Mapping genetic effects on cellular phenotypes with “cell villages”

Mitchell, Jana M.; Nemesh, James; Ghosh, Sulagna; Handsaker, Robert E.; Mello, Curtis J.; Meyer, David G.; Raghunathan, Kavya; Rivera, Heather de; Tegtmeyer, Matt; Hawes, Derek; Neumann, Anna; Nehme, Ralda; Eggan, Kevin; McCarroll, Steven A.

doi:10.1101/2020.06.29.174383

Cited by 55 publications

(60 citation statements)

References 58 publications

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“…Additional profiling of other cell types that are also vulnerable to PD-associated degeneration 56 could clarify whether loss outside the SNpc is also cell-autonomous, or secondary to DA neuronal loss. Furthermore, our work should help refine in vitro DA neuron differentiation protocols, which could be used to screen for neuronal susceptibility across many different genetic backgrounds 57 and with candidate therapeutic molecules. Xenotransplantation systems could also be useful to identify molecular regulators of neuronal vulnerability 58 , or to improve the performance of cellular replacement therapies 59 .…”

Section: Discussionmentioning

confidence: 99%

A molecular census of midbrain dopaminergic neurons in Parkinson’s disease

Kamath

Abdulraouf

Burris

et al. 2021

Preprint

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Midbrain dopamine (DA) neurons in the substantia nigra pars compacta (SNpc) project widely throughout the central nervous system, playing critical roles in voluntary movements, reward processing, and working memory. Many of these neurons are highly sensitive to neurodegeneration in Parkinson's Disease (PD), and their loss correlates strongly with the pathognomonic symptoms. To characterize these populations molecularly, we developed a protocol to enrich and transcriptionally profile DA neuron nuclei from postmortem human SNpc of both PD patients and matched controls. We identified a total of ten distinct populations, including one that was primate-specific. A single subtype, marked by the gene AGTR1, was highly susceptible to degeneration, and was enriched for expression of genes associated with PD in genetic studies, suggesting many risk loci act within this subtype to influence its neurodegeneration. The AGTR1 subtype also showed the strongest upregulation of TP53 and its downstream targets, nominating a potential pathway of degeneration in vivo. The transcriptional characterization of differentially disease-vulnerable DA neurons in the SNpc will inform the development of laboratory models, enable the nomination of novel disease biomarkers, and guide further studies of pathogenic disease mechanisms.

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Section: Discussionmentioning

confidence: 99%

A molecular census of midbrain dopaminergic neurons in Parkinson’s disease

Kamath

Abdulraouf

Burris

et al. 2021

Preprint

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“…Perturb-seq (Dixit et al, 2016) and ECCITE-seq (Mimitou et al, 2019)) and pooled eQTL screens (e.g. crisprQTL mapping (Gasperini et al, 2019) and Census-seq (Cuomo et al, 2020;Jerber et al, 2020;Mitchell et al, 2020;Neavin et al, 2020)) approaches will more rapidly identify host variants that impact the entry, replication and egress of SARS-CoV-2, cellular survival, and immune response.…”

Section: Discussionmentioning

confidence: 99%

Common genetic variation in humans impactsin vitrosusceptibility to SARS-CoV-2 infection

Dobrindt

Hoagland

Seah

et al. 2020

Preprint

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The host response to SARS-CoV-2, the etiologic agent of the COVID-19 pandemic, demonstrates significant inter-individual variability. In addition to showing more disease in males, the elderly, and individuals with underlying co-morbidities, SARS-CoV-2 can seemingly render healthy individuals with profound clinical complications. We hypothesize that, in addition to viral load and host antibody repertoire, host genetic variants also impact vulnerability to infection. Here we apply human induced pluripotent stem cell (hiPSC)-based models and CRISPR-engineering to explore the host genetics of SARS-CoV-2. We demonstrate that a single nucleotide polymorphism (rs4702), common in the population at large, and located in the 3’UTR of the protease FURIN, impacts alveolar and neuron infection by SARS-CoV-2 in vitro. Thus, we provide a proof-of-principle finding that common genetic variation can impact viral infection, and thus contribute to clinical heterogeneity in SARS-CoV-2. Ongoing genetic studies will help to better identify high-risk individuals, predict clinical complications, and facilitate the discovery of drugs that might treat disease.

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“…However, high-throughput methods for the rapid assessment of cellular phenotypes are being developed. For example, the Census-seq cell village approach allows cells from multiple donors to be plated and assayed together on a single dish 40 . In addition to enabling large-scale cell-level analyses, individual donor genetic associations with cellular phenotypes can be inferred computationally using this method, enabling polygenic score analyses.…”

Section: Discussionmentioning

confidence: 99%

Feasibility and application of polygenic score analysis to the morphology of human induced pluripotent stem cells

Coleman

2020

Preprint

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Genome-wide association studies have identified thousands of significant associations between genetic variants and complex traits. Inferring biological insights from these associations has been challenging. One approach attempted has been to examine the effects of individual variants in cellular models. Here, I demonstrate the feasibility of examining the aggregate effect of many variants on cellular phenotypes. I examine the effects of polygenic scores for cross-psychiatric disorder risk, schizophrenia, body mass index and height on cellular morphology, using 1.5 million induced pluripotent stem cells (iPSC) from 60 European-ancestry donors from the Human iPSC Initiative dataset. I show that measuring multiple cells per donor provides sufficient power for polygenic score analyses, and that cross-psychiatric disorder risk is associated with cell area (p = 0.004). Combined with emerging methods of high-throughput iPSC phenotyping, cellular polygenic scoring is a promising method for understanding potential biological effects of the polygenic component of complex traits.

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Mapping genetic effects on cellular phenotypes with “cell villages”

Cited by 55 publications

References 58 publications

A molecular census of midbrain dopaminergic neurons in Parkinson’s disease

A molecular census of midbrain dopaminergic neurons in Parkinson’s disease

Common genetic variation in humans impactsin vitrosusceptibility to SARS-CoV-2 infection

Feasibility and application of polygenic score analysis to the morphology of human induced pluripotent stem cells

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