Dr Stephen O'Brien Banquet Address

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Presented by Dr. Stephen O'Brien at the Alliance for Contraception in Cats & Dogs’ 4th International Symposium on Non-Surgical Contraceptive Methods of Pet Population Control, April 8-10, 2010, in Dallas, Texas, U.S.

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By: charmking (82 month(s) ago)

Dear doctor Stephen I am student of veterinary gynaecology as mains and i need to download your power point presentation as a reference for my research purpose please kindly oblige chethan

Presentation Transcript

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A Moving Landscape for Cat, Dog and Mammal Comparative Genomics 4th International Symposium On Non-surgical Contraceptive Methods of Pet Population Control Stephen J. O’Brien for NCI’s Laboratory of Genomic Diversity April 9, 2010

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"Nothing in Biology makes any sense except in light of evolution" Theodosius Dobzhansky

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700 million years ago

. : 

. . .

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May Mid April-May

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Late MAY 460MYA

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June 420 million years ago

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July 360 million years ago

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Mid August -late November 280-65 million years ago

Cretaceous landscape : 

Cretaceous landscape

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Early November 200 million years ago

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Chicxulub impact Yucatan Peninsula, Mexico 65MYA December 1 65 million years ago

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The amazing morphological and developmental diversity of mammals

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9:30PM December 31

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Dog Domestication 15,000 years ago 11:50 PM Dec 31

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PLEISTOCENE EXTINCTIONS of MAMMALS when 40 species of large mammals went extinct abruptly in North America 11:52 PM December 31

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Cat Domestication 10,000 years ago 11:52 PM Dec 31

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-7 seconds -4 seconds

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Human Genome Project

Human Genome Project(September, 2003) Cost $3.0 billion : 

Human Genome Project(September, 2003) Cost $3.0 billion 1) 2.8 billion base pair ~20,000 genes Genome sequence: • 2% = genes – coding exons • 98% = noncoding, intergenic, introns • 50% repetitive elements - SINES, LINES - Minisatellites, SNPs (single nucleotide polymorphisms) Annotated ~ 10+ million SNPs 5.) Haplotype Block Structure 5.) Structural Variation • 4-6% of Human genome is Segmental aneuploidy/duplications • Copy Number Variation - Transcriptome Variants (splicing expression)

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On Mammal's Natural History

Species Diversity : 

Species Diversity ~5000 species of mammals 25 orders Rodents 2052 species Bats 977 species Primates 279 species Carnivores 280 species Cetartiodactyls- 299 species Elephants 2*/3 species Tubulidentates 1 species Aardvark

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Sampling 64 species representing the principal lineages of all extant placental orders Genes nuclear gene segments (exons and 3’ untranslated regions) mitochondrial gene segments Phylogenetic Methodology Dating or Setting the Molecular Clock ~ 17,000 bp Solving the Eutherian Mammalian Radiation -Hierarchy and Time Frame By Murphy, Duda and Roca

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! KT Boundary ! __________________________________________________________________________

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8x-Vertebrate Genome Sequences today

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Beauceron Berger Allemand Caniche moyen Coton de Tuléar Westie Yorkshire Cocker Anglais Bouviers Bernois Borders Collies Setter Gordon Shih Tzu Lhassa-Apso Labrador Pointer Boxer D.Bordeaux Epagneul Breton for 2009-10 we and the dogs see a HAPPY Year of the Cat! 2005, The year of DOGS Soooo

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The Feline Genome Sequence ….

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Cinnamon - The Genomics Cat.!! courtesy Kristina Narfstrom

Annotating the cat genome Features the cat genome consortium described : : 

Annotating the cat genome Features the cat genome consortium described : Map coordinates Fosmids & BACs Assembly Contigs Supercontigs-Scaffolds 22,285 feline genes RBMs-Recip. Best match CSBs-Conserved Seq. blks. HSBs-Homlogus synteny blocks Repeats GC content track SNPs STRs STR primers DIPs Homozygous segments Micro RNA CpG Islands Numts ERVs GARFIELD browser Sigs of selection Segmental Duplications CNVs-

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APPLICATIONS & TRANSLATION

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Albinism, oculocutaneous Achondroplasia Alpha fucosidosis Alpha mannosidosis Amyloidosis, renal Amyloidosis, hepatic Anencephaly Anophthalmia congenital Aortic stenois Asthenia cutis Atresia ani Atresia coli Atrial septal defect Brachydactyly Calcium oxalate urinary calculi Cataract, congenital Cataract, nuclear Cataract, juvenile Chondrodysplasia Cerebellar abiothrophy Cerebellar hypoplasia Ceroid lipofucinosis Chediak-Higashi syndrome Ciliary dyskinesia Cleft palate, severe Cleft palate, mild Cholesterolester storage disease Chondrodysplasia Chylothorax Cobalamin malabsorption Coloboma Corneal dystrophy, stromal Corneal dystrophy, endothelial Corneal sequestration Congenital goiterous hypothyroidism Congenital hypothyroidism, aplastic Craniofacial defect Cryptorchism Curl tail Cystinuria type I Cystinuria, non-type I Deafness, white Deafness, other Dermoid Dermatosparaxia Diabetes mellitus Diaphragmatic hernia Dwarfism Dystrophin deficiency Ectrodactyly Ehrler-Danlos syndrome type I Endocardofibroelastosis Epibulbar dermoid Erythrocyte osmotic fragility Esophageal achalasia Exocrine pancreatic insufficiency Factor X deficiency Factor II deficiency Factor XII deficiency Femoral head epiphysal slip Fanconi syndrome Fold ear with osteodystrophy Gangliosidosis GM1 Gangliosidosis GM2 Globoid cell leukodystrophy Glaucoma Glycogenosis type IV Hairlessness Hemivertebrae Hemolytic transfusion reactions Hemophilia A Hemophilia B Heterochromia Hiatal hernia Hip dysplasia Hip (coxofemoral) luxation Hydrocephalus, internal Hydrocephalus, external Hyperchylomicronemia Hyperkalemic paralysis Hypertrophic cardiomyopathy Hypotrichosis Hypotrichosis with thymic aplasia Inguinal hernia Inflammatory bowel disease Intersex Isovaleric aciduria Kinked tail Lymphoma Lactic aciduria Lipoprotein lipase deficiency Lissencephaly Methylmalonic aciduria Megacolon, denervation Megaesophagus Meningiencaphalocele Methemoglobin reductase deficiency Microbrachia Microophthalmia Milliary dermatitis Mitral valve dysplasia Mucolipidosis type II Mucopolysaccharidosis Type I Mucopolysaccharidosis Type VI Mucopolysaccharidosis Type VII Myasthenia gravis Myotonia congenital Neonatal isoerythrolysis Albinism, oculocutaneous Achondroplasia Alpha fucosidosis Alpha mannosidosis Amyloidosis, renal Amyloidosis, hepatic Anencephaly Anophthalmia congenital Aortic stenois Asthenia cutis Atresia ani Atresia coli Atrial septal defect Brachydactyly Calcium oxalate urinary calculi Cataract, congenital Cataract, nuclear Cataract, juvenile Chondrodysplasia Cerebellar abiothrophy Cerebellar hypoplasia Ceroid lipofucinosis Chediak-Higashi syndrome Ciliary dyskinesia Cleft palate, severe Cleft palate, mild Cholesterolester storage disease Chondrodysplasia Chylothorax Cobalamin malabsorption Coloboma Corneal dystrophy, stromal Corneal dystrophy, endothelial Corneal sequestration Congenital goiterous hypothyroidism Congenital hypothyroidism, aplastic Craniofacial defect Cryptorchism Curl tail Cystinuria type I Cystinuria, non-type I Deafness, white Deafness, other Dermoid Dermatosparaxia Diabetes mellitus Diaphragmatic hernia Dwarfism Dystrophin deficiency Ectrodactyly Ehrler-Danlos syndrome type I Endocardofibroelastosis Epibulbar dermoid Erythrocyte osmotic fragility Esophageal achalasia Exocrine pancreatic insufficiency Factor X deficiency Factor II deficiency Factor XII deficiency Femoral head epiphysal slip Fanconi syndrome Fold ear with osteodystrophy Gangliosidosis GM1 Gangliosidosis GM2 Globoid cell leukodystrophy Glaucoma Glycogenosis type IV Hairlessness Hemivertebrae Hemolytic transfusion reactions Hemophilia A Hemophilia B Heterochromia Hiatal hernia Hip dysplasia Hip (coxofemoral) luxation Hydrocephalus, internal Hydrocephalus, external Hyperchylomicronemia Hyperkalemic paralysis Hypertrophic cardiomyopathy Hypotrichosis Hypotrichosis with thymic aplasia Inguinal hernia Inflammatory bowel disease Intersex Isovaleric aciduria Kinked tail Lymphoma Lactic aciduria Lipoprotein lipase deficiency Lissencephaly Methylmalonic aciduria Megacolon, denervation Megaesophagus Meningiencaphalocele Methemoglobin reductase deficiency Microbrachia Microophthalmia Milliary dermatitis Mitral valve dysplasia Mucolipidosis type II Mucopolysaccharidosis Type I Mucopolysaccharidosis Type VI Mucopolysaccharidosis Type VII Myasthenia gravis Myotonia congenital Neonatal isoerythrolysis Neuroaxonal dystrophy Neutrophil granulation Nieman-Pick disease type C Osteogenesis imperfecta, dominant Osteogenesis imperfecta, recessive Odontoclastic resorptive lesions Ornithin aminotransferase deficiency Open central fontanel Open lateral fontanel Patellar luxation Pectus excavatum Pelger Huet anomaly Perirenal pseudocysts Persistent ductus arteriosus Persistent hepatic ductus venosus Persistent Muellerian duct syndrome Persistent papillary membranes Persistent right aortic arch Persistent truncus arteriosus Polycystic kidney disease Polycythemia (erythrocytosis) Polydactyly Porphyria, dominant Porphyria with anemia, recessive Portocaval shunt Predisp. to feline infectious peritonitis Predisp. to ginigivitis Primary hyperoxaluria type I Primary hyperoxaluria type II Progressive retinal atrophy, Siamese Progressive retinal atrophy, Persian Progressive retinal atrophy, other Pulmonary stenosis Pyloric stenosis Pyruvate kinase deficiency Radial agenesis Renal dysplasia Renal tubular acidosis Retinal dystrophy Restrictive cardiomyopathy Sacrococcidial agenesis Situs inversus Spastic syndrome Spheroid lysosomal storage disease Sphingolipidosis C Spina bifida Spinal muscular atrophy Spondylosis deformans Spongiform encephalopathy Strabismus Syndactyly Syringomelia Taillessness Taurin deficiency/malabsorption Tendency for cotton chewing Testicular feminization Tetralogy of Fallot Thrombopathia Thyroid peroxidase deficiency Tracheal hypoplasia Tricuspid valve stenosis Umbilical hernia Urical diverticle Ventricular septal defect Vestibular defect Vitamin K dependent coagulopathy Von Willebrand disease type I XXY karyotype 250 Human Genetic Diseases with Cat models described Per Urs Giger and http://omia.angis.org.au/

Feline Genetic Diseases Characterized at the Molecular LevelRED Genes are LGD Discovered : 

Feline Genetic Diseases Characterized at the Molecular LevelRED Genes are LGD Discovered Parkinson, N.J. et al., 2008. Spinal muscular atrophy A1 LIX1 Menotti-Raymond, M. et al., 2007. Retinal degerneration II B4 Cep290 Mansfield, C.S. et al., 2005. Pyruvate kinase deficiency of erythrocyte F1 PKLR Helps, C. et al., 2007. Polysystic kidnesy disease E3 PKD1 Somers, K.L. et al., 2003. Niemann-Pick disease, type C D3 NPC1 Fletcher, S. et a., 2001. Muscular dystrophy, Duchenne and Becker types X DMD Schultheiss, P.C. et al., 2000. Mucopolysaccharidosis VII E3 GUSB Sleeper, M.M. et al, 2008. Mucopolysaccharidosis VI A1 ARSB Sleeper, M.M. et al, 2008. Mucopolysaccharidosis I - IDUA Giger, U. et al. 2006. Mucolipidosis II - GNPTAB Sun, H. et al. 1999. Mannosidosis, alpha A2 MAN2B1 Kanchuk, M.L. et al., 2003. Hyperlip[oproteinaemia B1 LPL Kehler, et. al. 2007. Hair Length B1 FGF5 Goree, M. et al. 2005. Haemophilia B X F9 Fyfe, J. et al. 2007. Glycogen storate disease IV C2 GBE1 Yamato, O., et al., 2008. Gangliosidosis, GM2, type II A1 HEXB Martin, D.R. et al., 2005. Gangliosidosis, GM2, GM2A deficiency A1 GM2A Ishida, Y. et al., 2006. Coat color, dilute C1 MLPH Lyons, L.A. et al, 2005. Coat color, brown D4 TYRP1 Giebel, L.B. et al., 1991. Coat color, albinism, oculocutaneous type I, temperature-sensitve D1 TYR Imes, DL. et al., 2006. Coat color albinism D1 TYR Eizirik, E., et al., 2003. Coat color, agouti A3 ASIP Macdonald, KA., et al., 2005. Cardiomyopathy, hypertropic D1 MYBPC3 Bighignoli, B. et al., 2007 Blood group system AB B2 CMAH Citation Disease-defect Cat Chromosome Gene Symbol

Recently resolved feline coat color genes(See Table 3 in Comparative Report for human disease models) : 

Recently resolved feline coat color genes(See Table 3 in Comparative Report for human disease models) Phenotype Gene Hsa 35 build Cat chr. Melanism(cat) ASIP 20:32.3Mb A3 Eizirik et al. 2003 Melanism(jaguar) MCIR 16:88.5 Mb E2 Eizirik et al. 2003 Brown TYRP1 9:8 Mb D4 Schmidt-Kunzel et al., 2005 Cinnamon TYRP1 9.8 Mb D4 Schmidt-Kunzel et al., 2005 Siamese TYR 11:88.6 Mb D1 Schmidt-Kunzel et al., 2005 Burmese TYR 11:88.6 Mb D1 Schmidt-Kunzel et al., 2005 Dilute MLPH 2:238.1 Mb C1 Ishida et al., 2006 Long hair FGF5 B1 Kehler et al 2007 Orange O Not there X Schmidt Kunzel et al 2009

Cat Viruses with Human Homologues : 

Cat Viruses with Human Homologues FeLV -HTLV leukemia FIV -HIV AIDS FeCV -SARS CoV FeSV ->20 Oncogenes Avian flu -Avian Flu Panleukopenia -Measles (and doggie parvovirus epidemic)

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Reproduction, & Very Interesting Behaviors

Spermatozoa Pleiomorphism in Felids : 

Spermatozoa Pleiomorphism in Felids ?

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“Forensic Applications A Snowball's Chance” PEI Canada 1995

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SNPs

SNPs technologies in the cat genome : 

SNPs technologies in the cat genome 57% of Cinnamon is homozygous Annotated 327,000 SNPs in het regions in 2x phase July 2008 ~2 million new SNPs discovered by Hill's Pet Food Funds. 3million at Wash U using cat breeds from LGD July 2009 Additional 4million SNPs discovered by NHGRI Total over 8,000,000 cat SNPs EST sequence 2M transcripts at Wash U using LGD tissue RNA preps 75,000SNP genotyping array to be developed thanks to Morris Animal Foundation and Hills and the feline genomics Consortium $1,000,000 committed Spring 2010 Illumina array available for translation to cat diseases and phenotypes Cinnamon's SNP heterozygosity profile

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So where did all these cat species come from?? The Felidae Family is made up of 37 species that all arose in the last ten million years

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Our Strategy Sampling of all 37 felid species and seven outgroup species Test of 35 genes for phylogenetic congruence

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22,789 bp (total) Timing calibrated with 16 Felidae species' fossils Johnson et al Science 311:74 January, 2006 5 X-linked (3,230 bp): ALAS,ATP-7A,IL2RG,PLP,ZFX 4 Y-linked (4,457 bp): SMCY,SRY,UBEY,ZFY 6 mtDNA gene fragments (3,936 bp): ND2, ND4, ND5, ATP8,CYTB,16S 20 autosomal gene fragments (11,166 bp): APP,CALB1,CHRNA1,CLU,CMA1 DGKG2,FES,GATA3,GHR,GNAZ,GNB1,HK1,NCL PNOC,RAG2,RASA2,SIL,TCP1,TTR A comprehensive gene sampling 37 Felidae species & outgroups

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Suppose we combine phylogeny, dates, geography ,geology, sea level dynamics, and paleontology? Can we impute how the cats came to be where they are today? We tried.

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ONE AMAZING JOURNEY On the Origins of Cat Species It all started in Asia. ~10MYA - Christmas day in the movie

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Africa Europe Asia Australia South America North America Equator Miocene Migrations

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Africa Europe Asia Australia South America North America Equator Late Pliocene Migrations

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Code Subspecies Common Name ALT P.t.altaica Amur AMO P.t.amoyensis South China COR P.t.corbetti Indochinese JAX P.t.jacksoni Malayan TIG P.t.tigris Bengal SUM P.t.sumatrae Sumatran SON P.t.sondaica Javan(extinct) BAL P.t.balica Bali(extinct) VIR P.t.virgata Caspian(extinct) VIR Coalescence of modern Panthera species Tiger: 72,000-108,000 yrs ago Leopard: 470,000-825,000 yrs ago Asian leopard: 170,000-300,000 yrs ago Jaguar: 280,000-510,000 yrs ago

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And that's How we believe the modern cats came to be

A few more vertebrate genomes : 

A few more vertebrate genomes

Genome -10K-Sequencing 10,000 Vertebrate Species : 

Genome -10K-Sequencing 10,000 Vertebrate Species How many species: ~61,000 spp. 5416 mammals 9723 birds 8443 reptiles 6547 amphibians 31,564 fish Announced October 2009 G10KCOS has gathered 17,256 vertebrate species now volunteered for whole genome sequence

` : 

` And now I really would like to say "Thanks" to…

The Cat Genome Annotation Consortium : 

The Cat Genome Annotation Consortium NCI - Laboratory of Genomic Diversity Joan Pontius Colm O h'Uigin Warren Johnson Stephen J. O'Brien Marilyn Raymond Al Roca Jill Slattery Mike Smith Naoya Yuhki Carlos Driscoll Agostinho Antunes Bailey Kessing NHGRI Jim Mullikin NIH Intramural Sequencing Center Agencourt Douglas Smith Broad Institute Sante Gnerre Jean Chang Michele Clamp Kerstin Lindblad-Toh Texas A & M Bill Murphy NCI - ABCC Bob Stephens Beena Neelam Natalia Volfovsky

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Thanks for your attention

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