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Genes and Society:
How a gene mutation changed the
course of world history
Eric Yap
Defence Medical Research Institute
Singapore Eye Research Institute
COFM Dept, National University of Singapore
[email protected]
Portrait of Queen
Victoria by Heinrich von
Angeli (1840-1925)
© Royal Collection
http://www.royal.gov.uk
/history/victoria.htm
Queen Victoria and Prince Albert with their nine children (1857).
Left to right: Prince Alfred, Prince Albert, Princess Helena, Prince Arthur, Princess Alice, Queen Victoria
with Beatrice, Princess Victoria, Princess Louise, Prince Leopold and Prince Edward.
The Royal Archives (copyright Her Majesty the Queen.)
Prince Leopold with Sir William Jenner at Balmoral in 1877.
(Hulton Deutsch Collection Ltd.)
http://129.128.91.75/de/genetics/70gen-hemophil.html
http://129.128.91.75/de/genetics/70gen-hemophil.html
Empress Alexandra at the Tsarevich's bedside during a haemophiliac crisis in 1912.
(Radio Times Hulton Picture Library.)
“The Khlysty sect (which influenced Rasputin) believed that one should sin
as much as possible so that repentance would be the greater and one’s
salvation the more resounding. For all that, he was a drunken, coarse,
treacherous and offensive rapist.”
RASPUTIN
Poet. Magician. Healer. Prophet. Holy Monk.
http://www.sptimes.ru/archive/
ifestyl/107/rasputin.jpg
An early practitioner of complementary medicine?
“the poor child lay in pain, dark patches under his eyes
and his little body all distorted and the leg terribly
swollen. The doctors were jus useless … more
frightened than any of us … kist whispering among
themselves. Alicky then sent a message to Rasputin
… he reached the palace around midnight. The
following morning, I just could not believe my eyes.
The little boy was not just alive but well. He was sitting
up in bed, the fear gone, his eyes clear and bright, not
a sign of swelling in the leg. Later I learned from Alicky
that Rasputin had not even touched the child, but
merely stood at the foot of the bed and prayed.”
Olga (Alexis’ older sister)
Portrait of Grigory Rasputin
Yelena Klokacheva
1871-after 1915
1914
http://www.hermitagemuseum.org/html_En/03/hm
3_6_7e.html
Assasinated Dec 1916
By two members of
Romanov family
- poisoned by cyanide
- shot twice in the chest
- shot twice in the head
- drowned in icy canal
Archduke Franz Ferdinand (heir to throne of Austro-Hungarian Empire) and wife
Sophie in Sarajevo, shortly before their assasination on 28 June 1914 by Gavrilo
Princip, a member of the Serbian Black Hand gang. This event was to lead to the First
World War.
4 million died in first year
of war
Government and military
incompetence
Food and fuel shortages
Bolshevik Revolution
1917
Nicholas II abdicated
Michael (brother)
abdicated
End of 300 yr Romanov
dynasty
British asylum refused by
King George V
16 July 1918
Ekaterinburg
All 7 members
of royal family,
doctor and 3
servants
executed.
http://129.128.91.75/de/genetics/70gen-hemophil.html
from VP Johnson, C Christianson
HEMA gene is 1000kb
from the Xq telomere
(Xqter) 186kb, 26 exons
Chromosomal localisation and structure of the factor VIII gene
http://europium.csc.mrc.ac.uk/usr/WWW/WebPages/database.dir/review.dir/Review txt.html
THE COAGULATION CASCADE
Amino acid homologies of factor VIII domains. The A and C domains have significant homology
with coagulation factor V. All three A domains have homology with ceruloplasmin and ferroxidase,
while the C domains also have homology with discoidin lectins from Dictyostelium discoides and
mouse milk fat globule membrane protein. Kazazian et al (1995).
http://europium.csc.mrc.ac.uk/usr/WWW/WebPages/database.dir/review.dir/Review_txt.html
Predicted binding-sites for FIXa and BiP on the FVIII model. FIXa: two loops, in A2 (S558-Q565)
and A3 (E1811-K1818), are shown in pink on the surface of a CPK FVIII image: view perpendicular
to the three-fold axis with 'top' and 'bottom' of the molecule marked. Also shown is the partly
exposed putative BiP binding site (T291-F309) in gold.
http://europium.csc.mrc.ac.uk/usr/WWW/WebPages/database.dir/otherstructure/htmlfiles/modelpaper.html
Transfusion / Blood Borne Diseases
VIRUSES
• HIV
• Hepatitis B
• Hepatitis C
• Hepatitis A
• Parvovirus B19
PROTEINS
• ?Prions new variant
CJD
MEASURES
• Viral inactivation
procedures by heat
inactivation and
solvent-detergent.
• Nucleic acid
screening
Somatic Cell Gene Therapy
Trials
1. Adenovirus
vector only
2. i/v Retroviral
vector + fVIII
3. Transfected
dermal
fibroblast
transplanted
peritoneally
Issues:
- Duration
- Plasma levels
- Ab inhibitors
Muscle positive for vector transduction: Canine/AAV system
courtesy of R. J. Samulski and Olivier Danos
http://www.med.unc.edu/thromb/gene.htm
Stem Cell Therapy
Almost 1000 bone pieces from five female and four male
skeletons recovered in 1989.
The Bones of Czar Nicholas II and his wife, Alexandra
http://www.best.com/users/~samsloan/czarbone.htm
STR Analysis of Ekaterinburg bones
Skeleton* HUMVAWA/31F HUMTH01 HUMF13A1 HUMFES/FPS
Tsar
15, 16
7, 10
7, 7
12, 12
Tsarina
15, 16
8, 8
3, 5
12, 13
Child
15, 16
8, 10
5, 7
12, 13
Child
15, 16
7, 8
5, 7
12, 13
Child
15, 16
8, 10
3, 7
12, 13
A
E
B
C
D
STR1
15,16
15,16
15,16
15,16
15,16
STR2
8,8
8,10
7,8
8,10
7,10
STR3
3,5
5,7
5,7
3,7
7,7
STR4
12,13
12,13
12,13
12,13
12,12
STR5
32,36
11,32
11,36
32,36
11,32
Tsarina Alix
Tsar Nicholas
A
E
B
C
D
STR1
15,16
15,16
15,16
15,16
15,16
STR2
8,8
8,10
7,8
8,10
7,10
STR3
3,5
5,7
5,7
3,7
7,7
STR4
12,13
12,13
12,13
12,13
12,12
STR5
32,36
11,32
11,36
32,36
11,32
http://129.128.91.75/de/genetics/70gen-hemophil.html
http://129.128.91.75/de/genetics/70gen-hemophil.html
Comparison of mtDNA sequence (nt 16084 - 16100) from the saliva and a single
hair shaft of the same individual.
http://www.promega.com/geneticidproc/ussymp7proc/0721.html
Where is Anastasia?
Anna Anderson
1896-1984
mtDNA sequencing
SUBJECTS
ORDER OF BASES
H.R.H. Philip, Duke of Edinburgh
(grand nephew of Tsarina)
.TCCT.
Anna Anderson (intestine sample)
Anna Anderson (hair sample)
.CTTC.
.CTTC.
Karl Maucher
(great nephew of Schanzkowska)
.CTTC.
Blood grouping
Gertrude Schanzkowska
A2 MN RH+CD e/c CW-P+K-
Anna Anderson
(Franziska Schanzkowska)
A2 MN RH+CD e/c CW-P+K-
Reburial of the Romanov family
Sts. Peter and Paul Cathedral
St Petersburg, Russia
17 July 1998 (80 years after their
deaths)
Attended by President Boris Yeltsin
http://129.128.91.75/de/genetics/70gen-hemophil.html
Of microbes, mice and men:
Variations on a Genetic Theme
1.
2.
3.
4.
5.
6.
Genes and Society – How a gene mutation changed
the course of world history
Human variation – DNA profiling with mtDNA and
microsatellites
Genetic epidemiology of monogenic and polygenic
disorders – retinitis pigmentosa and myopia
Genome wide linkage screens using microsatellites
– SLE mouse models and human sib-pair studies
Candidate gene linkage dysequilibrium studies –
case control and family based association
Microbial variation and comparative genomics –
melioidosis and novel viruses