Biology subjects

Arora, U. P.

Publications and source records attributed to Arora, U. P..

6 recordsLinked to original sources

bioRxiv2025

Inherited resilience to clonal hematopoiesis by modifying stem cell RNA regulation

Somatic mutations that increase hematopoietic stem cell (HSC) fitness drive their expansion in clonal hematopoiesis (CH) and predispose to blood cancers. Although CH frequently occurs with aging, it rarely progresses to overt malignancy. Population variation in the growth rate and potential of mutant clones suggests the presence of genetic factors protecting against CH, but these remain largely undefined. Here, we identify a non-coding regulatory variant, rs17834140-T, that significantly protects against CH and myeloid malignancies by downregulating HSC-selective expression and function of the RNA-binding protein MSI2. By modeling variant effects and mapping MSI2 binding targets, we uncover an RNA network that maintains human HSCs and influences CH risk. Importantly, rs17834140-T is associated with slower CH expansion rates in humans, and stem cell MSI2 levels modify ASXL1-mutant HSC clonal dominance in experimental models. These findings leverage natural resilience to highlight a key role for post-transcriptional regulation in human HSCs, and offer genetic evidence supporting inhibition of MSI2 or its downstream targets as rational strategies for blood cancer prevention.

genetics↗

bioRxiv2024

Transcription factor networks disproportionately enrich for heritability of blood cell phenotypes

Most phenotype-associated genetic variants map to non-coding regulatory regions of the human genome. Moreover, variants associated with blood cell phenotypes are enriched in regulatory regions active during hematopoiesis. To systematically explore the nature of these regions, we developed a highly efficient strategy, Perturb-multiome, that makes it possible to simultaneously profile both chromatin accessibility and gene expression in single cells with CRISPR-mediated perturbation of a range of master transcription factors (TFs). This approach allowed us to examine the connection between TFs, accessible regions, and gene expression across the genome throughout hematopoietic differentiation. We discovered that variants within the TF-sensitive accessible chromatin regions, while representing less than 0.3% of the genome, show a [~]100-fold enrichment in heritability across certain blood cell phenotypes; this enrichment is strikingly higher than for other accessible chromatin regions. Our approach facilitates large-scale mechanistic understanding of phenotype-associated genetic variants by connecting key cis-regulatory elements and their target genes within gene regulatory networks.

genomics↗

bioRxiv2023

Centromere Innovations Within a Mouse Species

Mammalian centromeres direct faithful genetic inheritance and are typically characterized by regions of highly repetitive and rapidly evolving DNA. We focused on a mouse species, Mus pahari, that we found has evolved to house centromere-specifying CENP-A nucleosomes at the nexus of a satellite repeat that we identified and term {pi}-satellite ({pi}-sat), a small number of recruitment sites for CENP-B, and short stretches of perfect telomere repeats. One M. pahari chromosome, however, houses a radically divergent centromere harboring [~]6 Mbp of a homogenized {pi}-sat-related repeat, {pi}-satB, that contains >20,000 functional CENP-B boxes. There, CENP-B abundance drives accumulation of microtubule-binding components of the kinetochore, as well as a microtubule-destabilizing kinesin of the inner centromere. The balance of pro and anti-microtubule-binding by the new centromere permits it to segregate during cell division with high fidelity alongside the older ones whose sequence creates a markedly different molecular composition. TeaserChromatin and kinetochore alterations arise in response to evolutionarily rapid changes to underlying repetitive centromere DNA.

genomics↗

bioRxiv2022

Strain level centromere variation influences CENP-A association dynamics and centromere function

Centromeres are rapidly evolving chromatin domains that fulfill essential roles in chromosome segregation. Rapid centromere sequence evolution imposes strong selection for compensatory changes in centromere-associated kinetochore proteins, leading to striking co-evolutionary trends across species. However, it remains unknown whether within species centromere sequence diversity leads to functional differences in kinetochore protein association. House mice (Mus musculus) exhibit significant variation in centromere satellite array size and sequence heterogeneity, but the amino acid sequence of CENP-A, a centromere-specific histone variant that specifies centromere identity, is conserved. We hypothesize that centromere satellite sequence variation leads to differences in the localization of CENP-A among house mice, with potential consequences for meiotic drive and genome stability. Using CENP-A chromatin immunoprecipitation with a customized k-mer based, reference-blind bioinformatic analysis strategy, we compare the CENP-A sequence association landscape in four diverse inbred mouse strains (C57BL/6J, CAST/EiJ, LEWES/EiJ, and PWK/PhJ). We uncover significant strain-level diversity in CENP-A associated sequences, with more closely related strains exhibiting more similar CENP-A association profiles. LEWES/EiJ and CAST/EiJ show mild association of CENP-A with the pericentromeric satellite repeat, countering the prevailing notion that functional centromere size is solely determined by the size of the minor satellite array. Strain-specific CENP-A association profiles are enriched for unique suites of transcription factor motifs, hinting at strain differences in centromere transcription. Given the importance of centromere-CENP-A association and centromere transcription for both kinetochore assembly and chromosome segregation fidelity, our findings suggest a potential mechanism for centromere-mediated variation in genome stability among inbred mouse strains.

genomics↗

bioRxiv2021

Selection shapes the landscape of functional variation in wild house mice

BackgroundThrough human-aided dispersal, house mice have recently colonized new and diverse habitats across the globe, promoting the emergence of new traits that confer adaptive advantages in distinct environments. Despite their status as the premiere mammalian model system, the impact of this demographic and selective history on the global patterning of disease-relevant trait variation in wild mouse populations is poorly understood. ResultsHere, we leveraged 154 whole-genome sequences from diverse wild house mouse populations, subspecies, and species to survey the geographic organization of functional variation and systematically identify signals of positive selection. We show that a significant proportion of wild mouse variation is private to single populations, including numerous predicted functional alleles. In addition, we report strong signals of positive selection at numerous genes associated with both complex and Mendelian diseases in humans. Notably, we detect a significant excess of selection signals at disease-associated genes relative to null expectations, pointing to the important role of adaptation in shaping the landscape of functional variation in wild mouse populations. We also uncover strong signals of selection at multiple genes involved in starch digestion, including Mgam and Amy1. We speculate that the successful emergence of the human-mouse commensalism may have been facilitated, in part, by dietary adaptations at these loci. Finally, our work uncovers multiple cryptic structural variants that manifest as putative signals of positive selection, highlighting an important and under-appreciated source of false-positive signals in genome-wide selection scans. ConclusionsOverall, our findings underscore the role of adaptation in shaping wild mouse genetic variation at human disease-associated genes. Our work highlights the biomedical relevance of wild mouse genetic diversity and unsdercores the potential for targeted sampling of mice from specific populations as a strategy for developing effective new mouse models of both rare and common human diseases.

evolutionary biology↗

bioRxiv2020

Population and species diversity at mouse centromere satellites

Centromeres are satellite-rich chromatin domains that are essential for chromosome segregation. Centromere satellites evolve rapidly between species but little is known about population-level diversity across these loci. We developed a k-mer based method to quantify centromere copy number and sequence variation from whole genome sequencing data. We applied this method to diverse inbred and wild house mouse (genus Mus) genomes and uncover pronounced variation in centromere architecture between strains and populations. We show that patterns of centromere diversity do not mirror the known ancestry of inbred strains, revealing a remarkably rapid rate of centromere sequence evolution. We document increased satellite homogeneity and copy number in inbred compared to wild mice, suggesting that inbreeding remodels mouse centromere architecture. Our results highlight the power of k-mer based approaches for probing variation across repetitive regions and provide the first in-depth, phylogenetic portrait of centromere variation across Mus musculus.

genomics↗