A5015879691- Genomic variations and chromosomal abnormalities
- Congenital heart defects research
- Chromosomal and Genetic Variations
- CRISPR and Genetic Engineering
- Genomics and Rare Diseases
- Genetics and Neurodevelopmental Disorders
- Genetics, Bioinformatics, and Biomedical Research
- Prenatal Screening and Diagnostics
- Autism Spectrum Disorder Research
- Genomics and Chromatin Dynamics
- Pluripotent Stem Cells Research
- Genetic Syndromes and Imprinting
- Immunodeficiency and Autoimmune Disorders
- Animal Genetics and Reproduction
- RNA Research and Splicing
- Developmental Biology and Gene Regulation
- Race, Genetics, and Society
- Genomics and Phylogenetic Studies
- Cerebrovascular and genetic disorders
- Advanced biosensing and bioanalysis techniques
- Cancer Genomics and Diagnostics
- Chromatin Remodeling and Cancer
- Epigenetics and DNA Methylation
Massachusetts General Hospital
2017-2025
Broad Institute
2017-2025
Harvard University
2017-2023
Massachusetts Institute of Technology
2021-2022
University of Washington
2012-2019
Gene duplication is an important source of phenotypic change and adaptive evolution. We leverage a haploid hydatidiform mole to identify highly identical sequences missing from the reference genome, confirming that cortical development gene Slit-Robo Rho GTPase-activating protein 2 (SRGAP2) duplicated three times exclusively in humans. show promoter first nine exons SRGAP2 1q32.1 (SRGAP2A) 1q21.1 (SRGAP2B) ∼3.4 million years ago (mya). Two larger duplications later copied SRGAP2B chromosome...
Recurrent deletions and duplications at chromosomal region 16p11.2 are a major genetic contributor to autism but also associate with wider range of pediatric diagnoses, including intellectual disability, coordination disorder, language disorder. In order investigate the potential basis for phenotype variability, we assessed parent origin copy-number variant (CNV) presence additional CNVs in 126 families which detailed data were available. Among de novo cases, found strong maternal bias...
Summary Genetic changes causing dramatic brain size expansion in human evolution have remained elusive. Notch signaling is essential for radial glia stem cell proliferation and a determinant of neuronal number the mammalian cortex. We find three paralogs human-specific NOTCH2NL are highly expressed cells. Functional analysis reveals different alleles varying potencies to enhance by interacting directly with NOTCH receptors. Consistent role signaling, ectopic expression delays differentiation...
Gene innovation by duplication is a fundamental evolutionary process but difficult to study in humans due the large size, high sequence identity, and mosaic nature of segmental blocks. The human-specific gene hydrocephalus-inducing 2, HYDIN2, was generated 364 kbp 79 internal exons ciliary HYDIN from chromosome 16q22.2 1q21.1. Because HYDIN2 locus lacks ancestral promoter seven terminal progenitor gene, we sought characterize transcription at this coupling reverse polymerase chain reaction...
SUMMARY Rare deletions and duplications of genomic segments, collectively known as rare copy number variants (rCNVs), contribute to a broad spectrum human diseases. To date, most disease-association studies rCNVs have focused on recognized disorders or the impact haploinsufficiency caused by deletions. By comparison, our understanding in disease remains rudimentary very few individual genes are be triplosensitive ( i . e ., duplication intolerant). In this study, we meta-analyzed from...
Autism spectrum disorder (ASD) is a heritable neurodevelopmental characterized by deficits in social interactions and communication. Protein-altering variants many genes have been shown to contribute ASD; however, understanding the convergence across remains challenge. We demonstrate that coexpression patterns from 993 human postmortem brains are significantly correlated with transcriptional consequences of CRISPR perturbations neurons. Across 71 ASD risk genes, there was significant...
Epigenome editing with DNA-targeting technologies such as CRISPR-dCas9 can be used to dissect gene regulatory mechanisms and potentially treat associated disorders. For example, Prader-Willi Syndrome (PWS) is caused by loss of paternally expressed imprinted genes on chromosome 15q11.2-q13.3, although the maternal allele intact but epigenetically silenced. Using CRISPR repression activation screens in human induced pluripotent stem cells (iPSCs), we identified genomic elements that control...
Abstract Recurrent copy-number variations (CNVs) at chromosome 16p11.2 are associated with neurodevelopmental diseases, skeletal system abnormalities, anemia, and genitourinary defects. Among the 40 protein-coding genes encompassed within rearrangement, some have roles in leukocyte biology immunodeficiency, like SPN CORO1A . We therefore investigated differential counts disease CNV carriers. In our clinically-recruited cohort, we identified three deletion carriers from two families (out of...
SUMMARY Recurrent deletion and duplication of ∼743 kilobases unique genomic sequence segmental duplications at chromosome 16p11.2 underlie a reciprocal disorder (RGD; OMIM 611913 614671) associated with neurodevelopmental psychiatric phenotypes, including intellectual disability, autism spectrum (ASD), schizophrenia (SCZ). To define molecular alterations the RGD, we performed transcriptome analyses mice copy number variants (CNVs) syntenic 7qF3 region human neuronal models derived from...
Key Clinical Message 16p11.2 deletions and duplications are commonly associated with autism spectrum disorder linked to mirrored phenotypes of physical characteristics higher penetrance for deletions. A male a rare triplication demonstrated similar phenotypic presentation deletion carriers neurocognitive adaptive skill deficits above‐average growth.
New technologies and large-cohort studies have enabled novel variant discovery association at unprecedented scale, yet functional characterization of these variants remains paramount to deciphering disease mechanisms. Approaches that facilitate parallelized genome editing cells interest or induced pluripotent stem (iPSCs) become critical tools toward this goal. Here, we developed an approach incorporates libraries CRISPR-Cas9 guide RNAs (gRNAs) together with inducible Cas9 into a piggyBac...
Novel gene and variant discoveries have reached unprecedented scale with the emergence of exome genome sequencing studies across a spectrum human disease initiatives. Highly parallelized functional characterization these variants is now paramount to deciphering mechanisms, approaches that facilitate editing induced pluripotent stem cells (iPSCs) derive otherwise inaccessible tissues interest (e.g., brain) become critical in genomics research. Here, we sought scalable multiple genes by...
Abstract Human-specific duplications at chromosome 16p11.2 mediate recurrent pathogenic 600 kbp BP4-BP5 copy number variations, one of the most common genetic causes autism. These polymorphic are under positive selection and include 3–8 copies BOLA2 , a gene involved in maturation cytosolic iron-sulfur proteins. To investigate potential advantage provided by rapid expansion we assessed hematological traits anemia prevalence 379,385 controls individuals who have lost or gained : 89 deletion...