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Functional Impact of Polymorphic Inversions in the Human Genome

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) +/### -- Doctor of Philosophyphy – UniversitatUniversitat Autònoma dede Barcelona – 2014 Doctor of Philosophy – Universitat Autònoma de Barcelona – 2014 “I've paid my dues Time after time. I've done my sentence But committed no crime. And bad mistakes ‒ I've made a few. I've had my share of sand kicked in my face But I've come through. […] But it's been no bed of roses, No pleasure cruise. […] We are the champions.” Queen “The most practical solution is a good theory.” Albert Einstein “The good thing about science is that it's true whether or not you believe in it.” Neil deGrasse Tyson Memòria presentada per Meritxell Oliva Pavia per optar al grau de Doctora en Genètica per la Universitat Autònoma de Barcelona Aquesta Tesi Doctoral ha estat realitzada sota la direcció del Dr. Mario Cáceres Aguilar a l’Institut de Biotecnologia i de Biomedicina de la Universitat Autònoma de Barcelona Mario Cáceres Aguilar Meritxell Oliva Pavia El Director de la Tesi L’Autora Doctor of Philosophy – Universitat Autònoma de Barcelona –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i @4> -)- . 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A %-)* &%*% ** ?=E i Acknowledgements Finalment. Semblava que no havia d’arribar mai. Després d’una ingesta quantitat de temps escrivint, corregint, re-escrivint, re-corregint i re-re-escrivint aquesta tesis, és un plaer indescriptible col·locar el plomí (virtual, és clar) en aquesta secció. Per on començo? Crec que l’inici del recorregut científic personal que dóna lloc a aquest treball es remunta a la decisió de cursar el màster de Bioinformàtica de la UPF (BIOINFO, 2007-2009). En aquests dos anys, a part d’adquirir els coneixements bàsics per poder fer aquesta tesis, vaig tenir el plaer de conèixer una colla d’entranyables “bioinfos” que em van acompanyar en els meus periples per comprendre l’apassionant (o no) món dels “scripts”, “pipelines” i “workflows”. Ignasi i Pau: gràcies per ensenyar-me la diferència entre “hash” i “array”, i a tu, Bàrbara, per compartir amb mi hores d’estudi i presentacions, a vosaltres Laia i Mª Dolors per no rebentar-me els timpans (tot i intentar-ho a força de crits aguts), també gràcies a tu Cristian per aportar la nota de color a l’hora de dinar amb els teus macarrons radioactius, i finalment a tu Eva, per ser única. Tu ets la culpable que relacioni bicicletes mal aparcades amb biologia estructural… No em vull oblidar de certs professors/coordinadors de BIOINFO als qui estic molt agraïda en varis aspectes: gràcies Arcadi per oferir-me el meu primer treball remunerat en recerca, que em va donar la oportunitat d’aprendre sobre genètica de poblacions i compartir, amb la gent del teu laboratori i de tot BIOEVO, interessants discussions científiques a part de xocolatines i dolços després de dinar cada dos per tres... Gràcies Olga, Rui, Ángel, Txema, Valeria, Belén, Hafid (mil gracies per tot H), Óscar, Marc, etc. Torno amb els professors de BIOINFO: gràcies Cedric per presentar l’alineament múltiple de seqüències d’una forma tan apassionant, gràcies Eduardo per fer-nos entendre les cadenes de Markov amb divertits exemples de casinos deshonestos, i finalment, merci Jordi Villà per ser una persona optimista, motivant i motivada. Després del laboratori de l’Arcadi, vaig aterrar al grup de Genòmica Comparativa del CRG liderat pel Cedric Notredame, on vaig fer les pràctiques del màster i vaig posar i treure el peu en un 1r doctorat. Dono gràcies a en Cedric per l’oportunitat donada, i també a tots els membres del seu grup i estimats “geeks” amb qui vaig coincidir: Ema B., Ema R., Jia-Ming, J.F., Paolo, Ionas, Giovanni, Mathias, Isabel, Thomas i sobretot a tu, Carsten, per ser tan bon amic. Merci per haver tingut ii la paciència de respondre les meves preguntes, donar-me un cop de mà quan em feia falta, per ser uns excel·lents companys, per participar en el “lunch club” (Jia-Ming: mai no oblidaré la teva sopa de fideus amb vedella taiwanesa. Mmmm...) i en general per ser com sou! Gràcies també als PIs i membres dels laboratoris del departament de Bioinformàtica i Genòmica del CRG: mencions especials per a en Toni Gabaldón (per ser una persona tan propera, a més a més del PI més “fiestero”), Fyodor Kondrashov (encarnació de la definició “científic” en el seu estat pur: digueu-me, qui més té articles amb el seu pare i la seva àvia???) i també per a en Roderic Guigó per dirigir amb entusiasme el departament i per donar-me consells científics (i personals) quan en necessitava. També no em vull oblidar d’en Juan Valcárcel i la Isabel Vernós, per la seva tasca de donar suport els estudiants de doctorat (jo inclosa) quan en necessiten, als “sysadmin” Óscar i la Judit, per donar-me suport (bio)informàtic, i en general, a tothom qui va contribuir a fer que la meva estada al CRG fos memorable. Al CRG vaig aprendre quelcom molt important: la recerca surt molt millor si es combina amb una “beer party” cada últim dijous de mes. Merci a tots els “CRGians” amb qui he compartit tans bons moments i converses científicoetíliques. M’agradaria anomenar-los a tots, però tinc certes llacunes... Si un encara vol veure augmentada la seva productivitat de manera espectacular, està clar que ha de participar en al torneig de vòlei platja del PRBB!!! Merci a totes les persones amb qui he compartit equip (“Geeks”, “Not only Geeks”, “Pringats”) i/o m’he enfrontat! Mai no m’hauria imaginat que guanyaria una lliga anomenada “Masters of Disaster” o “Quasi-que-no Cracks”; o que m’emocionaria al sentir aficionats (gràcies Colin, Sara, Sònia, Anne, Eric etc.) cridar fins a esgargamellar-se “Allez les geeks!!”. Qui em diria, també, que al CRG coneixeria la meva segona família? Mil gràcies a les meves “nenes”, l’Elena i l’Eli, amb qui he compartit de tot: rialles, llàgrimes, experiències nipones i en general, una amistat que espero que duri per sempre, fem el que fem i estem on estem. Gràcies a en Marc, per ser un molt bon amic amb qui he compartit xerrades de ciència i política tot assaborint experiències enogastronòmiques. Gràcies a en Peter per haver-me fet gaudir de moments inoblidables. Gràcies a l’Almer, home-enciclopèdia i inspirador d’un entrepà amb nom forani i a en Raik, el científic més aventurer i poc ortodox que he conegut. Gràcies a la Johanna per ensenyar-me que ser científica i “sex-symbol” no és incompatible. Gràcies a l’Ester pels bons “tannat-moments”. Gràcies a la Kiana, en Toni, en Tobias i la Camila. Gràcies a tots, nois! ii Vet aquí que arribo al vaixell on he navegat (a vegades amb rumb fix i a vegades a la deriva) al llarg d’aquesta tesis: el grup de Genòmica Comparativa i Funcional de l’IBB, a la UAB. Dono gràcies a tots els “grumets” amb qui he coincidit en aquesta travessia: a l’Ester, la “crack” il·luminada de les llibreries genòmiques, a la Marta per l’ajuda prestada al “wet lab”, a en David I. per la seva capacitat organitzativa tant al laboratori com fora (merci per organitzar les barbacoes i altres events de grup/departament!), a en Sergi per ser compartir alegries i penes amb la arxifamosa HsInv0102 i altres inversions, errors i encerts genotípics i per ser un alumne avantatjat en aprendre bioinformàtica a marxes forçades! Gràcies a l’Àlex, per la seva gran capacitat d’oratòria i per ser el meu company de “benchmarking” de GRIAL (entre els dos hem venut la moto que va molt bé, eh? Shhh...). Gràcies a la Sònia per l’ajuda bioinformàtica prestada i per la paciència i serenor infinites que té. Gàcies a eixe xic, l’Ignasi, per ensenyar-me un poc de valencià i per donar-me consell estadístic i suport bioinformàtic sempre que l’he necessitat. Gràcies a na Magda, una al·lota ben trempada que no se va cansar d’explicar-me una i altra vegada que rediantres és el “linkage desequilibrium”. Merci a la Carla per la seva curiositat i simpatia innata i a en David C. per ser un “crack” de la genètica de poblacions. Merci a en David V. per ser encarregar-se tan bé del “crick” i facilitar-nos la vida a tots els bioinformàtics del grup (i també al “xino” pel suport donat). Merci a la Lorena per ser tan competent i per donar-me un cop de mà sempre que l’he necessitat. Gràcies al capità del vaixell, en Mario, per fer possible INVFEST i per haver supervisat aquesta tesis.
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  • PRPSAP2 (NM 002767) Human Recombinant Protein – TP310719

    PRPSAP2 (NM 002767) Human Recombinant Protein – TP310719

    OriGene Technologies, Inc. 9620 Medical Center Drive, Ste 200 Rockville, MD 20850, US Phone: +1-888-267-4436 [email protected] EU: [email protected] CN: [email protected] Product datasheet for TP310719 PRPSAP2 (NM_002767) Human Recombinant Protein Product data: Product Type: Recombinant Proteins Description: Recombinant protein of human phosphoribosyl pyrophosphate synthetase-associated protein 2 (PRPSAP2) Species: Human Expression Host: HEK293T Tag: C-Myc/DDK Predicted MW: 40.7 kDa Concentration: >50 ug/mL as determined by microplate BCA method Purity: > 80% as determined by SDS-PAGE and Coomassie blue staining Buffer: 25 mM Tris.HCl, pH 7.3, 100 mM glycine, 10% glycerol Preparation: Recombinant protein was captured through anti-DDK affinity column followed by conventional chromatography steps. Storage: Store at -80°C. Stability: Stable for 12 months from the date of receipt of the product under proper storage and handling conditions. Avoid repeated freeze-thaw cycles. RefSeq: NP_002758 Locus ID: 5636 UniProt ID: O60256, A0A024QYY3 RefSeq Size: 2021 Cytogenetics: 17p11.2 RefSeq ORF: 1107 Synonyms: PAP41 This product is to be used for laboratory only. Not for diagnostic or therapeutic use. View online » ©2021 OriGene Technologies, Inc., 9620 Medical Center Drive, Ste 200, Rockville, MD 20850, US 1 / 2 PRPSAP2 (NM_002767) Human Recombinant Protein – TP310719 Summary: This gene encodes a protein that associates with the enzyme phosphoribosylpyrophosphate synthetase (PRS). PRS catalyzes the formation of phosphoribosylpyrophosphate which is a substrate for synthesis of purine and pyrimidine nucleotides, histidine, tryptophan and NAD. PRS exists as a complex with two catalytic subunits and two associated subunits. This gene encodes a non-catalytic associated subunit of PRS.
  • Co-Expression Network of Neural-Differentiation Genes Shows

    Co-Expression Network of Neural-Differentiation Genes Shows

    Maschietto et al. BMC Medical Genomics (2015) 8:23 DOI 10.1186/s12920-015-0098-9 RESEARCH ARTICLE Open Access Co-expression network of neural-differentiation genes shows specific pattern in schizophrenia Mariana Maschietto1,2†, Ana C Tahira1,2†, Renato Puga3, Leandro Lima4, Daniel Mariani4, Bruna da Silveira Paulsen5, Paulo Belmonte-de-Abreu6, Henrique Vieira4, Ana CV Krepischi7, Dirce M Carraro8, Joana A Palha9,10, Stevens Rehen5,11 and Helena Brentani1,2,12,13* Abstract Background: Schizophrenia is a neurodevelopmental disorder with genetic and environmental factors contributing to its pathogenesis, although the mechanism is unknown due to the difficulties in accessing diseased tissue during human neurodevelopment. The aim of this study was to find neuronal differentiation genes disrupted in schizophrenia and to evaluate those genes in post-mortem brain tissues from schizophrenia cases and controls. Methods: We analyzed differentially expressed genes (DEG), copy number variation (CNV) and differential methylation in human induced pluripotent stem cells (hiPSC) derived from fibroblasts from one control and one schizophrenia patient and further differentiated into neuron (NPC). Expression of the DEG were analyzed with microarrays of post-mortem brain tissue (frontal cortex) cohort of 29 schizophrenia cases and 30 controls. A Weighted Gene Co-expression Network Analysis (WGCNA) using the DEG was used to detect clusters of co-expressed genes that werenon-conserved between adult cases and controls brain samples. Results: We identified methylation alterations potentially involved with neuronal differentiation in schizophrenia, which displayed an over-representation of genes related to chromatin remodeling complex (adjP = 0.04). We found 228 DEG associated with neuronal differentiation.
  • Recombinant Human PRPSAP2 Protein Catalog Number: ATGP2461

    Recombinant Human PRPSAP2 Protein Catalog Number: ATGP2461

    Recombinant human PRPSAP2 protein Catalog Number: ATGP2461 PRODUCT INPORMATION Expression system E.coli Domain 1-369aa UniProt No. O60256 NCBI Accession No. NP_002758 Alternative Names phosphoribosyl pyrophosphate synthetase-associated protein 2, PAP41 PRODUCT SPECIFICATION Molecular Weight 43.3 kDa (392aa) confirmed by MALDI-TOF Concentration 0.25mg/ml (determined by Bradford assay) Formulation Liquid in. 20mM Tris-HCl buffer (pH 8.0) containing 0.15M NaCl, 20% glycerol, 1mM DTT Purity > 90% by SDS-PAGE Tag His-Tag Application SDS-PAGE Storage Condition Can be stored at +2C to +8C for 1 week. For long term storage, aliquot and store at -20C to -80C. Avoid repeated freezing and thawing cycles. BACKGROUND Description PRPSAP2 is a protein that associates with the enzyme phosphoribosylpyrophosphate synthetase (PRS). PRS catalyzes the formation of phosphoribosylpyrophosphate which is a substrate for synthesis of purine and pyrimidine nucleotides, histidine, tryptophan and NAD. PRS exists as a complex with two catalytic subunits and two associated subunits. This gene encodes a non-catalytic associated subunit of PRS. Alternate splicing results in multiple transcript variants. Recombinant human PRPSAP2 protein, fused to His-tag at N-terminus, was expressed in E. coli and purified by using conventional chromatography techniques. 1 Recombinant human PRPSAP2 protein Catalog Number: ATGP2461 Amino acid Sequence MGSSHHHHHH SSGLVPRGSH MGSMFCVTPP ELETKMNITK GGLVLFSANS NSSCMELSKK IAERLGVEMG KVQVYQEPNR ETRVQIQESV RGKDVFIIQT VSKDVNTTIM ELLIMVYACK TSCAKSIIGV IPYFPYSKQC KMRKRGSIVS KLLASMMCKA GLTHLITMDL HQKEIQGFFN IPVDNLRASP FLLQYIQEEI PDYRNAVIVA KSPASAKRAQ SFAERLRLGI AVIHGEAQDA ESDLVDGRHS PPMVRSVAAI HPSLEIPMLI PKEKPPITVV GDVGGRIAII VDDIIDDVDS FLAAAETLKE RGAYKIFVMA THGLLSSDAP RRIEESAIDE VVVTNTIPHE VQKLQCPKIK TVDISMILSE AIRRIHNGES MSYLFRNIGL DD General References Katashima,R., et al. (1998) Biochim. Biophys. Acta 1396 (3), 245-250 DATA SDS-PAGE 3ug by SDS-PAGE under reducing condition and visualized by coomassie blue stain.
  • WO 2013/022995 A2 14 February 2013 (14.02.2013) P O P C T

    WO 2013/022995 A2 14 February 2013 (14.02.2013) P O P C T

    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2013/022995 A2 14 February 2013 (14.02.2013) P O P C T (51) International Patent Classification: David [US/US]; 13539 N . 95th Way, Scottsdale, AZ G01N 33/53 (2006.01) 85260 (US). (21) International Application Number: (74) Agent: AKHAVAN, Ramin; Caris Science, Inc., 6655 N . PCT/US20 12/050030 Macarthur Blvd., Irving, TX 75039 (US). (22) International Filing Date: (81) Designated States (unless otherwise indicated, for every 8 August 2012 (08.08.2012) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, English (25) Filing Language: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, Publication Language: English DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (30) Priority Data: KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, 61/521,333 8 August 201 1 (08.08.201 1) US ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, 61/523,763 15 August 201 1 (15.08.201 1) US NO, NZ, OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, 61/526,623 23 August 201 1 (23.08.201 1) u s SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, 61/529,762 31 August 201 1 (3 1.08.201 1) u s TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, 61/534,352 13 September 201 1 (13.09.201 1) u s ZW.