Identifier Results
| Field | Value |
|---|---|
| Identifier | nemo:dat-ztfn3cc |
| Dataset Name | Long somatic DNA-repeat expansion drives neurodegeneration in Huntington's disease |
| Version | NA |
| Release Date | NA |
| DOI | NA |
| Source Data URL | The open access data is available at https://data.nemoarchive.org/other/grant/broad_mccarroll_HD_2024/mccarroll/transcriptome/sncell/. The restricted data can be accessed only upon approval from Broad's Data Access Committee (DAC). To request access to this restricted data at Broad's DUOS system, refer to the documentation - https://nemoarchive.org/resources/accessing-controlled-access-data#broad-dac-approval-process. The dataset name for this data at Broad's DUOS - HD_GeneExpression_McCarrollBerretta. |
| Dataset Collection URL | https://data.nemoarchive.org/publication_release/Broad_Huntingtons_Caudate_2024-bag-2025-01-28.tgz |
| Description | Huntington Disease (HD) is a fatal genetic brain disorder in which most of a person’s striatal projection neurons (SPNs) degenerate and die. Science has long sought to understand why SPNs are so vulnerable in HD, why this pathology follows decades of apparent health, and how the disease-causing inherited DNA repeat (CAGn, n > 36) in the huntingtin (HTT) gene leads to this neurodegeneration. This DNA repeat exhibits somatic mosaicism (variable length); we developed a way to measure its length together with genome-wide RNA expression in the same individual cells. We found that, in persons with typical inherited HD-causing alleles (of < 50 CAG repeats), the CAG-repeat tract routinely expanded to 100-500+ CAG repeats in SPNs but rarely if ever did so in striatal interneurons or glia. Surprisingly, gene expression in these persons’ individual SPNs exhibited no apparent relationship to those SPNs’ CAG-repeat lengths across a wide range (36-150 repeats). In contrast, sparse SPNs with longer (150-500+) CAG repeats had profound gene-expression distortions which affected hundreds of genes, escalated alongside further repeat expansion, and culminated in widespread gene de-repression and expression of senescence/apoptosis genes. Our experiments, analyses, and simulations suggest that individual SPNs undergo decades of biologically quiet DNA repeat expansion, then asynchronously enter a brief toxicity phase before dying. We conclude that, at any moment in time, most SPNs in persons with HD actually have a benign (but somewhat unstable) huntingtin gene; and that HD is a DNA process for almost all of a neuron’s life. |
| Keywords | human, caudate, cortex, Huntington's |
| Total Files in Collection | 19027 |
| Total Size in Collection (in GB) | 20797.6 |
| Authors | Robert E. Handsaker, Seva Kashin, Nora M. Reed, Steven Tan, Won-Seok Lee, Tara M. McDonald, Kiely Morris, Nolan Kamitaki, Christopher D. Mullally, Neda R. Morakabati, Melissa Goldman, Gabriel Lind, Rhea Kohli, Elisabeth Lawton, Marina Hogan, Kiku Ichihara, Sabina Berretta, Steven A. McCarroll |
| Organization | Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA; Department of Genetics, Harvard Medical School, Boston, MA; Program in Neuroscience, Harvard Medical School, Boston, MA; McLean Hospital, Belmont, MA; Department of Psychiatry, Harvard Medical School, Boston, MA |
| Contact Person | Melissa Goldman |
| Contact E-Mail | mgoldman@broadinstitute.org |
| External Identifier | https://doi.org/10.1016/j.cell.2024.11.038 |
| Grant Name | CHDI Foundation (A-15608) the Harvard Medical School Department of Genetics, and the Harvard Ludwig Initiative in Neurodegenerative Disease |
| Consortium | NA |
| Data Repository | NeMO |
| Data Repository RRID | RRID:SCR_016152 |
| Data License | NA |
| Data Access | NA |
| Community Standards | NA |
| Study Organism | human |
| Protocol ID | dx.doi.org/10.17504/protocols.io.4r3l22e3xl1y/v1; dx.doi.org/10.17504/protocols.io.36wgq3bmxlk5/v1 |
| Field | Value |
|---|---|
| Identifier | nemo:dat-z00ru7v |
| Description | Raw reads from 10xv3 snRNA-seq experiments (in Illumina FASTQ format) associated with the following publication: Handsaker RE, Kashin S, Reed NM, et al. Long somatic DNA-repeat expansion drives neurodegeneration in Huntington's disease. Cell. 2025 Jan 14:S0092-8674(24)01379-5. doi: 10.1016/j.cell.2024.11.038 |
| Source Data URL | The restricted data can be accessed only upon approval from Broad's Data Access Committee (DAC). To request access to this restricted data at Broad's DUOS system, refer to the documentation - https://nemoarchive.org/resources/accessing-controlled-access-data#broad-dac-approval-process. The dataset name for this data at Broad's DUOS - HD_GeneExpression_McCarrollBerretta. |
| Field | Value |
|---|---|
| Identifier | nemo:dat-mfqx9pe |
| Description | Aligned PacBio reads from HTT-CAG experiments (in bam format) associated with the following publication: Handsaker RE, Kashin S, Reed NM, et al. Long somatic DNA-repeat expansion drives neurodegeneration in Huntington's disease. Cell. 2025 Jan 14:S0092-8674(24)01379-5. doi: 10.1016/j.cell.2024.11.038 |
| Source Data URL | The restricted data can be accessed only upon approval from Broad's Data Access Committee (DAC). To request access to this restricted data at Broad's DUOS system, refer to the documentation - https://nemoarchive.org/resources/accessing-controlled-access-data#broad-dac-approval-process. The dataset name for this data at Broad's DUOS - HD_GeneExpression_McCarrollBerretta. |
| Field | Value |
|---|---|
| Identifier | nemo:dat-o8hdb2t |
| Description | Aligned reads from 10xv3 snRNA-seq experiments (in bam format) associated with the following publication: Handsaker RE, Kashin S, Reed NM, et al. Long somatic DNA-repeat expansion drives neurodegeneration in Huntington's disease. Cell. 2025 Jan 14:S0092-8674(24)01379-5. doi: 10.1016/j.cell.2024.11.038 |
| Source Data URL | The restricted data can be accessed only upon approval from Broad's Data Access Committee (DAC). To request access to this restricted data at Broad's DUOS system, refer to the documentation - https://nemoarchive.org/resources/accessing-controlled-access-data#broad-dac-approval-process. The dataset name for this data at Broad's DUOS - HD_GeneExpression_McCarrollBerretta. |
| Field | Value |
|---|---|
| Identifier | nemo:dat-oj75u6x |
| Description | Processed Counts from 10xv3 snRNA-seq data from human associated with the following publication: Handsaker RE, Kashin S, Reed NM, et al. Long somatic DNA-repeat expansion drives neurodegeneration in Huntington's disease. Cell. 2025 Jan 14:S0092-8674(24)01379-5. doi: 10.1016/j.cell.2024.11.038 |
| Source Data URL | https://data.nemoarchive.org/other/grant/broad_mccarroll_HD_2024/mccarroll/transcriptome/sncell/10x_v3.1/human/processed/counts/ |
| Field | Value |
|---|---|
| Identifier | nemo:dat-pi1wsi2 |
| Description | SNP array data (Illumina Global Screening Array) on each donor (in VCF format) associated with the following publication: Handsaker RE, Kashin S, Reed NM, et al. Long somatic DNA-repeat expansion drives neurodegeneration in Huntington's disease. Cell. 2025 Jan 14:S0092-8674(24)01379-5. doi: 10.1016/j.cell.2024.11.038 |
| Source Data URL | The restricted data can be accessed only upon approval from Broad's Data Access Committee (DAC). To request access to this restricted data at Broad's DUOS system, refer to the documentation - https://nemoarchive.org/resources/accessing-controlled-access-data#broad-dac-approval-process. The dataset name for this data at Broad's DUOS - HD_GeneExpression_McCarrollBerretta. |
| Field | Value |
|---|---|
| Identifier | nemo:dat-ue17119 |
| Description | Metadata files for PacBio data from human associated with the following publication: Handsaker RE, Kashin S, Reed NM, et al. Long somatic DNA-repeat expansion drives neurodegeneration in Huntington's disease. Cell. 2025 Jan 14:S0092-8674(24)01379-5. doi: 10.1016/j.cell.2024.11.038 |
| Source Data URL | https://data.nemoarchive.org/other/grant/broad_mccarroll_HD_2024/mccarroll/transcriptome/sncell/pacbio/human/processed/other/ |
| Field | Value |
|---|---|
| Identifier | nemo:dat-vca1oks |
| Description | Metadata files for 10xv3 snRNA-seq data from human associated with the following publication: Handsaker RE, Kashin S, Reed NM, et al. Long somatic DNA-repeat expansion drives neurodegeneration in Huntington's disease. Cell. 2025 Jan 14:S0092-8674(24)01379-5. doi: 10.1016/j.cell.2024.11.038 |
| Source Data URL | https://data.nemoarchive.org/other/grant/broad_mccarroll_HD_2024/mccarroll/transcriptome/sncell/10x_v3.1/human/processed/other |