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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