Konrad J. Karczewski
A5106691485- Genomics and Rare Diseases
- Genetic Associations and Epidemiology
- Genomic variations and chromosomal abnormalities
- Genomics and Phylogenetic Studies
- Cancer Genomics and Diagnostics
- Genomics and Chromatin Dynamics
- Gene expression and cancer classification
- RNA and protein synthesis mechanisms
- Bioinformatics and Genomic Networks
- CRISPR and Genetic Engineering
- RNA modifications and cancer
- Genetics and Neurodevelopmental Disorders
- Parallel Computing and Optimization Techniques
- Distributed and Parallel Computing Systems
- Epigenetics and DNA Methylation
- Nutrition, Genetics, and Disease
- Computability, Logic, AI Algorithms
- Genetic and phenotypic traits in livestock
- Genetic Mapping and Diversity in Plants and Animals
- Metabolism and Genetic Disorders
- Genetics, Bioinformatics, and Biomedical Research
- SARS-CoV-2 and COVID-19 Research
- Pharmacogenetics and Drug Metabolism
- Cancer-related molecular mechanisms research
- Mitochondrial Function and Pathology
Broad Institute
2016-2025
Massachusetts General Hospital
2016-2025
Foundation Center
2023-2024
Novo Nordisk (United States)
2023-2024
Stanley Center for Psychiatric Research
2024
Częstochowa University of Technology
2006-2023
Institute for Molecular Medicine Finland
2020-2023
University of Helsinki
2020-2023
Massachusetts Institute of Technology
2016-2022
Silesian University of Technology
2020
Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation DNA sequence changes. Here we describe aggregation analysis high-quality exome (protein-coding region) 60,706 individuals diverse ancestries generated as part Exome Aggregation Consortium (ExAC). This catalogue diversity contains an average one variant every eight bases exome, provides direct evidence presence widespread mutational recurrence. We have used this to calculate...
Abstract Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences gene disruption: crucial for function an organism will be depleted such in natural populations, whereas non-essential tolerate their accumulation. However, predicted loss-of-function enriched annotation errors, and tend to found at extremely low frequencies, so analysis requires careful variant very large sample sizes 1 . Here we describe aggregation 125,748...
As the sequencing of healthy and disease genomes becomes more commonplace, detailed annotation provides interpretation for individual variation responsible normal phenotypes. Current approaches focus on direct changes in protein coding genes, particularly nonsynonymous mutations that directly affect gene product. However, most occurs outside genes and, indeed, markers generated from genome-wide association studies (GWAS) identify variants segments. Identification potential regulatory perturb...
The contribution of rare and low-frequency variants to human traits is largely unexplored. Here we describe insights from sequencing whole genomes (low read depth, 7×) or exomes (high 80×) nearly 10,000 individuals population-based disease collections. In extensively phenotyped cohorts characterize over 24 million novel sequence variants, generate a highly accurate imputation reference panel identify alleles associated with levels triglycerides (APOB), adiponectin (ADIPOQ) low-density...
Summary Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences gene disruption: critical for an organism’s function will be depleted such in natural populations, while non-essential tolerate their accumulation. However, predicted loss-of-function (pLoF) enriched annotation errors, and tend to found at extremely low frequencies, so analysis requires careful variant very large sample sizes 1 . Here, we describe aggregation...
Abstract Scalable, integrative methods to understand mechanisms that link genetic variants with phenotypes are needed. Here we derive a mathematical expression compute PrediXcan (a gene mapping approach) results using summary data (S-PrediXcan) and show its accuracy general robustness misspecified reference sets. We apply this framework 44 GTEx tissues 100+ from GWAS meta-analysis studies, creating growing public catalog of associations seeks capture the effects variation on human...
Abstract X chromosome inactivation (XCI) silences transcription from one of the two chromosomes in female mammalian cells to balance expression dosage between XX females and XY males. XCI is, however, incomplete humans: up one-third X-chromosomal genes are expressed both active inactive (Xa Xi, respectively) cells, with degree ‘escape’ varying individuals 1,2 . The extent which is shared tissues remains poorly characterized 3,4 , as does manifests detectable sex differences gene 5 phenotypic...
Structural variants (SVs) rearrange large segments of DNA
Putting both heart and brain at risk For reasons that are unclear, newborns with congenital disease (CHD) have a high of neurodevelopmental disabilities. Homsy et al. performed exome sequence analysis 1200 CHD patients their parents to identify spontaneously arising (de novo) mutations. Patients disorders had much higher burden damaging de novo mutations, particularly in genes likely roles development. Thus, clinical genotyping may help those greatest disabilities, allowing surveillance...
Worldwide, hundreds of thousands humans have had their genomes or exomes sequenced, and access to the resulting data sets can provide valuable information for variant interpretation understanding gene function. Here, we present a lightweight, flexible browser framework display large population datasets genetic variation. We demonstrate its use exome sequence from 60 706 individuals in Exome Aggregation Consortium (ExAC). The ExAC provides gene- transcript-centric displays variation, critical...
Transcriptome sequencing improves the diagnostic rate for Mendelian disease in patients whom genetic analysis has not returned a diagnosis.
Differences in gene expression may play a major role speciation and phenotypic diversity. We examined genome-wide differences transcription factor (TF) binding several humans single chimpanzee by using chromatin immunoprecipitation followed sequencing. The sites of RNA polymerase II (PolII) key regulator immune responses, nuclear kappaB (p65), were mapped 10 lymphoblastoid cell lines, 25 7.5% the respective regions found to differ between individuals. Binding frequently associated with...
Large genomic reference data sets reveal a spectrum of pathogenicity in the prion protein gene and provide genetic validation for therapeutic strategy disease.
PurposeWhole-exome and whole-genome sequencing have transformed the discovery of genetic variants that cause human Mendelian disease, but discriminating pathogenic from benign remains a daunting challenge. Rarity is recognized as necessary, although not sufficient, criterion for pathogenicity, frequency cutoffs used in analysis are often arbitrary overly lenient. Recent very large reference datasets, such Exome Aggregation Consortium (ExAC), provide an unprecedented opportunity to obtain...
Abstract Given increasing numbers of patients who are undergoing exome or genome sequencing, it is critical to establish tools and methods interpret the impact genetic variation. While ability predict deleteriousness for any given variant limited, missense variants remain a particularly challenging class variation interpret, since they can have drastically different effects depending on both precise location specific amino acid substitution variant. In order better evaluate variation, we...
Imputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated data set 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down 0.1% minor allele frequency in British population. Here we demonstrate value this resource improving imputation accuracy rare...
Rare gene knockouts in adult humans On average, most people's genomes contain approximately 100 completely nonfunctional genes. These loss-of-function (LOF) mutations tend to be rare and/or occur only as a single copy within individuals. Narasimhan et al. investigated LOF Pakistani population with high levels of consanguinity. Examining alleles that were identical by descent, they found, expected, an absence homozygote for certain protein-coding However, also identified many no apparent...