Biology subjects

Haque, T.

Publications and source records attributed to Haque, T..

9 recordsLinked to original sources

bioRxiv2026

Environmental impacts on gene expression noise and its relationship with fitness

Genetically identical cells grown in the same environment show variation in gene expression known as expression noise. Expression noise can be heritable and impact fitness, making it subject to natural selection. Increasing expression noise for the Saccharomyces cerevisiae TDH3 gene was shown to be beneficial in glucose-based media when mean TDH3 expression was far from the fitness optimum but deleterious when it was close to this optimum. Here, we show that growth on different carbon sources alters the effects of new mutations on TDH3 expression noise and examine the fitness effects of changing expression noise. In galactose-based media, we observed the same relationship between expression noise and fitness seen in glucose-based media, but in glycerol- and ethanol-based media, we observed the opposite relationship or no significant relationship, respectively. Using simulations of single-cell organisms, we found that these differences were most likely explained by environment-specific relationships between gene expression and fitness. We also found that, far from the optimum, the fitness effects of noise were greatest when expression was highly heritable between mother and daughter cells. The empirical observations and simulations reported in this study show how environments influence both the production of expression noise and its impacts on fitness.

evolutionary biology↗

bioRxiv2025

MYD88 mutations in clonal hematopoiesis promote inflammation and hematopoietic stem cell expansion

Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by expansion of mutant hematopoietic stem and progenitor cells (HSPCs) and an increased risk of chronic diseases and cancers. While mutations in DNMT3A, TET2, and ASXL1 are common in CHIP, the contribution of less frequent gene mutations is not well understood. Here, we report MYD88 mutations, including lymphoma-associated and novel variants in blood cells of the general population and newly diagnosed solid cancer patients. MYD88 CHIP mutations in HSPCs activate NF-{kappa}B, indicating a gain-of-function activity. Modeling MYD88 CHIP in mice, Myd88L252P (equivalent of human L265P) expression resulted in a competitive fitness advantage of HSPCs. Myd88L252P HSPCs exhibit a myeloid cell bias and inflammation, leading to hematologic disease. Single-cell RNA sequencing indicated that Myd88L252P expands distinct hematopoietic and immune cell clusters and activates immune-related pathways in HSPCs. An IRAK1/4 inhibitor suppressed MYD88-dependent NF-{kappa}B activation and reversed Myd88L252P cell expansion. Overall, MYD88 mutations contribute to CHIP by inducing innate immune pathways in HSPCs and inflammatory disease.

cancer biology↗

bioRxiv2024

A FAN1 point mutation associated with accelerated Huntington's disease progression alters its PCNA-mediated assembly on DNA

FAN1 is an endo- and exo-nuclease involved in DNA and interstrand crosslink repair. Genome-wide association studies of people with Huntingtons disease revealed a strong association between the FAN1 R507H mutation and early disease onset, however the underlying mechanism(s) remains unclear. FAN1 has previously been implicated in modulating triplet repeat expansion in a PCNA dependent manner. To examine the role of PCNA on FAN1 activation, we solved the cryo-EM structures of a PCNA-FAN1-DNA complex. Our findings reveal that the FAN1 R507 residue directly interacts with PCNA D232. Biophysical interaction studies demonstrated that FAN1 enhances the binding affinity of PCNA for DNA, a synergistic effect disrupted in mutants carrying the R507H mutation. In contrast, PCNA does not affect the affinity of FAN1 for DNA but does modulate FAN1 activity upon ternary complex formation. The weakened and functionally altered FAN1 R507H-PCNA-DNA complex may partly impair the FAN1-mediated repair of CAG extrahelical extrusions, providing a potential explanation for the mutations role in accelerating disease progression.

biophysics↗

bioRxiv2023

Evolutionary analyses of gene expression divergence in Panicum hallii: exploring constitutive and plastic responses using reciprocal transplants

The evolution of gene expression is thought to be an important mechanism of local adaptation and ecological speciation. Gene expression divergence occurs through the evolution of cis-polymorphisms and through more widespread effects driven by trans-regulatory factors. Lovell et al. (2018) studied expression divergence between two ecotypes of Panicum hallii using expression quantitative trait loci (eQTL) analyses and discovered a pre-dominance of cis and several trans-regulatory divergences. Here, we explore expression and sequence divergence in a large sample of P. hallii accessions encompassing the species range using a reciprocal transplantation experiment. We observed widespread genotype and transplant site drivers of expression divergence, with a limited number of genes exhibited genotype-by-site interactions. We used a modified Fst-Qst outlier approach (QPC analysis) to detect local adaptation. We identified 514 genes with constitutive expression divergence above and beyond the levels expected under neutral processes. However, no plastic expression responses met our multiple testing correction as QPC outliers. Constitutive QPC outlier genes were involved in a number of developmental processes and responses to abiotic environments. Leveraging the earlier eQTL results, we found a strong enrichment of expression divergence, including for QPC outliers, in genes previously identified with cis and cis-drought interactions but found no patterns related to trans-factors. Population genetic analyses detected elevated sequence divergence (FST, DXY) of promoters and coding sequence of constitutive expression outliers, but little evidence for positive selection on these proteins. Our results are consistent with a hypothesis of cis-regulatory divergence as a primary driver of expression divergence in P. hallii.

evolutionary biology↗

bioRxiv2022

Natural variation identifies new effectors of water use efficiency in Arabidopsis.

Water use efficiency (WUE) is the ratio of biomass gained per unit of water consumed; thus, it can be altered by genetic factors that affect either side of the ratio. In the present study, we exploited natural variation for WUE as an unbiased approach to discover loci affecting either biomass accumulation or water use as factors affecting WUE. Genome-wide association (GWAS) analysis using integrated WUE measured through carbon isotope discrimination ({delta}13C) of Arabidopsis thaliana accessions identified genomic regions associated with WUE. Reverse genetic analysis of 70 candidate genes selected based on the GWAS results and transcriptome data identified 25 genes affecting WUE as measured by gravimetric and {delta}13C analyses. Mutants of four genes had higher WUE than wild type, while mutants of the other 21 genes had lower WUE. The differences in WUE were caused by either altered biomass or water consumption (or both). Stomatal density was not a primary cause of altered WUE in these mutants. Leaf surface temperatures indicated that transpiration differed for mutants of 16 genes, but generally biomass accumulation had greater effect on WUE. The genes we identified are involved in diverse cellular processes including hormone and calcium signaling, meristematic activity, photosynthesis, flowering time, leaf/vasculature development, and cell wall composition; however, none of them had been previously linked to WUE or traits related to plant water relations. Thus, our study successfully identified new effectors of WUE that can be used to understand the genetic basis of WUE and improve crop productivity.

plant biology↗

bioRxiv2022

Transcriptome and DNA methylome dynamics reveal differential characteristics of inflorescence development between two ecotypes in Panicum hallii

The morphological diversity of the inflorescence determines flower and seed production, which is critical for plant adaptation and fitness. Cytosine methylation is an epigenetic mark that contributes to gene expression regulation during inflorescence development. Panicum hallii is a wild perennial grass in the subfamily Panicoideae that has been developed as a model to study perennial grass biology and adaptive evolution. Highly divergent inflorescences have evolved between the two major ecotypes in P. hallii, the upland ecotype with compact inflorescence and large seed and the lowland ecotype with an open inflorescence and small seed. Here we performed a comparative transcriptome and DNA methylome analysis across different stages of inflorescence between these two divergent ecotypes of P. hallii. Global transcriptome analysis identified differentially expressed genes (DEGs) involved in panicle divergence, stage-specific expression, and co-expression modules underlying inflorescence development. Comparing DNA methylome profiles revealed a remarkable level of differential DNA methylation associated with the evolution of the P. hallii inflorescence. We found that most differentially methylated regions (DMRs) occurred within the flanking regulatory regions of genes, especially the promoter. Integrative analysis of DEGs and DMRs characterized the global features of DMR-associated DEGs in the divergence of P. hallii inflorescence, which includes homologs of important inflorescence and seed developmental genes that have been previously identified in domesticated crops. Evolutionary analysis measured by Ka/Ks ratio suggested that most DMR-associated DEGs are under relatively strong purifying selection. This study provides insights into the transcriptome and epigenetic landscape of inflorescence divergence in P. hallii and a novel genomic resource for perennial grass biology. One sentence summaryA comparative transcriptome and DNA methylome analysis of inflorescence between upland and lowland ecotypes reveal gene expression and DNA methylation variation underlying inflorescence divergence in Panicum hallii.

evolutionary biology↗

bioRxiv2022

A pleiotropic flowering time QTL exhibits gene-by-environmental interaction for fitness in a perennial grass

Flowering time is crucial for wild plant populations to adapt to their local environments. Although the genetic basis of flowering variation has been studied in many plant species, its mechanisms in non-model organisms and its adaptive value in the field are still poorly understood. Here, we report new insights into the genetic basis of flowering time and its effect on fitness in Panicum hallii, a native perennial grass. We conducted genetic mapping in populations derived from representative inland and coastal ecotypes to identify flowering time QTL and loci exhibited extensive QTL-by-environment interactions. Patterns of segregation within recombinant hybrids provide strong support for directional selection driving ecotypic divergence in flowering time. A major QTL on chromosome 5 (q-FT5) was detected in all experiments and is a key locus controlling flowering variation. Fine-mapping and expression studies identified a FLOWERING LOCUS T orthologue, FT-like 9 (PhFTL9), as the candidate underlying q-FT5. We used reciprocal transplant experiment to test for global local adaptation and the specific impact of q-FT5 on performance. We did not observe local adaptation in terms of fitness tradeoffs when contrasting ecotypes in home versus away habitats. However, we observed that the coastal allele of q-FT5 conferred a fitness advantage only in its local habitat but not at the inland site. Sequence analysis of the PhFTL9 promoter identified ecotypic specific cis-element variation associated with environmental responsiveness. Together, our findings demonstrate the genetic basis of flowering variation in a perennial grass and provide evidence for conditional neutrality underlying flowering divergence.

evolutionary biology↗

bioRxiv2020

Salt tolerance QTL derived from the Bangladeshi landrace Horkuch

Salinity has a significant negative impact on production of rice. To cope with the increased soil salinity due to climate change, we need to develop salt tolerant rice varieties that can maintain their high yield. Rice landraces indigenous to coastal Bangladesh can be a great resource to study the genetic basis of salt adaptation. In this study, we implemented a QTL analysis framework on a reciprocal mapping population between a salt tolerant landrace Horkuch and a high yieldingrice variety IR29. Our aim was to detect genetic loci that contributes to the salt adaptive responses of the two different developmental stages of rice which are very sensitive to salinity stress. We identified 14 QTL for 9 traits and found that most are unique to the specific developmental stage. In addition, we detected a significant effect of the cytoplasmic genome on the QTL model for some traits such as leaf total potassium and filled grain weight. This underscores the importance of considering cytoplasm-nuclear interaction for breeding programs. Along with this, we identified QTL co-localization for multiple traits that highlights the possible constraint of multiple QTL selection for breeding programs due to different contributions of a donor allele for different traits. HighlightsWe identified genetic loci for the salt tolerance response of two different developmental stages of the rice plant and detected significant contribution of cytoplasm-nuclear genome interaction for a few traits.

plant biology↗

bioRxiv2019

Whole genome sequencing of Herpes Simplex Virus 1 directly from human cerebrospinal fluid reveals selective constraints in neurotropic viruses.

Herpes Simplex Virus type 1 (HSV-1) chronically infects over 70% of the global population. Clinical manifestations are largely restricted to recurrent epidermal vesicles. However, HSV-1 also leads to encephalitis, the infection of the brain parenchyma, with high associated rates of mortality and morbidity. In this study, we performed target enrichment followed by direct sequencing of HSV-1 genomes, using target enrichment methods on the cerebrospinal fluid (CSF) of clinical encephalitis patients and from skin swabs of epidermal vesicles on non-encephalopathic patients. Phylogenetic analysis revealed high inter-host diversity and little population structure. By contrast, samples from different lesions in the same patient clustered with similar patterns of allelic variants. Comparison of consensus genome sequences shows HSV-1 has been freely recombining, except for distinct islands of linkage disequilibrium (LD). This suggests functional constraints prevent recombination between certain genes, notably those encoding pairs of interacting proteins. Distinct LD patterns characterised subsets of viruses recovered from CSF and skin lesions, which may reflect different evolutionary constraints in different body compartments. Functions of genes under differential constraint related to immunity or tropism and provide new hypotheses on tissue-specific mechanisms of viral infection and latency.

evolutionary biology↗