Genome duplication and fish models for toxicology John Postlethwait University of Oregon DIVISION OF COMPARATIVE ~\. National Institute of Environmental Health Sciences ,'~ National Toxicology Program MEDICINE liilllr'J' Your Environment. Your Health. ~ U.S. Department of Health and Human Services Genome duplication and fish models for toxicology Loren Frank von Hippel Buck N AZ U N AZ U Jesse Gologergen Sivuqaq Island Pete Batzel UO Tom Ingo Braasch Titus Tiffany Immingen UO Sivuqaq Island··-·• NIH ' DIVISION OF COMPARATIVE ~\. Nationa_l Institute of En~ir~nmental Hea~~S · - MEDICINE lilllr'/ Your Environment. Your Health. ciences The problem: People living a subsistence lifestyle in the Arctic are highly exposed to persistent organic pollutants. Annie Alowa, Sivuqaq Islander ,; The problem: Sources: t'@~""'~ Formerly used defense sites SLI a 1 Global distillation VA,. Point sources condense & fall move to ... -). _ Greenland. .. ·· ~i colder ·t.··.•~-- ... ~.• .. ,•.· ·••'.A. ...· . • . 11 . ·•. ' . •' '• • Norway climates 1 \ . Canada. 'II,_ !'· . • ·•. -~ ... • •.• : ,. ~''-~.--...... - ---. \.- -:: l·· 4_· organochlorines ····: ...: . ··. "\ .:· . : ·- . ·~ :- - --- evaporate aqumaps.org Biological magnification ' ' ~,v- ,; The problem: Point sources t@.,-Formerly used defense ~sites SLI : 1 Global distillation VA,. ·. -:·J. Greenland • ! ... .. ·· ~ : .. ...a·· . •· .A . ·· • • 1 \ I •• ••:• .' • · ••' .:• • • • Norway , .. .. ' •. .. Canada ~.... .. .. •. ·• .. · .. .:.:, ~- \ ... ' 9-spine ... ;.-.~.... ... I•. :l.. 4_· -:· ~ . _;· ~,. fyl stickleback ______ ..:, Teleost fish are convenient models for toxicology. aqumaps.org Biological magnification How to connect teleost genomes to human biology? How to connect teleost genomes to human biology? • Genome duplication in vertebrates • Genome duplication complicates connectivity • Ohnologs gone missing and lineage-specific evolution • Application: St. Lawrence Island How to connect teleost genomes to human biology? • Genome duplication in zebrafish vertebrates Ohnologs: duplicates from genome duplication bony fish Susumo Ohno Two rounds of Evolution by Gene genome Duplication (1970) duplication jawed vertebrates 1 Hox cluster e shark 4 Hox clusters cartilaginous fish How to connect teleost genomes to human biology? • Genome duplication in zebrafish vertebrates rayfin fish bony fish Two rounds of coelacanth genome duplication xenopus lobefin jawed fish vertebrates chicken mouse 1 Hox human cluster e shark 4 Hox clusters cartilaginous fish How to connect teleost genomes to human biology? • Genome duplication in zebrafish teleost vertebrates fish medaka rayfin cavefish fish goldeye eel bony fish gar Two rounds of coelacanth genome duplication xenopus lobefin jawed fish vertebrates chicken mouse 1 Hox human cluster e shark 4 Hox clusters cartilaginous fish How to connect teleost genomes to human biology? • Genome duplication in zebrafish teleost vertebrates fish Teleost genome medaka 7-8 Hox clusters Amores… duplication Postlethwait rayfin 1998 Science 3R, TGD cavefish fish goldeye eel 1R, 2R 4 Hox clusters Amores…Postlethwait bony fish gar 2011 Genetics VGD Two rounds of coelacanth genome duplication xenopus lobefin jawed fish vertebrates chicken mouse 1 Hox human cluster e shark 4 Hox clusters cartilaginous fish How to connect teleost genomes to human biology? • Genome duplication in zebrafish teleost vertebrates fish Teleost genome medaka 7-8 Hox clusters duplication 3R, TGD cavefish goldeye eel 1R, 2R 4 Hox clusters bony fish gar VGD Spotted gar: Two rounds of coelacanth • Diverged before the TGD genome duplication • Biology similar to zebrafish xenopus jawed vertebrates chicken mouse 1 Hox human cluster e shark 4 Hox clusters cartilaginous fish How to connect teleost genomes to human biology? • Genome duplication in zebrafish teleost vertebrates fish Teleost genome medaka 7-8 Hox clusters duplication 3R, TGD cavefish goldeye eel 1R, 2R 4 Hox clusters bony fish gar VGD Spotted gar: Two rounds of coelacanth • Diverged before the TGD genome duplication • Biology similar to zebrafish xenopus jawed • Genomics similar to tetrapods vertebrates chicken • Same duplication as human • Amenable to laboratory culture mouse • Can grow from embryos 1 Hox human cluster e shark 4 Hox clusters What does duplication cartilaginous fish mean for toxicology? What does duplication mean for toxicology? • Genome duplication in zebrafish How to connect teleost vertebrates genomes to human biology? Teleost genome medaka duplication 3R, TGD cavefish goldeye eel dioxins 1R, 2R bony fish gar VGD AHR Two rounds of coelacanth genome duplication xenopus AHR ARNT jawed chicken dioxin response cyp1a1 vertebrates element mouse nucleus 1 Hox human cytoplasm cluster e shark cartilaginous fish What does duplication mean for toxicology? dioxins How to connect teleost AHR genomes to human biology? AHR ARNT arnt arntl1a dioxin response cyp1a1 element arntl1b nucleus TGD cytoplasm zebrafish arnt2 arntl2 VGD1 Arnt Arntl VGD2 Arnt Arntl Arnt Arntl Tandem duplication Arnt Arntl Arnt2 Arntl2 ARNT ARNTL human ARNT2 ARNTL2 How do we know? Catchen…Postlethwait 2009 Genome Res. 19:1497 How do we know? gene tree ,-----Hsa.ARNTI. How to connect teleost ---Dre.amtl1a genomes to human biology? ---Dre.amtl1b r--------Hsa.ARNTL2 100 '--------Dre.amt12 ,______ -Rfl .110703 ,-----Hsa .ARNT2 arnt arntl1a 100 ,......__ --l Dre.amt2 ,--------Hsa.ARNT arnt2 arntl1b 81 ~-----Dre.amt orthologs TGD zebrafish arnt2 arntl2 arnt2b arntl2b VGD1 Arnt Arntl VGD2 Arnt Arntl Arnt Arntl Tandem duplication Arnt Arntl Arnt2 Arntl2 ARNT ARNTL Arnt3 Arntl3 human ARNT2 ARNTL2 Arnt4 Arntl4 Catchen…Postlethwait 2009 Genome Res. 19:1497 How do we know? gene tree ,-----Hsa.ARNTI. How to connect teleost ---Dre.amtl1a genomes to human biology? ---Dre.amtl1b r--------Hsa.ARNTL2 100 '--------Dre.amt12 ,______ -Rfl .110703 ,-----Hsa .ARNT2 arnt arntl1a 100 ,......__ --l Dre.amt2 ,--------Hsa.ARNT arntl1b 81 ~-----Dre.amt orthologs TGD zebrafish arnt2 arntl2 VGD1 Arnt Arntl VGD2 Arnt Arntl Arnt Arntl Tandem duplication Arnt Arntl Arnt2 Arntl2 ARNT ARNTL human ARNT2 ARNTL2 Catchen…Postlethwait 2009 Genome Res. 19:1497 How do we know? gene tree ,-----Hsa.ARNTI. How to connect teleost ---Dre.amtl1a genomes to human biology? ---Dre.amtl1b r--------Hsa.ARNTL2 100 '--------Dre.amt12 ,______ -Rfl .110703 ,-----Hsa .ARNT2 arnt arntl1a 100 ,......__ --l Dre.amt2 ,--------Hsa.ARNT orthologs arntl1b 81 ~-----Dre.amt TGD zebrafish arnt2 arntl2 VGD1 Arnt Arntl VGD2 Arnt Arntl Arnt Arntl Tandem duplication Arnt Arntl Arnt2 Arntl2 ARNT ARNTL human ARNT2 ARNTL2 Catchen…Postlethwait 2009 Genome Res. 19:1497 How do we know? gene tree ,-----Hsa.ARNTI. How to connect teleost ---Dre.amtl1a genomes to human biology? ---Dre.amtl1b Tree shows co-orthologs 100 '--------Dre.amt12 duplication after ,______ -R fl .110703 human-fish ,-----Hsa .ARNT2 arnt arntl1a 100 ,......__ --l divergence. Dre.amt2 ,--------Hsa.ARNT arntl1b 81 ~-----Dre.amt TGD zebrafish arnt2 arntl2 VGD1 Arnt Arntl VGD2 Arnt Arntl Arnt Arntl Tandem duplication Arnt Arntl Arnt2 Arntl2 ARNT ARNTL human ARNT2 ARNTL2 Catchen…Postlethwait 2009 Genome Res. 19:1497 How do we know? conserved syntenies How to connect teleost show duplicated genomes to human biology? chromosome ARNTL Tree shows arntl1b segments duplication after human-fish arnt arntl1a divergence. arntl1a arnt2 arntl1b TGD zebrafish arnt2 arntl2 arnt2b arntl2b VGD1 Arnt Arntl VGD2 Arnt Arntl Arnt Arntl Tandem duplication Arnt Arntl Arnt2 Arntl2 ARNT ARNTL Arnt3 Arntl3 human ARNT2 ARNTL2 How do we know? Arnt4 Arntl4 Catchen…Postlethwait 2009 Genome Res. 19:1497 How do we know? ♦ ARNT + +-++t++ + +♦ + ++++ + ♦ + + ++ + ♦++ + + + + -· -*• + + ♦ + ♦ How to connect teleost + * ·-+ + ♦ ++ ++ + + + ... + genomes to human biology? Human + + + + ++-I+ ♦ ++ + + + ++ + + ++ .....+ + + ..... + ++ chromosomes + -++- ++++ * ++ ♦ Duplicated + ++ ++ + + ARNTL++ + chromosome . +- _ __.._ - -- - ➔ -++- .. -+- ·+-·- ·- .... - - .,_.,... __ +-· ++ ♦ ♦ + ··-+++ ** + + + + segments in arnt arntl1a ARNTL2 -· + + human 0 + + + -HI-++ + ++ ARNT2 ♦ + + + + + + + + + + + + genome ++• arnt2 arntl1b + + + + + + + + - + + + + ............ +++++ + ·- .... TGD + + + ... + ♦ + ♦- zebrafish arnt2 arntl2 Genes on human chromosome 11 arnt2b arntl2b VGD1 Arnt Arntl VGD2 Arnt Arntl Arnt Arntl Tandem duplication Arnt Arntl Arnt2 Arntl2 ARNT ARNTL Arnt3 Arntl3 human ARNT2 ARNTL2 How do we know? Arnt4 Arntl4 Catchen…Postlethwait 2009 Genome Res. 19:1497 How do we know? ♦ ARNT + +-++t++ + +♦ + ++++ + ♦ + + ++ + ♦++ + + + + -· -*• + + ♦ + ♦ How to connect teleost + * ·-+ + ♦ ++ ++ + + + ... + genomes to human biology? Human + + + + ++-I+ ♦ ++ + + + ++ + + ++ .....+ + + ..... + ++ chromosomes + -++- ++++ * ++ ♦ Duplicated + ++ ++ + + ARNTL++ + chromosome How do . +- _ __.._ - -- - ➔ -++- .. -+- ·+-·- ·- .... - - .,_.,... __ +-· ++ ♦ ♦ + ··-+++ ** + + + + segments in arnt arntl1a fish ARNTL2 -· + + human genes 0 + + + -HI-++ + ++ ARNT2 ♦ + + + + + + + + + + + + genome relate to ++• arnt2 arntl1b + + + + + + + + - + + + + ............ +++++ + human ·- .... TGD genes? + + + ... + ♦ + ♦- zebrafish arnt2 arntl2 Genes on human chromosome 11 arnt2b arntl2b VGD1 Arnt Arntl VGD2 Arnt Arntl Arnt Arntl Tandem duplication Arnt Arntl Arnt2 Arntl2 • Genome ARNT ARNTL duplication Arnt3 Arntl3 human complicates ARNT2 ARNTL2 How do we know? connectivity Arnt4 Arntl4 Catchen…Postlethwait 2009 Genome Res. 19:1497 How to connect teleost genomes to human biology? • Genome duplication in vertebrates • Genome duplication