A5032756679- Genetic Neurodegenerative Diseases
- DNA Repair Mechanisms
- RNA Research and Splicing
- Mitochondrial Function and Pathology
- RNA and protein synthesis mechanisms
- Fungal and yeast genetics research
- Epigenetics and DNA Methylation
- Cancer Genomics and Diagnostics
- Molecular Biology Techniques and Applications
- Advanced biosensing and bioanalysis techniques
- Neuroinflammation and Neurodegeneration Mechanisms
- CRISPR and Genetic Engineering
- Genomics and Chromatin Dynamics
- Genomics and Rare Diseases
- DNA and Nucleic Acid Chemistry
- Bacteriophages and microbial interactions
- Genomics and Phylogenetic Studies
- Single-cell and spatial transcriptomics
- Immune cells in cancer
- Chromosomal and Genetic Variations
Harvard University
2020-2025
Tufts University
2013-2023
Allen Institute
2023
Allen Institute for Brain Science
2023
Brigham and Women's Hospital
2020-2021
The mammalian brain consists of millions to billions cells that are organized into many cell types with specific spatial distribution patterns and structural functional properties1-3. Here we report a comprehensive high-resolution transcriptomic cell-type atlas for the whole adult mouse brain. was created by combining single-cell RNA-sequencing (scRNA-seq) dataset around 7 million profiled (approximately 4.0 passing quality control), approximately 4.3 using multiplexed error-robust...
Gauging the spectrum of human mutations It has become increasing clear that mutation affects phenotypic variation and disease risk across humans. However, there are many different types mutation. Seplyarskiy et al . applied a matrix factorization method to large genomic datasets identify germline mutational processes in an unsupervised manner. From this survey, nine robust components were identified specific mechanisms generating seven these proposed from correlations with features. These...
Abstract CANVAS is a recently characterized repeat expansion disease, most commonly caused by homozygous expansions of an intronic (A2G3)n in the RFC1 gene. There are multitude motifs found human population at this locus, some which pathogenic and others benign. In study, we conducted structure-functional analyses nonpathogenic (A4G)n repeats. We that pathogenic, but not nonpathogenic, presents potent, orientation-dependent impediment to DNA polymerization vitro. The pattern blockage...
Although homologous recombination between transposable elements can drive genomic evolution in yeast by facilitating chromosomal rearrangements, the details of underlying mechanisms are not fully clarified. In genome Saccharomyces cerevisiae, most common class transposon is retrotransposon Ty1. Here, we explored how Cas9-induced double-strand breaks (DSBs) directed to Ty1 produce alterations this species. Following Cas9 induction, observed a significant elevation chromosome rearrangements...
Abstract Using the Telomere-to-Telomere reference, we assembled distribution of simple repeat lengths present in human genome. Analyzing over two hundred mammalian genomes, found remarkable consistency shape across evolutionary epochs. All observed genomes harbor an excess long repeats, which are prone to developing into expansion disorders. We measured mutation rates for length instability, quantitatively modeled per-generation action mutations, and corresponding long-term behavior shaping...
Improper DNA double-strand break (DSB) repair results in complex genomic rearrangements (CGRs) many cancers and various congenital disorders humans. Trinucleotide repeat sequences, such as (GAA)n repeats Friedreich's ataxia, (CTG)n myotonic dystrophy, (CGG)n fragile X syndrome, are also subject to breaks within the repetitive tract followed by repair. Mapping outcomes of CGRs is important for understanding their causes potential phenotypic effects. However, high-resolution mapping has...
Significance The inheritance of long (GAA) n repeats in the frataxin gene causes debilitating neurodegenerative disease Friedreich’s ataxia. Subsequent expansions these throughout a patient’s lifetime affected tissues, like nervous system, may contribute to onset. We developed an experimental model characterize mechanisms repeat instability nondividing cells better understand how mutations can occur as age chronologically. show that expand cells. Notably, however, large deletions are major...
Expansions of simple DNA repeats cause numerous hereditary disorders in humans. Replication, repair, and transcription are implicated the expansion process, but their relative contributions yet to be distinguished. To separate roles replication Friedreich's ataxia (GAA)n repeats, we designed two yeast genetic systems that utilize a galactose-inducible GAL1 promoter contain these either transcribed or nontranscribed region selectable cassette. We found large-scale repeat expansions can occur...
Expansions of microsatellite repeats are responsible for numerous hereditary diseases in humans, including myotonic dystrophy and Friedreich's ataxia. Whereas the length an expandable repeat is main factor determining disease inheritance, recent data point to genomic trans modifiers that can impact likelihood expansions progression. Detection these may lead understanding treating expansion diseases. Here, we describe a method rapid, genome-wide identification yeast experimental system. Using...
Mechanistic processes underlying human germline mutations remain largely unknown. Variation in mutation rate and spectra along the genome is informative about biological mechanisms. We statistically decompose this variation into separate using a blind source separation technique. The analysis of large-scale whole sequencing dataset (TOPMed) reveals nine that explain properties between loci. Seven these lend themselves to interpretation. One process driven by bulky DNA lesions resolve...
CANVAS is a recently characterized repeat expansion disease, most commonly caused by homozygous expansions of an intronic (A
Expansions of simple repetitive DNA sequences are responsible for a large number human hereditary diseases. The severity and age onset each disorder can be estimated from the length inherited repeat tract; however, subsequent expansion rate is itself heritable trait. This points to role trans-acting modifier genes, whose actions may altered by single nucleotide polymorphisms. Previously, our lab has used yeast system study large-scale expansions GAA trinucleotide repeats, gene knockouts have...