Kvin Kialoj Kial Akademiaj Sciencaj Esploristoj Devus Instrui

De Paul Denny | Eldonita: Majo 30, 2014

Mi #?us revenis, Albeit partatempa, labori en academia kaj mi estis proponita la #?anco instrui. Multaj docentoj en scienca esploro neniam instrui, Alia ol eble unu-al-unu “Instruanta” De nova doktoreca studento. &Nbsp;En la pasinteco, Mi prezentis mian laboron al aliaj sciencistoj #kaj anka? donita kelkajn gastajn lekciojn al studentoj; Sed #tio ?i estis la unua okazo kiam la valoro kaj graveco instrui vere frapita min kaj I??E provita kapti ke malsupre. &Nbsp;Sekve, Kial mi pensas sciencaj esploristoj devus instrui?

Studentoj demandas grandajn demandojn

Lasi min skribas ke denove, #?Ar ?i?? Tiel grava: Studentoj demandas GRANDAJN demandojn. &Nbsp;”Kial estas #tio ?i farita en #?i tiu vojo?”, “Kiel povis min aplikas #?i tiu #alproksimi?o en malsama situacio?”, “Kiel povis min klarigas #?i tiu problemon al alia studento?”. Iliaj demandoj provokas pensita & Diskuto kun #amba? studentoj kaj viaj kolegoj. &Nbsp;Kaj ili #anka? instigas vin pridemandi vin mem – Kiom bone vi scias via temo? &Nbsp;Einstein estas asertita diri “Se vi povas?? Klarigas ?in simple, Vi surmetas?? Komprenas ?in bone #sufi?a”. &Nbsp;Instruado estas bela vojo plibonigi vian komprenon de via propra temo.

Instruanta estas bonega vojo al varbito estontaj mastroj kaj doktorecaj studentoj

Se via instruado estas bona, Vi produktos #na?ejo de homoj kiu scios kiun vi estas kaj kio vi fari – #?I tiu homoj kaj iu ajn ili diras pri vi, Estas fonto de potencialaj varbitoj al via laboritorio.

Publicising via esploro

Estas multaj vojoj disvastigi la vorton pri via laboro, La plej evidenta kaj rekompencita estas tradicia eldono – Prefere en pinta-fluga revuo, Nature. &Nbsp;Malpli evidenta, Tamen, Estas la valoro de diskonigo de vorto-de-#bu?o; #Malgra? la stereotipoj, Viaj studentoj surmetas?? Nura parolado pri sportoj, #Reala?o televido kaj trinkanta ludojn; Ili #anka? diros homojn pri via esploro.

Studenta utilo de estanta instruita de praktikanta esploristojn

Oh, Jes, Eble #tio ?i devus esti nombro 1? &Nbsp;Tie estos subtila diferenco inter la #alproksimi?o kaj enhavo instrui de aktiva esploristo kaj la ne-esploristo. &Nbsp; Tinge pli da entuziasmo, La plej lastaj metodoj, La plej novaj eltrovoj – #?I tiu estas pli probable de aktiva esploristo. &Nbsp;Ili ne povas esti la tre plej bonaj komunikiloj, Sed kelkaj de tiu manko estas farita supre por de estanta pli proksima al la akra rando.

Instruanta helpojn via departemento

Universitataj administrantoj amas ?in kiam iliaj docentoj instruas, #?Ar (Flustri #tio ?i) – ?i helpas kun la malsupra linio.

Tiel, Mia konsilo al #?iuj tiuj sciencistoj tie, Kiam ili estas demandita se ili?? Esti volanta fari iun instruadon, Estas: Iri por ?i!

#Po?ti en Scienca Komunikado | 1 Respondo

Aplikoj & #?Topejo En Sekvanta Generacio Sequencing, Tago 2

De Paul Denny | Eldonita: Decembro 18, 2013

#?I tiu vorta nubo montras la vortojn ke homoj uzita en la glacio-rompanta sesion, KE mi menciis en mia lasta #Po?to, &Nbsp;priskribi kion ili esperis akiri de la konferenco.

Sur Tago 2, Nia Keynote parolanto estis:

Inter aliaj aferoj, d-ro Seller, Direktoro de Genetics Laboratorioj, Oxford,&Nbsp;dirita nin kiom tutaj familioj profitigita de pli bona difino de la pathogenic potencialo de variantoj fondas uzanta NGS, Foriganta, En kelkaj kazoj, La bezono #da?ri klinikan #sekva?o.

La sekvanta prezento, De Magnus Rattray, Profesoro de Computational & Sistema Biologio, Universitato de Manchester,&Nbsp;estis foriro de la #?efa temo de klinika genaro sequencing kaj estis rajtigita:

“Konkludanta #transskriba?o esprimon niveloj de RNA-Seq datumo kaj trafanta diferencialan esprimon inter reproduktita #kondi?o”

Profesoro. Rattray priskribita kiel lian grupon uzis statistikajn metodojn kompensi por la “Bruo” Kaj eblaj #anta?ju?o en datumo de la NGS de cDNA, Sciita kiel RNA-Seq, Por identigi genojn  tio estas differentially esprimita en diversaj biologiaj statoj. &Nbsp;ligo al unu el la iloj uzis,&Nbsp;Bitseq, Estas en la Tweet sub:

#?I tiu teknikoj ne estas tiel ege de la kliniko ekz. Je Kelkaj kanceroj, RNA-seq estas estanta uzita provizi subskribon kiu povas diskriminacii sub-tipoj. Revenanta nin squarely en la kliniko, Tamen, Estis nia sekvanta parolanto, D-ro. Klaus Brusgaard, Asociita Profesoro Klinika Genetics, Odense Universitato & Direktoro #?e Amplexa Genetics,&Nbsp;kies titolo estis:

“Komparo de NGSaj Platformoj & Softvaro”

d-ro Brusgaard gvidis la spektantaron tra la tuta klinika NGSa procezo, De ekzemplo pritraktanta al fina analizo. &Nbsp;Multaj de la ilustraj ekzemploj uzis estis de pacientoj kun epilepsio, Precipe #infana?o ekkomenco, Kie #la?cela sequencing de gena panelo estis montrita esti tre potenca.

Nia sekvanta parolanto, Mick Watson, De KESTO-Genomics #?e la Universitato de Edinburgo, Rememorigis nin ke homoj ne estas nuraj primasoj, Sed #anka? gastigas al microbial komunumo – Niaj ventroj enhavas proksimume dek oble pli da bacteria ol la nombro de eukaryotic #?elo en la ripozo de niaj korpoj!

Tamen, Kiel vi povas diri de la mallongigita titolon en la Tweet sur, Mick?? Temo estis la NGS kaj analizo de la sumigitaj genaroj de la mikroboj (Metagenome) Trovita en la ventroj de ruminants. &Nbsp;Li montris kelkajn devigantajn datumojn kiu implicis ke ni surmetas?? Bezono al Vidi reindeer diferencigi ?in de, Diri, #?Iovendejeto bovino, Male ni povus diri ilin dise de analizo de la metagenome sinsekvoj en iliaj ventroj. Mick #anka? nelonge diskutita la manifold influoj de ventraj mikroboj sur iliaj gastigantoj.

Les Mara, De Databiology, Donis la sekvantan prezenton, Rajtigita:

“Evitanta la ??Mics Cunamo”

- cautionary rakonto pri la graveco de fortika, Scalable kaj facile #deploji?i Bioinformatics solvoj, Por ne nur elteni la Grandan Datuman inundon, Sed eltiri plej bonan valoron de via investo.

La lasta parolado #anta? #lun?o sur Tago 2 Estis donita de Kim Brugger, &Nbsp;Kapo de Bioinformatics, EASIH, Universitato de Cambridge, Kiu #?an?i la titolon de lia parolado de:

Al:

“Administranta ITajn rimedojn kaj NGSa LIMS por libera”

La emfazo de #?i tiu parolado estis kiom libera, Malferma-fonta softvaro povus esti kunmetita en potenca Dukto Pritraktanta varion de NGSa datumo, Spuranta #?iuj #?isdatigo, altgradigoj #a? aliaj #?an?o kiu postulus re-validumado kaj #ankora? #konsili?i konfidon en rezultoj de unu kurita al alia.

La posttagmeza sesio estis piedbatita de de d-ro Jim White, NanoString Teknologioj,&Nbsp;kiu prenis nin pretere NGS, Al teknologio celita #?e sekvanta-supre sur kopio-nombraj variantoj #a? diferencoj en esprimo eltrovita en la esploro #a? klinika NGSa laboritorio:

TEKNOLOGIA LABOREJO ?? ??AnoString hipotezo veturita esploran ilon stirada NGS Eltrovoj al la Kliniko”

Uzanta fluoreskan enketon hybridisation-kapto, #?Is 800 Malsama cela RNA #transskriba?o #a? genomic sinsekvoj povas esti kvantigita.

Nia sekvanta parolanto, Kevin Blighe, Gvida Bioinformatician #?e la Sheffield Infanoj?? NHSa Fundamento Fido, Diris nin proksimume:

Li donis nin verukoj-kaj-#?iu indikas de vido enkonduki NGS en klinika medio, Inkluzivanta la defiojn de la perceptoj de Britio Nacia Sana Servo raportita de la amaskomunikilaro…

La #anta?lasta prezento de la tago venis de – Mi! &Nbsp;mi donis la spektantaron mia punkto de vido sur la malfacilecoj esenca en:

“#Anta?vidi Efikojn de Sinsekvaj Variantoj sur Phenotype”

Inspirita de blogo #Po?to, Mi donis superrigardon de la defioj kaj tiam provita alrespondi kelkaj de #?i tiu, Emfazanta la gravecon de modelaj organismaj studoj plibonigi komprenanta de  genetikaj fonaj efikoj, Geno-mediaj interrilatadoj kaj ne-kodanta variantojn.

Nia lasta parolado estis donita de:

#Po?to-Doktoreca Esplora Samrangulo en la Lernejo de Biomedicinaj Sciencoj, Universitato de Leeds. &Nbsp;d-ro Ivorra-Martinez diris nin kiel zorgeme konstruita familian genealogion kaj bonan komprenon de la #hereda?o skemo de skizofrenio, Kiam kombinita kun exome sequencing permesas la identigon de romano, Probabla causative, Variantoj.

 

Bazita sur la retrosciigo ke ni ricevis, La konferenco kaj laborejoj atingis multaj de niaj celoj, En aparta, Stimulanta konversaciojn kaj proponanta #?anco por partnerecoj – Eble ni volas #?is revido sekvanta tempo?!

#Po?ti en Genomics, Scienca Komunikado | 1 Respondo

Aplikoj & #?Topejo En Sekvanta Generacio Sequencing

De Paul Denny | Eldonita: Novembro 21, 2013

Post kiam monatoj de preparo kaj la foja sendorma nokto, 5a de novembro alvenita. &Nbsp;?i wasn?? Nura #?ojfajro Nokto, Sed #anka? la komenco de  du-taga konferenco, Koncentranta sur NGS en klinika genetics laboratorioj. &Nbsp;Organizita de miaj kolegoj kaj amikoj de Biotexcel Kaj mi mem, ?i estis tenita en la Manchester Konferenca Centro, Je, Nature #sufi?a, Manchester, Britio.

Por rompi la glacion, Mi decidis #devoji?i de la titolo de mia komenca prezento

Kaj akiri la delegitojn paroli al iliaj najbaroj, Klariganta kion ili esperis akiri ekstere de la konferenco kaj skribanta #tio ?i sur folio de flip-mapa papero, Pasanta #la? #?iu disputo. &Nbsp;#Tio ?i provokis hubbub de konversacio – Kiu estis kio mi deziris! &Nbsp;Post kiam #?i tiu volonta interrompo, Mi enkondukis la basics de genaro-#lar?a asociaj studoj (GWAS) Kaj klarigita kiel NGS estis uzita en #ser?i causative variantoj #kaj anka? #?asi por maloftaj variantoj.

Donanta la Keynote prezento sur la unua tago estis Profesoro. Tim Aitman, Kiu diris nin proksimume:

“Efektiviganta NGS en esploro kaj la kliniko”

Li donis #Travoja?o-de-forto, Varianta de la analizo de NGSa datumo de la genaroj de malsana modelo organismoj tra al la defioj enkonduki #la?cela NGS kiel klinika diagnoza ilo.

Poste supre estis Clark Mason, Prezentanta sur:

“#?Elo izoleco de Fluo Cytometry por Sekvanta Gen Sequencing kaj Sinsekva #Malka?o”

#Tio ?i estis fascinanta apliko parolado, Priskribanta la potencon de #?Elo ordiganta Faciligi sequencing de ununura-#?elo genaroj.

D-ro Jon Strefford diris nin pri la unmet klinika bezono prezentita de kronika lymphocytic #le?kemio (CLL) Kaj kiel lia laboritorio estas elfaranta sinsekva NGSa mutacio analizo sur ununuraj pacientoj dum terapio. Cetere, Li priskribis kiom uzanta NGS povas plibonigi prognozon por CLL.

Varsha Khodiyar donis la sekvantan paroladon, telling us about F1000Research,&Nbsp;revuo uzanta la Malferman Aliran modelon kaj kiel ili estas kampanjantaj por pli bona aliro al kruda scienca datumo ekz. De NGSaj eksperimentoj. &Nbsp;Sekvanta supre sur #tio ?i, Kiel speco de duobla-ago, Ted Kalbfleisch diris nin pri iloj faciliganta vojojn al visualise NGS datasets, Kiu povus esti utila fiksrigardi reviewers kaj nature, Al aliaj sciencistoj.

La #lun?o-#rompi?o estis granda #?anco paroli al aliaj delegitoj, Foliumi la eksponantojn’ Starejoj kaj peruse la #afi?o. Mi akiris la impreson ke #sufi?e da interkonektanta estis #da?rigi en #?i tiu #rompi?o – Nemalhavebla parto de ajna konferenco.

Nick Downey, De Integraj DNAaj Teknologioj, Parolis proksimume:

??Nhanced solvo bazita celan #ri?igo uzanta oligonucleotide enketoj kaj tutnova #kunmeta?o bloki oligonucleotides?

Asertanta ke iliaj #ri?igo enketoj por #la?cela NGS donis pli bonajn rezultojn sur GC-#ri?a sinsekvoj ol produktoj de rivalaj firmaoj. Ni #anka? #a?di pri Kancera gena panelo por #la?cela sequencing de genoj okupita en akuta myeloid #le?kemio (AML).

Nia sekvanta parolanto diskutis kritikan areon por klinika genetics:

Simon Patton gvidis nin tra la rezultoj de vasta enketo de La uzo de NGS en diagnoza genetics laboritorioj En Britio, Donanta fascinantan bildon de  kiom rapide la teknologio estas estanta prenita supre. &Nbsp;Li #anka? emfazis la defiojn taksi la indicojn de concordance inter laboritorioj uzanta NGS sur la samaj ekzemploj.

Conrad Lichtenstein parolis pri teknologioj evoluigita de #Lo?antaro Genetics:

“Faranta la plejparto de Sequencing: Preciza targetted sequencing en pooled #lo?antaro de 1000?? De DNAaj ekzemploj”

Unu el la #alproksimi?o ke  li priskribis estis esence tre lerta vojo #senmovi?i sinsekvon “Barcodes” Al longdistancaj PCRaj produktoj derivita de multoblaj genaroj, Permesanta tre alta nivelo de multiplexing.

Nia sekvanta parolanto, De Bio-Prodict,

Priskribita kiel proteinajn strukturojn de ne-homa specio tamen povas esti utila en #anta?vidi la efikon de homaj sinsekvaj variantoj, Kiam integrigita kun alia datumo ekz. De la literaturo. Cetere, Li asertis ke la 3DMa platformo outperformed puto-sciita ilojn kiel Kribri kaj Polyphen.

La lasta parolanto sur tago 1 Estis Kate Thomson, Parolanta proksimume:

“Evoluiganta NGSajn strategiojn por uzo en diagnoza fikso”

d-ro Thomson revenita nin al la klinika laboritorio, Rememoriganta nin de la potenco de NGS por identiganta tutnovajn variantojn, Sed #anka? la reguligaj kaj etikaj defioj ?i prezentas.

En mia Sekvanta #po?to, I??L diri vin pri la parolantoj sur tago 2.

#Po?ti en Genomics, Scienca Komunikado | Lasi rimarkon

Tiel, Kio Fari Viajn Genojn FARI?

De Paul Denny | Eldonita: Novembro 12, 2013

abnormal development of the heart in mutant mice

Genoj ne estas pasivaj. &Nbsp;Ili estas la celo de molekula “Dimmer #?altilo”; Tipe (Sed ne #?iam) Specifaj proteinoj, Kiu turnas supre #a? #?irado malsupren ilia aktiveco. &Nbsp;Plejpartoj de genoj estas tradukita en proteinoj, Sed eltrovanta la veran rolo de tiuj proteinoj, En la vivo de #?elo #a? tuta organismo, Estas #ankora? unu el la grandaj defioj de moderna biologio.

La plej bonaj vojoj kiu ni povas asigni funkcion al proteinoj estas de vidanta kion okazas kiam nin #a? #?alti genojn de tute, Deklivirejo supre ilia aktiveco al eksternormaj niveloj, #A? enkonduki hazardajn #?an?o en proteinoj. &Nbsp;Cetere, Se vi estas vere interesita en la funkcio de geno, La plej bona testo estas #?an?i vian genon en ?i?? Natura “Medio”, de kiu mi signifas tutan vivan beston #a? fabrikejon, Prefere ol en  solula #?elo en  laboratoria testo-tubo. &Nbsp;#Tio ?i estas #?ar alia #karakteriza?o de genoj kaj proteinoj estas ke ili malofte agas en izoleco – Pli ofte, Ili agas en koncerto kun aliaj proteinoj formanta pathways #a? retoj.

En #anta?a #Po?to, Mi priskribis kiel nin trovis ekstere kiun genoj estis perdita en muso kun parto de unu kromosomo forigis. Ni deziris fari #tio ?i #?ar kiel #?anco havus ?in, Kelkaj homoj havas la malbonokazon #naski?i kun kelkaj de la ekvivalentaj homaj genoj #anka? #perdi?i. &Nbsp;Sed kiu de tiuj genoj estis rilata al la simptomaj homoj elmontris? Faris #?iu la genoj kontribuas al la malordoj, #A? estis kelkaj genoj pli grava? Nature, La nura vojo trovi ke ekstere kun konfido estus trovi (#A? krei!) Homoj en kiu #?iu geno en la regiono estis modifita – etike tre dubinda kaj teknike tre malfacila. Tiel, En la manko de homoj, Unu el nia plej potencaj iloj estas studi genetically modifita musojn, Kun #?an?o en ununuraj genoj #anstata? forigoj de la tuta kromosoma regiono.

Eksternorma evoluado estas vidita en homaj embrioj en kiu specifaj genoj estas perdita kaj niaj mutaciintaj musoj mimicked multaj de la samaj trajtoj; Kelkaj montris #?an?i cerbon kaj kranion, Aliaj koro kaj renaj mankoj. &Nbsp;#Nenormala?o en kelkaj de la musoj influis plenkreskan konduto, Kiel #?an?i aktiveco #a? maltrankvilo, #E? en tiuj kun nura unu kopio de geno modifis. Neatendite, Ni trovis ke pluraj malsamaj genoj, Fizike egale kune, #?Iu donis similajn #nenormala?o kiam ili portis mutaciojn ekz. Kvar #?an?i koran evoluadon, Du donis renajn mankojn kaj pluraj #?an?i konduton.

La rakonto niaj musoj Diris nin Estis ke ?i estas probable ke en homoj kun forigoj de pluraj genoj,&Nbsp;multaj de la #nenormala?o estas #ver?ajne ensemblaj efikoj #ekesti?i de la perdo de pluraj genoj kun similaj funkcioj, Prefere ol la influo de ununura,&Nbsp;kritika,&Nbsp;”Mastro” Geno.

#Po?ti en Malsanaj Modeloj, Genomics, Cela eltrovo | Lasi rimarkon

Kelkaj de niaj genoj mankas…Sed kiu ones?

De Paul Denny | Eldonita: Majo 28, 2013

Image courtesy of renjith krishnan / FreeDigitalPhotos.netUnu povas pensi de Genoj En nombro de vojoj:

  1. #?E la nivelo de la DNA – Simple kiel linia sinsekvo de nucleotides, En ONE riparita ordon, En la “Normala” Stato, #A?
  2. Denove kiel DNAa molekulo, Sed memoras ke genoj en organismoj, Prefere ol en pecoj de DNA en testo-tubo, Estas submetata al vario en malsamaj individuoj, #A?
  3. La tria vojo estas al metaphorically elzomas kaj pensi pri genoj de la punkto de vido de la tuta organismo kaj varioj en tiuj genoj donanta #alti?o al varioj en Phenotypes.&Nbsp;Varioj en phenotype estas la #a?o de Darwin, La kruda materialo sur kiu Natura elekto Laboroj.

Mi skribis #Anta?e Pri Malgranda muso (Jargon nomo – Del(13)36H) Kiu havis Perdita Kelkaj de ?i?? Genoj Kaj ke #?i tiu perdo estis asociita kun tre komplikita Phenotype, Priskribita en nia papero Kaj simila en kelkaj vojoj al Homoj Kiu havis #anka? Perdita Bloko de Genoj.

Kiam ni unue studis #?i tiu muson, Unu el nia Faletanta blokojn Estis ke ni Sciis Pri nur Malabunda De la Genoj Kiu estis forigita – Ni estis en la fruaj stadioj de la genaro sequencing revolucio, Kiam nuraj pecoj de la muso (Kaj homo) Genaroj estis sequenced kaj genoj elmapis. #Tio ?i estis grava #?ar ni deziris esti kapabla al Transversa-kompari muso kaj homo Phenotypes Kaj por fari #tio ?i, Ni devis scii #?u la Genoj Perdita en la Muso Havis Ekvivalentoj Je Homoj Kaj #kutima?o-versa.

Tiel, La defio ni alfrontis estis al Trovi Tiuj #Perdi?i Genoj. &Nbsp; Estis #da?ranta filozofia kaj teknika argumento pri la plej bona vojo trovi genojn de DNA sequencing, Kiu povas esti disigita en du tendaroj – La Mappers kaj la Improvisers. &Nbsp;La Mappers prenis Mapon Unue, Sinsekvo Pli Lasta #alproksimi?o kaj la Improvisers preferita al Sinsekvo Unue, Mapi Kontroli Sinsekvon Poste.

Ni falis en la unua tendaro – Do nia unua laborposteno estis konstrui mapon trans la regiono forigita en nia malgranda muso. Sed kiel vi konstruas mapo de “Nevidebla” #Pejza?o?

Evidente, De demandanta kion estas Donaco Je Normala Musoj kaj #Ne?eesta En nia Malgrandaj musoj – #Tio ?i estis farita pli malfacilan #?ar musoj kiu heredis forigita kromosomojn de #amba? gepatroj faris Ne supervivi Multe da pretere implantation. Ni devis konstrui mapojn uzanta musojn kiu #a? havis unu #a? du kopioj de la rilataj genoj prefere ol la pli simpla situacio de du kopioj #a? neniu. &Nbsp;?i povas veni kiel surprizo ke ?i estas pli malfacila alrespondi la demandon – #?u ni havas Unu #A? Du Prefere ol Du #A? Neniu? &Nbsp;Tamen, Ni konstruis mapon, Kaj #malgra? kio mi skribis sur, Ni Sequenced Partoj de la mapo Kiel ni iris #anta?en, Prefere ol atendo #?is ni havis la kompletajn konturojn de la #pejza?o determinita. Tiel, Ni estis mapantaj partojn de la #pejza?o kaj unufoje ni estis certaj de tiu parto, Sendanta ?in ekstere por sequencing. &Nbsp;Tuj kiam la DNAaj sinsekvoj estis revenita, La Genoj Entombigita en la sinsekvo estis Malkovrita Kaj malrapide, a Kompleta gena mapo Estis Kudris kune. &Nbsp;Ni rutine sekvis supre #a?tomatigi genon “Annotations” Kun mana inspekto kaj eraro-kontrolado, Kiu ni kredis provizita Oran Norman genan mapon.

Do kio ni trovis?

Puto, ?i rezultis tion 236 Genoj Estis Forigita En nia malgranda muso, Plus #anka? 95 “Pseudogenes” – Genoj kun necertaj funkcioj – #A? ili estas negravaj  al la viva muso sed eble agi kiel materialan por evolua elekto #a? ili Povas reguligi aliajn genojn? De la genoj kiu ni povis Rekoni, Unu el la plej videblaj aferoj estis ke estis pluraj Grapoloj de genoj Kiu montris altajn nivelojn de simileco al unu alia – Ili apartenis al Genaj familioj. &Nbsp;Kiam ni komparis #?i tiu genajn familiojn al iliaj homaj ekvivalentoj, La #?efa surprizo estis ke la Grandeco De la Familio Povus esti Tre malsama. Unu familio de tri genoj kodanta proteinojn okupita en #?alti aliajn genojn sur kaj ekstere (Gena reguligo) Estis #Preska? Identa Je Muso Kaj Homa – Dum alia familio, Faranta Proteinoj Tio Interrilati Kun Pheromones Okupita en amika elekto, Estis Kvin fojoj pli granda en nombro en musoj ol en homoj. Efektive, La homa pheromone interrilatadaj genoj aperis ne-praktika; Ili estis “Pseudogenes”. &Nbsp;Eble ni ne devus esti sekve surprizita de #tio ?i kiam ni pensas pri la diferencoj en #pari?i konduton inter musoj kaj homoj…

La entuta temo kiu aperis estas de Frakciado – La forigita regionon enhavas Genoj Kiu estas Tre simila al homo Genoj kaj Aliaj Kiu povas Ne Havas praktikan Homaj ekvivalentoj. &Nbsp;Sed vere fari senton de la listo de genoj forigita en nia malgranda muso kaj ?i?? Rilato al  homa phenotypes #a? patologio, Ni devas al Kompreni Kio tiuj genoj efektive fari?

Kaj ke estas rakonto por alia tago.

Posted in Disease Models, Genomics | 1 Response

Genetics Society Spring Meeting: Genomics for Health and Society

By Paul Denny | Published: May 14, 2013

The aim of of the meeting was to begin to answer the question:

“What will be the impact of large-scale sequencing of human populations in the 21st Century?”

Held at The Royal Society in London on 19th April 2013, the meeting brought together some distinguished figures from clinical genetics, population genomics, DNA fingerprinting and the legal implications of genomics. There is an excellent summary of the meeting on Storify, as a collection of Tweets from several authors assembled by DJ de Koning, but I have included some highlights in this post.

Speakers at the meeting were Kate Bushby and the people shown below:

First to present was Jim Lupski from Baylor College of Medicine, Houston, on “Personal Genomes”.

According to Jim, one of his claims to fame should be that he was the first person in the world to be both first author and the subject of study on a personal genome paper.  His whole genome was sequenced and analysed because he is part of a pedigree or “clan”  (as he called it) segregating a peripheral neuropathy called Charcot-Marie-Tooth disease.  Jim Lupski’s talk was a bit of a romp with paper, case study and human stories tumbling out so fast it sometimes seemed difficult for him to draw breath.  The last story was particularly compelling – a tale of fraternal twins, with a movement disorder, that had undergone numerous inconclusive medical investigations before whole genome sequencing enabled a clear diagnosis and improved therapy.

Sir John Burn entitled his talk “Power to the People”. One of his main themes was that we were heading towards a clinical genome sequence data “traffic jam”.  An example of this is the recently announced NHS plan to spend 100M pounds on sequencing about 100,000 patient genomes. Some of the other issues this project raises are discussed in an excellent blog post, here.  Sir John emphasised that, in order to extract maximum value from these date, it will be vital to share information on variants in a way that preserves patient confidentiality.  One way to encourage sharing these data is to use “microattribution“, where scientists who have annotated a sequence variant gain credit for their efforts.

Posted in Genomics, Science Communication | Leave a comment

Gene & Cell Therapy For the People

By Paul Denny | Published: April 29, 2013

BSGCT Conference 2013 Venue - Royal HollowayThe Annual meeting of the British Society for Gene and Cell Therapy, as well as being aimed at the expert, included a day of presentations intended for students and the public.  Aimed primarily at GCSE and A-level students, but open to all,  this one day interactive event provided an opportunity to discuss and debate gene and cell therapy research with scientists, patients, journalists and clinicians, and to think about the impact that this research has on society.

The events of the day included talks by scientists working on gene therapy and stem cell research, followed by a question and answer session.  Students asked about career advice, current progress in gene and stem cell therapy research as well as the ethical issues raised.  For those reluctant to speak in public, the organisers encouraged people to ask questions using the Twitter hashtag #bsgctped or #bsgct

First speaker of the day was Dr Tassos Georgiadis:

Curing Blindness with Gene Therapy

Dr Georgiadis told us about different forms of inherited blindness and explained how gene therapy works in the eye. Some therapies halt a disease that would otherwise get progressively worse and others may actually improve sight.  The most awe-inspiring part of the whole talk was a short video ( you can watch it here – there is a 15 second advert first) showing how one person had his eyesight improved dramatically by gene therapy.

Next up was Dr Tristan (Tris) McKay:

What is Stem Cell Therapy?

Dr McKay explained that not all “stem cells” were equal; the different types, embryonic, fetal, and adult, have subtly differing potencies to develop into the specialised cells in the body. He also talked about a recent development that has contradicted a previously long-held dogma that specialised cells, such as skin cells, cannot become stem cells.  This breakthrough, allowing stem cells to be generated much more easily from adults, led to the discoverers, Sir John B. Gurdon & Shinya Yamanaka, being awarded the Nobel Prize for Physiology or Medicine in 2012. Anyone who would like to know more about Stem Cell Therapy could listen to the three lectures downloadable (for free) from iTunes U.

Stem Cell Therapy and Transplantation

Dr Emma Morris told us how she had asked her own children how best to talk about her work, on Stem Cell Therapy, with teenagers studying for their GCSEs or A-levels. Their answer was to do the same as she had done for primary-school children; the outcome was not patronising, but entertaining, enthusiastic and engaging.  Dr Morris studies, and uses in therapy, the stem cells found in the bone marrow that can specialise as blood cells. She told us about how bone marrow transplantation was first tried in 1959, to cure five Yugoslavian nuclear workers whose own marrow had been damaged by a nuclear accident. Unfortunately this failed because the workers’ immune systems rejected the transplants.  Since that time, as we have learned to control or avoid the problem of rejection, bone marrow transplantation has become a highly successful technique for treating cancers of the blood.  And not only can we use transplants from an adult donor, but also stem cells from the blood of umbilical cords or even our own blood stem cells – after “filtering” out the specialised cells.

Dr Morris also mentioned some of the more attention-grabbing experimental therapies such as building new tracheae with a plastic framework on which bone marrow stem cells can grow, given the right growth-stimulating factors, or “designer” stem cells programmed to attack cancer cells.  Some of these approaches remain highly speculative and in many cases have only been tested in mice, nevertheless, they are promising.

Have to mention that the audience was not composed entirely of students, but also a few general members of the public and during one of the breaks I:

The next presenter had a uniquely passionate point of view, because he was both a patient (with haemophilia) and a scientist; Dr Adam Jones:

Gene Therapy – A Patient’s Perspective

Dr Jones started by giving us a brief history of haemophilia – the earliest written record being in the Jewish sacred text, the Talmud, which dates back to between 200 and 500 AD.  He then launched into a semi-autobiographical series of stories – he was a good story-teller – about life as a haemophiliac, required to take a drug, called Factor IX, in order to avoid bleeding to death.  These stories were blackly comic and thought-provoking; particularly when he compared the cost of the NHS buying Factor IX for one person (£157,872 per year) with paying a Premier League footballer (~£250,000 per **week**)…

But what has this to do with gene therapy, you may be thinking?

Well, despite the existence of therapies for haemophilia, they are not a cure. Gene therapy is expensive, perhaps  ~£30,000 per treatment and indeed may not be a permanent cure, but may need to be repeated once or twice per year.  However, if such a therapy existed it would do two things:

  1. release haemophiliacs from the need for several injections of Factor IX per week into their veins.
  2. save money for the NHS.

Fortunately, research to achieve this goal is ongoing, with some early promising results.

The final speaker was Ed Yong, a science writer who left the lab after realising that it really didn’t suit him, because he enjoyed talking about science far more than doing it.
His topic was:

Beyond “The Gene for X”

Ed warned us that he was going to deviate from the main theme of the day and take us into the new territory of personal genome tests and the unfortunate tendency of the media to over-simplify genetics. He listed stories about genes that “cause” everything from our DIY skills, to risk-taking, being politically liberal, or even eating a whole bag of crisps. Of course, none of these are simple, deterministic Mendelian genetic “effects”. But these subtleties rarely get reported, or if they do, they are buried well down the published text.  So, reader, beware.

In the area of personal genome tests, Ed related his experience with having his own genome tested by a company called 23andme – this threw up some strange results. Ed is of east-Asian origin and has black, ramrod-straight hair, but his genetic test results predict that he should have curly hair!

One of the most entertaining moments occurred when the PC temporarily froze and so Ed told the audience another story, about a girl called Lily with a mysterious disease for whom genome sequencing had offered hope for the future. This was a fascinating story of scientific discovery, yet tinged with an element of sadness because although the cause of Lily’s illness has been found, there is, as yet, no cure.

The final session consisted of the speakers and other scientists with expertise in stem cell and gene therapies, answering questions directly from the audience, or from tweets sent to #bsgctped during the day. There were some great questions e.g.

  • “How does the way stem cell research is done vary between countries?”  A: Significantly – regulations in UK are strict, but relaxed by comparison with the USA.
  • “What A-levels do I need to study medicine at University?” A: the only subject that is obligatory is Chemistry, but another speaker also mentioned that a slow route, but possible at some Medical schools, allows you to study any combination of A-levels, then study whatever first degree course your heart draws you to, then go into medicine later.
  • “How did the panel’s religious beliefs affect their science?” This drew a lot of very interesting replies…

This rounded up an entertaining and informative day and I would recommend it highly for science teachers or for GCSE / A-level students, especially if studying biology or for any member of the public, curious about this area of science, in future.

Posted in Science Communication | 1 Response

Moving Next-Generation Sequencing into the Clinic, part 2

By Paul Denny | Published: March 21, 2013

In my last post, I summarised the first four talks from this symposium:

1st Oxford Workshop and Symposium, 4th Techgene Knowledge Network Meeting,
“NGS2013 Next generation Sequencing: Bioinformatics and Data Analysis”

You could also read the Tweets from the meeting here. But I digress. The afternoon session started impressively with Marcel Nelen, from Radboud University Medical Centre, Nijmegen, Netherlands speaking about:

“Clinical utility of exome sequencing in heterogeneous diseases.”

Dr Nelen described how a strong collaboration between research and diagnostics labs led to the application of exome sequencing in diagnosis of heterogeneous genetic diseases.  He emphasised the importance of a multidisciplinary team effort to define “packages” of genes for which there was evidence of involvement in either intellectual disability (ID), inherited blindness, inherited deafness, movement disorder or oxidative phosphorylation disorders.  The wide diversity of genetic variants that can cause such diseases means that Sanger sequencing, once the gold standard, has become too time consuming and expensive and gives a lower “diagnostic yield” than exome sequencing.

One critical aspect of applying high-throughput sequencing of exomes in a diagnostic setting is gaining appropriate informed consent from patients and their families.  Patients and/or their parents gave informed consent for the entire exome analysis. The sequence data from the exomes of ~550 patients entered a generic annotation pipeline and exome analysis was based on either a ‘de novo’ strategy for ID or a ‘in silico’ targeted strategy for the other diseases.

Analysis is based on a two stage approach:

  1.  Analysis of a “package” of genes defined as highly likely to carry pathogenic variants:
    • Search for variants in only these disease-related genes.
    • If pathogenic variant found, end analysis and report.
    • If no pathogenic variant found, move on to the second stage:
  2. Whole exome analysis:
    • If no pathogenic variant found, search for mutations in a specific  set of candidate genes.
    • If a pathogenic variant is found and there is solid proof for clinical interpretation, report.
    • Finally, if the earlier analyses fail, the remainder of the exome  is searched in collaboration with researchers and might be reported on if this “new” data holds.

One success story recounted by Dr Nelen concerned a specific case of intellectual disability, in which no causative variant had been identified over several years of investigation by Sanger sequencing of successive candidate genes, whereas whole exome analysis identified a pathogenic variant in the PACS1 gene.

In cases where “incidental” variants are identified, that appear to bear no relationship to the disease under investigation, these are passed to and assessed by an independent team of experts for advice, prior to reporting.

This tiered analysis has gained certification by the Dutch medical authorities as a genetic test and so might act as a model for other EU countries.

We heard next from Michael Mueller, from the NIHR Biomedical Research Centre, Imperial College London, UK, about:

“Rapid whole-genome sequencing: optimising the bioinformatics pipeline for faster turnaround times.”

Using whole-genome sequencing (WGS) for mutation detection can be more powerful than analysis restricted to just the exome. However, the data processing and handling challenges posed by moving WGS into the diagnostic lab are immense.  Dr Mueller described how different hardware and approaches to parallel processing of NGS data could be optimised, presenting some dramatic improvements.  By systematically identifying bottlenecks at each stage, he was able to reduce the time taken to produce  annotated variants, starting with raw Illumina short-read data from a ~ 30x coverage single genome, from ~24 to ~7 hours.  This appeared to be achieved without compromising read-mapping or variant calling quality.

In a follow-up to the talk from Marcel Nelen, Kornelia Neveling, also from  the Radboud University Medical Centre, Nijmegen, spoke about:

“Data analysis for diagnostic exome sequencing”

Dr Neveling began by describing the technical setup at the Radboud University Medical Centre, then sample handling and quality control and finally software tools to help in exome sequence variant filtering and analysis.   The diagnostics lab has access to three Life Technologies 5500 sequencers using the SOLiD platform and also two Ion Torrent PGM sequencers.

A critical step in sample and data handling is quality control (QC) to ensure that final clinical decisions are robust; some of the QC steps outlined by Dr Neveling were:

  1. Reliable identification of individuals and relationships (sibling / parent / unrelated)
  2. Accurate recording of metadata for each sample e.g. which software version was used for analysis? What was the date of analysis?, etc.
  3. That sequence data are highly specific and sensitive e.g. give sufficient, even coverage of all exons.
  4. Sequence variant calls meet biological expectations e.g. the ratio of transitions to transversions reflects natural variation.

The Radboud sequencing diagnostics team now have a database of about 1500 individual exomes and have found that a typical exome yields about 40,000 variants, with ~150-200 of those variants being “private” to each sample. Dr Neveling presented a variant filtering tool, with a graphical user interface that looked reminiscent of the software described earlier by Elliot Margulies and described briefly using the tool in a case of hereditary spastic paraplegia to aid in identifying the most likely etiologic variant.

Prof. Anthony J Brookes ended the Symposium, talking about:

“Assigning pathogenicity to NGS-derived variants”

Prof. Brookes was fizzing with ideas, provoking us to think about what we really mean by “pathogenic”.  Focusing on rare diseases, we were reminded that the concept of pathogenicity is a slippery, multi-faceted one.  Inferring pathogenicity can mean some combination of:

  • knowing allele frequencies in case and control populations
  • whether a variant has been described by others as pathogenic
  • whether a variant is absent from databases that are assumed (sometimes wrongly) to consist mainly of “normal” variants e.g. dbSNP
  • whether a variant co-segregates with disease in a pedigree
  • what the predicted (or known) effect of a variant is on protein structure
  • predictions in silico from tools such as PolyPhen or Sift
  • functional assays performed in living human cells
  • functional or phenotypic assays conducted in model organisms e.g. mouse mutants

Another level of subtlety in the way in which we define pathogenicity is that we can think of two contexts:

  1. has a variant ’caused’ a phenotype in a particular patient or family (which relates to expressivity)?
  2. can a variant ’cause’ a phenotype in a population (penetrance)?

Prof. Brookes argued that the clinical actionability of a variant should be thought of as a combination of pathogenicity, penetrance and expressivity. He went on to point out that too little is known about the relationship between genotype and phenotype and that we need a number of developments to bridge that gap and improve our ability to recognise pathogenic variants. In particular, he argued that a intermediary database system was required to link together primary resources such as dbSNP or Ensembl with clinical databases, to facilitate data-sharing without compromising confidentiality.  Combining this database  ’ecosystem’ with high data-quality electronic health records should improve our understanding of the genotype-phenotype relationship.

 

The symposium gave a good overview of the way in which NGS is being taken up in diagnostic genetic labs and used to improve the success rate in identifying causative variants.  In turn, this technological development should lead to better informed choice of therapies or treatments.  It will be intriguing to see how far we have progressed in a year’s time, when a followup meeting is planned.

If anyone would like to get in touch to discuss, correct or update my summaries, please post a comment, below, or send me a tweet:


Posted in Genomics | 1 Response

Moving Next-Generation Sequencing into the Clinic

By Paul Denny | Published: March 15, 2013

On a glorious day (but with Arctic-like winds!) earlier this week, I attended a symposium on exploiting NGS in the diagnostic genetics clinic:

The speakers were clinicians, bioinformaticians and biomedical researchers; a good mix.  The organisers got things off to a smooth start and the keynote talk was given by:

Dr. Anneke Seller, Director of Genetics Laboratories, Oxford NHS trusts

“Transforming genetic testing in the NHS: the application of next generation sequencing to the diagnosis of Mendelian disorders”

Dr Seller guided us along a timeline of the development of genetic testing in the Oxford region NHS, noting that their main methods were focused on small panels of genes typed by either Sanger sequencing or one of the NGS platforms.  She explained how diagnosis of the variants causing hypertrophic cardiomyopathy (HCM) has moved from using denaturing HPLC onto high-resolution melting curve analysis and now to Haloplex PCR and the Illumina MiSeq platform.  Using NGS increased clinical sensitivity or “diagnostic yield” and when combined with control population data, improved classification of variants found in HCM, making it easier to define them as “unclassified” rather than as “likely pathogenic”.

The Oxford Clinical Genetics Labs validate variants using Sanger sequencing, but plan to stop this soon.  Looking ahead, their goal was to use sequencing of whole exomes to increase the success rate in finding causative variants.  Dr Seller emphasised the need to introduce better bioinformatics, rather than to struggle with data in Excel spreadsheets. Finally, she proposed that it was essential that the NHS transformed clinical genetic testing by the widespread introduction of NGS.

Elliott Margulies, from Illumina UK, spoke about:

“Whole Genome Sequencing and Analyses for the Clinic”

Dr Margulies introduced the Illumina sequencing platform briefly and then talked about some recent technical developments including:

  • the ability to use smaller size samples as sources of DNA, e.g. formalin-fixed paraffin wax embedded tissues
  • an open-source software alignment and variant calling tool, iSAAC
  • a modified file format for sequence variants, called gVCF.
  • a tool to facilitate easier filtering of a list of DNA sequence variants, tentatively called iAFT.

iSAAC is claimed to be able to align and call variants from a whole-genome sequence dataset in about 24 hrs, if it is run on a 12 core computer with 64 Gb RAM.

The variant filtering tool has a graphical user interface and is built upon open-source underpinnings e.g. the Ensembl VEP and uses data from various sources, including the Exome variant project and is provisionally called iAFT.  Using this tool reduces the scale of the problem of finding causative  variants, but when questioned by an audience member, Dr Margulies emphasised that, in the final analysis, the last decision is still the responsibility of the clinician.

Looking ahead, Elliott Margulies predicted a clinical “ecosystem” starting with taking a DNA sample at birth, much like the current heel-prick blood sampling, used for whole-genome sequencing, following up some individuals with exome sequences and linked with an electronic health record maintained throughout life.

The third speaker of the morning session was Matthew Addis, from Arkivum:

“Managing retention and access of genomics data”

We were presented with some salutary and entertaining tales of catastrophic data loss and then Matthew Addis explained the painstaking and rigorous approach that Arkivum take to ensure that their clients always have a backup copy.  Physical copies in multiple locations and regular checks on data integrity are key aspects to the system, including even a backup kept by a third party, in escrow.

In the last talk of the morning, Bas Vroling, from Bio-Prodict, spoke about:

“3DM: Data integration and next-generation variant effect predictions”

Using 3-dimensional protein models for every protein in a superfamily as their starting point, Bio-Prodict have built a tool that integrates multiple data sources in order to, or so they claim, infer the functional effect of sequence variants.  The delightful aspect of this approach is that 3-D models of proteins from non-humans can be used to infer the effect of variants in the human homolog.

One example that Dr Vroling gave was of a variant found in a protein involved in long-QT syndrome in horses could be used to predict the effect of variants in the equivalent human protein.  Using a large set of validated variants found in long-QT syndrome, the detection sensitivity of 3DM was 95% compared with ~65% achieved by another standard tool, PolyPhen.  The potential of the 3DM tool is clear, but whether it can be scaled up to cope with a complete set of all the proteins encoded in the human genome remains to be seen.

I’ve put summaries for the afternoon talks in another post.

Posted in Genomics | 1 Response

What might a small mouse teach us about human congenital abnormalities?

By Paul Denny | Published: March 4, 2013

Mice are born with their eyes tightly shut, opening them for the first time only a few days later. So when a mouse was noticed that was smaller than normal and had been born with it’s eyes open, it drew attention. Abnormalities like this arise spontaneously in all animal facilities, but sometimes they are not one-offs, but inherited. It was not unexpected in this case, because the mother of this mouse was treated with X-rays to deliberately induce mutations, as part of a larger program of research aimed at producing animals that would be studied as models of human disease.

X-rays are the blunderbusses of genetic modification – almost no aim yet causing massive damage if they hit the target. Sometimes, they cause loss of whole chromosomes, or bits of chromosome are lost and the cellular DNA repair machinery sticks the pieces back together. In the rare cases where the damage is not lethal either to the germ cell or very early in development, congenital abnormalities are seen in some of the live-born.

It turned out that our small mouse had lost a chunk of one chromosome, resulting in many genes being present in only single copies, rather than the normal pairs.

There were two things we most wanted to know about our mouse – firstly, what other abnormalities did it have and secondly, how many (and which) genes had been deleted? These gaps in our knowledge were important because if we could fill them, it would help us to understand the pathological effects of the deletion and be in a better position to compare mouse and human. It turned out that our mouse had a constellation of symptoms – altered head shape, a mild tail kink together with eyes open at birth and smallness. Furthermore, some painstaking developmental studies showed that many mice with the partially deleted chromosome died between mid- and full-term of gestation.

We first found this mouse back when whole genome sequencing was very expensive and financially impractical, so we relied on a combination of other, older methods to find out which genes had been lost. The simplest method uses a chemical stain that marks chromosomes with a characteristic pattern of bands, visible down the microscope (it’s shown in the picture at the top of this post), allowing an estimate of the percentage of the genome lost – this gave surprisingly close agreement with another method, based on genetic mapping, suggesting that 200-500 genes were lost (we later worked out exactly how many – but that’s another story).

Despite the obvious differences, at the level of the genes, mice are a lot like humans – by chance, many of the genes deleted in our mouse have also been deleted in some humans. Furthermore, people with these partially deleted chromosomes have one of a number of complex congenital disorders or syndromes, depending upon which specific genes are lost. These deletions are fortunately rare, but some of the associated disorders are common e.g. hearing loss or heart defects. Paradoxically, rare genetic events like this can teach us something about the other more common causes of these conditions.

Our small mice may be useful in studying why the genes lost in people cause these specific abnormalities and even lead us to new therapies.

The work we did on this mouse was carried out at MRC Harwell and is described in detail here.

Posted in Disease Models | 1 Response

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