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| Status |
Public on Jan 17, 2018 |
| Title |
Ultraconserved Enhancers Are Required for Normal Development [Drop-seq] |
| Organisms |
Homo sapiens; Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Non-coding ultraconserved regions showing hundreds of consecutive bases of perfect evolutionary sequence conservation across mammalian genomes have intrigued biologists in the decade since they were first described. While many of these sequences are known to represent distant-acting enhancers, initial deletion studies in mice showed that their loss had no obvious impact on viability or fertility. To explore the discrepancy between extraordinary evolutionary constraint and an apparent lack of phenotypes when deleted in vivo, we used genome editing to create an expanded series of knockout mice lacking individual or combinations of ultraconserved brain enhancers near the essential neuronal transcription factor Arx. While the loss of any single or pair of ultraconserved enhancers resulted in viable and fertile mice, detailed phenotyping revealed neurological or growth abnormalities in nearly all cases, including substantial alterations of neuron populations and abnormalities of the dentate gyrus. Our results demonstrate the functional importance of ultraconserved enhancers and highlight that extreme sequence conservation may result from evolutionary selection against fitness deficits that appear subtle in a laboratory setting.
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| Overall design |
Cell suspensions were prepared from E12.5 mouse forebrains, and single-cell mRNAseq libraries were generated with Drop-Seq. Experiments were performed on transgenics embryos in which a validated forebrain enhancer (hs119, hs121, hs122, hs123, http://enhancer.lbl.gov/) controlled the expression of a reporter gene (either GFP or mCherry).
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| Contributor(s) |
Dickel DE, Ypsilanti AR, Pla R, Zhu Y, Barozzi I, Mannion BJ, Khin Y, Fukuda-Yuzawa Y, Plajzer-Frick I, Pickle CS, Lee EE, Harrington AN, Pham QT, Garvin TH, Kato M, Akiyama JA, Afzal V, Rubenstein JL, Visel A, Pennacchio LA |
| Citation(s) |
29358049 |
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| Submission date |
Jun 22, 2017 |
| Last update date |
May 15, 2019 |
| Contact name |
Iros Barozzi |
| E-mail(s) |
iros.barozzi@meduniwien.ac.at
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| Organization name |
Medical University Vienna
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| Street address |
Borschkegasse 8a
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| City |
Vienna |
| ZIP/Postal code |
1090 |
| Country |
Austria |
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| Platforms (2) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
| GPL22245 |
Illumina HiSeq 2500 (Homo sapiens; Mus musculus) |
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| Samples (6)
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| This SubSeries is part of SuperSeries: |
| GSE100394 |
Ultraconserved Enhancers Are Required for Normal Development |
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| Relations |
| BioProject |
PRJNA391516 |
| SRA |
SRP110203 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE100384_dropseq_data.digital_expression.bulk.txt.gz |
70.9 Kb |
(ftp)(http) |
TXT |
| GSE100384_dropseq_data.digital_expression.txt.gz |
7.4 Mb |
(ftp)(http) |
TXT |
| GSE100384_mm10_hg19.refFlat.txt.gz |
5.0 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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