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7. Identification of aberrant luminal progenitors and mTORC1 as a potential breast cancer prevention target in BRCA2 mutation carriers

Author

Joyce, Rachel, Pascual, Rosa, Heitink, Luuk, Capaldo, Bianca D., Vaillant, François, Christie, Michael, Tsai, Minhsuang, Surgenor, Elliot, Anttila, Casey J. A., Rajasekhar, Pradeep, Jackling, Felicity C., Trussart, Marie, Milevskiy, Michael J. G., Song, Xiaoyu, Li, Mengbo, Teh, Charis E., Gray, Daniel H. D., Smyth, Gordon K., Chen, Yunshun, Lindeman, Geoffrey J., and Visvader, Jane E.

Published
2024
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12. Systemic inflammatory response syndrome triggered by blood-borne pathogens induces prolonged dendritic cell paralysis and immunosuppression

Author

Ashayeripanah, Mitra, Vega-Ramos, Javier, Fernandez-Ruiz, Daniel, Valikhani, Shirin, Lun, Aaron T.L., White, Jason T., Young, Louise J., Yaftiyan, Atefeh, Zhan, Yifan, Wakim, Linda, Caminschi, Irina, Lahoud, Mireille H., Lew, Andrew M., Shortman, Ken, Smyth, Gordon K., Heath, William R., Mintern, Justine D., Roquilly, Antoine, and Villadangos, Jose A.

Published
2024
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13. Increasing histone acetylation improves sociability and restores learning and memory in KAT6B-haploinsufficient mice

Author

Bergamasco, Maria I., Vanyai, Hannah K., Garnham, Alexandra L., Geoghegan, Niall D., Vogel, Adam P., Eccles, Samantha, Rogers, Kelly L., Smyth, Gordon K., Blewitt, Marnie E., Hannan, Anthony J., Thomas, Tim, and Voss, Anne K.

Subjects
Diagnosis, Care and treatment, Analysis, Genetic aspects, Phenotypes -- Analysis, Intellectual disabilities -- Diagnosis -- Care and treatment -- Genetic aspects, Gene expression -- Analysis, Histones -- Analysis, Mental retardation -- Diagnosis -- Care and treatment -- Genetic aspects, Phenotype -- Analysis
Abstract

Introduction Heterozygous mutations in the gene encoding the MYST family histone acetyltransferase, KAT6B, underlie 2 main intellectual disability disorders: the Say-Barber-Biesecker-Young-Simpson variant of Ohdo syndrome (SBBYSS) (OMIM 603736) (1) and [...], Mutations in genes encoding chromatin modifiers are enriched among mutations causing intellectual disability. The continuing development of the brain postnatally, coupled with the inherent reversibility of chromatin modifications, may afford an opportunity for therapeutic intervention following a genetic diagnosis. Development of treatments requires an understanding of protein function and models of the disease. Here, we provide a mouse model of Say-Barber- Biesecker-Young-Simpson syndrome (SBBYSS) (OMIM 603736) and demonstrate proof-of-principle efficacy of postnatal treatment. SBBYSS results from heterozygous mutations in the KAT6B (MYST4/MORF/QFK) gene and is characterized by intellectual disability and autism-like behaviors. Using human cells carrying SBBYSS-specific KAT6B mutations and Kat6b heterozygous mice ([Kat6b.sup.-/-]), we showed that KAT6B deficiency caused a reduction in histone H3 lysine 9 acetylation. Kat6b mice displayed learning, memory, and social deficits, mirroring SBBYSS individuals. Treatment with a histone deacetylase inhibitor, valproic acid, or an acetyl donor, acetyL-carnitine (ALCAR), elevated histone acetylation levels in the human cells with SBBYSS mutations and in brain and blood cells of [Kat6b.sup.-/-] mice and partially reversed gene expression changes in [Kat6b.sup.-/-] cortical neurons. Both compounds improved sociability in Kat6b mice, and ALCAR treatment restored learning and memory. These data suggest that a subset of SBBYSS individuals may benefit from postnatal therapeutic interventions.

Published
2024
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17. Benchmarking cell type annotation methods for 10x Xenium spatial transcriptomics data.

Author

Cheng, Jinming, Jin, Xinyi, Smyth, Gordon K., and Chen, Yunshun

Subjects
GENE expression profiling, TRANSCRIPTOMES, RNA sequencing, LIFE sciences, BREAST cancer
Abstract

Background: Imaging-based spatial transcriptomics technologies allow us to explore spatial gene expression profiles at the cellular level. Cell type annotation of imaging-based spatial data is challenging due to the small gene panel, but it is a crucial step for downstream analyses. Many good reference-based cell type annotation tools have been developed for single-cell RNA sequencing and sequencing-based spatial transcriptomics data. However, the performance of the reference-based cell type annotation tools on imaging-based spatial transcriptomics data has not been well studied yet. Results: We compared performance of five reference-based methods (SingleR, Azimuth, RCTD, scPred and scmapCell) with the marker-gene-based manual annotation method on an imaging-based Xenium data of human breast cancer. A practical workflow has been demonstrated for preparing a high-quality single-cell RNA reference, evaluating the accuracy, and estimating the running time for reference-based cell type annotation tools. Conclusions: SingleR was the best performing reference-based cell type annotation tool for the Xenium platform, being fast, accurate and easy to use, with results closely matching those of manual annotation. [ABSTRACT FROM AUTHOR]

Published
2025
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23. statmod: Probability Calculations for the Inverse Gaussian Distribution

Author

Giner, Göknur and Smyth, Gordon K.

Subjects
Statistics - Computation
Abstract

The inverse Gaussian distribution (IGD) is a well known and often used probability distribution for which fully reliable numerical algorithms have not been available. Our aim in this article is to develop software for this distribution for the R programming environment. We develop fast, reliable basic probability functions (dinvgauss, pinvgauss, qinvgauss and rinvgauss) that work for all possible parameter values and which achieve close to full machine accuracy. The most challenging task is to compute quantiles for given cumulative probabilities and we develop a simple but elegant mathematical solution to this problem. We show that Newton's method for finding the quantiles of a IGD always converges monotonically when started from the mode of the distribution. Simple Taylor series expansions are used to improve accuracy on the log-scale. The IGD probability functions provide the same options and obey the same conventions as do probability functions provided in the standard R stats package. The IGD functions are part of the statmod package available from the CRAN repository., Comment: 18 pages, 2 figures. Accepted for publication in The R Journal, Volume 8 (2016)

Published
2016

24. Permutation p-values should never be zero: calculating exact p-values when permutations are randomly drawn

Author

Phipson, Belinda and Smyth, Gordon K.

Subjects
Statistics - Applications, 62G09, 62G10
Abstract

Permutation tests are amongst the most commonly used statistical tools in modern genomic research, a process by which p-values are attached to a test statistic by randomly permuting the sample or gene labels. Yet permutation p-values published in the genomic literature are often computed incorrectly, understated by about 1/m, where m is the number of permutations. The same is often true in the more general situation when Monte Carlo simulation is used to assign p-values. Although the p-value understatement is usually small in absolute terms, the implications can be serious in a multiple testing context. The understatement arises from the intuitive but mistaken idea of using permutation to estimate the tail probability of the test statistic. We argue instead that permutation should be viewed as generating an exact discrete null distribution. The relevant literature, some of which is likely to have been relatively inaccessible to the genomic community, is reviewed and summarized. A computation strategy is developed for exact p-values when permutations are randomly drawn. The strategy is valid for any number of permutations and samples. Some simple recommendations are made for the implementation of permutation tests in practice., Comment: 12 pages, 2 figures

Published
2016
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25. Targeting histone acetylation dynamics and oncogenic transcription by catalytic P300/CBP inhibition

Author

Hogg, Simon J., Motorna, Olga, Cluse, Leonie A., Johanson, Timothy M., Coughlan, Hannah D., Raviram, Ramya, Myers, Robert M., Costacurta, Matteo, Todorovski, Izabela, Pijpers, Lizzy, Bjelosevic, Stefan, Williams, Tobias, Huskins, Shannon N., Kearney, Conor J., Devlin, Jennifer R., Fan, Zheng, Jabbari, Jafar S., Martin, Ben P., Fareh, Mohamed, Kelly, Madison J., Dupéré-Richer, Daphné, Sandow, Jarrod J., Feran, Breon, Knight, Deborah, Khong, Tiffany, Spencer, Andrew, Harrison, Simon J., Gregory, Gareth, Wickramasinghe, Vihandha O., Webb, Andrew I., Taberlay, Phillippa C., Bromberg, Kenneth D., Lai, Albert, Papenfuss, Anthony T., Smyth, Gordon K., Allan, Rhys S., Licht, Jonathan D., Landau, Dan A., Abdel-Wahab, Omar, Shortt, Jake, Vervoort, Stephin J., and Johnstone, Ricky W.

Published
2021
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27. Robust hyperparameter estimation protects against hypervariable genes and improves power to detect differential expression

Author

Phipson, Belinda, Lee, Stanley, Majewski, Ian J., Alexander, Warren S., and Smyth, Gordon K.

Subjects
Statistics - Applications, Quantitative Biology - Genomics, 62F35 (primary), 62P10 (secondary)
Abstract

One of the most common analysis tasks in genomic research is to identify genes that are differentially expressed (DE) between experimental conditions. Empirical Bayes (EB) statistical tests using moderated genewise variances have been very effective for this purpose, especially when the number of biological replicate samples is small. The EB procedures can however be heavily influenced by a small number of genes with very large or very small variances. This article improves the differential expression tests by robustifying the hyperparameter estimation procedure. The robust procedure has the effect of decreasing the informativeness of the prior distribution for outlier genes while increasing its informativeness for other genes. This effect has the double benefit of reducing the chance that hypervariable genes will be spuriously identified as DE while increasing statistical power for the main body of genes. The robust EB algorithm is fast and numerically stable. The procedure allows exact small-sample null distributions for the test statistics and reduces exactly to the original EB procedure when no outlier genes are present. Simulations show that the robustified tests have similar performance to the original tests in the absence of outlier genes but have greater power and robustness when outliers are present. The article includes case studies for which the robust method correctly identifies and downweights genes associated with hidden covariates and detects more genes likely to be scientifically relevant to the experimental conditions. The new procedure is implemented in the limma software package freely available from the Bioconductor repository., Comment: 23 pages, 4 figures

Published
2016
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28. Loss of PHF6 causes spontaneous seizures, enlarged brain ventricles and altered transcription in the cortex of a mouse model of the Börjeson–Forssman–Lehmann intellectual disability syndrome.

Author

McRae, Helen M., Leong, Melody P. Y., Bergamasco, Maria I., Garnham, Alexandra L., Hu, Yifang, Corbett, Mark A., Whitehead, Lachlan, El-Saafin, Farrah, Sheikh, Bilal N., Wilcox, Stephen, Hannan, Anthony J., Gécz, Jozef, Smyth, Gordon K., Thomas, Tim, and Voss, Anne K.

Subjects
TRANSCRIPTION factors, CEREBRAL ventricles, PLANT mutation, ATTENTION-deficit hyperactivity disorder, NERVOUS system
Abstract

Börjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked intellectual disability and endocrine disorder caused by pathogenic variants of plant homeodomain finger gene 6 (PHF6). An understanding of the role of PHF6 in vivo in the development of the mammalian nervous system is required to advance our knowledge of how PHF6 mutations cause BFLS. Here, we show that PHF6 protein levels are greatly reduced in cells derived from a subset of patients with BFLS. We report the phenotypic, anatomical, cellular and molecular characterization of the brain in males and females in two mouse models of BFLS, namely loss of Phf6 in the germline and nervous system-specific deletion of Phf6. We show that loss of PHF6 resulted in spontaneous seizures occurring via a neural intrinsic mechanism. Histological and morphological analysis revealed a significant enlargement of the lateral ventricles in adult Phf6-deficient mice, while other brain structures and cortical lamination were normal. Phf6 deficient neural precursor cells showed a reduced capacity for self-renewal and increased differentiation into neurons. Phf6 deficient cortical neurons commenced spontaneous neuronal activity prematurely suggesting precocious neuronal maturation. We show that loss of PHF6 in the foetal cortex and isolated cortical neurons predominantly caused upregulation of genes, including Reln, Nr4a2, Slc12a5, Phip and ZIC family transcription factor genes, involved in neural development and function, providing insight into the molecular effects of loss of PHF6 in the developing brain. Author summary: The Börjeson-Forssman-Lehmann Syndrome (BFLS) is an intellectual disability and endocrine disorder. Mutations in the plant homeodomain finger 6 gene (PHF6) cause the disorder. We show here that a subset of BFLS patients lack PHF6 and report the effects of loss of PHF6 in an animal model with complete loss of PHF6 from conception. The cerebral cortex is the site of higher brain functions, including cognition and decision-making. We report here the effects of lack of PHF6 on the developing brain, cerebral cortex and neuronal cells isolated from this structure. Since PHF6 associates with the genetic material in the cell nucleus and has been proposed to regulate gene activity, we also report the effects of lack of PHF6 on gene expression in the cerebral cortex and purified neuronal cells. We observed that loss of PHF6 results in the dysregulation of neuronal development and differentiation genes, including genes involved in disorders such as Parkinson's disease, epilepsy, neuroblastoma, attention deficit disorder, autism and schizophrenia. Lastly, we report that mice lacking PHF6 mirror BFLS patients in that they also suffer from spontaneous epileptic seizures. Our mouse models and findings will be useful to further investigate BFLS neuronal function and other aspects of the disorder in the adult. [ABSTRACT FROM AUTHOR]

Published
2024
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31. Assessing Technical Performance in Differential Gene Expression Experiments with External Spike-in RNA Control Ratio Mixtures

Author

Munro, Sarah A., Lund, Steve P., Pine, P. Scott, Binder, Hans, Clevert, Djork-Arné, Conesa, Ana, Dopazo, Joaquin, Fasold, Mario, Hochreiter, Sepp, Hong, Huixiao, Jafari, Nederah, Kreil, David P., Łabaj, Paweł P., Li, Sheng, Liao, Yang, Lin, Simon, Meehan, Joseph, Mason, Christopher E., Santoyo, Javier, Setterquist, Robert A., Shi, Leming, Shi, Wei, Smyth, Gordon K., Stralis-Pavese, Nancy, Su, Zhenqiang, Tong, Weida, Wang, Charles, Wang, Jian, Xu, Joshua, Ye, Zhan, Yang, Yong, Yu, Ying, and Salit, Marc

Subjects
Quantitative Biology - Genomics
Abstract

There is a critical need for standard approaches to assess, report, and compare the technical performance of genome-scale differential gene expression experiments. We assess technical performance with a proposed "standard" dashboard of metrics derived from analysis of external spike-in RNA control ratio mixtures. These control ratio mixtures with defined abundance ratios enable assessment of diagnostic performance of differentially expressed transcript lists, limit of detection of ratio (LODR) estimates, and expression ratio variability and measurement bias. The performance metrics suite is applicable to analysis of a typical experiment, and here we also apply these metrics to evaluate technical performance among laboratories. An interlaboratory study using identical samples shared amongst 12 laboratories with three different measurement processes demonstrated generally consistent diagnostic power across 11 laboratories. Ratio measurement variability and bias were also comparable amongst laboratories for the same measurement process. Different biases were observed for measurement processes using different mRNA enrichment protocols., Comment: 65 pages, 6 Main Figures, 33 Supplementary Figures

Published
2014
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32. Molecular profiling reveals features of clinical immunity and immunosuppression in asymptomatic P. falciparum malaria

Author

Studniberg, Stephanie I, Ioannidis, Lisa J, Utami, Retno A S, Trianty, Leily, Liao, Yang, Abeysekera, Waruni, Li‐Wai‐Suen, Connie S N, Pietrzak, Halina M, Healer, Julie, Puspitasari, Agatha M, Apriyanti, Dwi, Coutrier, Farah, Poespoprodjo, Jeanne R, Kenangalem, Enny, Andries, Benediktus, Prayoga, Pak, Sariyanti, Novita, Smyth, Gordon K, Cowman, Alan F, Price, Ric N, Noviyanti, Rintis, Shi, Wei, Garnham, Alexandra L, and Hansen, Diana S

Published
2022
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40. Chapter 2: Linear Regression Models

Author

Dunn, Peter K., Smyth, Gordon K., DeVeaux, Richard, Series Editor, Fienberg, Stephen E., Series Editor, Olkin, Ingram, Series Editor, Dunn, Peter K., and Smyth, Gordon K.

Published
2018
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42. Chapter 1: Statistical Models

Author

Dunn, Peter K., Smyth, Gordon K., DeVeaux, Richard, Series Editor, Fienberg, Stephen E., Series Editor, Olkin, Ingram, Series Editor, Dunn, Peter K., and Smyth, Gordon K.

Published
2018
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43. Chapter 13: Extra Problems

Author

Dunn, Peter K., Smyth, Gordon K., DeVeaux, Richard, Series Editor, Fienberg, Stephen E., Series Editor, Olkin, Ingram, Series Editor, Dunn, Peter K., and Smyth, Gordon K.

Published
2018
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44. Chapter 12: Tweedie GLMs

Author

Dunn, Peter K., Smyth, Gordon K., DeVeaux, Richard, Series Editor, Fienberg, Stephen E., Series Editor, Olkin, Ingram, Series Editor, Dunn, Peter K., and Smyth, Gordon K.

Published
2018
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46. Targeting triple-negative breast cancers with the Smac-mimetic birinapant

Author

Lalaoui, Najoua, Merino, Delphine, Giner, Goknur, Vaillant, François, Chau, Diep, Liu, Lin, Kratina, Tobias, Pal, Bhupinder, Whittle, James R., Etemadi, Nima, Berthelet, Jean, Gräsel, Julius, Hall, Cathrine, Ritchie, Matthew E., Ernst, Matthias, Smyth, Gordon K., Vaux, David L., Visvader, Jane E., Lindeman, Geoffrey J., and Silke, John

Published
2020
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47. featureCounts: An efficient general-purpose program for assigning sequence reads to genomic features

Author

Liao, Yang, Smyth, Gordon K, and Shi, Wei

Subjects
Quantitative Biology - Genomics, Quantitative Biology - Quantitative Methods
Abstract

Next-generation sequencing technologies generate millions of short sequence reads, which are usually aligned to a reference genome. In many applications, the key information required for downstream analysis is the number of reads mapping to each genomic feature, for example to each exon or each gene. The process of counting reads is called read summarization. Read summarization is required for a great variety of genomic analyses but has so far received relatively little attention in the literature. We present featureCounts, a read summarization program suitable for counting reads generated from either RNA or genomic DNA sequencing experiments. featureCounts implements highly efficient chromosome hashing and feature blocking techniques. It is considerably faster than existing methods (by an order of magnitude for gene-level summarization) and requires far less computer memory. It works with either single or paired-end reads and provides a wide range of options appropriate for different sequencing applications. featureCounts is available under GNU General Public License as part of the Subread (http://subread.sourceforge.net) or Rsubread (http://www.bioconductor.org) software packages., Comment: This manuscript has now been published on Bioinformatics Yang Liao, Gordon K Smyth and Wei Shi. featureCounts: an efficient general-purpose program for assigning sequence reads to genomic features. Bioinformatics 2013

Published
2013
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