Denise Sheer Inaugural Lecture
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Transcript of Denise Sheer Inaugural Lecture
De Generatione Animalium On the Generation of Animals William Harvey, 1651
Ex ovo omnia From the egg, everything
1578-1657
Denise Sheer ~ Inaugural Lecture 10th May 2010
From the chromosome… everything
Denise Sheer
Centre for Neuroscience & Trauma
Denise Sheer ~ Inaugural Lecture 10th May 2010
Walther Flemming 1843-1905
Antonie van Leeuwenhoek 1632-1723
Polytene chromosomes in Chironomus
Dividing cells Chick red blood cells
Denise Sheer ~ Inaugural Lecture 10th May 2010
Cells behave as they do because of their genes
Cell nucleus
46 chromosomes
Genes DNA
Denise Sheer ~ Inaugural Lecture 10th May 2010
Where do genes map onto chromosomes?
What is the architecture of the chromosome?
Which genetic abnormalities are involved in cancer?
Denise Sheer ~ Inaugural Lecture 10th May 2010
A path travelled well….
Denise Sheer ~ Inaugural Lecture 10th May 2010
Dr Jenni Tsafrir Genetics of eye colour
What was known then about chromosomes? 1965 - Barbara McClintock, Cornell University-Aspects of Gene Control in Higher Organisms
“mechanisms related to.. .the chromosomes…and the highly organized nuclei”.
Down Syndrome
Denise Sheer ~ Inaugural Lecture 10th May 2010
1969-1973 University of the Witwatersrand Johannesburg B.Sc - Zoology & Embryology BSc (Hons) - Zoology
Prof Barry Fabian Prof Boris Balinsky Professor Barry Fabian
nature Lifetime Mentoring Award 2007
Denise Sheer ~ Inaugural Lecture 10th May 2010
Hamburger & Hamilton 1951
Balinsky 1925
Amabis & Cabral 1970
Denise Sheer ~ Inaugural Lecture 10th May 2010
1974-1975 South African Institute of Medical Research
Anti-Snake Venom Primate Research
Prof Trefor Jenkins
Diagnostic genetics
Genetic counselling
Chromosome banding
“Effects of dagga on primate chromosomes”
Down Syndrome
Denise Sheer ~ Inaugural Lecture 10th May 2010
Supervisor: Dr Martin Bobrow
1976-1980 University of Oxford D.Phil.
Sir Walter Bodmer
Reproduced with kind permission of Juliet Wood
X X
x X
X x v
v v v v v v v v v v v v
v v v v v v v
v v v
X
v v v v v v v
v v v v
v v v v v v v
v v v
x
Human Cells
Mouse Cells
Gene 1 Gene 2 Gene 3
Human-Mouse Hybrid Cells
Mapping genes onto chromosomes
Denise Sheer ~ Inaugural Lecture 10th May 2010
Imperial Cancer Research Fund/ Cancer Research UK 1980-1982 Post-Doctoral Research Fellow with Dr. Ellen Solomon 1982-2006 Head: Human Cytogenetics Laboratory
Mapping genes onto chromosomes
Denise Sheer ~ Inaugural Lecture 10th May 2010
Mapping genes onto chromosomes
LIMK1
TP53
XPG
ERBA2
ERBA1
APC
MHC
KIR/ILT
TOP2B
FRAX
EIF-5A
NOS1 ELK3
NOS3
HOXB
Denise Sheer ~ Inaugural Lecture 10th May 2010
Mapping the APC gene on chromosome 5
Adenomatous Polyposis Coli APC gene at 5q21
Bodmer et al 1987
Denise Sheer ~ Inaugural Lecture 10th May 2010
Genetic abnormalities in cancer
At the cellular level, cancer is a genetic disease
Denise Sheer ~ Inaugural Lecture 10th May 2010
Acute Lymphoblastic Leukaemia Acute Myelomonocytic Leukaemia
Acute Promyelocytic Leukaemia
Breast Carcinoma
Chronic Myeloid Leukaemia
Colorectal Adenoma
Congenital Fibrosarcoma
Ewing’s Sarcoma
Glioblastoma Krukenberg Tumour
Neuroblastoma
Ovarian Carcinoma
Pancreatic Carcinoma
Primitive Neuro-ectodermal Tumour
Genetic abnormalities in cancer
Ovarian Carcinoma
Glioblastoma
Neuroblastoma
Breast Carcinoma
Denise Sheer ~ Inaugural Lecture 10th May 2010
15;17 identified in all cases of APL Mapping the breakpoints
15;17 chromosome translocation in Acute Promyelocytic Leukaemia
X X
x X
X x
v
V v v v v v v v v v v v
v
Human Cells
Mouse Cells
v v v v v v v
v v V Gene 1
v v v v v v v
v v v
x
Gene 2
Sheer et al 1983
Sheer et al 1985
Denise Sheer ~ Inaugural Lecture 10th May 2010
What is the architecture of the chromosome?
“The great tragedy of science - the slaying of a beautiful hypothesis by an ugly fact” Thomas Henry Huxley (1870)
Thomas & Marion Cremer
Comings 1968 Cremer et al 1976
Chinese Hamster cells after focal laser UV irradiation
Chromosome Territories Inter-Chromosome Domain
Cremer et al 1993
Denise Sheer ~ Inaugural Lecture 10th May 2010
Chromosomes occupy discrete territories
Cremer & Cremer 2006 Bolzer et al 2005
Denise Sheer ~ Inaugural Lecture 10th May 2010
6!
TAP2
PS
MB
8 TA
P1
PSM
B9
C2
BF
C4
HLA
-F
HLA
-G
HLA
-A
HLA
-E
HLA
-C
HLA
-B
MIC
B
C6o
rf10
H
LA-D
RA
HLA
-DQ
A1,
2
HLA
-DQ
B1,
2 H
LA-D
OB
HLA
-DM
A H
LA-D
OA
HLA
-DPA
1
RIN
G1
HLA
-DPB
1
TAPB
P
TNF
HSP
A1
TNXB
NO
TCH
4
HLA
-DR
B1,
3,4,
5
* * * *
*
* * *
* *
* * * * * *
* * * *
*
The Major Histocompatibility Complex - a perfect model
MHC-
Cell-Type Specific & Inducible Gene Activity
Denise Sheer ~ Inaugural Lecture 10th May 2010
MHC
Chr 6
Inac&ve Ac&ve
Chromosome architecture is related to gene activity
Volpi et al 2000
Inac&ve Ac&ve
* *
* *
*
*
Ac&ve
Denise Sheer ~ Inaugural Lecture 10th May 2010
2006 Centre for Neuroscience & Trauma Blizard Institute of Cell & Molecular Science Barts & the London School of Medicine & Dentistry Queen Mary University of London
What is the architecture of the chromosome? What are the molecular determinants?
Which genetic abnormalities are involved in cancer? How do children’s brain tumours arise?
Denise Sheer ~ Inaugural Lecture 10th May 2010
Chromosome architecture is dependent on signalling pathways
Inac&ve
Ac&ve
Interferon Gamma
JAK-STAT SIGNALLING
Christova et al 2007 Denise Sheer ~ Inaugural Lecture 10th May 2010
Chromosome architecture is related to gene activity
Inac&ve
Ac&ve
Anchored sites
Ottaviani et al 2008a,b
Denise Sheer ~ Inaugural Lecture 10th May 2010
Genetic abnormalities in paediatric low grade astrocytoma
SEER Denise Sheer ~ Inaugural Lecture 10th May 2010
Tiny duplication on chromosome 7 in pilocytic astrocytoma
Denise Sheer ~ Inaugural Lecture 10th May 2010
Forshew et al 2009; Tatevossian et al 2010; Lawson et al 2010
Tiny duplication on chromosome 7 in pilocytic astrocytoma
Denise Sheer ~ Inaugural Lecture 10th May 2010
KIAA1549 BRAF
Genes duplicated on chromosome 7
Forshew et al 2009; Tatevossian et al 2010; Lawson et al 2010 Denise Sheer ~ Inaugural Lecture 10th May 2010
KIAA1549 BRAF
KIAA1549 BRAF KIAA1549- BRAF fusion
Forshew et al 2009; Tatevossian et al 2010; Lawson et al 2010
Genes duplicated on chromosome 7
Denise Sheer ~ Inaugural Lecture 10th May 2010
The MAP kinase signalling pathway
BRAF
MEK1/2
ERK1/2
RAS NF1
Signals from outside the cell
Forshew et al 2009; Tatevossian et al 2010; Lawson et al 2010
Regulated Cell Division
Denise Sheer ~ Inaugural Lecture 10th May 2010
BRAF
MEK1/2
ERK1/2
RAS
P
P
Regulated Cell Division
NF1
Signals from outside the cell
The MAP kinase signalling pathway
Denise Sheer ~ Inaugural Lecture 10th May 2010
BRAF fusion causes cells to keep dividing
MEK1/2
ERK1/2
RAS
P
P
NF1
Signals from outside the cell
BRAF KIAA1549
Increased Cell Division
Denise Sheer ~ Inaugural Lecture 10th May 2010
MEK1/2
ERK1/2
RAS
P
P
NF1
Signals from outside the cell
BRAF KIAA1549
New opportunities for treatment for pilocytic astrocytoma
Inhibitor
Increased Cell Division
Denise Sheer ~ Inaugural Lecture 10th May 2010
BRAF fusions: A microhomology mediated mechanism?
microhomology
insertion
microhomology
microhomology
microhomology
microhomology
insertion
Lawson, Hindley et al Denise Sheer ~ Inaugural Lecture 10th May 2010
BRAF fusions: A microhomology mediated mechanism?
Denise Sheer ~ Inaugural Lecture 10th May 2010
Where to now?
Where do genes map onto chromosomes? What is the architecture of the chromosome?
Which genetic abnormalities are involved in cancer?
Cremer et al 2006
Denise Sheer ~ Inaugural Lecture 10th May 2010
Centre for Neuroscience and Trauma Prof John Priestley ~ Prof Gavin Giovannoni
Surinder Pal ~ Carol Brown
Sir Nick Wright Prof Tom MacDonald
Prof Mike Curtis Jo Kirner ~ Kerry Newbury
Josie Dance
BLIZARD INSTITUTE OF CELL AND MOLECULAR SCIENCE
Denise Sheer ~ Inaugural Lecture 10th May 2010
Johan Aarum Pavel Bezecny Rossi Christova
Tim Forshew Guy Hindley
Gabriel Jamie Tania Jones
Andrew Lawson Elliott Lever
William Ogunkolade Diego Ottaviani
Chris Pieri Jarek Szary
Ruth Tatevossian Denise Sheer ~ Inaugural Lecture 10th May 2010
Jane Babbage Srinjan Basu Andi Bolzer
Guiseppe Calabrese Edith Chevret Rossen Donev Ceri Edwards
Luda Federova Rachel Gillingham
Pat Gorman Vikki Groves
Peter Johonnett Fiona Kiely
Xin Mao Chiara Mazzanti Paul Mulholland Rosella Muresu Alistair Newall
Rodger Palmer Ketan Patel
Chrys Poulikas Sue Rider
Rebecca Roylance Gabi Senger Carol Shiels
Janet Shipley Petros Takousis
Badmavady Segarane Clare Taylor
Radost Vatcheva Emanuela Volpi Jayson Wang
Sarah Williams Jill Williamson
Pei Jun Wu
Stephan Beck Walter Bodmer Marion Cremer
Thomas Cremer Thomas Down David Ellison
Thomas Jacques Chris Jones Gavin Kelly
David Kelsell Steve Krawetz
Mike Levin Andrew Lister
Antony Michalski Richard Mitter
Paul Mulholland
Dean Nizetic Andrew Pearson
Jon Pritchard Jiannis Ragoussis
Peter Sasieni Janet Shipley Andrew Silver Jeremy Squire
John Trowsdale Frank Uhlmann
Bryan Young
Denise Sheer ~ Inaugural Lecture 10th May 2010
Denise Sheer ~ Inaugural Lecture 10th May 2010