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• W2899780910 abstract "Because CRISPR-based rapid-throughput biology often entails analysis of G0 somatic mutants, there is a need to improve our ability to discern and interpret variable phenotypes arising from mosaicism. Here, we examine mechanisms underlying mosaic patterns in crispant zebrafish, and assess the benefits of phenomics--i.e., in depth phenotyping at a large number of sites--in discerning variable phenotypes arising from mosaicism. We characterize spatial and size characteristics of loss-of-function cell clusters in the skeleton. Despite inter-animal differences in mutation efficiency, we identify a distinctive size distribution in bones of separate developmental lineages, replicating that predicted from clonal fragmentation and merger events. Using a microCT-based workflow enabling hundreds of measures per animal, we describe diverse phenotypic manifestations in mosaic models of brittle bone diseases (plod2 and bmp1a). At the population level, we show convergence between somatic and germline mutant phenomes. We demonstrate that vertebral patterns confer heightened sensitivity in discriminating somatic mutant populations compared to single readouts. We also establish a framework to quantify spatial phenotypic variation, and show this is differentially altered in disease models. Finally, we detect a low bone mass phenotype in adult somatic mutants for wnt16, a gene implicated in heritable risk for osteoporosis, and validate this phenotype in germline mutants. Our studies demonstrate mosaic analysis and phenomic approaches to help detect and interpret spatially variable phenotypes in G0 animals. Applied to the skeleton, microCT-based phenomics, in concert with CRISPR-based G0 screens, is a promising direction for the identification of causal genes and targeted therapies for mono- and multigenic skeletal diseases." @default.
• W2899780910 created "2018-11-16" @default.
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• W2899780910 date "2018-11-08" @default.
• W2899780910 modified "2023-09-27" @default.
• W2899780910 title "Deep Phenotyping Enhances Somatic Mutant Detection and Mosaic Pattern Recognition in the Zebrafish Skeleton" @default.
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