ReviewsREVIEW

Intersection of diverse neuronal genomes and neuropsychiatric disease: The Brain Somatic Mosaicism Network

See allHide authors and affiliations

Science  28 Apr 2017:
Vol. 356, Issue 6336, eaal1641
DOI: 10.1126/science.aal1641
  • Collectively, somatic SNVs, indels, structural variants (e.g., CNVs), and MEIs (e.g., L1 retrotransposition events) shape the genomic landscape of individual neurons.

    The Brain Somatic Mosaicism Network aims to systematically generate pioneering data on the types and frequencies of brain somatic mutations in both neurotypical individuals and those with neuropsychiatric disease. The resulting data will be shared as a large community resource.

  • Fig. 1 An overview of approaches employed by the BSMN.

    The general approach of the BSMN is to identify mosaic variants in primary human brain tissue from large cohorts of neurotypical individuals and neuropsychiatric disease patients. The methods include bulk sequencing of tissues or sorted neurons (top), sequencing of single cells after whole-genome amplification (middle), or clonal expansion from single cells followed by bulk sequencing (bottom). Each method offers a trade-off between sensitivity and specificity.

  • Fig. 2 An example of brain somatic mosaicism that leads to a focal overgrowth condition.

    (A) Axial brain magnetic resonance imaging (MRI) of focal overgrowth of one hemisphere (arrows) from a 2-month-old child with intractable epilepsy and intellectual disability. MRI showed poor differentiation between the gray and white matter with dysplasia of the cortical gyri and sulci (arrows). (B) Brain mapping using high-resolution MRI or functional imaging such as positron emission tomography (PET), together with electrocorticography to fine-map specific epileptic foci, is followed by surgical resection of diseased brain tissue. (C) Histological analysis with hematoxylin/eosin showing characteristic balloon cells (arrows) consisting of large nuclei, distinct nucleoli, and glassy eosinophilic cytoplasm. (D) Immunostained section for phospho-S6 (green), as evidence of increased mTOR pathway activation. Arrows highlight large dysplastic cell showing strongest immunosignal. Scale bar, 50 μm. Bulk tissue sequencing showed somatic activating mutation in the MTOR gene c.6644C>T leading to p.S2215F in 15% of brain cells from the diseased hemisphere. After surgery, the patient showed clinical improvement.

  • Fig. 3 A potential strategy to determine functional consequences of mosaic variants.

    In utero electroporation (IUE) transfects a subpopulation of cortical neurons within a local area and will be combined with genome editing to generate mosaic mouse models for functional analysis. For example, a red fluorescent construct (CAG-TdTom) is shown labeling a transfected subset of neurons, shown in the context of a coronal brain section in which nuclei are stained blue with 4′,6-diamidino-2-phenylindole (DAPI). Scale bar, 500 μm.

  • Table 1 Mosaic mutations in genes and their associated signaling pathways and diseases.

    Disease abbreviations: CLOVES, Congenital lipomatous overgrowth, vascular malformations, and epidermal nevi; FCD, focal cortical dysplasia; GPCR, G protein–coupled receptor; HME, hemimegalencephaly; MCAP, megalencephaly-capillary malformation-polymicrogyria syndrome; MPPH2, megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome-2; NF, neurofibromatosis; RALD, Ras-associated autoimmune leukoproliferative disorder; TSC, tuberous sclerosis complex. Mosaicism abbreviations: G, germline; S, somatic; OS, obligatory somatic; MS, milder somatic; SHS, second-hit somatic.

    Gene(s)Signaling
    pathway(s)
    Disease(s)Cellular
    function(s)
    Cancer(s)Cancer roleMosaicism
    PIK3CA (100104)PI3K-AKT-mTORHME, mosaic
    overgrowth syndrome,
    type 2 segmental,
    CLOVES, MCAP
    PI3K subunit,
    serine/threonine
    kinase
    Cervical, various
    neoplasms, colorectal
    OncogeneOS
    AKT1 (105)PI3K-AKT-mTORProteus syndromeSerine/threonine
    kinase
    Breast, ovarian,
    colorectal
    OncogeneOS
    AKT2 (106)PI3K-AKT-mTORDiabetes mellitusSerine/threonine
    kinase
    Ovarian, pancreatic,
    breast, colorectal,
    lung cancer
    OncogeneG/S
    AKT3 (101, 103, 13, 107)PI3K-AKT-mTORHME, MCAP, MPPH2Serine/threonine
    kinase
    Melanoma, glioma,
    ovarian cancer
    OncogeneOS
    MTOR (108)PI3K-AKT-mTORFCD type IISerine/threonine
    kinase
    Carcinoma,
    glioblastoma,
    melanoma
    OncogeneOS
    DEPDC5 (109, 110)PI3K-AKT-mTOREpilepsy with FCDmTORC1
    repressor
    Glioblastoma and
    ovarian tumors
    Tumor
    suppressor
    G/S
    TSC1 (111, 112)PI3K-AKT-mTORTSCNegative
    regulator of
    mTORC1
    Renal angiomyolipomasTumor
    suppressor
    SHS
    TSC2 (111, 112)PI3K-AKT-mTORTSCNegative
    regulator of
    mTORC1
    Renal angiomyolipomasTumor
    suppressor
    SHS
    NRAS, BRAF,
    FGFR3, PIK3CA
    (113118)
    RAS, PI3K-AKT-
    mTOR
    Congenital
    melanocytic,
    other nevi;
    seborrheic
    keratosis
    Cell cycle
    regulation
    (FGFR3) bladder,
    cervical, urothelial
    OncogeneG/S
    NF2 (119)RAS, PI3K-AKT-
    mTOR
    NF type 2Negative regulator
    of Ras, mTOR
    pathways
    NeurofibromasTumor
    suppressor
    G/MS
    NF1 (120124)RASNF type 1, Watson
    syndrome
    Negative regulator
    of Ras pathway
    Neurofibromas,
    leukemia
    Tumor
    suppressor
    SHS
    BRAF, NRAS,
    KRAS (125)
    RASPyogenic granulomaCell cycle
    regulation
    (KRAS) breast,
    colorectal, other;
    (NRAS) thyroid,
    melanoma, other;
    (BRAF) melanoma,
    colorectal
    OncogeneOS
    HRAS, KRAS (126)RASSchimmelpenning-Feuerstein-
    Mims syndrome
    Cell cycle
    regulation
    (KRAS) bladder,
    breast, colorectal,
    pancreatic, other;
    (HRAS) Colorectal,
    bladder, kidney, other
    OncogeneOS
    KRAS (127, 128)RASRALDCell cycle
    regulation
    Breast, bladder, otherOncogeneOS
    GNAQ (129)GPCR, MAPKSturge-Weber syndromeG protein
    alpha subunit
    MelanomaOncogeneOS
    GNAQ, GNA11 (130)GPCR, MAPKDermal melanocytosis
    and phakomatosis
    pigmentovascularis
    G protein
    alpha subunit
    MelanomaOncogeneOS
    MAP3K3 (131)MAPKVerrucous venous
    malformation
    Cell cycle
    regulation
    Breast, colon,
    rectal cancers
    OncogeneOS
    GNAS (132, 133)GPCRMcCune-Albright
    syndrome
    G protein alpha
    subunit
    Adenomas,
    carcinomas,
    ovarian neoplasms
    OncogeneOS
    JAK2 (134, 135)JAK-STATMyelofibrosis,
    polycythemia vera,
    and essential
    thrombocythemia
    Cell cycle
    regulation
    LeukemiaOncogeneSHS
    SCN1A (136)Sodium channelDravet syndromeNeural excitationG/MS
    NLRP3 (137)Caspase/
    inflammasome
    CINCA syndromeInflammasome
    subunit
    G/MS
    PORCN (138)WntFocal dermal
    hypoplasia
    O-acyltransferaseG/MS
    PIGA (139)HematopoiesisParoxysmal
    nocturnal
    hemoglobinuria
    ER protein
    processing
    LeukemiaOS

Supplementary Materials

  • Intersection of diverse neuronal genomes and neuropsychiatric disease: The Brain Somatic Mosaicism Network

    Michael J. McConnell, John V. Moran, Alexej Abyzov, Schahram Akbarian, Taejeong Bae, Isidro Cortes-Ciriano, Jennifer A. Erwin, Liana Fasching, Diane A. Flasch, Donald Freed, Javier Ganz, Andrew E. Jaffe, Kenneth Y. Kwan, Minseok Kwon, Michael A. Lodato, Ryan E. Mills, Apua C. M. Paquola, Rachel E. Rodin, Chaggai Rosenbluh, Nenad Sestan, Maxwell A. Sherman, Joo Heon Shin, Saera Song, Richard E. Straub, Jeremy Thorpe, Daniel R. Weinberger, Alexander E. Urban, Bo Zhou, Fred H. Gage, Thomas Lehner, Geetha Senthil, Christopher A. Walsh, Andrew Chess, Eric Courchesne, Joseph G. Gleeson, Jeffrey M. Kidd, Peter J. Park, Jonathan Pevsner, Flora M. Vaccarino, Brain Somatic Mosaicism Network

    Materials/Methods, Supplementary Text, Tables, Figures, and/or References

    Download Supplement
    • Brain Somatic Mosaicism Network Members List

Navigate This Article