WIMM PI
Curriculum Vitae
Personal Data
Name
Nationality
Email
Andrew Wilkie
UK
andrew.wilkie@imm.ox.ac.uk
Present Position
2003-present
Nuffield Professor of Pathology, Nuffield Department of Clinical Laboratory
Sciences, University of Oxford
1993-present
Honorary Consultant in Clinical Genetics at the Department of Medical
Genetics, Churchill Hospital, Oxford, and the Craniofacial Unit, John
Radcliffe Hospital, Oxford
Previous Positions
1995-2003
Wellcome Trust Senior Research Fellow in Clinical Science, WIMM
1993-1995
Wellcome Trust Advanced Research Fellow, WIMM
1992-1993
Senior Registrar in Genetics, University Hospital of Wales, Cardiff
1991-1992
Clinical Research Fellow in Dysmorphology, Institute of Child Health, London,
and Locum Senior Registrar in Paediatric Genetics, Hospital for Sick Children,
Great Ormond Street, London.
1987-1990
MRC Training Fellow at the MRC Molecular Haematology Unit, IMM, Oxford
1986-1987
Senior House Officer in Paediatrics, Bristol
1985-1986
Senior House in Cardiology, Brompton Hospital, London
1985
Senior House Officer in Neurology, St. Bartholomew's Hospital London
1984-1985
Senior House Officer in Gastroenterology, Hammersmith Hospital, London
1984
House Physician, Nuffield Department of Medicine, John Radcliffe Hospital,
Oxford
1983-1984
House Surgeon in Urology and General Surgery, Battle Hospital, Reading
Research Achievements
As a practicing clinical geneticist I aim to exploit the molecular genetic analysis of individual
patients presenting with congenital disorders, both to reveal the cause of their condition and
to uncover genetic principles of wider biological and pathological relevance. Since starting as
a group leader in Oxford in 1993 I have fostered very close clinical contacts with the
craniofacial unit in Oxford, one of five covering the entire UK. As a result of this ongoing 20year collaboration, the Oxford patients probably represent the best characterized cohort of
craniofacial patients internationally from a molecular genetic standpoint. During this period
my group has discovered many genes that, when mutated, cause serious craniofacial
conditions, notably various types of craniosynostosis (premature fusion of the cranial
sutures). Many of these discoveries have led to the development of molecular genetic
diagnostic tests now in clinical use; the Churchill Hospital provides one of two national
diagnostic services for craniofacial disorders and I sign off all lab reports issued by the
service. Work on mouse models carrying equivalent mutations has helped to further
elucidate the developmental mechanisms of several craniosynostosis syndromes.
Starting from the identification of mutations in fibroblast growth factor receptor 2 (FGFR2) in
Apert syndrome (a cause of craniosynostosis), and the deduction that these mutations were
arising with unexpectedly high frequency in the healthy fathers, my group discovered a novel
mechanism whereby pathogenic mutations within the testis can promote the enrichment of
mutant spermatogonia. Recent work has identified similar mutations in testicular tumours,
linking the processes of somatic and germline mutation to events occurring in the same cell.
This work provides fundamental novel insights into mutational processes that may have
implications beyond congenital malformations to include common complex diseases such as
cancer and neuropsychiatric disorders.
Lay Summary of Research
About 1 in 2,000 children is born with a serious malformation of the skull: the most frequent
type is termed “craniosynostosis”, the premature fusion of the cranial sutures. Parents want
to know why this has happened, whether it could happen again, and whether any tests are
available to determine the answers to these questions.
Working closely with surgeons in Oxford who treat these children, our laboratory aims to
identify new genetic causes of these malformations. Over the past 20 years we have
identified over ten new causative genes, which have been introduced into laboratory testing
in the NHS and around the world. Using modern technologies that combine the ability to
sequence an entire human genome in a single experiment with computational methods to
analyse the data, we now aim to compile a comprehensive compendium of the possible gene
mutations, and their relative frequency over the next few years, so that more families can get
answers to their questions.
Additional benefits of this work are that we can learn more both about how the skull
develops, and why the causative genetic changes (mutations) arise. To answer the first
question, we need to use mice that recapitulate several features of the human disorder,
since it would be unethical to investigate the origins of developmental malformation in the
human fetus. Working on the mechanisms of mutation, we have stumbled on an unexpected
process whereby changes to genes arising in the healthy father’s testis that are harmful in
the offspring, are paradoxically beneficial to cells within the testis itself. We term this process
“selfish selection”. Again exploiting new technologies, the other major thrust of our laboratory
is to explore the wider consequences of this new mechanism for causing disease.
All Publications Over the Past 5 Years (*corresponding author)
Mansour SL, Twigg SRF, Freeland RM, Wall SA, Li C & Wilkie AOM (2009). Hearing loss in
a mouse model of Muenke syndrome. Hum Mol Genet18:43-50.
Bochukova EG, Roscioli T, Hedges DJ, Taylor IB, Johnson D, David DJ, Deininger PL &
Wilkie AOM* (2009). Rare mutations of FGFR2 causing Apert syndrome: identification of
the first partial gene deletion, and an Alu element insertion from a new subfamily. Hum
Mutat 30:204-211.
Twigg SRF, Healy C, Babbs C, Sharpe JA, Wood WG, Sharpe PT, Morriss-Kay GM & Wilkie
AOM* (2009). Skeletal analysis of the Fgfr3P244R mouse, a genetic model for the Muenke
craniosynostosis syndrome. Dev Dyn 238:331-342.
Twigg SRF, Versnel SL, Nürnberg G, Lees MM, Bhat M, Hammond P, Hennekam RCM,
Hoogeboom AJM, Hurst JA, Johnson D, Robinson AA, Scambler PJ, Gerrelli D, Nürnberg
P, Mathijssen IMJ & Wilkie AOM* (2009). Frontorhiny, a distinctive presentation of
frontonasal dysplasia caused by recessive mutations in the ALX3 homeobox gene. Am J
Hum Genet 84:698-705.
Woods RH, Ul-Haq E, Wilkie AOM, Jayamohan J, Richards PG, Johnson D, Lester T & Wall
SA (2009). Reoperation for intracranial hypertension in TWIST1 confirmed SaethreChotzen syndrome: a 15 year review. Plast Reconstr Surg 123:1801-1810.
Furniss D, Kan S-h, Taylor IB, Johnson D, Critchley PS, Giele HP & Wilkie AOM* (2009).
Genetic screening of 202 individuals with congenital limb malformations and requiring
reconstructive surgery. J Med Genet 46:730-735.
Goriely A, Hansen RMS, Taylor IB, Olesen IA, Jacobsen GK, McGowan SJ, Pfeifer SP,
McVean GAT, Rajpert-De Meyts E & Wilkie AOM* (2009). Activating mutations in FGFR3
and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors.
Nature Genet 41:1247-1252.
Kini U, Hurst JA, Byren JC, Wall SA, Johnson D & Wilkie AOM (2010). Etiological
heterogeneity and clinical characteristics of metopic synostosis: evidence from a tertiary
craniofacial unit. Am J Med Genet 152A:1383-1389.
Goriely A, Lord H, Lim J, Johnson D, Lester T, Firth HV & Wilkie AOM* (2010). Germline and
somatic mosaicism for FGFR2 mutation in the mother of a child with Crouzon syndrome:
implications for genetic testing in ‘paternal age-effect’ syndromes. Am J Med Genet
152A:2067-2073.
Wilkie AOM*, Byren JC, Hurst JA, Jayamohan J, Johnson D, Knight SJL, Lester T, Richards
PG, Twigg SRF & Wall SA (2010). Prevalence and complications of single gene and
chromosomal disorders in craniosynostosis. Pediatrics 126:e391-e400.
Bochukova EG, Soneji S, Wall SA & Wilkie AOM* (2010). Scalp fibroblasts have a shared
expression profile in monogenic craniosynostosis. J Med Genet 47:803-808.
Jenkins D, Baynam G, De Catte L, Elcioglu N, Gabbett MT, Hudgins L, Hurst JA, Jehee FS,
Oley C & Wilkie AOM* (2011). Carpenter syndrome: extended RAB23 mutation spectrum
and analysis of nonsense-mediated mRNA decay. Hum Mutat 32:E2069-78.
Hurst JA, Jenkins D, Vasudevan PC, Kirchhoff M, Skovby F, Rieubland C, Gallati S, Rittinger
O, Kroisel PM, Johnson D, Biesecker LG & Wilkie AOM* (2011). Metopic and sagittal
synostosis in Greig cephalopolysyndactyly syndrome: five cases with intragenic mutations
or complete deletions of GLI3. Eur J Hum Genet 19:757-762
Nieminen P, Morgan NV, Fenwick AL, Parmanen S, Veistinen L, Mikkola ML, van der Spek
PJ, Giraud A, Judd L, Arte S, Brueton LA, Wall SA, Mathijssen IMJ, Maher ER, Wilkie
AOM, Kreiborg S & Thesleff I (2011). Inactivation of IL11 signaling causes
craniosynostosis, delayed tooth eruption and supernumerary teeth. Am J Hum Genet
89:67-81.
Lim J, Goriely A, Turner GDH, Ewen KA, Jacobsen GK, Graem N, Wilkie AOM & Rajpert-De
Meyts E (2011). OCT2, SSX and SAGE1 reveal the phenotypic heterogeneity of
spermatocytic seminoma reflecting distinct subpopulations of spermatogonia. J Pathol
224:473-483.
Babbs C, Stewart HS, Williams LJ, Connell L, Goriely A, Twigg SRF, Smith K, Lester T &
Wilkie AOM* (2011). Duplication of the EFNB1 gene in familial hypertelorism: imbalance
in ephrin-B1 expression and abnormal phenotypes in humans and mice. Hum Mutat
32:930-938.
Fenwick AL, Bowdin SC, Klatt REM & Wilkie AOM (2011). A deletion of FGFR2 creating a
chimeric IIIb/IIIc exon in a child with Apert syndrome. BMC Med Genet 12:122.
Barroso E, Pérez-Carrizosa V, García-Recuero I, Glucksman MJ, Wilkie AO, García-Minaur
S & Heath KE (2011). Mild isolated craniosynostosis due to a novel FGFR3 mutation,
p.Ala334Thr. Am J Med Genet A 155:3050-3053.
Sharma VP, Wall SA, Lord H, Lester T & Wilkie AOM* (2012). Atypical Crouzon syndrome
with a novel Cys62Arg mutation in FGFR2 presenting with sagittal synostosis. Cleft
Palate Craniofac J 49:373-377.
Lim J, Maher GJ, Turner GDH, Dudka-Ruszkowska W, Taylor S, Rajpert-De Meyts E,
Goriely A & Wilkie AOM* (2012). Selfish spermatogonial selection: evidence from an
immunohistochemical screen in testes of elderly men. PLoS ONE 7:e42382.
Twigg SRF, Lloyd D, Jenkins D, Elcioglu N, Cooper CDO, Al-Sannaa N, Annagür A,
Gillessen-Kaesback G, Stefanova I, Knight SJL, Goodship JA, Keavney B, Beales PL,
Gileadi O, McGowan SJ & Wilkie AOM* Mutations in the multidomain protein MEGF8
identify a new subtype of Carpenter syndrome associated with defective lateralization.
Am J Hum Genet 91:897-905.
Eley KA, Johnson D, Wilkie AOM, Jayamohan J, Richards P & Wall SA (2012). Raised
intracranial pressure is frequent in untreated non-syndromic unicoronal synostosis and
does not correlate with severity of phenotypic features. Plast Reconstr Surg 130:690e697e.
Bendon CL, Fenwick AL, Hurst JA, Nürnberg G, Nürnberg P, Wall SA, Wilkie AOM &
Johnson D (2012). Frank-ter Haar syndrome associated with sagittal craniosynostosis
and raised intracranial pressure. BMC Med Genet 13:104.
Justice CM, Yagnik G, Kim Y, Peter I, Jabs EW, Erazo M, Ye X, Ainehsazan E, Shi L,
Cunningham ML, Kimonis V, Roscioli T, Wall SA, Wilkie AOM, Stoler J, Richtsmeier JT,
Heuzé Y, Sanchez-Lara PA, Buckley MF, Druschel CM, Mills JL, Caggana M, Romitti PA,
Kay DM, Senders C, Taub PJ, Klein OD, Boggan J, Zwienenberg-Lee M, Naydenov C,
Kim J, Wilson AF & Boyadjiev SA (2012). A genome-wide association study identifies
susceptibility loci for non-syndromic sagittal craniosynostosis near BMP2 and within
BBS9. Nature Genet 44:1360-1364.
Varvagiannis K, Stefanidou A, Gyftodimou Y, Lord H, Williams L, Sarri C, Pandelia E,
Bazopoulou-Kyrkanidou E, Noakes C, Lester T, Wilkie AOM & Petersen MB (2013). Pure
de novo partial trisomy 6p in a girl with craniosynostosis. Am J Med Genet A 161A:343351.
Shanks ME, Downes SM, Copley RR, Lise S, Broxholme J, Hudspith KAZ, Kwasniewska A,
Davies WIL, Hankins MW, Packham E, Clouston P, Seller A, Wilkie AOM, Taylor JC,
Ragoussis J & Németh (2013). Next Generation Sequencing (NGS) as a diagnostic tool
for retinal degeneration reveals a much higher detection rate in early onset disease. Eur J
Hum Genet 21:274-280.
Vodopiutz J, Zoller H, Fenwick AL, Arnhold R, Schmid M, Prayer D, Müller T, Repa A, Pollak
A, Aufricht C, Wilkie AOM & Janecke AR (2013). Homozygous SALL1 mutation causes a
novel multiple congenital anomaly - mental retardation syndrome. J Pediatr 162:612-617.
Sharma VP, Fenwick AL, Brockop MS, McGowan SJ, Goos JAC, Hoogeboom AJM, Brady
AF, Jeelani NuO, Lynch SA, Mulliken JB, Murray DJ, Phipps JM, Sweeney E, Tomkins
SE, Wilson LC, Bennett S, Cornall RJ, Broxholme J, Kanapin A, WGS500, Johnson D,
Wall SA, van der Spek PJ, Mathijssen IMJ, Maxson RE, Twigg SRF & Wilkie AOM*
(2013). Mutations of TCF12, encoding a basic-helix-loop-helix partner of TWIST1, are a
frequent cause of coronal craniosynostosis. Nature Genet 45:304-307.
Twigg SRF, Vorgia E, McGowan SJ, Peraki I, Fenwick AL, Sharma VP, Allegra M,
Zaragkoulias A, Akha ES, Knight SJL, Lord H, Lester T, Izatt L, Lampe AK, Mohammed
SN, Stewart FJ, Verloes A, Wilson LC, Healy C, Sharpe PT, Hammond P, Hughes J,
Taylor S, Johnson D, Wall SA, Mavrothalassitis G & Wilkie AOM* (2013). Reduced
dosage of ERF causes complex craniosynostosis in humans and mice, and links ERK1/2
signalling to regulation of osteogenesis. Nature Genet 45:308-313.
Twigg SRF, Babbs C, van den Elzen MEP, Goriely A, Taylor S, McGowan SJ, Giannoulatou
E, Lonie L, Ragoussis I, Akha ES, Knight SJL, Ceide RZ, Hoogeboom AJM, PassosBueno MR, Pober BR, Toriello HV, Wall SA, Brunner HG, Mathijssen IMJ & Wilkie AOM*
(2013). Cellular interference in craniofrontonasal syndrome: males mosaic for mutations
in the X-linked EFNB1 gene are more severely affected than true hemizygotes. Hum Mol
Genet 22:1654-1662.
Jay S, Wiberg A, Swan M, Lester T, Williams LJ, Taylor IB, Johnson D & Wilkie AOM*
(2013). The fibroblast growth factor receptor 2 p.Ala172Phe mutation in Pfeiffer syndrome
– history repeating itself. Am J Med Genet 161A:1158-1163.
Reviews
Wilkie AOM* (2009). Pitfalls in the phylogenomic evaluation of human disease-causing
mutations. J Biol 8:26.1-26.5.
Johnson D & Wilkie AOM* (2011). Craniosynostosis. Eur J Hum Genet 19:369-376.
Goriely A* & Wilkie AOM* (2012). Paternal age effect mutations and selfish spermatogonial
selection: causes and consequences for human disease. Am J Hum Genet 90:175-200.
Clarke AJ, Cooper DN, Krawczak M, Tyler-Smith C, Wallace HM, Wilkie AOM, Raymond FL,
Chadwick R,Craddock N, John R, Gallacher J & Chiano M (2012). ‘Sifting the significance
from the data’ - the impact of high-throughput genomic technologies on human genetics
and health care. Hum Genomics 6:11.
Goriely A, McGrath JJ, Hultman CM, Wilkie AOM & Malaspina D (2013). "Selfish
spermatogonial selection": a novel mechanism for the association between advanced
paternal age and neurodevelopmental disorders. Am J Psych 170:599-608.
Book chapters
Wilkie AOM (2013). Genetics of craniosynostosis. In: Maloy S & Hughes K (eds). Brenner’s
Encyclopedia of Genetics 2nd edition, Academic Press, San Diego, Vol 2 pp. 208–211.
Letters/short reports
Kurth I, Klopocki E, Stricker S, van Oosterwijk J, Vanek S, Altmann J, van Harssel J, de
Ravel T, Wilkie AOM, Gal A & Mundlos S (2009). Duplications of non-coding elements 5´
of SOX9 are associated with brachydactyly/anonychia. Nature Genet 41: 862-863.
Twigg SRF, Versnel SL, Mathijssen IMJ & Wilkie AOM (2010). Another family with
frontorhiny. Cleft Palate Craniofac J 47: 430.
Goriely A & Wilkie AOM (2010). Missing heritability: paternal age effect mutations and selfish
spermatogonia. Nature Rev Genet 11:589.
Ten Key Publications Throughout your Career (* Corresponding author)
Wilkie AOM, Lamb J, Harris PC, Finney RD & Higgs DR (1990). A truncated human
chromosome 16 associated with α thalassaemia is stabilized by addition of telomeric
repeat (TTAGGG)n. Nature 346:868-871.
Wilkie AOM*, Slaney SF, Oldridge M, Poole MD, Ashworth GJ, Hockley AD, Hayward RD,
David DJ, Pulleyn LJ, Rutland P, Malcolm S, Winter RM & Reardon W (1995). Apert
syndrome results from localized mutations of FGFR2 and is allelic with Crouzon
syndrome. Nature Genet 9:165-172.
Moloney DM, Slaney SF, Oldridge M, Wall SA, Sahlin P, Stenman G & Wilkie AOM* (1996).
Exclusive paternal origin of new mutations in Apert syndrome. Nature Genet 13: 48-53.
Wilkie AOM*, Tang Z, Elanko N, Walsh S, Twigg SRF, Hurst JA, Wall SA, Chrzanowska KH
& Maxson RE Jr (2000). Functional haploinsufficiency of the human homeobox gene
MSX2 causes defects in skull ossification. Nature Genet 24: 387-390.
Goriely A, McVean GAT, Röjmyr M, Ingemarsson B & Wilkie AOM* (2003). Evidence for
selective advantage of pathogenic FGFR2 mutations in the male germline. Science
301:643-646.
Twigg SRF, Kan R, Babbs C, Bochukova EG, Robertson SP, Wall SA, Morriss-Kay GM &
Wilkie AOM* (2004). Mutations of ephrin-B1 (EFNB1), a marker of tissue boundary
formation, cause craniofrontonasal syndrome. Proc Natl Acad Sci USA 101:8652-8657.
Goriely A, McVean GAT, van Pelt AMM, O’Rourke AW, Wall SA, de Rooij DG & Wilkie
AOM* (2005). Gain-of-function amino acid substitutions drive positive selection of FGFR2
mutations in human spermatogonia. Proc Natl Acad Sci USA 102:6051-6056.
Goriely A, Hansen RMS, Taylor IB, Olesen IA, Jacobsen GK, McGowan SJ, Pfeifer SP,
McVean GAT, Rajpert-De Meyts E & Wilkie AOM* (2009). Activating mutations in FGFR3
and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors.
Nature Genet 41:1247-1252.
Sharma VP, Fenwick AL, Brockop MS, McGowan SJ, Goos JAC, Hoogeboom AJM, Brady
AF, Jeelani NuO, Lynch SA, Mulliken JB, Murray DJ, Phipps JM, Sweeney E, Tomkins
SE, Wilson LC, Bennett S, Cornall RJ, Broxholme J, Kanapin A, WGS500, Johnson D,
Wall SA, van der Spek PJ, Mathijssen IMJ, Maxson RE, Twigg SRF & Wilkie AOM*
(2013). Mutations of TCF12, encoding a basic-helix-loop-helix partner of TWIST1, are a
frequent cause of coronal craniosynostosis. Nature Genet 45:304-307.
Twigg SRF, Vorgia E, McGowan SJ, Peraki I, Fenwick AL, Sharma VP, Allegra M,
Zaragkoulias A, Akha ES, Knight SJL, Lord H, Lester T, Izatt L, Lampe AK, Mohammed
SN, Stewart FJ, Verloes A, Wilson LC, Healy C, Sharpe PT, Hammond P, Hughes J,
Taylor S, Johnson D, Wall SA, Mavrothalassitis G & Wilkie AOM* (2013). Reduced
dosage of ERF causes complex craniosynostosis in humans and mice, and links ERK1/2
signalling to regulation of osteogenesis. Nature Genet 45:308-313.
Markers of Esteem
2000
Professor of Genetics in the recognition of distinction exercise, University of
Oxford
2002
Oon International Prize in Preventive Medicine, Downing College, Cambridge and
Cambridge University Medical School
2002
Fellow of the Academy of Medical Sciences
2006
Member of European Molecular Biology Organisation
2013
Fellow of the Royal Society
Current Grant Support
1.11.10-31.10.15
Wellcome Trust Programme Grant: Selfish mutations in the testis:
impact on evolution and disease. £1,135,718 ref 091182/Z/10/Z
1.2.11-31.1.14
Wellcome Trust Project Grant: Genetic basis of craniofacial
malformations. £489,226 ref 093329/Z/10/Z
1.04.13-31.03.14
NIHR Oxford Biomedical Research Centre Genomic Medicine
Theme: Genetics of craniosynostosis. £37,449 (PI; £20k
consumables plus salaries for predoc RA and postdoc RA,
1.02.14-31.03.14)
1.8.13-31.7.14
Royal College of Surgeons One Year Research Fellowship for Mr
Vikram Sharma: Improved diagnostic outcomes in craniofacial
surgery by use of next-generation DNA sequencing. £55,854