Imperial College London

Dr Nick Quaife

Faculty of MedicineNational Heart & Lung Institute

Research Postgraduate
 
 
 
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Contact

 

n.quaife

 
 
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Location

 

Guy Scadding BuildingRoyal Brompton Campus

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Summary

 

Publications

Publication Type
Year
to

11 results found

Wright CF, Quaife NM, Ramos-Hernández L, Danecek P, Ferla MP, Samocha KE, Kaplanis J, Gardner EJ, Eberhardt RY, Chao KR, Karczewski KJ, Morales J, Gallone G, Balasubramanian M, Banka S, Gompertz L, Kerr B, Kirby A, Lynch SA, Morton JEV, Pinz H, Sansbury FH, Stewart H, Zuccarelli BD, Genomics England Research Consortium, Cook SA, Taylor JC, Juusola J, Retterer K, Firth HV, Hurles ME, Lara-Pezzi E, Barton PJR, Whiffin Net al., 2021, Non-coding region variants upstream of MEF2C cause severe developmental disorder through three distinct loss-of-function mechanisms, American Journal of Human Genetics, Vol: 108, Pages: 1083-1094, ISSN: 0002-9297

Clinical genetic testing of protein-coding regions identifies a likely causative variant in only around half of developmental disorder (DD) cases. The contribution of regulatory variation in non-coding regions to rare disease, including DD, remains very poorly understood. We screened 9,858 probands from the Deciphering Developmental Disorders (DDD) study for de novo mutations in the 5' untranslated regions (5' UTRs) of genes within which variants have previously been shown to cause DD through a dominant haploinsufficient mechanism. We identified four single-nucleotide variants and two copy-number variants upstream of MEF2C in a total of ten individual probands. We developed multiple bespoke and orthogonal experimental approaches to demonstrate that these variants cause DD through three distinct loss-of-function mechanisms, disrupting transcription, translation, and/or protein function. These non-coding region variants represent 23% of likely diagnoses identified in MEF2C in the DDD cohort, but these would all be missed in standard clinical genetics approaches. Nonetheless, these variants are readily detectable in exome sequence data, with 30.7% of 5' UTR bases across all genes well covered in the DDD dataset. Our analyses show that non-coding variants upstream of genes within which coding variants are known to cause DD are an important cause of severe disease and demonstrate that analyzing 5' UTRs can increase diagnostic yield. We also show how non-coding variants can help inform both the disease-causing mechanism underlying protein-coding variants and dosage tolerance of the gene.

Journal article

Whiffin N, Karczewski KJ, Zhang X, Chothani S, Smith MJ, Evans DG, Roberts AM, Quaife NM, Schafer S, Rackham O, Alfoeldi J, O'Donnell-Luria AH, Francioli LC, Armean IM, Aguilar Salinas CA, Cook SA, Barton PJR, MacArthur DG, Ware JSet al., 2021, Characterising the loss-of-function impact of 5 ' untranslated region variants in 15,708 individuals (vol 11, 2523, 2020), Nature Communications, Vol: 12, Pages: 1-1, ISSN: 2041-1723

Journal article

Whiffin N, Armean IM, Kleinman A, Marshall JL, Minikel EV, Goodrich JK, Quaife NM, Cole JB, Wang Q, Karczewski KJ, Cummings BB, Francioli L, Laricchia K, Guan A, Alipanahi B, Morrison P, Baptista MAS, Merchant KM, Armean IM, Armean IM, Banks E, Bergelson L, Cibulskis K, Collins RL, Connolly KM, Covarrubias M, Cummings B, Daly MJ, Donnelly S, Farjoun Y, Ferriera S, Gabriel S, Gauthier LD, Gentry J, Gupta N, Jeandet T, Kaplan D, Laricchia KM, Llanwarne C, Munshi R, Neale BM, Novod S, O'Donnell-Luria AH, Petrillo N, Poterba T, Roazen D, Ruano-Rubio V, Saltzman A, Samocha KE, Schleicher M, Seed C, Solomonson M, Soto J, Tiao G, Tibbetts K, Tolonen C, Vittal C, Wade G, Wang A, Watts NA, Weisburd B, Aguilar-Salinas CA, Aguilar-Salinas CA, Ahmad T, Albert CM, Ardissino D, Atzmon G, Barnard J, Beaugerie L, Benjamin EJ, Boehnke M, Bonnycastle LL, Bottinger EP, Bowden DW, Bown MJ, Chambers JC, Chan JC, Chasman D, Cho J, Chung MK, Cohen B, Correa A, Dabelea D, Darbar D, Duggirala R, Dupuis J, Ellinor PT, Elosua R, Erdmann J, Farkkila M, Florez J, Franke A, Getz G, Glaser B, Glatt SJ, Goldstein D, Gonzalez C, Groop L, Haiman C, Hanis C, Harms M, Hiltunen M, Holi MM, Hultman CM, Kallela M, Kaprio J, Kathiresan S, Kim B-J, Kim YJ, Kirov G, Kooner J, Koskinen S, Krumholz HM, Kugathasan S, Kwak SH, Laakso M, Lehtimaki T, Loos RJF, Lubitz SA, Ma RCW, MacArthur DG, Marrugat J, Mattila KM, McCarroll S, McCarthy MI, McGovern D, McPherson R, Meigs JB, Melander O, Metspalu A, Nilsson PM, O'Donovan MC, Ongur D, Orozco L, Owen MJ, Palmer CNA, Palotie A, Park KS, Pato C, Pulver AE, Rahman N, Remes AM, Riou JD, Ripatti S, Roden DM, Saleheen D, Salomaa V, Samani NJ, Scharf J, Schunkert H, Shoemaker MB, Sklar P, Soininen H, Sokol H, Spector T, Sullivan PF, Suvisaari J, Tai ES, Teo YY, Tiinamaija T, Tsuang M, Turner D, Tusie-Luna T, Vartiainen E, Vawter MP, Ware JS, Watkins H, Weersma RK, Wessman M, Wilson JG, Xavier RJ, Ware JS, Havulinna AS, Iliadou B, Lee J-J, Nadkarni GN, Whiteman C, Agee Met al., 2021, The effect of LRRK2 loss-of-function variants in humans (vol 26, pg 869, 2020), Publisher: NATURE RESEARCH

Other

Whiffin N, Armean IM, Kleinman A, Marshall JL, Minikel EV, Goodrich JK, Quaife NM, Cole JB, Wang Q, Karczewski KJ, Cummings BB, Francioli L, Laricchia K, Guan A, Alipanahi B, Morrison P, Baptista MAS, Merchant KM, Ware JS, Havulinna AS, Iliadou B, Lee J-J, Nadkarni GN, Whiteman C, Daly M, Esko T, Hultman C, Loos RJF, Milani L, Palotie A, Pato C, Pato M, Saleheen D, Sullivan PF, Alfoldi J, Cannon P, MacArthur DGet al., 2020, The effect of LRRK2 loss-of-function variants in humans, NATURE MEDICINE, Vol: 26, Pages: 869-+, ISSN: 1078-8956

Journal article

Whiffin N, Karczewski KJ, Zhang X, Chothani S, Smith MJ, Evans DG, Roberts AM, Quaife NM, Schafer S, Rackham O, Alföldi J, O'Donnell-Luria AH, Francioli LC, Genome Aggregation Database Production Team, Genome Aggregation Database Consortium, Cook SA, Barton PJR, MacArthur DG, Ware JSet al., 2020, Characterising the loss-of-function impact of 5' untranslated region variants in 15,708 individuals, Nature Communications, Vol: 11, Pages: 1-12, ISSN: 2041-1723

Upstream open reading frames (uORFs) are tissue-specific cis-regulators of protein translation. Isolated reports have shown that variants that create or disrupt uORFs can cause disease. Here, in a systematic genome-wide study using 15,708 whole genome sequences, we show that variants that create new upstream start codons, and variants disrupting stop sites of existing uORFs, are under strong negative selection. This selection signal is significantly stronger for variants arising upstream of genes intolerant to loss-of-function variants. Furthermore, variants creating uORFs that overlap the coding sequence show signals of selection equivalent to coding missense variants. Finally, we identify specific genes where modification of uORFs likely represents an important disease mechanism, and report a novel uORF frameshift variant upstream of NF2 in neurofibromatosis. Our results highlight uORF-perturbing variants as an under-recognised functional class that contribute to penetrant human disease, and demonstrate the power of large-scale population sequencing data in studying non-coding variant classes.

Journal article

Chothani S, Schäfer S, Adami E, Viswanathan S, Widjaja AA, Langley SR, Tan J, Wang M, Quaife NM, Pua CJ, D'Agostino G, Shekeran SG, George BL, Lim S, Cao EY, van Heesch S, Witte F, Felkin LE, Christodoulou EG, Dong J, Blachut S, Patone G, Barton PJR, Hubner N, Cook SA, Rackham OJLet al., 2019, Widespread translational control of fibrosis in the human heart by RNA-binding proteins, Circulation, Vol: 140, Pages: 937-951, ISSN: 0009-7322

BACKGROUND: Fibrosis is a common pathology in many cardiac disorders and is driven by the activation of resident fibroblasts. The global post-transcriptional mechanisms underlying fibroblast-to-myofibroblast conversion in the heart have not been explored. METHODS: Genome-wide changes of RNA transcription and translation during human cardiac fibroblast activation were monitored with RNA sequencing and ribosome profiling. We then used an RNA-binding protein-based analyses to identify translational regulators of fibrogenic genes. The integration with cardiac ribosome occupancy levels of 30 dilated cardiomyopathy patients demonstrates that these post-transcriptional mechanisms are also active in the diseased fibrotic human heart. RESULTS: We generated nucleotide-resolution translatome data during the TGFβ1-driven cellular transition of human cardiac fibroblasts to myofibroblasts. This identified dynamic changes of RNA transcription and translation at several time points during the fibrotic response, revealing transient and early-responder genes. Remarkably, about one-third of all changes in gene expression in activated fibroblasts are subject to translational regulation and dynamic variation in ribosome occupancy affects protein abundance independent of RNA levels. Targets of RNA-binding proteins were strongly enriched in post-transcriptionally regulated genes, suggesting genes such as MBNL2 can act as translational activators or repressors. Ribosome occupancy in the hearts of patients with dilated cardiomyopathy suggested the same post-transcriptional regulatory network was underlying cardiac fibrosis. Key network hubs include RNA-binding proteins such as PUM2 and QKI that work in concert to regulate the translation of target transcripts in human diseased hearts. Furthermore, silencing of both PUM2 and QKI inhibits the transition of fibroblasts toward pro-fibrotic myofibroblasts in response to TGFβ1. CONCLUSIONS: We reveal widespread translational effects of

Journal article

van Heesch S, Witte F, Schneider-Lunitz V, Schulz JF, Adami E, Faber AB, Kirchner M, Maatz H, Blachut S, Sandmann C-L, Kanda M, Worth CL, Schafer S, Calviello L, Merriott R, Patone G, Hummel O, Wyler E, Obermayer B, Mücke MB, Lindberg EL, Trnka F, Memczak S, Schilling M, Felkin LE, Barton PJR, Quaife NM, Vanezis K, Diecke S, Mukai M, Mah N, Oh S-J, Kurtz A, Schramm C, Schwinge D, Sebode M, Harakalova M, Asselbergs FW, Vink A, de Weger RA, Viswanathan S, Widjaja AA, Gärtner-Rommel A, Milting H, dos Remedios C, Knosalla C, Mertins P, Landthaler M, Vingron M, Linke WA, Seidman JG, Seidman CE, Rajewsky N, Ohler U, Cook SA, Hubner Net al., 2019, The translational landscape of the human heart, Cell, Vol: 178, Pages: 242-260.e29, ISSN: 0092-8674

Gene expression in human tissue has primarily been studied on the transcriptional level, largely neglecting translational regulation. Here, we analyze the translatomes of 80 human hearts to identify new translation events and quantify the effect of translational regulation. We show extensive translational control of cardiac gene expression, which is orchestrated in a process-specific manner. Translation downstream of predicted disease-causing protein-truncating variants appears to be frequent, suggesting inefficient translation termination. We identify hundreds of previously undetected microproteins, expressed from lncRNAs and circRNAs, for which we validate the protein products in vivo. The translation of microproteins is not restricted to the heart and prominent in the translatomes of human kidney and liver. We associate these microproteins with diverse cellular processes and compartments and find that many locate to the mitochondria. Importantly, dozens of microproteins are translated from lncRNAs with well-characterized noncoding functions, indicating previously unrecognized biology.

Journal article

Perbellini F, Watson SA, Scigliano M, Alayoubi S, Tkach S, Bardi I, Quaife N, Kane C, Dufton NP, Simon A, Sikkel MB, Faggian G, Randi AM, Gorelik J, Harding S, Terracciano CMNet al., 2017, Investigation of cardiac fibroblasts using myocardial slices, Cardiovascular Research, Vol: 114, Pages: 77-89, ISSN: 1755-3245

AimsCardiac fibroblasts (CFs) are considered the principal regulators of cardiac fibrosis. Factors that influence CF activity are difficult to determine. When isolated and cultured in vitro, CFs undergo rapid phenotypic changes including increased expression of α-SMA. Here we describe a new model to study CFs and their response to pharmacological and mechanical stimuli using in vitro cultured mouse, dog and human myocardial slices.Methods and resultsUnloading of myocardial slices induced CF proliferation without α-SMA expression up to 7 days in culture. CFs migrating onto the culture plastic support or cultured on glass expressed αSMA within 3 days. The cells on the slice remained αSMA(−) despite transforming growth factor-β (20 ng/ml) or angiotensin II (200 µM) stimulation. When diastolic load was applied to myocardial slices using A-shaped stretchers, CF proliferation was significantly prevented at Days 3 and 7 (P < 0.001).ConclusionsMyocardial slices allow the study of CFs in a multicellular environment and may be used to effectively study mechanisms of cardiac fibrosis and potential targets.

Journal article

Quaife NM, Watson O, Chico TJA, 2012, Zebrafish: an emerging model of vascular development and remodelling, CURRENT OPINION IN PHARMACOLOGY, Vol: 12, Pages: 608-614, ISSN: 1471-4892

Journal article

Quaife NM, Chico TJA, 2012, BLOOD FLOW IS REQUIRED FOR ENDOTHELIAL REPAIR IN A NOVEL IN VIVO MODEL USING ZEBRAFISH EMBRYOS, HEART, Vol: 98, Pages: A68-A68, ISSN: 1355-6037

Journal article

, 2012, Trainees' presentations: Publication of Abstracts from the Best Regional Presentations, Annals of The Royal College of Surgeons of England, Vol: 94, Pages: 46-54, ISSN: 0035-8843

Journal article

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