D.N. Cooper
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View article: Expanding the utility of variant effect predictions with phenotype-specific models
Expanding the utility of variant effect predictions with phenotype-specific models Open
Current methods for variant effect prediction do not differentiate between pathogenic variants resulting in different disease outcomes and are restricted in application due to a focus on variants with a single molecular consequence. We hav…
View article: Forward and reverse genomic screens enhance the understanding of phenotypic variation in a large Chinese rhesus macaque cohort
Forward and reverse genomic screens enhance the understanding of phenotypic variation in a large Chinese rhesus macaque cohort Open
Combining genotype and phenotype data promises to greatly increase the value of macaque as biomedical models for human disease. Here we launch the Macaque Biobank project by deeply sequencing 919 captive Chinese rhesus macaques (CRM) while…
View article: Disease-specific variant pathogenicity prediction using multimodal biomedical language models
Disease-specific variant pathogenicity prediction using multimodal biomedical language models Open
Missense variants play a key role in the diagnosis of genetic disorders and in disease risk prediction. Existing methods focus primarily on the prediction of variant effects in terms of their deleteriousness, without taking into account th…
View article: Repurposing the memory-promoting meclofenoxate hydrochloride as a treatment for Parkinson’s disease through integrative multi-omics analysis
Repurposing the memory-promoting meclofenoxate hydrochloride as a treatment for Parkinson’s disease through integrative multi-omics analysis Open
Parkinson's disease (PD) is a devastating neurodegenerative disorder with growing prevalence worldwide and, as yet, no effective treatment. Drug repurposing is invaluable for detecting novel PD therapeutics. Here, we compiled gene expressi…
View article: A combination of transcriptomics and epigenomics identifies genes and regulatory elements involved in embryonic tail development in the mouse
A combination of transcriptomics and epigenomics identifies genes and regulatory elements involved in embryonic tail development in the mouse Open
Our work brings new insights and provides exploitable fundamental datasets for the elucidation of the complex genetic mechanisms responsible for the formation of the vertebrate/mammalian tail.
View article: Critical assessment of missense variant effect predictors on disease-relevant variant data
Critical assessment of missense variant effect predictors on disease-relevant variant data Open
Regular, systematic, and independent assessments of computational tools that are used to predict the pathogenicity of missense variants are necessary to evaluate their clinical and research utility and guide future improvements. The Critic…
View article: Expanding drug targets for 112 chronic diseases using a machine learning-assisted genetic priority score
Expanding drug targets for 112 chronic diseases using a machine learning-assisted genetic priority score Open
Identifying genetic drivers of chronic diseases is necessary for drug discovery. Here, we develop a machine learning-assisted genetic priority score, which we call ML-GPS, that incorporates genetic associations with predicted disease pheno…
View article: Forward and reverse genomic screens enhance the understanding of phenotypic variation in a large Chinese rhesus macaque cohort
Forward and reverse genomic screens enhance the understanding of phenotypic variation in a large Chinese rhesus macaque cohort Open
Combining genotype and phenotype data promises to greatly increase the value of macaque as biomedical models for human disease. Here we launch the Macaque Biobank project by deeply sequencing 919 captive Chinese rhesus macaques (CRM) while…
View article: <i>SEC16A</i> Variants Predispose to Chronic Pancreatitis by Impairing ER‐to‐Golgi Transport and Inducing ER Stress
<i>SEC16A</i> Variants Predispose to Chronic Pancreatitis by Impairing ER‐to‐Golgi Transport and Inducing ER Stress Open
Chronic pancreatitis (CP) is a complex disease with genetic and environmental factors at play. Through trio exome sequencing, a de novo SEC16A frameshift variant in a Chinese teenage CP patient is identified. Subsequent targeted next‐gener…
View article: Critical assessment of missense variant effect predictors on disease-relevant variant data
Critical assessment of missense variant effect predictors on disease-relevant variant data Open
Regular, systematic, and independent assessment of computational tools used to predict the pathogenicity of missense variants is necessary to evaluate their clinical and research utility and suggest directions for future improvement. Here,…
View article: Meta-analysis of 46,000 germline de novo mutations linked to human inherited disease
Meta-analysis of 46,000 germline de novo mutations linked to human inherited disease Open
Background De novo mutations (DNMs) are variants that occur anew in the offspring of noncarrier parents. They are not inherited from either parent but rather result from endogenous mutational processes involving errors of DNA repair/replic…
View article: Uganda Genome Resource Enables Insights into Population History and Genomic Discovery in Africa
Uganda Genome Resource Enables Insights into Population History and Genomic Discovery in Africa Open
Genomic studies in African populations provide unique opportunities to understand disease etiology, human diversity, and population history. In the largest study of its kind, comprising genome-wide data from 6,400 individuals and whole-gen…
View article: Divergent Evolutionary Rates of Primate Brain Regions as Revealed by Genomics and Transcriptomics
Divergent Evolutionary Rates of Primate Brain Regions as Revealed by Genomics and Transcriptomics Open
Although the primate brain contains numerous functionally distinct structures that have experienced diverse genetic changes during the course of evolution and development, these changes remain to be explored in detail. Here we utilize two …
View article: Deciphering the Role of Rapidly Evolving Conserved Elements in Primate Brain Development and Exploring Their Potential Involvement in Alzheimer's Disease
Deciphering the Role of Rapidly Evolving Conserved Elements in Primate Brain Development and Exploring Their Potential Involvement in Alzheimer's Disease Open
Although previous studies have identified human-specific accelerated regions as playing a key role in the recent evolution of the human brain, the characteristics and cellular functions of rapidly evolving conserved elements (RECEs) in anc…
View article: Genome-wide prediction of pathogenic gain- and loss-of-function variants from ensemble learning of a diverse feature set
Genome-wide prediction of pathogenic gain- and loss-of-function variants from ensemble learning of a diverse feature set Open
Gain-of-function (GOF) variants give rise to increased/novel protein functions whereas loss-of-function (LOF) variants lead to diminished protein function. Experimental approaches for identifying GOF and LOF are generally slow and costly, …
View article: Genome-wide detection of human intronic AG-gain variants located between splicing branchpoints and canonical splice acceptor sites
Genome-wide detection of human intronic AG-gain variants located between splicing branchpoints and canonical splice acceptor sites Open
Human genetic variants that introduce an AG into the intronic region between the branchpoint (BP) and the canonical splice acceptor site (ACC) of protein-coding genes can disrupt pre-mRNA splicing. Using our genome-wide BP database, we del…
View article: Genome-wide identification of dominant polyadenylation hexamers for use in variant classification
Genome-wide identification of dominant polyadenylation hexamers for use in variant classification Open
Polyadenylation is an essential process for the stabilization and export of mRNAs to the cytoplasm and the polyadenylation signal hexamer (herein referred to as hexamer) plays a key role in this process. Yet, only 14 Mendelian disorders ha…
View article: Frameshift coding sequence variants in the LPL gene: identification of two novel events and exploration of the genotype–phenotype relationship for variants reported to date
Frameshift coding sequence variants in the LPL gene: identification of two novel events and exploration of the genotype–phenotype relationship for variants reported to date Open
Background Lipoprotein lipase (LPL) is the rate-limiting enzyme for triglyceride hydrolysis. Homozygous or compound heterozygous LPL variants cause autosomal recessive familial chylomicronemia syndrome (FCS), whereas simple heterozygous LP…