Download Founder Effect for Ullrich-Type CMD in French Canadians

Introduction to Human
Genetics
Bernard Brais M.D., M.Phil., Ph.D.
Neurogénéticien
Professeur-adjoint, Département de Médecine
Service de médecine génique
Centre de recherche du CHUM
Hôpital Notre-Dame-CHUM
Montréal, Québec, Canada
[email protected]
Outline: First hour
• Charting the uncovering of the genetic basis of
human diseases
• Human genetics is technology driven
• Refresher on Mendelian genetics
• Other ways to influence the penetrance of a genetic
trait
• Mutation nomenclature
• Positional cloning of genes responsible for Mendelian
traits
• Positional cloning of genes responsible for complex
traits
• Competing strategies to identify the genetic basis of
diseases
• Overview of the successes in discovering the genes
responsible for diseases
Outline: Second hour
• Thinking of the variable distribution of
genetic variants in a population
• The constitution of the French-Canadian
gene pool
• The impact of the French-Canadian
founder effect on the variable regional
carrier rates of mutations
• Converging paths: The identification of
the gene mutated in LGMD2L
History of human genetics (1)
1858 Charles Darwin
Joint announcement of the theory of
Alfred Russel
natural selection-that members
Wallace
of a population who are better
adapted to the environment
survive and pass on their traits.
1859 Charles Darwin
Published The Origin of Species.
1866 Gregor Mendel
Published the results of his
investigations of the inheritance
of "factors" in pea plants.
1900 Carl Correns
Hugo de
Vries Erich
von
Tschermak
Mendel's principles were
independently discovered and
verified, marking the beginning
of modern genetics.
History of human genetics (2)
1905 Nettie Stevens
Edmund Wilson
Independently described the
behavior of sex chromosomes-XX
determines female; XY determines
male.
1908 Archibald Garrod
Proposed that some human
diseases are due to "inborn errors
of metabolism" that result from the
lack of a specific enzyme.
1910 Thomas Hunt Morgan Proposed a theory of sex-linked
inheritance for the first mutation
discovered in the fruit fly,
Drosophila, white eye. This was
followed by the gene theory,
including the principle of linkage.
1944 Oswald Avery, Colin
MacLeod, Maclyn
McCarty
Reported that they had purified the
transforming principle in Griffith's
experiment and that it was DNA.
History of human genetics (3)
Francis Crick and James
Watson
Solved the three-dimensional structure of the DNA
molecule.
1958
Arthur Kornberg
Purified DNA polymerase I from E. coli, the first enzyme
that made DNA in a test tube.
1966
Marshall Nirenberg and
H. Gobind Khorana
Led teams that cracked the genetic code- that triplet
mRNA codons specify each of the twenty amino acids.
1970
Hamilton Smith and Kent
Wilcox
Isolated the first restriction enzyme, HindII, that could cut
DNA molecules within specific recognition sites.
1972
Paul Berg and Herb
Boyer
Produced the first recombinant DNA molecules.
1973
Annie Chang and
Stanley Cohen
Showed that a recombinant DNA molecule can be
maintained and replicated in E. coli.
Fred Sanger
Developed the chain termination (dideoxy) method for
sequencing DNA.
1953
1977
1977
The first genetic engineering company (Genentech) is
founded, using recombinant DNA methods to make
medically important drugs.
1978
Somatostatin became the first human hormone produced
using recombinant DNA technology.
History of human genetics (4)
1983
James
Gusella
Used blood samples collected by Nancy Wexler and her coworkers to demonstrate that the Huntington's disease gene is
on chromosome 4. First positional victory.
1985
Kary B.
Mullis
Published a paper describing the polymerase chain reaction
(PCR), the most sensitive assay for DNA yet devised.
1988
The Human Genome Project began with the goal of
determining the entire sequence of DNA composing human
chromosomes.
1989
Coined the term DNA fingerprinting and was the first to use
DNA polymorphisms in paternity, immigration, and murder
cases.
Alec
Jeffreys
Francis
Collins
1989
1990
Lap-Chee
Tsui
Identified the gene coding for the cystic fibrosis
transmembrane conductance regulator protein (CFTR) on
chromosome 7 that, when mutant, causes cystic fibrosis.
First gene replacement therapy. T cells of a four-year old girl
were exposed outside of her body to retroviruses containing
an RNA copy of a normal ADA gene. This allowed her
immune system to begin functioning.
History of human genetics (5)
1995 First complete genome sequence for any organism:
the bacterium Haemophilus influenzae.
1998 First sequence of multicellular animal: the nematode
worm Caenorhabditis elegans.
2000 First draft of the human genome was announced. It
was published in 2001.
2003 The Human Genome Project was completed in 2003.
We are in the “post-genomic” era!
Human genetics is technology driven
Mendelian genetics
Dominant trait
Recessive trait
X-Linked transmission
X-Linked dominant
X-Linked recessive
Extrachromosomal Inheritance :
Mitochondrial transmission
Multifactorial Inheritance :
Complex trait
Other ways to influence the
penetrance of a genetic trait
• Imprinting
• Mosaicism
• DNA rearrangements
• Copy number
variation
Other ways to influence the
penetrance of a genetic trait
• Imprinting
• Mosaicism
• Chromosome aberrations
• Copy number
variation
Other ways to influence the
penetrance of a genetic trait
• Imprinting
• Mosaicism
• DNA rearrangements
• Copy number
variation
Other ways to influence the
penetrance of a genetic trait
•
•
•
•
Imprinting
Mosaicism
DNA rearrangements
Copy number variation
Mutation nomenclature:
Deletions and insertions
Mutation nomenclature:
Missense (faux-sense) and
nonsense (non-sense) mutations
Mutation nomenclature:
Repeat expansion mutations
(mutations de triplets répétés)
Positional cloning of genes
responsible for Mendelian traits
• Primary mapping by linkage
analysis in families or
association study in cohorts.
• Fine mapping
• Sequencing of genomic or
cDNA in cases and controls
• Confirmation that the
variants are mutations
Positional cloning of genes
responsible for complex traits
Association studies
QTL mapping
Competing strategies to identify
the genetic basis of diseases
The gene cartographer’s
strategies
The candidate gene
strategies
Overview of the successes in discovering
the genes responsible for diseases
Autosomal
X-Linked
Y-Linked
Mitochondrial
Total
* Gene with known sequence
11840
565
48
37
12490
+ Gene with known sequence
and phenotype
348
30
0
0
378
# Phenotype description,
molecular basis known
2169
200
2
26
2397
% Mendelian phenotype or locus,
molecular basis unknown
1504
136
5
0
1645
Other, mainly phenotypes with
suspected mendelian basis
1935
140
2
0
2077
17796
1071
57
63
18987
Total
OMIM, 2 October 2008
Mutations described according to HGMD
Data type
Mutation data
Number of entries (public release for
academic/non-profits only)
Number of entries according to HGMD
TOTAL (public release) 60379
TOTAL (HGMD Professional 2008.2)
80887
34790
45751
5635
7845
801
1280
Small deletions
9783
12974
Small insertions
3905
5290
Small indels
879
1184
Repeat variations
149
223
Gross
insertions/duplicatio
ns
545
915
Complex
rearrangements
440
690
Gross deletions
3452
4735
Genes
2260
3064
cDNA reference
sequences
2213
2936
Missense/nonsense
Splicing
Regulatory
Gene/sequence data
HGMD: Human Gene Mutation Database, February 2008
Mutations described according to HGMD
Mutations/Year
10000
6000
Série1
4000
Série2
2000
0
19
79
19
82
19
85
19
88
19
91
19
94
19
97
20
00
20
03
20
06
Mutations
8000
Year
Outline: Second hour
• Thinking of the variable distribution of
genetic variants in a population
• The constitution of the French-Canadian
gene pool
• The impact of the French-Canadian
founder effect on the variable regional
carrier rates of mutations
• Converging paths: The identification of
the gene mutated in LGMD2L
Scientific Discovery Path
Humans share a genome but
genetic variants are variably
distributed in different populations
André Barbeau
(1931-1986)
PART 1
•
•
•
Review the demographic history of the FrenchCanadian population.
Discuss the impact of history on the variable
regional distribution of mutations in Quebec.
Describe our method to identify diseases with
regional founder effects.
PART 1.1
• Review the demographic history of
the French-Canadian population.
Major characteristics of the
French-Canadian founder effect
• Only approximately 9,500 French
pioneers settled during the French
Regime (1608-1760), including only
1200 women.
• Very few mixed marriages until the
20th century.
• Very high fertility rates for two
centuries until the 1930’s.
The diversity of the original FC gene pool
is largely explained by the varied regional
origins of settlers (1608-1680)
S: Pour la Science,
september, 2001.
Disproportional contribution of
early pioneers to the FC gene pool
Proportion of pairs of subjects (p. 100000)
having at least one common ancestor, per
generation
High birth rate leads to rapid
population growth
80
70
60
Birth rate
50
Québec*
Ontario*
France**
Allemagne**
Angleterre**
Suède**
Québec
40
30
France
20
10
0
1831
1841
1851
1861
1871
1881
Year
1891
1901
1911
1921
Large French-Canadian families!
12,0
Fertility (average number of
children/women)
10,0
8,0
Québec
6,0
4,0
2,0
France
0,0
1667 1681 1730 1851 1871 1891 1911 1921 1937 1945 1959 1965
Year
Québec*
Canada
France**
Allemagne**
Angleterre**
Large family = pioneer front
12,0
8,0
6,0
Quebec
Manitoba
Saskatchewan
4,0
2,0
0,0
16
67
16
81
17
30
18
51
18
71
18
91
19
11
19
21
19
37
19
45
19
59
19
65
Fertility (average number of
children/women)
10,0
Year
Québec*
Ontario*
Canada
Manitoba
Saskatchewan
Topography and soil quality
influenced the settlement pattern
9,500BC
Montréal
Sea of Champlain
7,000BC
Montréal
6,000BC
Montréal
Present
Montréal
Valley of Montréal
Present
Progressive breaking of new land
1760: 70 000 inhabitants
Quebec City
Trois-Rivières
●
●
Acadia
Montreal
●
English
Colonies
1850: 670 000 French Canadians
Saguenay
Outaouais
Beauce
Eastern Townships
1900: 1 350 000 French Canadians
Côte-Nord
Gaspésie
Abitibi-Témiscamingue
Laurentides
Ontario
New England
Midwest
Pioneer fronts
Opening of new regions in
the XIXth century:
Saguenay-Lac Saint-Jean
(1837)
PART 1.2
• Discuss the impact of history on the
variable regional distribution of
mutations in Quebec.
The French-Canadian gene pool:
divergent regional gene pools!
Mean inbreeding coefficients
at the 13th generation
Mean inbreeding coefficients
at the 4th generation
A list of genetic disorders more prevalent
in French Canadians
Laberge et al. Clin Genet 2005
50% of genetic disorders more frequent in
the French-Canadian population have
neurological manifestations
Name
M. Trans.
Frequency
Gene
ARSACS
AR
1/1519
SACS
ACCPN
AR
1/2117
SLC12A6
Leigh syndrome french canadian type
AR
1/2178
LRPPRC
Jumping Frenchman of Maine
AD
Tyrosinemia type I
AR
1/1846
Tay Sachs
AR
5882;1/160 HEXA
Oculopharyngeal muscular dystrophy
AD
>1/7500
HHH
AR
Methylmalonic acidemia
AR
Carbohydrate deficient glycoprotein type Ib
AR
MPI
mtDNA
ND6
Leber's hereditary optic neuropathy
--FAH
PABPN1
ORNT1
1/83,131
Myotonic dystrophy
AD
1/530
Myotonin
Phenylketonuria
AR
1/24985
PAH
Friedreich's ataxia
AR
Fragile X syndrome
X
X-linked hereditary neuropathy
X
Juvenile Myoclonic Epilepsy
AD
FRDA
female
FMR1
GJB1
GABRA1
Early descriptions of dominant diseases
in the French Canadians
DM1
10kd deletion
LDL receptor
OPMD
Early descriptions of recessive diseases
in French Canadians
ARSACS
Tyrosinemia
Québec City
Charting the introduction and
diffusion of the T14484C Leber
optic atrophy mutation in Quebec
Laberge et al. AJHG 2005
Oculopharyngeal Muscular Dystrophy (OPMD):
An example of the variable regional prevalence
of mutation carriers
(A) Relative frequency of proven
OPMD case per administrative
Region.
(B) Calculated genetic contribution
to the regional gene pools of the
three sisters that introduced the
common OPMD mutation in
Quebec.
The Quebec population should be viewed as
a mosaic of different regional gene pools
Québec
Montréal
PART 1.3
• Describe our method to identify
diseases with regional founder
effects.
The bases for the competitive edge
of neurogenetics research in Quebec
• Large families
• Regional clusters of rare diseases
• Large cohorts of patients carrier of the
same mutation
• Networking of clinician-scientists
What is left to discover?
Jean-Martin Charcot (1825-1893)
Autosomal
Dominant
Autosomal
Dominant
Mitochondrial
X-Linked
Autosomal
Dominant
Mitochondrial
X-Linked
Recessive
Recessive
Marc-Aurèle Fortin (1888-1970)
2)
1)
+
3)
4)
IGPR: Identification de Grappes Phénotypiques Régionales
IRPC: Identification of Regional Phenotype Clusters
PROJETS SUPPORTED FOR DISEASES
WITH NEW FOUNDER EFFECTS
Late Onset Cerebellar
Ataxia/MSA-C
3 mutations, Mutation 1: 68%
Congenital Myotonia
SLSJ
Ataxia AOA2, Gaspésie
7 mutations, mutation 1: 85%
5 mutations, 2 genes, mutation
1: > 60%
Autosomal Recessive
Spastic Ataxia with
frequent
leukoencephalopathy
(ARSAL, SPAX3) Portneuf
4 mutations*, mutation 1: 70%
CMT4C, Gaspésie
2 mutations, mutation 1: 62.5%
Sensory neuropathy
(NHSAII), Lanaudière
2 mutations, mutation 1: 75%
LGMD with quadriceps
atrophy,
Outaouais-Montréal
3 mutations*, mutation 1: 81,3%
Congenital Muscular
Dystrophy, Montréal
5 mutations*, mutation 1:
45,5%
NEW DISEASES WITH FOUNDER EFFECTS
Congenital myasthenia,
Charlevoix and SLSJ,
DOK7, mutation 1: 80%
Herculean strength,
myalgia and elevated CK
Severe spastic ataxia with
leukoencepahlopathy,
Gaspésie
Sensory neuropathy of
Pasbébiac, mutation 1:
100%
LGMD
of the
Madeleine
Islands
Mutation:
100%
PART 1.4
• What have we learned from the
successful identifications of new
diseases with founder effects in
Québec?
There are still numerous diseases
with regional founder effects to
uncover
Diseases studied in the Brais Lab
Disease
Original
Original
Description
Founder
Locus
Gene
Mutations
effect
1
DMOP
NO
NO
1995
1998
YES
2
NHSAN2
NO
YES
2004
2004
YES
3
AOA2
NO
YES
NO
NO
YES
4
LGMDL
YES
YES
2005
5
CMDH
YES
YES
2005
6
ARSAL
YES
YES
2006
YES
YES
7
LOCA
YES
YES
2007
YES
YES
8
CONG MYOT
NO
YES
NO
NO
YES
9
LGMD MI
YES
YES
YES
YES
YES
10
STRONG MAN
YES?
YES
YES
11
HSN Pasb
NO
YES
NO
12
CMT4C
NO
YES
NO
NO
YES
13
CMD- Dok7
NO
YES
NO
NO
YES
14
PIANFULL N.
YES
YES
YES
15
SEVERE ATX
YES?
YES
YES
6-8/14
14
9/14
(43-57%)
(64%)
4/14
Regions with diseases with known
founder effects
FD
FD
FD
FD
FD
FD
FD
FD
FD
FD
FD FD FD: Founder disease(s)
Carriers of recessive mutations
may have a phenotype
Lanaudière cluster of cases of
HSANII
homozygotes for HSN2 mutation
c.943C→T
homozygotes for mutation c.918-919insA
heterozygotes for both mutations
Herculean strength, myalgia and elevated CK
Conclusions
• There are still numerous neuro-muscular
disorders with founder effects to be
uncovered in Quebec
• The identification of founder mutations will
help understand the shaping of the different
regional gene pools
• Identification of the mutations more frequent
in different regions will lead to better
information, genetic counselling, population
mutation screening and care of patients and
family members
• LGMD2L cohort / clinical description • Positional cloning
• TMEM16E gene and mutations
Véronique Bolduc
Réunion des sciences neurologiques du CHUM, 24 septembre 2009
Génétique de maladies neuromusculaires
Ataxies
Ataxia‐oculomotor
apraxia 2 : AOA2 (SETX)
Ataxie récessive
spastique
autosomique
Charlevoix‐Saguenay: ARSACS (SACS)
Ataxie récessive
spastique avec leucoencéphalo
pathie: ARSAL
Ataxie tardive: LOCA
Neuropathies
Névrites sensitives: NHSAII (HSN2), etc.
Polynévrite (CMT4C)
Polynévrite Charcot‐
Marie‐Tooth (CMT ‐
motrice)
Maladies de la jonction
neuromusculaire
Myasthénie congénitale des ceintures (DOK7)
Myopathies
Dystrophie oculopharyngée:
DMOP (PABPN1) Dystrophie musculaire
congénitale avec hyperlaxicité ligamentaire
Dystrophie musculaire des ceintures avec atrophie des quadriceps: LGMD2L (ANO5)
Myotonie congénitale SLSJ
(SCN4A)
Dystrophie congénitale des Îles‐de‐la‐Madeleine
Dystrophie musculaire des ceintures avec syndrome d’irritabilité musculaire
POMT1
Fukutin
De Guglieri et al, Curr Opin Neurol, 2008
Zatz et al., Neuromuscul Dis, 2003
Septembre 2009 46 atteints
32 familles
140 ADN
(Patient IX‐11, age 66)
(Patient IX‐15, age 48)
(Patient XXXI‐1, age 64)
Patient IX‐15 (age: 48)
Jarry et al, Brain 2007
Recrutement familial
(clusters régionaux)
Criblage du génome
Marqueurs microsatellites
Marqueurs SNPs (polymorphismes
de nucléotides simples)
Analyse
Étude de liaison
Recherche homozygotie
Identification loci potentiels
Séquençage de gènes candidats (génomique ou ADNc)
Identification de variants / mutations
• Homozygotie : famille consanguine
• Polymorphisme de nucléotide simple (SNP): grande résolution (Illumina Hap300)
Chromosome 11p15.1‐11p14.3 :
612 SNPs consécutifs (4,7Mb)
*
*
*
*
*
Chromosome 11p15.1‐11p14.3
rs4073508 (19 369 237) ‐ rs10834273 (24 048 258)
c.1295C>G
Bolduc et al, En préparation
c.191dupA
c.692G>T / G231V
Bolduc et al, En préparation
Finlande
Pays-Bas
c.191dupA
Bolduc et al, En préparation
Bolduc et al, En préparation
Malicdan et Nonaka, Neurol India, 2008
• LGMD2B (proximal) et MMD1 (distal)
Han and Campbell, Curr Opin Cell Biol, 2007
Bolduc et al, En préparation
Dysplasie Gnatho‐dyaphysale (GDD1)
Anoctamin 9
Anoctamin 1
Anoctamin 2
Anoctamin 3
Anoctamin 4
Anoctamin 5 / GDD1
Anoctamin 6
Anoctamin 7
Anoctamin 8
Anoctamin 10
Schroeder et al, Cell 2008
• Identification de mutations récessives gène ANO5
– LGMD2L
• Atrophie quadriceps
• Asymétrie
– MMD3
• Atrophie quadriceps
• Faiblesse distale
• Fonction ANO5 dans le muscle : inconnue
• Canal Cl‐ activé par le Ca++ ?
• Réparation de la membrane ?
• Potentiel autres mutations… 30 familles
• Tester fonction canal chlorique (Dr Lucie Parent)
• Fonction Anoctamin5 dans le muscle
Montréal
Durham, Angleterre
Laboratoire de neurogénétique
Rumaisa Bashir
Lina Loisel, CHUM
Yves Robitaille, CHU Ste‐Justine
Georges Karpati, MNI
Tokushima, Japon
Vivian Khoury, CHUM
Hiroshi Inoue
Marie‐Pierre Dubé, ICM
Lucie Parent, UdeM
Yolaine Dodier, UdeM
Patients et
Centre d’Innovation Génome familles !
Québec – U McGill
Absents de la photo: Geneviève Bernard, Roxanne Larivière
Québec et Saguenay
Jean‐Pierre Bouchard
Jean Mathieu