DOCSLIB.ORG

Mouse Nsfl1c Conditional Knockout Project (CRISPR/Cas9)

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Mouse Nsfl1c Conditional Knockout Project (CRISPR/Cas9) https://www.alphaknockout.com Mouse Nsfl1c Conditional Knockout Project (CRISPR/Cas9) Objective: To create a Nsfl1c conditional knockout Mouse model (C57BL/6J) by CRISPR/Cas-mediated genome engineering. Strategy summary: The Nsfl1c gene (NCBI Reference Sequence: NM_198326 ; Ensembl: ENSMUSG00000027455 ) is located on Mouse chromosome 2. 10 exons are identified, with the ATG start codon in exon 1 and the TAA stop codon in exon 10 (Transcript: ENSMUST00000089140). Exon 3~5 will be selected as conditional knockout region (cKO region). Deletion of this region should result in the loss of function of the Mouse Nsfl1c gene. To engineer the targeting vector, homologous arms and cKO region will be generated by PCR using BAC clone RP23-112E9 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: Exon 3 starts from about 18.28% of the coding region. The knockout of Exon 3~5 will result in frameshift of the gene. The size of intron 2 for 5'-loxP site insertion: 4033 bp, and the size of intron 5 for 3'-loxP site insertion: 931 bp. The size of effective cKO region: ~2965 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 5' gRNA region gRNA region 3' 1 3 4 5 6 7 10 Targeting vector Targeted allele Constitutive KO allele (After Cre recombination) Legends Exon of mouse Nsfl1c 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. No significant tandem repeat is found in the dot plot matrix. So this region is suitable for PCR screening or sequencing analysis. Overview of the GC Content Distribution Window size: 300 bp Sequence 12 Summary: Full Length(9465bp) | A(26.1% 2470) | C(21.43% 2028) | T(30.99% 2933) | G(21.49% 2034) Note: The sequence of homologous arms and cKO region is analyzed to determine the GC content. No significant high GC-content region is found. So this region is suitable for PCR screening or sequencing analysis. 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% chr2 + 151497466 151500465 3000 browser details YourSeq 97 2806 2960 3000 82.0% chr1 - 190767584 190989909 222326 browser details YourSeq 93 2818 2985 3000 78.0% chr1 + 178387571 178387739 169 browser details YourSeq 89 2748 2898 3000 84.5% chr11 - 32029271 32029407 137 browser details YourSeq 84 2776 2941 3000 81.2% chr4 + 150067939 150068100 162 browser details YourSeq 81 2834 2961 3000 84.1% chr11 + 94021855 94022255 401 browser details YourSeq 77 2812 2940 3000 77.4% chr12 - 16596890 16597009 120 browser details YourSeq 75 2758 2919 3000 75.9% chr15 - 38353216 38353378 163 browser details YourSeq 72 2834 2942 3000 83.5% chr8 - 110567759 110567868 110 browser details YourSeq 72 2810 2960 3000 77.3% chr7 + 24336936 24337086 151 browser details YourSeq 72 2758 2945 3000 88.3% chr3 + 34760679 34760867 189 browser details YourSeq 72 2803 2943 3000 82.4% chr11 + 62626091 62626231 141 browser details YourSeq 71 2812 2940 3000 78.9% chr17 - 26436735 26436864 130 browser details YourSeq 70 2814 2959 3000 75.4% chr14 - 50842321 50842467 147 browser details YourSeq 69 2764 2884 3000 76.7% chr11 - 63703609 63703704 96 browser details YourSeq 69 2808 2918 3000 81.9% chr11 + 83806371 83806483 113 browser details YourSeq 68 2753 2922 3000 86.1% chr3 - 144429470 144429639 170 browser details YourSeq 68 2819 2945 3000 77.2% chr1 - 183746554 183746681 128 browser details YourSeq 68 2810 2925 3000 78.8% chr9 + 53401903 53402016 114 browser details YourSeq 67 2814 2923 3000 81.7% chr15 - 79634894 79635006 113 Note: The 3000 bp section upstream of Exon 3 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% chr2 + 151503431 151506430 3000 browser details YourSeq 322 681 2954 3000 90.3% chr5 + 49552602 49552942 341 browser details YourSeq 171 4 332 3000 92.1% chr12 - 50039361 50039965 605 browser details YourSeq 151 12 317 3000 92.3% chr8 - 83337846 83338497 652 browser details YourSeq 150 9 214 3000 93.7% chr1 - 96960044 96960430 387 browser details YourSeq 150 1 173 3000 93.6% chr14 + 24719097 24719270 174 browser details YourSeq 149 6 173 3000 93.4% chr19 - 42851959 42852124 166 browser details YourSeq 149 6 193 3000 92.1% chr10 + 39859951 39860184 234 browser details YourSeq 148 12 173 3000 95.7% chrX - 39648135 39648296 162 browser details YourSeq 148 6 192 3000 92.5% chr3 + 121004068 121004297 230 browser details YourSeq 146 6 173 3000 93.5% chr2 - 148662032 148662199 168 browser details YourSeq 146 1 171 3000 93.5% chr19 - 39928327 39928497 171 browser details YourSeq 146 1 173 3000 93.0% chr17 - 77816281 77816453 173 browser details YourSeq 146 11 173 3000 95.1% chr9 + 90145061 90145226 166 browser details YourSeq 145 6 173 3000 93.5% chr7 - 92460154 92460321 168 browser details YourSeq 145 11 173 3000 94.5% chr5 - 68952060 68952222 163 browser details YourSeq 145 11 173 3000 94.5% chr12 - 35094459 35094621 163 browser details YourSeq 145 1 171 3000 92.9% chr6 + 22977565 22977738 174 browser details YourSeq 145 11 225 3000 91.5% chr12 + 29431218 29431771 554 browser details YourSeq 144 4 184 3000 90.6% chr3 - 139484190 139484476 287 Note: The 3000 bp section downstream of Exon 5 is BLAT searched against the genome. No significant similarity is found. Page 4 of 8 https://www.alphaknockout.com Gene and protein information: Nsfl1c NSFL1 (p97) cofactor (p47) [ Mus musculus (house mouse) ] Gene ID: 386649, updated on 12-Aug-2019 Gene summary Official Symbol Nsfl1c provided by MGI Official Full Name NSFL1 (p97) cofactor (p47) provided by MGI Primary source MGI:MGI:3042273 See related Ensembl:ENSMUSG00000027455 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 Also known as p47; Stxbp3a; Munc-18c Expression Ubiquitous expression in CNS E11.5 (RPKM 67.7), CNS E14 (RPKM 54.4) and 28 other tissues See more Orthologs human all Genomic context Location: 2; 2 G3 See Nsfl1c in Genome Data Viewer Exon count: 10 Annotation release Status Assembly Chr Location 108 current GRCm38.p6 (GCF_000001635.26) 2 NC_000068.7 (151494182..151511310) Build 37.2 previous assembly MGSCv37 (GCF_000001635.18) 2 NC_000068.6 (151320044..151337041) Chromosome 2 - NC_000068.7 Page 5 of 8 https://www.alphaknockout.com Transcript information: This gene has 10 transcripts Gene: Nsfl1c ENSMUSG00000027455 Description NSFL1 (p97) cofactor (p47) [Source:MGI Symbol;Acc:MGI:3042273] Gene Synonyms p47 Location Chromosome 2: 151,494,182-151,511,414 forward strand. GRCm38:CM000995.2 About this gene This gene has 10 transcripts (splice variants), 218 orthologues, 3 paralogues and is a member of 1 Ensembl protein family. Transcripts Name Transcript ID bp Protein Translation ID Biotype CCDS UniProt Flags Nsfl1c- ENSMUST00000089140.12 1486 372aa ENSMUSP00000086542.6 Protein coding CCDS16868 Q3UVN5 TSL:5 202 Q9CZ44 GENCODE basic APPRIS P3 Nsfl1c- ENSMUST00000028949.15 1364 370aa ENSMUSP00000028949.9 Protein coding CCDS71160 Q9CZ44 TSL:1 201 GENCODE basic APPRIS ALT1 Nsfl1c- ENSMUST00000103160.4 1369 339aa ENSMUSP00000099449.4 Protein coding - A2AT02 TSL:5 203 GENCODE basic Nsfl1c- ENSMUST00000153333.7 1631 No - Retained - - TSL:5 209 protein intron Nsfl1c- ENSMUST00000139229.1 930 No - Retained - - TSL:2 207 protein intron Nsfl1c- ENSMUST00000134081.1 899 No - Retained - - TSL:2 206 protein intron Nsfl1c- ENSMUST00000146695.7 789 No - Retained - - TSL:2 208 protein intron Nsfl1c- ENSMUST00000125270.7 744 No - Retained - - TSL:2 204 protein intron Nsfl1c- ENSMUST00000133197.1 685 No - Retained - - TSL:2 205 protein intron Nsfl1c- ENSMUST00000156182.1 447 No - lncRNA - - TSL:3 210 protein Page 6 of 8 https://www.alphaknockout.com 37.23 kb Forward strand 151.49Mb 151.50Mb 151.51Mb 151.52Mb Genes (Comprehensive set... Nsfl1c-202 >protein coding Nsfl1c-209 >retained intron Nsfl1c-207 >retained intron Nsfl1c-204 >retained intron Nsfl1c-210 >lncRNA Nsfl1c-201 >protein coding Nsfl1c-203 >protein coding Nsfl1c-205 >retained intron Nsfl1c-206 >retained intron Nsfl1c-208 >retained intron Contigs AL928719.6 > Regulatory Build 151.49Mb 151.50Mb 151.51Mb 151.52Mb Reverse strand 37.23 kb Regulation Legend CTCF Open Chromatin Promoter Promoter Flank Gene Legend Protein Coding Ensembl protein coding merged Ensembl/Havana Non-Protein Coding RNA gene processed transcript Page 7 of 8 https://www.alphaknockout.com Transcript: ENSMUST00000089140 17.13 kb Forward strand Nsfl1c-202 >protein coding ENSMUSP00000086... MobiDB lite Low complexity (Seg) Superfamily UBA-like superfamily NSFL1 cofactor p47, SEP domain superfamily Ubiquitin-like domain superfamily SMART SEP domain UBX domain Pfam PF14555 SEP domain UBX domain PROSITE profiles SEP domain UBX domain PANTHER PTHR23333:SF24 PTHR23333 Gene3D 1.10.8.10 NSFL1 cofactor p47, SEP domain superfamily 3.10.20.90 CDD cd14348 cd17162 All sequence SNPs/i... Sequence variants (dbSNP and all other sources) Variant Legend start lost missense variant synonymous variant Scale bar 0 40 80 120 160 200 240 280 320 372 We wish to acknowledge the following valuable scientific information resources: Ensembl, MGI, NCBI, UCSC. Page 8 of 8.
Load more

Recommended publications
  • Genomic Selection Signatures in Sheep from the Western Pyrenees Otsanda Ruiz-Larrañaga, Jorge Langa, Fernando Rendo, Carmen Manzano, Mikel Iriondo, Andone Estonba
    Genomic selection signatures in sheep from the Western Pyrenees Otsanda Ruiz-Larrañaga, Jorge Langa, Fernando Rendo, Carmen Manzano, Mikel Iriondo, Andone Estonba To cite this version: Otsanda Ruiz-Larrañaga, Jorge Langa, Fernando Rendo, Carmen Manzano, Mikel Iriondo, et al.. Genomic selection signatures in sheep from the Western Pyrenees. Genetics Selection Evolution, BioMed Central, 2018, 50 (1), pp.9. 10.1186/s12711-018-0378-x. hal-02405217 HAL Id: hal-02405217 https://hal.archives-ouvertes.fr/hal-02405217 Submitted on 11 Dec 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution| 4.0 International License Ruiz-Larrañaga et al. Genet Sel Evol (2018) 50:9 https://doi.org/10.1186/s12711-018-0378-x Genetics Selection Evolution RESEARCH ARTICLE Open Access Genomic selection signatures in sheep from the Western Pyrenees Otsanda Ruiz‑Larrañaga1* , Jorge Langa1, Fernando Rendo2, Carmen Manzano1, Mikel Iriondo1 and Andone Estonba1 Abstract Background: The current large spectrum of sheep phenotypic diversity
    [Show full text]
  • Chapter 2 Gene Regulation and Speciation in House Mice
    UC Berkeley UC Berkeley Electronic Theses and Dissertations Title Gene regulation and the genomic basis of speciation and adaptation in house mice (Mus musculus) Permalink https://escholarship.org/uc/item/8ck133qd Author Mack, Katya L Publication Date 2018 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California Gene regulation and the genomic basis of speciation and adaptation in house mice (Mus musculus) By Katya L. Mack A dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in Integrative Biology in the Graduate Division of the University of California, Berkeley Committee in charge: Professor Michael W. Nachman, Chair Professor Rasmus Nielsen Professor Craig T. Miller Fall 2018 Abstract Gene regulation and the genomic basis of speciation and adaptation in house mice (Mus musculus) by Katya Mack Doctor of Philosophy in Integrative Biology University of California, Berkeley Professor Michael W. Nachman, Chair Gene expression is a molecular phenotype that is essential to organismal form and fitness. However, how gene regulation evolves over evolutionary time and contributes to phenotypic differences within and between species is still not well understood. In my dissertation, I examined the role of gene regulation in adaptation and speciation in house mice (Mus musculus). In chapter 1, I reviewed theoretical models and empirical data on the role of gene regulation in the origin of new species. I discuss how regulatory divergence between species can result in hybrid dysfunction and point to areas that could benefit from future research. In chapter 2, I characterized regulatory divergence between M.
    [Show full text]
  • Gene Regulation Underlies Environmental Adaptation in House Mice
    Downloaded from genome.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press Research Gene regulation underlies environmental adaptation in house mice Katya L. Mack,1 Mallory A. Ballinger,1 Megan Phifer-Rixey,2 and Michael W. Nachman1 1Department of Integrative Biology and Museum of Vertebrate Zoology, University of California, Berkeley, California 94720, USA; 2Department of Biology, Monmouth University, West Long Branch, New Jersey 07764, USA Changes in cis-regulatory regions are thought to play a major role in the genetic basis of adaptation. However, few studies have linked cis-regulatory variation with adaptation in natural populations. Here, using a combination of exome and RNA- seq data, we performed expression quantitative trait locus (eQTL) mapping and allele-specific expression analyses to study the genetic architecture of regulatory variation in wild house mice (Mus musculus domesticus) using individuals from five pop- ulations collected along a latitudinal cline in eastern North America. Mice in this transect showed clinal patterns of variation in several traits, including body mass. Mice were larger in more northern latitudes, in accordance with Bergmann’s rule. We identified 17 genes where cis-eQTLs were clinal outliers and for which expression level was correlated with latitude. Among these clinal outliers, we identified two genes (Adam17 and Bcat2) with cis-eQTLs that were associated with adaptive body mass variation and for which expression is correlated with body mass both within and between populations. Finally, we per- formed a weighted gene co-expression network analysis (WGCNA) to identify expression modules associated with measures of body size variation in these mice.
    [Show full text]
  • PINK1 Interacts with VCP/P97 and Activates PKA to Promote NSFL1C/P47 Phosphorylation and Dendritic Arborization in Neurons
    New Research Disorders of the Nervous System PINK1 Interacts with VCP/p97 and Activates PKA to Promote NSFL1C/p47 Phosphorylation and Dendritic Arborization in Neurons † † † Kent Z. Q. Wang,1 Erin Steer,1 P. Anthony Otero,1 Nicholas W. Bateman,2 Mary Hongying Cheng,3 Ana Ligia Scott,3 Christine Wu,2 Ivet Bahar,3 Yu-Tzu Shih,4 Yi-Ping Hsueh,4 and Charleen T. Chu1,5 https://doi.org/10.1523/ENEURO.0466-18.2018 1Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, 2Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, 3Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, 4Academia Sinica, Institute of Molecular Biology, Taipei, Taiwan 11529, and 5Pittsburgh Institute for Neurodegenerative Diseases, McGowan Institute for Regenerative Medicine, Center for Protein Conformational Diseases and Center for Neuroscience at the University of Pittsburgh, Pittsburgh, PA 15213 Visual Abstract Significance Statement This study delineates a novel molecular mechanism by which PTEN-induced kinase 1 (PINK1) and valosin-containing protein (VCP) interact to promote dendritic arborization. The interaction of PINK1 with VCP results in phosphorylation of the VCP co-factor NSFL1C/p47 at a novel site, eliciting more robust dendritic arbors. Mechanistically, PINK1 functions in a dual kinase/scaffolding role, activating PKA to phosphor- ylate p47. Given that mutations in PINK1 and VCP are known to cause Parkinson’s disease (PD) and fronto- temporal dementia (FTD), conditions affecting primarily neurons, the discovery that they act in a common pathway to support dendritic arborization has important implications for neuronal health and disease.
    [Show full text]
  • The DNA Sequence and Comparative Analysis of Human Chromosome 20
    articles The DNA sequence and comparative analysis of human chromosome 20 P. Deloukas, L. H. Matthews, J. Ashurst, J. Burton, J. G. R. Gilbert, M. Jones, G. Stavrides, J. P. Almeida, A. K. Babbage, C. L. Bagguley, J. Bailey, K. F. Barlow, K. N. Bates, L. M. Beard, D. M. Beare, O. P. Beasley, C. P. Bird, S. E. Blakey, A. M. Bridgeman, A. J. Brown, D. Buck, W. Burrill, A. P. Butler, C. Carder, N. P. Carter, J. C. Chapman, M. Clamp, G. Clark, L. N. Clark, S. Y. Clark, C. M. Clee, S. Clegg, V. E. Cobley, R. E. Collier, R. Connor, N. R. Corby, A. Coulson, G. J. Coville, R. Deadman, P. Dhami, M. Dunn, A. G. Ellington, J. A. Frankland, A. Fraser, L. French, P. Garner, D. V. Grafham, C. Grif®ths, M. N. D. Grif®ths, R. Gwilliam, R. E. Hall, S. Hammond, J. L. Harley, P. D. Heath, S. Ho, J. L. Holden, P. J. Howden, E. Huckle, A. R. Hunt, S. E. Hunt, K. Jekosch, C. M. Johnson, D. Johnson, M. P. Kay, A. M. Kimberley, A. King, A. Knights, G. K. Laird, S. Lawlor, M. H. Lehvaslaiho, M. Leversha, C. Lloyd, D. M. Lloyd, J. D. Lovell, V. L. Marsh, S. L. Martin, L. J. McConnachie, K. McLay, A. A. McMurray, S. Milne, D. Mistry, M. J. F. Moore, J. C. Mullikin, T. Nickerson, K. Oliver, A. Parker, R. Patel, T. A. V. Pearce, A. I. Peck, B. J. C. T. Phillimore, S. R. Prathalingam, R. W. Plumb, H. Ramsay, C. M.
    [Show full text]
  • Gene Regulation and the Genomic Basis of Speciation and Adaptation in House Mice (Mus Musculus)
    Gene regulation and the genomic basis of speciation and adaptation in house mice (Mus musculus) By Katya L. Mack A dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in Integrative Biology in the Graduate Division of the University of California, Berkeley Committee in charge: Professor Michael W. Nachman, Chair Professor Rasmus Nielsen Professor Craig T. Miller Fall 2018 Abstract Gene regulation and the genomic basis of speciation and adaptation in house mice (Mus musculus) by Katya Mack Doctor of Philosophy in Integrative Biology University of California, Berkeley Professor Michael W. Nachman, Chair Gene expression is a molecular phenotype that is essential to organismal form and fitness. However, how gene regulation evolves over evolutionary time and contributes to phenotypic differences within and between species is still not well understood. In my dissertation, I examined the role of gene regulation in adaptation and speciation in house mice (Mus musculus). In chapter 1, I reviewed theoretical models and empirical data on the role of gene regulation in the origin of new species. I discuss how regulatory divergence between species can result in hybrid dysfunction and point to areas that could benefit from future research. In chapter 2, I characterized regulatory divergence between M. m. domesticus and M. m. musculus associated with male hybrid sterility. The major model for the evolution of post-zygotic isolation proposes that hybrid sterility or inviability will evolve as a product of deleterious interactions (i.e., negative epistasis) between alleles at different loci when joined together in hybrids. As the regulation of gene expression is inherently based on interactions between loci, disruption of gene regulation in hybrids may be a common mechanism for post-zygotic isolation.
    [Show full text]
  • Renoprotective Effect of Combined Inhibition of Angiotensin-Converting Enzyme and Histone Deacetylase
    BASIC RESEARCH www.jasn.org Renoprotective Effect of Combined Inhibition of Angiotensin-Converting Enzyme and Histone Deacetylase † ‡ Yifei Zhong,* Edward Y. Chen, § Ruijie Liu,*¶ Peter Y. Chuang,* Sandeep K. Mallipattu,* ‡ ‡ † | ‡ Christopher M. Tan, § Neil R. Clark, § Yueyi Deng, Paul E. Klotman, Avi Ma’ayan, § and ‡ John Cijiang He* ¶ *Department of Medicine, Mount Sinai School of Medicine, New York, New York; †Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China; ‡Department of Pharmacology and Systems Therapeutics and §Systems Biology Center New York, Mount Sinai School of Medicine, New York, New York; |Baylor College of Medicine, Houston, Texas; and ¶Renal Section, James J. Peters Veterans Affairs Medical Center, New York, New York ABSTRACT The Connectivity Map database contains microarray signatures of gene expression derived from approximately 6000 experiments that examined the effects of approximately 1300 single drugs on several human cancer cell lines. We used these data to prioritize pairs of drugs expected to reverse the changes in gene expression observed in the kidneys of a mouse model of HIV-associated nephropathy (Tg26 mice). We predicted that the combination of an angiotensin-converting enzyme (ACE) inhibitor and a histone deacetylase inhibitor would maximally reverse the disease-associated expression of genes in the kidneys of these mice. Testing the combination of these inhibitors in Tg26 mice revealed an additive renoprotective effect, as suggested by reduction of proteinuria, improvement of renal function, and attenuation of kidney injury. Furthermore, we observed the predicted treatment-associated changes in the expression of selected genes and pathway components. In summary, these data suggest that the combination of an ACE inhibitor and a histone deacetylase inhibitor could have therapeutic potential for various kidney diseases.
    [Show full text]
  • Evolutionary History of the Human Multigene Families Reveals
    Pervaiz et al. BMC Evolutionary Biology (2019) 19:128 https://doi.org/10.1186/s12862-019-1441-0 RESEARCH ARTICLE Open Access Evolutionary history of the human multigene families reveals widespread gene duplications throughout the history of animals Nashaiman Pervaiz1, Nazia Shakeel1, Ayesha Qasim1, Rabail Zehra1, Saneela Anwar1, Neenish Rana1, Yongbiao Xue2, Zhang Zhang2, Yiming Bao2* and Amir Ali Abbasi1* Abstract Background: The hypothesis that vertebrates have experienced two ancient, whole genome duplications (WGDs) is of central interest to evolutionary biology and has been implicated in evolution of developmental complexity. Three-way and Four-way paralogy regions in human and other vertebrate genomes are considered as vital evidence to support this hypothesis. Alternatively, it has been proposed that such paralogy regions are created by small-scale duplications that occurred at different intervals over the evolution of life. Results: To address this debate, the present study investigates the evolutionary history of multigene families with at least three-fold representation on human chromosomes 1, 2, 8 and 20. Phylogenetic analysis and the tree topology comparisons classified the members of 36 multigene families into four distinct co-duplicated groups. Gene families falling within the same co-duplicated group might have duplicated together, whereas genes belong to different co-duplicated groups might have distinct evolutionary origins. Conclusion: Taken together with previous investigations, the current study yielded no proof in favor of WGDs hypothesis. Rather, it appears that the vertebrate genome evolved as a result of small-scale duplication events, that cover the entire span of the animals’ history. Keywords: Human, Whole genome duplications, Segmental duplications, Paralogons, Paralogy regions, Vertebrate, Multigene families, Phylogenetic analysis Background explanation for the complexity of modern-day vertebrate To elucidate the genetic underpinnings of major changes genome [1].
    [Show full text]
  • Cell-Type, Single-Cell, and Spatial Signatures of Brain-Region Specific
    bioRxiv preprint doi: https://doi.org/10.1101/2020.08.27.268730; this version posted August 27, 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 4.0 International license. Cell-type, single-cell, and spatial signatures of brain-region specific splicing in postnatal development Anoushka Joglekar1, Andrey Prjibelski2, Ahmed Mahfouz3,4,5, Paul Collier1, Susan Lin6,7, Anna Katharina Schlusche1, Jordan Marrocco8, Stephen R. Williams9, Bettina Haase10, Ashley Hayes9, Jennifer G. Chew9, Neil I Weisenfeld9, Man Ying Wong11, Alexander N. Stein12, Simon Hardwick1, Toby Hunt13, Zachary Bent9, Olivier Fedrigo10, Steven A. Sloan14, Davide Risso15, Erich D. Jarvis10,17, Paul Flicek13, Wenjie Luo11, Geoffrey S. Pitt6,7, Adam Frankish13, August B. Smit16, M. Elizabeth Ross1, Hagen U. Tilgner1 Author Affiliations: 1. Brain and Mind Research Institute and Center for Neurogenetics, Weill Cornell Medicine, New York, New York, USA. 2. Center for Algorithmic Biotechnology, Institute of Translational Biomedicine, St. Petersburg State University 3. Department of Human Genetics, Leiden University Medical Center, Leiden 2333 ZC, The Netherlands 4. Leiden Computational Biology Center, Leiden University Medical Center, Leiden 2333 ZC, The Netherlands 5. Delft Bioinformatics Lab, Delft University of Technology, Delft 2628 XE, The Netherlands 6. Graduate Program in Neuroscience, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10065, USA 7. Cardiovascular Research Institute, Weill Cornell Medicine, New York, NY 8. Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, USA 9.
    [Show full text]
  • Alterations of the Pro-Survival Bcl-2 Protein Interactome in Breast Cancer
    bioRxiv preprint doi: https://doi.org/10.1101/695379; this version posted July 12, 2019. 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. 1 Alterations of the pro-survival Bcl-2 protein interactome in 2 breast cancer at the transcriptional, mutational and 3 structural level 4 5 Simon Mathis Kønig1, Vendela Rissler1, Thilde Terkelsen1, Matteo Lambrughi1, Elena 6 Papaleo1,2 * 7 1Computational Biology Laboratory, Danish Cancer Society Research Center, 8 Strandboulevarden 49, 2100, Copenhagen 9 10 2Translational Disease Systems Biology, Faculty of Health and Medical Sciences, Novo 11 Nordisk Foundation Center for Protein Research University of Copenhagen, Copenhagen, 12 Denmark 13 14 Abstract 15 16 Apoptosis is an essential defensive mechanism against tumorigenesis. Proteins of the B-cell 17 lymphoma-2 (Bcl-2) family regulates programmed cell death by the mitochondrial apoptosis 18 pathway. In response to intracellular stresses, the apoptotic balance is governed by interactions 19 of three distinct subgroups of proteins; the activator/sensitizer BH3 (Bcl-2 homology 3)-only 20 proteins, the pro-survival, and the pro-apoptotic executioner proteins. Changes in expression 21 levels, stability, and functional impairment of pro-survival proteins can lead to an imbalance 22 in tissue homeostasis. Their overexpression or hyperactivation can result in oncogenic effects. 23 Pro-survival Bcl-2 family members carry out their function by binding the BH3 short linear 24 motif of pro-apoptotic proteins in a modular way, creating a complex network of protein- 25 protein interactions.
    [Show full text]
  • Linkage to 20P13 Including the ANGPT4 Gene in Families With
    Journal of Human Genetics (2010) 55, 649–655 & 2010 The Japan Society of Human Genetics All rights reserved 1434-5161/10 $32.00 www.nature.com/jhg ORIGINAL ARTICLE Linkageto20p13includingtheANGPT4 gene in families with mixed Alzheimer’s disease and vascular dementia Anna Sille´n1, Jesper Brohede1, Lena Lilius1, Charlotte Forsell1, Jorge Andrade2,5, Jacob Odeberg2, Hayao Ebise3, Bengt Winblad1 and Caroline Graff1,4 This study aimed at identifying novel susceptibility genes for a mixed phenotype of Alzheimer’s disease and vascular dementia. Results from a genome scan showed strongest linkage to 20p13 in 18 families, and subsequent fine mapping was performed with both microsatellites and single-nucleotide polymorphisms in 18 selected candidate transcripts in an extended sample set of 30 families. The multipoint linkage peak was located at marker rs2144151 in the ANGPT4 gene, which is a strong candidate gene for vascular disease because of its involvement in angiogenesis. Although the significance of the linkage decreased, we find this result intriguing, considering that we included additional families, and thus the reduced linkage signal may be caused by genetic heterogeneity. Journal of Human Genetics (2010) 55, 649–655; doi:10.1038/jhg.2010.79; published online 1 July 2010 Keywords: Alzheimer’s disease; ANGPT4; association study; candidate genes; familial dementia; linkage analysis; SNP INTRODUCTION Previous genome-wide family-based linkage analyses have identified Alzheimer’s disease (AD; MIM104300) is the major cause of dementia several loci linked to AD9–19 and confirmed linkage by several in the elderly. Its main neuropathological signs are extracellular groups has been reported to chromosome (chr.) 9p, 9q, 10q, 12p depositions of amyloid b-protein and intracellular neurofibrillary and 19q.20–24 Extensive follow-up and fine mapping studies have been tangles composed of hyperphosphorylated tau.
    [Show full text]
  • Glucagon-Like Peptide-1 Receptor Agonists Increase Pancreatic Mass by Induction of Protein Synthesis
    Page 1 of 73 Diabetes Glucagon-like peptide-1 receptor agonists increase pancreatic mass by induction of protein synthesis Jacqueline A. Koehler1, Laurie L. Baggio1, Xiemin Cao1, Tahmid Abdulla1, Jonathan E. Campbell, Thomas Secher2, Jacob Jelsing2, Brett Larsen1, Daniel J. Drucker1 From the1 Department of Medicine, Tanenbaum-Lunenfeld Research Institute, Mt. Sinai Hospital and 2Gubra, Hørsholm, Denmark Running title: GLP-1 increases pancreatic protein synthesis Key Words: glucagon-like peptide 1, glucagon-like peptide-1 receptor, incretin, exocrine pancreas Word Count 4,000 Figures 4 Tables 1 Address correspondence to: Daniel J. Drucker M.D. Lunenfeld-Tanenbaum Research Institute Mt. Sinai Hospital 600 University Ave TCP5-1004 Toronto Ontario Canada M5G 1X5 416-361-2661 V 416-361-2669 F [email protected] 1 Diabetes Publish Ahead of Print, published online October 2, 2014 Diabetes Page 2 of 73 Abstract Glucagon-like peptide-1 (GLP-1) controls glucose homeostasis by regulating secretion of insulin and glucagon through a single GLP-1 receptor (GLP-1R). GLP-1R agonists also increase pancreatic weight in some preclinical studies through poorly understood mechanisms. Here we demonstrate that the increase in pancreatic weight following activation of GLP-1R signaling in mice reflects an increase in acinar cell mass, without changes in ductal compartments or β-cell mass. GLP-1R agonists did not increase pancreatic DNA content or the number of Ki67+ cells in the exocrine compartment, however pancreatic protein content was increased in mice treated with exendin-4 or liraglutide. The increased pancreatic mass and protein content was independent of cholecystokinin receptors, associated with a rapid increase in S6 kinase phosphorylation, and mediated through the GLP-1 receptor.
    [Show full text]