response for production and adaptation traits in the Vrindavani genome is not explored. In this study, we provide the first overview of the selection signatures in the Vrindavani genome. 96 Vrindavani cattle were genotyped using the BovineSNP50 BeadChip and the SNP genotype data of its constituent breeds were collected from a public database. Within-breed selection signatures in Vrindavani were investigated using the integrated haplotype score (iHS). Vrindavani was also compared to each of its parental breeds to discover between-population signatures of selection using two approaches, cross-population extended haplotype homozygosity (XP-EHH) and fixation index (FST). Selection of signature identifies 11 common region identified by more than one harbouring genes such as LRP1B, TNNI3K, APOB, CACNA2D1, FAM110B and SPATA17 associated with production and adaptation. Overall, our results suggested stronger selective pressure on regions responsible for adaptation compared to milk yield.

genetics↗

bioRxiv2020

Genome-wide SNP data unravel the ancestry and signatures of divergent selection in Ghurrah pigs of India

The evolution and domestication of pigs is a complex and ongoing process. Despite its rich biodiversity and proximity to the geographical origins of Sus scrofa domesticus, the place of Indian pigs in the global phylogeny is unclear. Using microarray-derived (porcine 60K SNP chip) genotypes of 11 Ghurrah pigs from North-Western India and a public dataset comprising 2113 pigs of 146 breeds, we determined the genomic ancestry of Ghurrah pigs and compared their genetic constitution to European and Asian breeds to ascertain signatures of divergent selection. Results showed that Ghurrah pigs contain genes of Asian and European ancestry with signs of inter-species introgression. Using Admixture LD - decay statistics, the European admixture event was dated to the recent past, coinciding with the start of cross-breeding efforts in India. The complex Asian ancestry pattern of the breed resembled that of wild boars of South - Central China and Thailand, possibly suggesting introgression from an Indian wild boar relative. FST and XP - EHH comparisons with Asian breeds highlighted divergent selection in genomic regions associated with odontogenesis and skeletal muscle development. Comparisons with European commercial breeds revealed that genomic regions governing olfaction and response to sensory stimulation were under selection in Ghurrah pigs. QTL for meat and carcass traits also showed divergent selection between European breeds and Ghurrah pigs. Our results present the first genomic characterization of an Indian pig breed using dense microarray-derived genotypes and highlight the importance of further genomic characterization of Indian domestic and wild pigs.

genomics↗

bioRxiv2018

Measures of neural similarity

One fundamental question is what makes two brain states similar. For example, what makes the activity in visual cortex elicited from viewing a robin similar to a sparrow? One common assumption in fMRI analysis is that neural similarity is described by Pearson correlation. However, there are a host of other possibilities, including Minkowski and Mahalanobis measures, with each differing in its mathematical, theoretical, neural computational assumptions. Moreover, the operable measures may vary across brain regions and tasks. Here, we evaluated which of several competing similarity measures best captured neural similarity. Our technique uses a decoding approach to assess the information present in a brain region and the similarity measures that best correspond to the classifiers confusion matrix are preferred. Across two published fMRI datasets, we found the preferred neural similarity measures were common across brain regions, but differed across tasks. Moreover, Pearson correlation was consistently surpassed by alternatives.

neuroscience↗