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Mouse Shank1 Conditional Knockout Project (CRISPR/Cas9)

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https://www.alphaknockout.com Mouse Shank1 Conditional Knockout Project (CRISPR/Cas9) Objective: To create a Shank1 conditional knockout Mouse model (C57BL/6J) by CRISPR/Cas-mediated genome engineering. Strategy summary: The Shank1 gene (NCBI Reference Sequence: NM_001034115 ; Ensembl: ENSMUSG00000038738 ) is located on Mouse chromosome 7. 25 exons are identified, with the ATG start codon in exon 2 and the TGA stop codon in exon 25 (Transcript: ENSMUST00000107938). Exon 13~15 will be selected as conditional knockout region (cKO region). Deletion of this region should result in the loss of function of the Mouse Shank1 gene. To engineer the targeting vector, homologous arms and cKO region will be generated by PCR using BAC clone RP23-361D8 as template. Cas9, gRNA and targeting vector will be co-injected into fertilized eggs for cKO Mouse production. The pups will be genotyped by PCR followed by sequencing analysis. Note: Homozygous mutation of this gene results in smaller pyramidal neuron dendritic spines, smaller and thinner postsynaptic density of central excitatory synapses, weaker synaptic transmission, increased anxiety-related behavior, and impaired contextual fearmemory, but enhanced spatial learning. Exon 13 starts from about 26.89% of the coding region. The knockout of Exon 13~15 will result in frameshift of the gene. The size of intron 12 for 5'-loxP site insertion: 6065 bp, and the size of intron 15 for 3'-loxP site insertion: 8038 bp. The size of effective cKO region: ~1268 bp. The cKO region does not have any other known gene. Page 1 of 8 https://www.alphaknockout.com Overview of the Targeting Strategy Wildtype allele gRNA region 5' gRNA region 3' 14 1 13 15 25 Targeting vector Targeted allele Constitutive KO allele (After Cre recombination) Legends Exon of mouse Shank1 Homology arm cKO region loxP site Page 2 of 8 https://www.alphaknockout.com Overview of the Dot Plot Window size: 10 bp Forward Reverse Complement Sequence 12 Note: The sequence of homologous arms and cKO region is aligned with itself to determine if there are tandem repeats. Tandem repeats are found in the dot plot matrix. It may be difficult to construct this targeting vector. Overview of the GC Content Distribution Window size: 300 bp Sequence 12 Summary: Full Length(7768bp) | A(18.15% 1410) | C(28.06% 2180) | T(27.23% 2115) | G(26.56% 2063) Note: The sequence of homologous arms and cKO region is analyzed to determine the GC content. Significant high GC-content regions are found. It may be difficult to construct this targeting vector. Page 3 of 8 https://www.alphaknockout.com BLAT Search Results (up) QUERY SCORE START END QSIZE IDENTITY CHROM STRAND START END SPAN ----------------------------------------------------------------------------------------------- browser details YourSeq 3000 1 3000 3000 100.0% chr7 + 44330043 44333042 3000 browser details YourSeq 276 686 1055 3000 97.7% chr3 - 129236924 129237514 591 browser details YourSeq 256 693 1054 3000 95.4% chr7 - 118187042 118187474 433 browser details YourSeq 247 685 974 3000 91.5% chr8 + 15680795 15681072 278 browser details YourSeq 237 685 1002 3000 91.3% chr19 - 17668449 17668736 288 browser details YourSeq 237 695 950 3000 97.3% chr4 + 33695569 33695955 387 browser details YourSeq 237 711 1055 3000 93.8% chr17 + 66230455 66230899 445 browser details YourSeq 235 695 1055 3000 91.6% chr10 + 95991770 95992070 301 browser details YourSeq 231 754 1054 3000 94.9% chr9 + 22392473 22392882 410 browser details YourSeq 229 695 1055 3000 89.8% chr10 - 88880205 88880472 268 browser details YourSeq 225 697 1055 3000 91.4% chr5 + 88800707 88800937 231 browser details YourSeq 225 695 1030 3000 96.7% chr4 + 33695576 33695955 380 browser details YourSeq 215 700 1055 3000 87.5% chr10 + 7486636 7486945 310 browser details YourSeq 213 685 943 3000 94.7% chr16 - 94115544 94115899 356 browser details YourSeq 209 699 1055 3000 89.5% chr12 + 67693595 67693848 254 browser details YourSeq 204 733 976 3000 94.9% chrX - 7182756 7183037 282 browser details YourSeq 203 772 1012 3000 91.5% chr5 + 126017776 126018010 235 browser details YourSeq 199 700 1054 3000 92.6% chr8 + 102122588 102122829 242 browser details YourSeq 196 695 1056 3000 96.4% chr2 - 140018940 140019380 441 browser details YourSeq 193 787 1055 3000 91.5% chr5 - 65310135 65310686 552 Note: The 3000 bp section upstream of Exon 13 is BLAT searched against the genome. No significant similarity is found. BLAT Search Results (down) QUERY SCORE START END QSIZE IDENTITY CHROM STRAND START END SPAN ----------------------------------------------------------------------------------------------- browser details YourSeq 3000 1 3000 3000 100.0% chr7 + 44334311 44337310 3000 browser details YourSeq 39 2557 2633 3000 93.2% chr1 - 39145875 39145972 98 browser details YourSeq 36 2557 2633 3000 92.9% chr12 - 19884180 19884427 248 browser details YourSeq 32 2605 2649 3000 92.2% chr5 + 105403636 105403680 45 browser details YourSeq 31 2600 2638 3000 92.4% chr5 - 142045666 142045708 43 browser details YourSeq 29 2600 2633 3000 84.4% chr2 - 179048894 179048925 32 browser details YourSeq 27 2602 2634 3000 93.4% chr5 - 103014262 103014303 42 browser details YourSeq 27 1351 1389 3000 79.4% chr2 - 170317206 170317239 34 browser details YourSeq 25 1357 1389 3000 75.0% chr6 + 122666632 122666659 28 browser details YourSeq 24 1595 1624 3000 84.7% chr3 + 143806061 143806088 28 browser details YourSeq 23 1691 1715 3000 96.0% chr15 - 93336884 93336908 25 browser details YourSeq 22 2720 2743 3000 87.0% chr1 - 113330979 113331001 23 Note: The 3000 bp section downstream of Exon 15 is BLAT searched against the genome. No significant similarity is found. Page 4 of 8 https://www.alphaknockout.com Gene and protein information: Shank1 SH3 and multiple ankyrin repeat domains 1 [ Mus musculus (house mouse) ] Gene ID: 243961, updated on 1-Oct-2019 Gene summary Official Symbol Shank1 provided by MGI Official Full Name SH3 and multiple ankyrin repeat domains 1 provided by MGI Primary source MGI:MGI:3613677 See related Ensembl:ENSMUSG00000038738 Gene type protein coding RefSeq status VALIDATED Organism Mus musculus Lineage Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus Expression Biased expression in frontal lobe adult (RPKM 16.9), cortex adult (RPKM 13.3) and 9 other tissues See more Orthologs human all Genomic context Location: 7; 7 B3 See Shank1 in Genome Data Viewer Exon count: 32 Annotation release Status Assembly Chr Location 108 current GRCm38.p6 (GCF_000001635.26) 7 NC_000073.6 (44308916..44360094) Build 37.2 previous assembly MGSCv37 (GCF_000001635.18) 7 NC_000073.5 (51565634..51613723) Chromosome 7 - NC_000073.6 Page 5 of 8 https://www.alphaknockout.com Transcript information: This gene has 6 transcripts Gene: Shank1 ENSMUSG00000038738 Description SH3 and multiple ankyrin repeat domains 1 [Source:MGI Symbol;Acc:MGI:3613677] Location Chromosome 7: 44,310,253-44,360,572 forward strand. GRCm38:CM001000.2 About this gene This gene has 6 transcripts (splice variants), 223 orthologues, 2 paralogues, is a member of 1 Ensembl protein family and is associated with 12 phenotypes. Transcripts Name Transcript ID bp Protein Translation ID Biotype CCDS UniProt Flags Shank1-203 ENSMUST00000107938.7 9826 2167aa ENSMUSP00000103571.1 Protein coding CCDS52229 D3YZU1 TSL:5 GENCODE basic APPRIS P2 Shank1-202 ENSMUST00000107935.7 6649 2159aa ENSMUSP00000103568.1 Protein coding - D3YZU4 TSL:5 GENCODE basic APPRIS ALT2 Shank1-201 ENSMUST00000107934.1 6477 2158aa ENSMUSP00000103567.1 Protein coding - D3YZU5 TSL:5 GENCODE basic APPRIS ALT2 Shank1-206 ENSMUST00000154776.1 987 No protein - Retained intron - - TSL:1 Shank1-204 ENSMUST00000127164.1 784 No protein - Retained intron - - TSL:2 Shank1-205 ENSMUST00000134470.7 608 No protein - lncRNA - - TSL:3 Page 6 of 8 https://www.alphaknockout.com 70.32 kb Forward strand Genes (Comprehensive set... Shank1-203 >protein coding Gm44780-201 >lncRNA Shank1-202 >protein coding Shank1-201 >protein coding Gm44757-201 >TEC Shank1-205 >lncRNA Shank1-204 >retained intron Shank1-206 >retained intron Contigs AC152939.2 > Genes < Gm7238-201processed pseudogene < 1700008O03Rik-201protein coding (Comprehensive set... < Clec11a-201protein coding < 1700008O03Rik-203retained intron < 1700008O03Rik-205protein coding < 1700008O03Rik-204lncRNA Regulatory Build Reverse strand 70.32 kb Regulation Legend CTCF Open Chromatin Promoter Promoter Flank Transcription Factor Binding Site Gene Legend Protein Coding Ensembl protein coding merged Ensembl/Havana Non-Protein Coding RNA gene pseudogene processed transcript Page 7 of 8 https://www.alphaknockout.com Transcript: ENSMUST00000107938 50.32 kb Forward strand Shank1-203 >protein coding ENSMUSP00000103... MobiDB lite Low complexity (Seg) Coiled-coils (Ncoils) Superfamily Ankyrin repeat-containing domain superfamily Sterile alpha motif/pointed domain superfamily SH3-like domain superfamily PDZ superfamily SMART Ankyrin repeat SH3 domain Sterile alpha motif domain PDZ domain Pfam PDZ domain 6 Sterile alpha motif domain SH3 domain Ankyrin repeat-containing domain PROSITE profiles Ankyrin repeat PDZ domain Sterile alpha motif domain Ankyrin repeat-containing domain SH3 domain PANTHER PTHR24135 PTHR24135:SF3 Gene3D 3.10.20.90 1.25.40.960 2.30.30.40 Sterile alpha motif/pointed domain superfamily 2.30.42.10 Ankyrin repeat-containing domain superfamily CDD cd17175 cd00992 cd09506 All sequence SNPs/i... Sequence variants (dbSNP and all other sources) Variant Legend missense variant synonymous variant Scale bar 0 200 400 600 800 1000 1200 1400 1600 1800 2167 We wish to acknowledge the following valuable scientific information resources: Ensembl, MGI, NCBI, UCSC. Page 8 of 8.
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  • Towards a Gene-Level Map of Resilience to Genetic Variants Associated with Autism Thomas Rolland1*, Freddy Cliquet1, Richard

    Towards a Gene-Level Map of Resilience to Genetic Variants Associated with Autism Thomas Rolland1*, Freddy Cliquet1, Richard

    medRxiv preprint doi: https://doi.org/10.1101/2021.02.12.21251621; this version posted February 13, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in Rolland et al. Towards a gene-level map of resilience to geneticperpetuity. variants associated with autism It is made available under a CC-BY-NC 4.0 International license . Towards a gene-level map of resilience to genetic variants associated with autism Thomas Rolland1*, Freddy Cliquet1, Richard J.L. Anney2, Nicolas Traut1,3, Alexandre Mathieu1, Guillaume Huguet4,5, Claire S. Leblond1, Elise Douard4,5, Frédérique Amsellem1,6, Simon Malesys1, Anna Maruani1,6, Roberto Toro1,3, Alan Packer7, Wendy K. Chung7,8, Sébastien Jacquemont4,5, Richard Delorme1,6, Thomas Bourgeron1* 1 Human Genetics and Cognitive Functions, Institut Pasteur, UMR3571 CNRS, Université de Paris, Paris, France 2 MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, CF24 4HQ, UK 3 Center for Research and Interdisciplinarity (CRI), Université Paris Descartes, Paris, France 4 Department of Pediatrics, Université de Montréal, Montreal, QC, Canada 5 Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, QC, Canada 6 Department of Child and Adolescent Psychiatry, Assistance Publique-Hôpitaux de Paris, Robert Debré Hospital, Paris, France 7 Simons Foundation, New York, NY, USA. 8 Department of Pediatrics, Columbia University Medical Center, New York, NY, USA. * e-mail: [email protected] , [email protected] NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
  • SHANK1 Deletions in Males with Autism Spectrum Disorder

    SHANK1 Deletions in Males with Autism Spectrum Disorder

    Please cite this article in press as: Sato et al., SHANK1 Deletions in Males with Autism Spectrum Disorder, The American Journal of Human Genetics (2012), doi:10.1016/j.ajhg.2012.03.017 REPORT SHANK1 Deletions in Males with Autism Spectrum Disorder Daisuke Sato,1 Anath C. Lionel,1,2 Claire S. Leblond,3,4,5 Aparna Prasad,1 Dalila Pinto,1 Susan Walker,1 Irene O’Connor,6 Carolyn Russell,6 Irene E. Drmic,7 Fadi F. Hamdan,8 Jacques L. Michaud,8 Volker Endris,9 Ralph Roeth,9 Richard Delorme,3,4,5,10 Guillaume Huguet,3,4,5 Marion Leboyer,11,12 Maria Rastam,13 Christopher Gillberg,14,15 Mark Lathrop,16 Dimitri J. Stavropoulos,17 Evdokia Anagnostou,18 Rosanna Weksberg,19 Eric Fombonne,20 Lonnie Zwaigenbaum,21 Bridget A. Fernandez,22 Wendy Roberts,7,18 Gudrun A. Rappold,9 Christian R. Marshall,1,2 Thomas Bourgeron,3,4,5 Peter Szatmari,6,* and Stephen W. Scherer1,2,* Recent studies have highlighted the involvement of rare (<1% frequency) copy-number variations and point mutations in the genetic etiology of autism spectrum disorder (ASD); these variants particularly affect genes involved in the neuronal synaptic complex. The SHANK gene family consists of three members (SHANK1, SHANK2, and SHANK3), which encode scaffolding proteins required for the proper formation and function of neuronal synapses. Although SHANK2 and SHANK3 mutations have been implicated in ASD and intellectual disability, the involvement of SHANK1 is unknown. Here, we assess microarray data from 1,158 Canadian and 456 European individuals with ASD to discover microdeletions at the SHANK1 locus on chromosome 19.

  • Exploratory Neuroimmune Profiling Identifies CNS-Specific Alterations in COVID-19 Patients with Neurological Involvement

    bioRxiv preprint doi: https://doi.org/10.1101/2020.09.11.293464; this version posted December 9, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Exploratory neuroimmune profiling identifies CNS-specific alterations in COVID-19 patients with neurological involvement Authors: Eric Song1,†,*, Christopher M. Bartley2,3,4†, Ryan D. Chow5, Thomas T. Ngo3,4, Ruoyi Jiang1, Colin R. Zamecnik3,6, Ravi Dandekar3,6, Rita P. Loudermilk3,6, Yile Dai1, Feimei Liu1, Isobel A. Hawes3,6,7, Bonny D. Alvarenga3,6, Trung Huynh3,6, Lindsay McAlpine8, Nur-Taz Rahman9, Bertie Geng10, Jennifer Chiarella8, Benjamin Goldman-Israelow1,9, Chantal B.F. Vogels11, Nathan D. Grubaugh11, Arnau Casanovas-Massana11, Brett S. Phinney12, Michelle Salemi12, Jessa Alexander3,6, Juan A. Gallego13-15, Todd Lencz13-15, Hannah Walsh9, Carolina Lucas1, Jon Klein1, Tianyang Mao1, Jieun Oh1, Aaron Ring1, Serena Spudich8, Albert I. Ko10,11, Steven H. Kleinstein1,16,17, Joseph L. DeRisi18,19, Akiko Iwasaki1,20,21, Samuel J. Pleasure3,6,b Michael R. Wilson3,6, ‡,*, Shelli F. Farhadian8,10, ‡,* Affiliations: 1 Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA. 2 Hanna H. Gray Fellow, Howard Hughes Medical Institute, Chevy Chase, MD, USA. 3 Weill Institute for Neurosciences, University of California, San Francisco, CA, USA. 4 Department of Psychiatry, University of California, San Francisco, CA, USA. 5 Department of Genetics, Yale School of Medicine, New Haven, CT, USA.