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利用基因断裂蛋白陷阱文库构建脊椎动物编码体。

Building the vertebrate codex using the gene breaking protein trap library.

机构信息

Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States.

Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, United States.

出版信息

Elife. 2020 Aug 11;9:e54572. doi: 10.7554/eLife.54572.

DOI:10.7554/eLife.54572
PMID:32779569
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7486118/
Abstract

One key bottleneck in understanding the human genome is the relative under-characterization of 90% of protein coding regions. We report a collection of 1200 transgenic zebrafish strains made with the gene-break transposon (GBT) protein trap to simultaneously report and reversibly knockdown the tagged genes. Protein trap-associated mRFP expression shows previously undocumented expression of 35% and 90% of cloned genes at 2 and 4 days post-fertilization, respectively. Further, investigated alleles regularly show 99% gene-specific mRNA knockdown. Homozygous GBT animals in , , , and phenocopied established mutants. 204 cloned lines trapped diverse proteins, including 64 orthologs of human disease-associated genes with 40 as potential new disease models. Severely reduced skeletal muscle Ca transients in GBT homozygous animals validated the ability to explore molecular mechanisms of genetic diseases. This GBT system facilitates novel functional genome annotation towards understanding cellular and molecular underpinnings of vertebrate biology and human disease.

摘要

理解人类基因组的一个关键瓶颈是对 90%的蛋白质编码区域相对特征不足。我们报告了一个由 1200 个转基因斑马鱼品系组成的集合，这些品系是使用基因断裂转座子（GBT）蛋白陷阱制成的，以同时报告和可逆地敲低标记基因。蛋白陷阱相关的 mRFP 表达分别在受精后 2 天和 4 天显示克隆基因的 35%和 90%的以前未记录的表达。此外，研究的等位基因通常显示 99%的基因特异性 mRNA 敲低。在 、 、 、 和 中，GBT 纯合动物表现出与已建立的突变体相同的表型。204 个克隆系捕获了多种蛋白质，包括 64 个人类疾病相关基因的同源物，其中 40 个可能是新的疾病模型。GBT 纯合动物的骨骼肌 Ca 瞬变严重减少验证了探索遗传疾病分子机制的能力。该 GBT 系统有助于对脊椎动物生物学和人类疾病的细胞和分子基础进行新的功能基因组注释。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a887/7486118/d21c84f188dd/elife-54572-fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a887/7486118/dc41542dcbc1/elife-54572-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a887/7486118/e3ee2558212a/elife-54572-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a887/7486118/c760471ef679/elife-54572-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a887/7486118/3cc6b26c91bb/elife-54572-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a887/7486118/b897804718e6/elife-54572-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a887/7486118/d84b65955c1b/elife-54572-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a887/7486118/48cf28daa5e8/elife-54572-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a887/7486118/275853ec9eae/elife-54572-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a887/7486118/a3bc30289651/elife-54572-fig6-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a887/7486118/d21c84f188dd/elife-54572-fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a887/7486118/dc41542dcbc1/elife-54572-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a887/7486118/e3ee2558212a/elife-54572-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a887/7486118/c760471ef679/elife-54572-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a887/7486118/3cc6b26c91bb/elife-54572-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a887/7486118/b897804718e6/elife-54572-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a887/7486118/d84b65955c1b/elife-54572-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a887/7486118/48cf28daa5e8/elife-54572-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a887/7486118/275853ec9eae/elife-54572-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a887/7486118/a3bc30289651/elife-54572-fig6-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a887/7486118/d21c84f188dd/elife-54572-fig7.jpg

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