Biology subjects

White, S. M.

Publications and source records attributed to White, S. M..

7 recordsLinked to original sources

bioRxiv2024

Comparative atlas of genome-wide chromatin-associated protein co-occupancy

Accurate transcriptional regulation and chromatin dynamics requires the coordination and activity of chromatin-associated proteins (CAPs) at distinct loci. While the combinatorial activity of a select set of CAPs has been previously examined, these studies are limited by the underrepresentation of proteins and cell types explored, making it difficult to identify the global associations as well as the conservation of these associations across different cell types. Here, we performed 270 CAP chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-Seq) experiments in both K562 and HepG2 cancer cell lines and explored the relationship between cell identity and CAP co-association using three distinct approaches. We employed a machine learning algorithm to organize the genome-wide binding profiles into 56 and 70 interpretable co-association modules for HepG2 and K562 cell lines, respectively. We found CAP co-association modules are mostly cell type-specific, however those present in both cell lines are largely comprised of TFs from a single TF family and anchor to unique loci via lineage-specific factors. While enhancer-associated co-binding modules were largely composed of cell type-specific CAPs, we found regulatory activity at promoter-enhancer module contacts to be enriched for chromatin remodeling proteins. Additionally, we used colocalization information derived from co-association models in conjunction with neural network models of transcription factor (TF) activity to identify high-confidence candidate TF cooperative pairs. Finally, through comparing CAP enrichment in high occupancy target (HOT) regions in K562 and HepG2 cell lines, we found cell type-specific HOT sites, but not common HOT sites, are selectively enriched at high copy number loci. Overall, this study uncovers principles of sequence-level and large-scale CAP genomic organization and demonstrates how this contributes to cell type-specific regulatory mechanisms and cellular functions.

genomics↗

bioRxiv2024

Neural basis of cognitive control signals in anterior cingulate cortex during delay discounting

Cognitive control involves allocating cognitive effort according to internal needs and task demands. The anterior cingulate cortex (ACC) is hypothesized to play a central role in this process. We investigated the neural basis of cognitive control in the ACC of rats performing an adjusting-amount delay discounting task, with a 4s or 8s delay between lever choice and reward. A reinforcement learning model indicated that decision making on this task can be guided by either a value tracking strategy, requiring a resource-based form of cognitive control or a delay-lever biased strategy requiring a resistance-based form of cognitive control. This was then tested in vivo by multiple single unit recordings and local field potentials acquired from male rats performing the task. On this task, the behavioral manifestation of resistance-based control is an excessive focus on delayed lever choices which was observed during a substantial portion of 4s but not 8s delay sessions. On a neural level, this was associated with an increase in Theta (6-12Hz) oscillations prior to delay choices which was present exclusively on 4s delay sessions. By contrast, evidence of a resource-based control signal was found in spike trains that closely tracked lever value prior to choice, and was far more prevalent on 8s delay sessions. These data provide candidate neural signatures of resource-based versus resistance-based forms of cognitive control. While mediated by distinct neural mechanisms, either form could be engaged by individual subjects under different task conditions.

neuroscience↗

bioRxiv2023

Flexible coding schemes in dorsomedial prefrontal cortex underlie decision-making during delay discounting

Determining how an agent decides between a small, immediate versus a larger, delayed reward has provided insight into the psychological and neural basis of decision-making. The tendency to excessively discount the value of delayed rewards is thought to reflect deficits in brain regions critical for impulse control such as the prefrontal cortex (PFC). This study tested the hypothesis that dorsomedial PFC (dmPFC) is critically involved in flexibly managing neural representations of strategies that limit impulsive choices. Optogenetic silencing of neurons in the rat dmPFC increased impulsive choices at an 8 sec, but not 4 sec, delay. Neural recordings from dmPFC ensembles revealed that, at the 8-sec delay, the encoding landscape transitions to reflect a deliberative-like process rather than the schema-like processes observed at the 4-sec delay. These findings show that changes in the encoding landscape reflect changes in task demands and that dmPFC is uniquely involved in decisions requiring deliberation.

neuroscience↗

bioRxiv2022

A genome-wide atlas of recurrent repeat expansions in human cancer

Expansion of a single repetitive DNA sequence, termed a tandem repeat (TR), is known to cause more than 50 diseases. However, repeat expansions are often not explored beyond neurological and neurodegenerative disorders. In some cancers, mutations accumulate in short tracts of TRs (STRs), a phenomenon termed microsatellite instability (MSI); however larger repeat expansions have not been systematically analyzed in cancer. Here, we identified TR expansions in 2,622 cancer genomes, spanning 29 cancer types. In 7 cancer types, we found 160 recurrent repeat expansions (rREs); most of these (155/160) were subtype specific. We found that rREs were non-uniformly distributed in the genome with an enrichment near candidate cis-regulatory elements, suggesting a role in gene regulation. One rRE located near a regulatory element in the first intron of UGT2B7 was detected in 34% of renal cell carcinoma samples and was validated by long-read DNA sequencing. Moreover, targeting cells harboring this rRE with a rationally designed, sequence-specific DNA binder led to a dose-dependent decrease in cell proliferation. Overall, our results demonstrate that rREs are an important but unexplored source of genetic variation in human cancers, and we provide a comprehensive catalog for further study.

genomics↗

bioRxiv2019

Rapid diagnosis of SCA36 in a three-generation family using short-read whole genome sequencing data

BackgroundSpinocerebellar ataxias (SCA) are often caused by expansions of short tandem repeats (STRs). Recent methodological advances have made repeat expansion (RE) detection with whole genome sequencing (WGS) feasible. ObjectivesTo determine the genetic basis of ataxia in a multigenerational Australian pedigree, with autosomal dominant inheritance. Methods and ResultsWGS was performed on three affected relatives. The sequence data was screened for known pathogenic REs using two repeat expansion detection tools: exSTRa and ExpansionHunter. This screen provided a clear and rapid diagnosis (<five days from receiving the sequencing data) of SCA36, a rare form of ataxia caused by an intronic GGCCTG RE in NOP56. Conclusionsthe that diagnosis of rare ataxias caused by REs is highly feasible and cost effective with WGS. We propose that WGS be implemented as the frontline, cost effective methodology for molecular testing of individuals with a clinical diagnosis of ataxia.

genomics↗

bioRxiv2019

Pooled-parent exome sequencing to prioritise de novo variants in genetic disease

In the clinical setting, exome sequencing has become standard-of-care in diagnosing rare genetic disorders, however many patients remain unsolved. Trio sequencing has been demonstrated to produce a higher diagnostic yield than singleton (proband-only) sequencing. Parental sequencing is especially useful when a disease is suspected to be caused by a de novo variant in the proband, because parental data provide a strong filter for the majority of variants that are shared by the proband and their parents. However the additional cost of sequencing the parents makes the trio strategy uneconomical for many clinical situations. With two thirds of the sequencing budget being spent on parents, these are funds that could be used to sequence more probands. For this reason many clinics are reluctant to sequence parents.\n\nHere we propose a pooled-parent strategy for exome sequencing of individuals with likely de novo disease. In this strategy, DNA from all the parents of a cohort of unrelated probands is pooled together into a single exome capture and sequencing run. Variants called in the proband can then be filtered if they are also found in the parent pool, resulting in a shorter list of prioritised variants. To evaluate the pooled-parent strategy we performed a series of simulations by combining reads from individual exomes to imitate sample pooling. We assessed the recall and false positive rate and investigated the trade-off between pool size and recall rate. We compared the performance of GATK HaplotypeCaller individual and joint calling, and FreeBayes to genotype pooled samples. Finally, we applied a pooled-parent strategy to a set of real unsolved cases and showed that the parent pool is a powerful filter that is complementary to other commonly used variant filters such as population variant frequencies.

bioinformatics↗

bioRxiv2018

A meta-analysis of the diagnostic sensitivity and clinical utility of genome sequencing, exome sequencing and chromosomal microarray in children with suspected genetic diseases

IMPORTANCEGenetic diseases are a leading cause of childhood mortality. Whole genome sequencing (WGS) and whole exome sequencing (WES) are relatively new methods for diagnosing genetic diseases.\n\nOBJECTIVESCompare the diagnostic sensitivity (rate of causative, pathogenic or likely pathogenic genotypes in known disease genes) and rate of clinical utility (proportion in whom medical or surgical management was changed by diagnosis) of WGS, WES, and chromosomal microarrays (CMA) in children with suspected genetic diseases.\n\nDATA SOURCES AND STUDY SELECTIONSystematic review of the literature (January 2011 - August 2017) for studies of diagnostic sensitivity and/or clinical utility of WGS, WES, and/or CMA in children with suspected genetic diseases. 2% of identified studies met selection criteria.\n\nDATA EXTRACTION AND SYNTHESISTwo investigators extracted data independently following MOOSE/PRISMA guidelines.\n\nMAIN OUTCOMES AND MEASURESPooled rates and 95% Cl were estimated with a random-effects model. Metaanalysis of the rate of diagnosis was based on test type, family structure, and site of testing.\n\nRESULTSIn 36 observational series and one randomized control trial, comprising 20,068 children, the diagnostic sensitivity of WGS (0.41, 95% Cl 0.34-0.48, I2=44%) and WES (0.35, 95% Cl 0.31-0.39, I2=85%) were qualitatively greater than CMA (0.10, 95% Cl 0.08-0.12, I2=81%). Subgroup meta-analyses showed that the diagnostic sensitivity of WGS was significantly greater than CMA in studies published in 2017 (P<.0001, I2=13% and I2=40%, respectively), and the diagnostic sensitivity of WES was significantly greater than CMA in studies featuring within-cohort comparisons (P<001, I2=36%). Evidence for a significant difference in the diagnostic sensitivity of WGS and WES was lacking. In studies featuring within-cohort comparisons of singleton and trio WGS/WES, the likelihood of diagnosis was significantly greater for trios (odds ratio 2.04, 95% Cl 1.62-2.56, I2=12%; P<.0001). The diagnostic sensitivity of WGS/WES with hospital-based interpretation (0.41, 95% Cl 0.38-0.45, I2=50%) was qualitatively higher than that of reference laboratories (0.28, 95% Cl 0.24-0.32, I2=81%); this difference was significant in meta-analysis of studies published in 2017 (P=.004, I2=34% and I2=26%, respectively). The rates of clinical utility of WGS (0.27, 95% Cl 0.17-0.40, I2=54%) and WES (0.18, 95% Cl 0.13-0.24, I2-77%) were higher than CMA (0.06, 95% Cl 0.05-0.07, I2=42%); this difference was significant in meta-analysis of WGS vs CMA (P<.0001).\n\nCONCLUSIONS AND RELEVANCEIn children with suspected genetic diseases, the diagnostic sensitivity and rate of clinical utility of WGS/WES were greater than CMA. Subgroups with higher WGS/WES diagnostic sensitivity were trios and those receiving hospital-based interpretation. WGS/WES should be considered a first-line genomic test for children with suspected genetic diseases.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSWhat is the relative diagnostic sensitivity and clinical utility of different genome tests in children with suspected genetic diseases?\n\nFindingsWhole genome sequencing had greater diagnostic sensitivity and clinical utility than chromosomal microarrays. Testing parent-child trios had greater diagnostic sensitivity than proband singletons. Hospital-based testing had greater diagnostic sensitivity than reference laboratories.\n\nMeaningTrio genomic sequencing is the most sensitive diagnostic test for children with suspected genetic diseases.

genomics↗