human genetics

+ animal models

19.7.’17

Human genetics

+ animal models

introduction; animal models -

natural + breed(ing)

progressive retinal atrophy

perspectives

introduction; animal models -

natural + breed

progressive retinal atrophy

perspectives

asexual reproduction sexual reproduction

genome retained

genomerecombination

mutation retained

mutation

why sex?

sex accelerates adaptation

♂♀

♀ ♂

ttgctgtgtgaggcagaacctgcgggggcaggggcgggctggttccctggccagccattggcagagtccgcaggctagggctgtcaatcatgctggccggcgtggccccgcctccgccggcgcggccccgcctccgccggcgcacgtctgggacgcaaggcgccgtgggggctgccgggacgggtccaagatgga

cggccgctcaggttctgcttttacctgcggcccagagccccattcattgccccggtgctgagcggcgccgcgagtcggcccgaggcctccggggactgccgtgccgggcgggagaccgccatggcgaccctggaaaagctgatgaaggccttcgagtccctcaagtccttccagcagcagcagcagcagcagcag

cagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcag

cagcagcagcagcagcagcagcagcagcagcagcagcagcaacagccgccaccgccgccgccgccgccgccgcctcctcagcttcctcagccgccgccgcaggcacagccgctgctgcctcagccgcagccgcccccgccgccgcccccgccgccacccggcccggctgtggctgaggagccgctgcaccgacca

aagaaagaactttcagctaccaagaaagaccgtgtgaatcattgtctgacaatatgtgaaaacatagtggcacagtctgtcagaaattctccagaatttcagaaacttctgggcatcgctatggaactttttctgctgtgcagtgatgacgcagagtcagatgtcaggatggtggctgacgaatgcctcaacaaa

gttatcaaagctttgatggattctaatcttccaaggttacagctcgagctctataaggaaattaaaaagaatggtgcccctcggagtttgcgtgctgccctgtggaggtttgctgagctggctcacctggttcggcctcagaaatgcaggccttacctggtgaaccttctgccgtgcctgactcgaacaagcaag

agacccgaagaatcagtccaggagaccttggctgcagctgttcccaaaattatggcttcttttggcaattttgcaaatgacaatgaaattaaggttttgttaaaggccttcatagcgaacctgaagtcaagctcccccaccattcggcggacagcggctggatcagcagtgagcatctgccagcactcaagaagg

acacaatatttctatagttggctactaaatgtgctcttaggcttactcgttcctgtcgaggatgaacactccactctgctgattcttggcgtgctgctcaccctgaggtatttggtgcccttgctgcagcagcaggtcaaggacacaagcctgaaaggcagcttcggagtgacaaggaaagaaatggaagtctct

ccttctgcagagcagcttgtccaggtttatgaactgacgttacatcatacacagcaccaagaccacaatgttgtgaccggagccctggagctgttgcagcagctcttcagaacgcctccacccgagcttctgcaaaccctgaccgcagtcgggggcattgggcagctcaccgctgctaaggaggagtctggtggc

cgaagccgtagtgggagtattgtggaacttatagctggagggggttcctcatgcagccctgtcctttcaagaaaacaaaaaggcaaagtgctcttaggagaagaagaagccttggaggatgactctgaatcgagatcggatgtcagcagctctgccttaacagcctcagtgaaggatgagatcagtggagagctg

gctgcttcttcaggggtttccactccagggtcagcaggtcatgacatcatcacagaacagccacggtcacagcacacactgcaggcggactcagtggatctggccagctgtgacttgacaagctctgccactgatggggatgaggaggatatcttgagccacagctccagccaggtcagcgccgtcccatctgac

cctgccatggacctgaatgatgggacccaggcctcgtcgcccatcagcgacagctcccagaccaccaccgaagggcctgattcagctgttaccccttcagacagttctgaaattgtgttagacggtaccgacaaccagtatttgggcctgcagattggacagccccaggatgaagatgaggaagccacaggtatt

cttcctgatgaagcctcggaggccttcaggaactcttccatggcccttcaacaggcacatttattgaaaaacatgagtcactgcaggcagccttctgacagcagtgttgataaatttgtgttgagagatgaagctactgaaccgggtgatcaagaaaacaagccttgccgcatcaaaggtgacattggacagtcc

actgatgatgactctgcacctcttgtccattgtgtccgccttttatctgcttcgtttttgctaacagggggaaaaaatgtgctggttccggacagggatgtgagggtcagcgtgaaggccctggccctcagctgtgtgggagcagctgtggccctccacccggaatctttcttcagcaaactctataaagttcct

cttgacaccacggaataccctgaggaacagtatgtctcagacatcttgaactacatcgatcatggagacccacaggttcgaggagccactgccattctctgtgggaccctcatctgctccatcctcagcaggtcccgcttccacgtgggagattggatgggcaccattagaaccctcacaggaaatacattttct

ttggcggattgcattcctttgctgcggaaaacactgaaggatgagtcttctgttacttgcaagttagcttgtacagctgtgaggaactgtgtcatgagtctctgcagcagcagctacagtgagttaggactgcagctgatcatcgatgtgctgactctgaggaacagttcctattggctggtgaggacagagctt

ctggaaacccttgcagagattgacttcaggctggtgagctttttggaggcaaaagcagaaaacttacacagaggggctcatcattatacagggcttttaaaactgcaagaacgagtgctcaataatgttgtcatccatttgcttggagatgaagaccccagggtgcgacatgttgccgcagcatcactaattagg

cttgtcccaaagctgttttataaatgtgaccaaggacaagctgatccagtagtggccgtggcaagagatcaaagcagtgtttacctgaaacttctcatgcatgagacgcagcctccatctcatttctccgtcagcacaataaccagaatatatagaggctataacctactaccaagcataacagacgtcactatg

gaaaataacctttcaagagttattgcagcagtttctcatgaactaatcacatcaaccaccagagcactcacatttggatgctgtgaagctttgtgtcttctttccactgccttcccagtttgcatttggagtttaggttggcactgtggagtgcctccactgagtgcctcagatgagtctaggaagagctgtacc

gttgggatggccacaatgattctgaccctgctctcgtcagcttggttcccattggatctctcagcccatcaagatgctttgattttggccggaaacttgcttgcagccagtgctcccaaatctctgagaagttcatgggcctctgaagaagaagccaacccagcagccaccaagcaagaggaggtctggccagcc

ctgggggaccgggccctggtgcccatggtggagcagctcttctctcacctgctgaaggtgattaacatttgtgcccacgtcctggatgacgtggctcctggacccgcaataaaggcagccttgccttctctaacaaaccccccttctctaagtcccatccgacgaaaggggaaggagaaagaaccaggagaacaa

gcatctgtaccgttgagtcccaagaaaggcagtgaggccagtgcagcttctagacaatctgatacctcaggtcctgttacaacaagtaaatcctcatcactggggagtttctatcatcttccttcatacctcaaactgcatgatgtcctgaaagctacacacgctaactacaaggtcacgctggatcttcagaac

agcacggaaaagtttggagggtttctccgctcagccttggatgttctttctcagatactagagctggccacactgcaggacattgggaagtgtgttgaagagatcctaggatacctgaaatcctgctttagtcgagaaccaatgatggcaactgtttgtgttcaacaattgttgaagactctctttggcacaaac

ttggcctcccagtttgatggcttatcttccaaccccagcaagtcacaaggccgagcacagcgccttggctcctccagtgtgaggccaggcttgtaccactactgcttcatggccccgtacacccacttcacccaggccctcgctgacgccagcctgaggaacatggtgcaggcggagcaggagaacgacacctcg

ggatggtttgatgtcctccagaaagtgtctacccagttgaagacaaacctcacgagtgtcacaaagaaccgtgcagataagaatgctattcataatcacattcgtttgtttgaacctcttgttataaaagctttaaaacagtacacgactacaacatgtgtgcagttacagaagcaggttttagatttgctggcg

cagctggttcagttacgggttaattactgtcttctggattcagatcaggtgtttattggctttgtattgaaacagtttgaatacattgaagtgggccagttcagggaatcagaggcaatcattccaaacatctttttcttcttggtattactatcttatgaacgctatcattcaaaacagatcattggaattcct

aaaatcattcagctctgtgatggcatcatggccagtggaaggaaggctgtgacacatgccataccggctctgcagcccatagtccacgacctctttgtattaagaggaacaaataaagctgatgcaggaaaagagcttgaaacccaaaaagaggtggtggtgtcaatgttactgagactcatccagtaccatcag

gtgttggagatgttcattcttgtcctgcagcagtgccacaaggagaatgaagacaagtggaagcgactgtctcgacagatagctgacatcatcctcccaatgttagccaaacagcagatgcacattgactctcatgaagcccttggagtgttaaatacattatttgagattttggccccttcctccctccgtccggtagacatgcttttacggagtatgttcgtcactccaaacacaatggcgtccgtgagcactgttcaactgtggatatcgggaattctggccattttgagggttctgatttcccagtcaactgaagatattgttctttctcgtattcaggagctctccttctctccgtatttaatctcctgtacagtaattaatagg

ttaagagatggggacagtacttcaacgctagaagaacacagtgaagggaaacaaataaagaatttgccagaagaaacattttcaaggtttctattacaactggttggtattcttttagaagacattgttacaaaacagctgaaggtggaaatgagtgagcagcaacatactttctattgccaggaactaggcaca

ctgctaatgtgtctgatccacatcttcaagtctggaatgttccggagaatcacagcagctgccactaggctgttccgcagtgatggctgtggcggcagtttctacaccctggacagcttgaacttgcgggctcgttccatgatcaccacccacccggccctggtgctgctctggtgtcagatactgctgcttgtc

aaccacaccgactaccgctggtgggcagaagtgcagcagaccccgaaaagacacagtctgtccagcacaaagttacttagtccccagatgtctggagaagaggaggattctgacttggcagccaaacttggaatgtgcaatagagaaatagtacgaagaggggctctcattctcttctgtgattatgtctgtcag

aacctccatgactccgagcacttaacgtggctcattgtaaatcacattcaagatctgatcagcctttcccacgagcctccagtacaggacttcatcagtgccgttcatcggaactctgctgccagcggcctgttcatccaggcaattcagtctcgttgtgaaaacctttcaactccaaccatgctgaagaaaact

cttcagtgcttggaggggatccatctcagccagtcgggagctgtgctcacgctgtatgtggacaggcttctgtgcacccctttccgtgtgctggctcgcatggtcgacatccttgcttgtcgccgggtagaaatgcttctggctgcaaatttacagagcagcatggcccagttgccaatggaagaactcaacaga

atccaggaataccttcagagcagcgggctcgctcagagacaccaaaggctctattccctgctggacaggtttcgtctctccaccatgcaagactcacttagtccctctcctccagtctcttcccacccgctggacggggatgggcacgtgtcactggaaacagtgagtccggacaaagactggtacgttcatctt

gtcaaatcccagtgttggaccaggtcagattctgcactgctggaaggtgcagagctggtgaatcggattcctgctgaagatatgaatgccttcatgatgaactcggagttcaacctaagcctgctagctccatgcttaagcctagggatgagtgaaatttctggtggccagaagagtgccctttttgaagcagcc

cgtgaggtgactctggcccgtgtgagcggcaccgtgcagcagctccctgctgtccatcatgtcttccagcccgagctgcctgcagagccggcggcctactggagcaagttgaatgatctgtttggggatgctgcactgtatcagtccctgcccactctggcccgggccctggcacagtacctggtggtggtctcc

aaactgcccagtcatttgcaccttcctcctgagaaagagaaggacattgtgaaattcgtggtggcaacccttgaggccctgtcctggcatttgatccatgagcagatcccgctgagtctggatctccaggcagggctggactgctgctgcctggccctgcagctgcctggcctctggagcgtggtctcctccaca

gagtttgtgacccacgcctgctccctcatctactgtgtgcacttcatcctggaggccgttgcagtgcagcctggagagcagcttcttagtccagaaagaaggacaaataccccaaaagccatcagcgaggaggaggaggaagtagatccaaacacacagaatcctaagtatatcactgcagcctgtgagatggtg

gcagaaatggtggagtctctgcagtcggtgttggccttgggtcataaaaggaatagcggcgtgccggcgtttctcacgccattgctcaggaacatcatcatcagcctggcccgcctgccccttgtcaacagctacacacgtgtgcccccactggtgtggaagcttggatggtcacccaaaccgggaggggatttt

ggcacagcattccctgagatccccgtggagttcctccaggaaaaggaagtctttaaggagttcatctaccgcatcaacacactaggctggaccagtcgtactcagtttgaagaaacttgggccaccctccttggtgtcctggtgacgcagcccctcgtgatggagcaggaggagagcccaccagaagaagacaca

gagaggacccagatcaacgtcctggccgtgcaggccatcacctcactggtgctcagtgcaatgactgtgcctgtggccggcaacccagctgtaagctgcttggagcagcagccccggaacaagcctctgaaagctctcgacaccaggtttgggaggaagctgagcattatcagagggattgtggagcaagagatt

caagcaatggtttcaaagagagagaatattgccacccatcatttatatcaggcatgggatcctgtcccttctctgtctccggctactacaggtgccctcatcagccacgagaagctgctgctacagatcaaccccgagcgggagctggggagcatgagctacaaactcggccaggtgtccatacactccgtgtgg

ctggggaacagcatcacacccctgagggaggaggaatgggacgaggaagaggaggaggaggccgacgcccctgcaccttcgtcaccacccacgtctccagtcaactccaggaaacaccgggctggagttgacatccactcctgttcgcagtttttgcttgagttgtacagccgctggatcctgccgtccagctca

gccaggaggaccccggccatcctgatcagtgaggtggtcagatcccttctagtggtctcagacttgttcaccgagcgcaaccagtttgagctgatgtatgtgacgctgacagaactgcgaagggtgcacccttcagaagacgagatcctcgctcagtacctggtgcctgccacctgcaaggcagctgccgtcctt

gggatggacaaggccgtggcggagcctgtcagccgcctgctggagagcacgctcaggagcagccacctgcccagcagggttggagccctgcacggcgtcctctatgtgctggagtgcgacctgctggacgacactgccaagcagctcatcccggtcatcagcgactatctcctctccaacctgaaagggatcgcc

cactgcgtgaacattcacagccagcagcacgtactggtcatgtgtgccactgcgttttacctcattgagaactatcctctggacgtagggccggaattttcagcatcaataatacagatgtgtggggtgatgctgtctggaagtgaggagtccaccccctccatcatttaccactgtgccctcagaggcctggag

cgcctcctgctctctgagcagctctcccgcctggatgcagaatcgctggtcaagctgagtgtggacagagtgaacgtgcacagcccgcaccgggccatggcggctctgggcctgatgctcacctgcatgtacacaggaaaggagaaagtcagtccgggtagaacttcagaccctaatcctgcagcccccgacagc

gagtcagtgattgttgctatggagcgggtatctgttctttttgataggatcaggaaaggctttccttgtgaagccagagtggtggccaggatcctgccccagtttctagacgacttcttcccaccccaggacatcatgaacaaagtcatcggagagtttctgtccaaccagcagccatacccccagttcatggcc

accgtggtgtataaggtgtttcagactctgcacagcaccgggcagtcgtccatggtccgggactgggtcatgctgtccctctccaacttcacgcagagggccccggtcgccatggccacgtggagcctctcctgcttctttgtcagcgcgtccaccagcccgtgggtcgcggcgatcctcccacatgtcatcagc

aggatgggcaagctggagcaggtggacgtgaaccttttctgcctggtcgccacagacttctacagacaccagatagaggaggagctcgaccgcagggccttccagtctgtgcttgaggtggttgcagccccaggaagcccatatcaccggctgctgacttgtttacgaaatgtccacaaggtcaccacctgctga

gcgccatggtgggagagactgtgaggcggcagctggggccggagcctttggaagtctgtgcccttgtgccctgcctccaccgagccagcttggtccctatgggcttccgcacatgccgcgggcggccaggcaacgtgcgtgtctctgccatgtggcagaagtgctctttgtggcagtggccaggcagggagtgtc

tgcagtcctggtggggctgagcctgaggccttccagaaagcaggagcagctgtgctgcaccccatgtgggtgaccaggtcctttctcctgatagtcacctgctggttgttgccaggttgcagctgctcttgcatctgggccagaagtcctccctcctgcaggctggctgttggcccctctgctgtcctgcagtag

aaggtgccgtgagcaggctttgggaacactggcctgggtctccctggtggggtgtgcatgccacgccccgtgtctggatgcacagatgccatggcctgtgctgggccagtggctgggggtgctagacacccggcaccattctcccttctctcttttcttctcaggatttaaaatttaattatatcagtaaagaga

ttaattttaacgaactctttctatgcccgtgtaaagtatgtgaatcgcaaggcctgtgctgcatgcgacagcgtccggggtggtggacagggcccccggccacgctccctctcctgtagccactggcatagccctcctgagcacccgctgacatttccgttgtacatgttcctgtttatgcattcacaaggtgac

tgggatgtagagaggcgttagtgggcaggtggccacagcaggactgaggacaggcccccattatcctaggggtgcgctcaactgcagcccctcctcctcgggcacagacgactgtcgttctccacccaccagtcagggacagcagcctccctgtcactcagctgagaaggccagccctccctggctgtgagcagc

ctccactgtgtccagagacatgggcctcccactcctgttccttgctagccctggggtggcgtctgcctaggagctggctggcaggtgttgggacctgctgctccatggatgcatgccctaagagtgtcactgagctgtgttttgtctgagcctctctcggtcaacagcaaagcttggtgtcttggcactgttagt

gacagagcccagcatcccttctgcccccgttccagctgacatcttgcacggtgaccccttttagtcaggagagtgcagatctgtgctcatcggagactgccccacggccctgtcagagccgccactcctatccccaggacaggtccctggaccagcctcctgtttgcaggcccagaggagccaagtcattaaaat

ggaagtggattctggatggccgggctgctgctgatgtaggagctggatttgggagctctgcttgccgactggctgtgagacgaggcaggggctctgcttcctcagccctagaggcgagccaggcaaggttggcgactgtcatgtggcttggtttggtcatgcccgtcgatgttttgggtattgaatgtggtaagt

ggaggaaatgttggaactctgtgcaggtgctgccttgagacccccaagcttccacctgtccctctcctatgtggcagctggggagcagctgagatgtggacttgtatgctgcccacatacgtgagggggagctgaaagggagcccctgctcaaagggagcccctcctctgagcagcctctgccaggcctgtatga

ggcttttcccaccagctcccaacagaggcctcccccagccaggaccacctcgtcctcgtggcggggcagcaggagcggtagaaaggggtccgatgtttgaggaggcccttaagggaagctactgaattataacacgtaagaaaatcaccattcttccgtattggttgggggctcctgtttctcatcctagctttt

tcctggaaaagcccgctagaaggtttgggaacgaggggaaagttctcagaactgttgctgctccccacccgcctcccgcctcccccgcaggttatgtcagcagctctgagacagcagtatcacaggccagatgttgttcctggctagatgtttacatttgtaagaaataacactgtgaatgtaaaacagagccat

tcccttggaatgcatatcgctgggctcaacatagagtttgtcttcctcttgtttacgacgtgatctaaaccagtccttagcaaggggctcagaacaccccgctctggcagtaggtgtcccccacccccaaagacctgcctgtgtgctccggagatgaatatgagctcattagtaaaaatgacttcacccacgcat

atacataaagtatccatgcatgtgcatatagacacatctataattttacacacacacctctcaagacggagatgcatggcctctaagagtgcccgtgtcggttcttcctggaagttgactttccttagacccgccaggtcaagttagccgcgtgacggacatccaggcgtgggacgtggtcagggcagggctcat

tcattgcccactaggatcccactggcgaagatggtctccatatcagctctctgcagaagggaggaagactttatcatgttcctaaaaatctgtggcaagcacccatcgtattatccaaattttgttgcaaatgtgattaatttggttgtcaagttttgggggtgggctgtggggagattgcttttgttttcctgc

tggtaatatcgggaaagattttaatgaaaccagggtagaattgtttggcaatgcactgaagcgtgtttctttcccaaaatgtgcctcccttccgctgcgggcccagctgagtctatgtaggtgatgtttccagctgccaagtgctctttgttactgtccaccctcatttctgccagcgcatgtgtcctttcaagg

ggaaaatgtgaagctgaaccccctccagacacccagaatgtagcatctgagaaggccctgtgccctaaaggacacccctcgcccccatcttcatggagggggtcatttcagagccctcggagccaatgaacagctcctcctcttggagctgagatgagccccacgtggagctcgggacggatagtagacagcaat

aactcggtgtgtggccgcctggcaggtggaacttcctcccgttgcggggtggagtgaggttagttctgtgtgtctggtgggtggagtcaggcttctcttgctacctgtgagcatccttcccagcagacatcctcatcgggctttgtccctcccccgcttcctccctctgcggggaggacccgggaccacagctgc

tggccagggtagacttggagctgtcctccagaggggtcacgtgtaggagtgagaagaaggaagatcttgagagctgctgagggaccttggagagctcaggatggctcagacgaggacactcgcttgccgggcctggccctcctgggaaggagggagctgctcagaatgccgcatgacaactgaaggcaacctgga

aggttcagggcccgctcttcccccatgtgcctgtcacgctctggtgcagtcaaaggaacgccttcccctcagttgtttctaagagcagagtctcccgctgcaatctgggtggtaactgccagccttggaggatcgtggccaacgtggacctgcctacggagggtgggctctgacccaagtggggcctccttgccc

ggaggaaatgttggaactctgtgcaggtgctgccttgagacccccaagcttccacctgtccctctcctatgtggcagctggggagcagctgagatgtggacttgtatgctgcccacatacgtgagggggagctgaaagggagcccctgctcaaagggagcccctcctctgagcagcctctgccaggcctgtatga

aggtctcactgctttgcaccgtggtcagagggactgtcagctgagcttgagctcccctggagccagcagggctgtgatgggcgagtcccggagccccacccagacctgaatgcttctgagagcaaagggaaggactgacgagagatgtatatttaattttttaactgctgcaaacattgtacatccaaattaaag

tggccagggtagacttggagctgtcctccagaggggtcacgtgtaggagtgagaagaaggaagatcttgagagctgctgagggaccttggagagctcaggatggctcagacgaggacactcgcttgccgggcctggccctcctgggaaggagggagctgctcagaatgccgcatgacaactgaaggcaacctgga

aggtctcactgctttgcaccgtggtcagagggactgtcagctgagcttgagctcccctggagccagcagggctgtgatgggcgagtcccggagccccacccagacctgaatgcttctgagagcaaagggaaggactgacgagagatgtatatttaattttttaactgctgcaaacattgtacatccaaattaaag

genetic sex determinationHermaphroditos Salmakis

intersex roe deer: cryptorchism

testis, right

epidydimis

spermatic duct

testis, left

bladder

morphological vs.

genetic variability

Africa

Eurasia

Americas

100 000 000 1 000 000 10 000 100 1

years before today

Africa

Eurasia

Americas

100 000 000 1 000 000 10 000 100 1

years before today

evolution

>30 000 years ?

When and how developed the dog?

Taymir “wolf“

35 000 years

graywolf

arcticbreeds

Canis lupusfamiliaris

>30 000 years ?

Skoglund et al. Curr Biol. 2015

When and how developed the dog?

Frantz et al. Science 2016

deep split between east Asian +

western Eurasian dogs: dual origin

Newgrange dog, Ireland 4800 b.p.

canine breedrelations

► breeds of working dogs unrelated:

herding breeds indifferent regions atdifferent times

► functional diversify-cation 1000s of years ago -exterieur variabilityonly a few 100 years

Y chromosome mitochondria

Y chromosomal + mitochondrial inheritance

Lundehund: genetic bottle necks

LadyMorsk Pan ?

Piljo BusterRune Rind Eir

1 puppy 3 pups 9 pups 5 pups 7 pups

? ?

Mosti ?Kvikk 2

1 ♀ + 1 ♂ forebear each

ad genetic variability

dogs + wolves

wolvesonly

Lundehund

human + canine genetics

ENCODE Encyclopedia of DNA Elements FANTOMS Functional Annotation of Mammalian

Genomes

CanFam Dog Genome Assembly

Human genetics

+ animal models

introduction; animal models -

natural + breed(ing)

progressive retinal atrophy

perspectives

genes and behavior – association study

pointing dog herding dog

Weimaraner

Großer Münsterländer

Berger des Pyrénées

Schapendoes

vs.

behavioral traits

pointers

herders

bo

ldn

ess

soci

abili

ty

trainability

calmness

herder

pointer

pointer

herder

pointers vs. herders

pointers vs. herderschr22:4,947,993-5,990,536 (1Mb)

…

…

next generation sequencing (putative) genes

gene chr. reference change genotype protein

pointers vs. herders ATP5H 22 G GAGA G/G ins K

T A T/T Stop

SETDB2 22 C T C/C S>N

CYSLTR2 22 A G A/A L>L

22 C G G/G P>R

22 C G G/G 5'UTR

ATP7B 22 GCCGCCC G G/G delAP

herders vs. pointers RSPO2 13 3'UTR

13 promoter

EIF3E 13 promoter

ZNF407 1 G A G/G G>D

1 T C T/T V>A

additional breeds

pointersgene genotype Berger d. Pyr.

N=40Schapendoes

N=66Golden Retr.

N=29KuvacN=14

Riesenschn.N=41

GITN=47

JagdteckelN=23

Dt. Wachtelh.N=22

SETDB2 11 5 34 2 7 5 26 1 -

12 20 29 15 5 15 16 4 7

22 15 3 11 2 20 4 18 15

CYSLTR2 rs*730 11 10 54 4 7 8 33 1 2

12 15 2 5 3 8 6 5 5

22 15 10 12 3 24 4 13 15

CYSLTR2 rs*728 11 11 2 16 3 25 6 15 15

12 16 24 11 4 14 22 6 6

22 2 27 - 6 1 17 - 1

gene function ?

SETDB2Histone-Methyltransferase modulates gene expression

epigenetically

DNAmethy-lation

histonemodi-fication

histone

histone

chromosome

Human genetics

+ animal models

introduction; animal models -

natural + breeds

progressive retinal atrophy

perspectives

phenotype

KIT gene mutations

piebaldismmastocytosis

gastrointestinal stromal and germ cell tumours

KIT exon 13: c.1960_1962delCTC p.L654del, heterocygous

KIT mutationsin mast cell tumours in dogs

Letard 2008

summary I

natural animal models occur haphazardly

- useful for understanding human ?

understanding breeding models

Human genetics

+ animal models

introduction animal models –

natural + breed(ing)

progressive retinal atrophy

perspectives

genes and retinal diseases

OMIM16.4.‘15

RETNET20.5.‘17

RP / PRA

PRAnormal retina

cones + rods

outer nuclear layer

inner nuclear layer

ganglion cell layer

pigment epithel

PRA in Schapendoes

3/04start genome screen

7/051. gene

characterised6/20051. linkage

2/0811. gene

8/20062. gene

all chromosomes 20 before DNA testing

10%20%

all chromosomes 20 after selective breeding

12,5%

all chromosomes 20 selecting exterieur

25%

chromosome 20 → variable ↓

10%

Ccdc66 gene and chromosome 20

Ccdc66

Ccdc66

haplotype frequencies including 2 flanking markers variable markers flanking Ccdc66 gene

2015mutation

A B C D E F G H I J K L M N O P Q R S T U V

35%

30%

25%

20%

15%

10%

5%

new

→ new haplotypes in the population, variability ↑

2004

consequences of eradication policyfor a gPRA mutation in Schapendoes

► mutation frequency ↓

► paradoxon: genet. variability not ↓ but ↑ - why ?

► secondary morbid gain, breeding strategy changed:

lines used not used before (inbreeding coeff. 30→20)

→ kidney problems ↑

brain teaser: prudent breeding policies

PRA: Schapendoes vs. Weimaraners

3/04genome screen

7/051. gene

characterised6/2005chromosome identified

2/0811. gene

8/20062. gene

7/15exome sequen-ced

8/151.-15. genes

9/15

inherited disease ?

C EAF B

I…G… H… K…

D N

inherited disease ?

C EAF B

I…G… H… K…

D N

DNA biobank

ND

C EAF B

G… H… K… I…

CE EAF B

GE… HE… KE…

ND

IE…

LE…JE…

AS…

ME…

XLPRA mutation carryers

1 3 5 7 9 11 Exons

5 7 9 11 Exons

intragenic deletion

→ no functional protein

→ retina degeneration → loss of vision

animal models for retinal degeneration

mutation of the Ccdc66 (coiled coil domain containing 66) gene leads to

retinal degeneration in Schapendoes dogs & mice

natural artificial

superovulated mouseCcdc66 construct

micro-injection

oviduct transfer

transgenicoffspring?

transgenic mouselines

transgenecontrol

pseudopregnantmouse

Ccdc66 knock-out mice

CCDC66, PNA, DAPI

+/+ -/-

Ccdc66-/- mouse model

Gerding et al., 2011

+/+ -/-

P13 7mo

+/+ -/-+/+ -/-+/-

retina

What is the role of Ccdc66 gene products

in the retina & beyond?

● CCDC66 pathway

retina ◦ CCDC66 interaction partners

retina & brain ◦ sub-cellular localization of CCDC66

● Ccdc66 expression

retina ◦ function ?

brain ◦ extra-retinal structures → function ?

& other tissues ◦ consequences of impaired Ccdc66 expression (brain)

What is the role of Ccdc66 gene products

in the retina & beyond?

CCDC66 - interaction partner candidatesMPDZ (Multiple PDZ Domain) + EPS8 (Epidermal Growth Factor Receptor Kinase Substrate 8)

EPS8**

MPDZ*/EPS8** • brain, olfactory epithelium (MPDZ) & cochlear hair cells (EPS8)

• cytoskeleton stabilization & remodelling

→ CCDC66 pathway ?

MPDZ

EPS8

Human genetics

+ animal models

introduction; animal models –

natural + breed(ing)

progressive retinal atrophy

perspectives

Alopezie (Colour Dilution Alopecia / CDA) Beagle, Deutscher Pinscher, Dobermann, Großer Münsterländer, Rhodesian Ridgeback, Dackel, Schnauzer, verschiedene Hunderassen

Alport Syndrom (AS / Hereditäre Nephritis / HN) Bull Terrier, Dalmatiner AD

Autosomal Recessive Hereditary Nephropathy English Cocker Spaniel

XLAS (X-Linked Alport Syndrom) Mischlinge, Navasota Dog, Samojede XD

Canine Leukozyten-Adhäsionsdefizienz (CLAD) Irish Setter, Irish Red und White Setter

Canine Multifokale Retinopathie (CMR / VMD2) Bullmastiff, English Mastiff, Pyrenäen-Berghund, Coton de Tulear

Cerebellare Ataxie (CA) Bulldogge, Coton de Tulear, Gordon Setter, Greyhound, Ital. Hound, Ital. Spinone, Fox-, Airdail + Kerry Blue + Scotch Terrier, Austr. Shepherd, Beagle, Border Collie, Riesenschnauzer

Collie Eye Anomalie (CEA / Choroidale Hypoplasie) Austr. Shepherd, Border Collie, Boykin Spaniel (Amer. Water Sp.), Collie (Lang-, Kurzh.), Lancashire Heeler, Nova Scotia Duck Tolling Retr, Shetland Sheepdog, Whippet Langhaar

Cystinurie Typ I Neufundländer

C3-Komplementdefizienz Brittany Spaniel

Dystrophische Epidemolysis Bullosa (DEB) Golden Retriever, (Akita Inu)

Elliptozytose (HE / Hereditary Elliptocytosis) Australian Silky Terrier, Mischlinge

Epidermolysis Bullosa Junctionalis (JEB) Deutsch Kurzhaar

Epidermolytische Hyperkeratose Norfolk Terrier

Faktor VII Defizienz Alaskian Kee Kai Dog, Beagle

Reduzierte Plasmakoagulationsfaktor-VII-Aktivität English Springer Spaniel, Kerry Blue Terrier, Pyrenäen-Berghund

Fanconi Syndrom Basenji

Fukosidose (alpha) Aktivität English Springer Spaniel

Globoid-Zell-Leukodystrophie (Krabbe-Krankheit) Cairn Terrier, WHWT, Irish Setter

Verminderte Galaktocerebrosidaseaktivität Cairn T., WHWT: DV, HG, LAG, LK, SL, VML

Glycogenose Typ I (GSD Ia) Malteser, Beagle-, Mischlinge

G6PC / Glucose-6-Phosphatase / GM1 Gangliosidose Portugiesischer Wasserhund, Shiba Inu, Alaskan Husky

Gray Collie Syndrom (Zyklishe Neutropenie / CN) Collie

Hämophilie A viele Rassen

Hämophilie B (Faktor IX-Mangel) Lhasa Apso, Labrador Retriever, Airdale T., Pit Bull T., Mischlinge, Deutsch Drahthaar, viele andere Rassen und Mischlinge

Hypohydrotic Ectodermal Dysplasia, X-gebunden (XHED) Deutscher Schäferhund

Ivermectin Sensitivität (Multidrug Resistance / MDR1) Austr. Shepherd, Collie, English Shepherd, Langhaar Whippet, McNab, Min. Australian Shepherd, Schweizer Weißer Schäferh., Old English + Shetland Sheepdog, Silken Windhound

Juvenile Nierendysplasie (JRD / Renal Dysplasia) English Cocker Spaniel, Lhasa Apso, Shih Tzu, Soft Coated Wheaten T.

Kongenitale Hypothyreose (CH) Fox Terrier, Rat Terrier

Kongenitale Stationäre Nachtblindheit (CSNB) Briard, Briard-Beagle Mischlinge

Kongenitales Myastenie Syndrom Old Danish Pointing Dog

Kupferintoxikation (Wilson Krankheit) Bedlington Terrier (Dalmatiner, Labrador, Skye T., West Highland White Terr.)

Kurzschwänzigkeit (Brachyurie / Anurie) Pembroke Welsh Corgi AD

Leukoencephalo-Myelopathie (Leukodystrophie) mt Australian Cattle Dog, Shetland Sheepdog

L-2-Hydroxyglutaric-Aciduria Staffordshire Bull Terrier, West Higland White Terrier

Maligne Hyperthermie (MHS) viele Rassen

Merle Faktor alle Rassen mit Merle Phänotyp

Mukopolysaccharidose (MPS) Plott-Houndo

MPS Typ IIIa Rauhaardackel, Neuseeländischer Huntaway

o MPS Typ IIIb Schipperke

o MPS Typ VI Chesapeake Bay Retriever, Welsh Corgi, Zwergpinscher, Z-schnauzer

o MPS Typ VII Deutscher Schäferhund, Mischlinge

Muskeldystrophie (CXMD / GMRD) Golden Retriever, Deutsch Kurzhaar, Rottweiler

Müller-Gang-Persistenzsyndrom Basset, Zw ergschnauzer

Myopathie (CNM / zentronukleär / LRM) Labrador Retriever

Myostatindefizienz Whippet

Myotonia Congenita Zwergschnauzer, Australian Cattle Dog (Chow Chow , Cocker Spaniel)

Narkolepsie Dackel, Dobermann, Labrador Retriever

Neuronale Ceroid Lipofuzidose (NCL) Border Collie, English Setter, American Bulldog, Langhaardackel

Nierenzellkarzinom und Dermatofibrose (RNCD) Deutscher Schäferhund

Osteogenesis imperfecta (Glasknochenkrankheit) Golden Retriever, Beagle, viele Rassen

PFK-Defizienz (Phosphofruktokinasedefizienz) American Cocker Spaniel, Cocker Spaniel, English Springer Spaniel

PK-Defizienz (Pyruvatkinasedefizienz) Basenji, West Highland White Terrier, American Eskimo Dog, Beagle, Cairn Terrier, Langhaardackel, Zwergpudel

Primärer Katarakt Staffordshire Bull Terrier, Boston Terrier, Australian Shepherd

Progressive Retinaatrophie (PRA) AHT, DV, HG, LK, SL, TG, UG, UM, VG, VT

o ad PRA (autosomal dominant) Bullmastiff, English Mastiff

o cd PRA rezessiv (cone deg. / Achromatopsia-3) Alaskan Malamute, Deutsch Kurzhaar

o cord1 PRA rezessiv (cone-rod dystrophy1) Zwerg-Langhaardackel

o crd (cord2) PRA rezessiv (cone-rod dystrophy 2) Rauhaardackel

o erd PRA (canine early retinal degeneration) Norwegischer Elchhund

o prcd PRA rezessiv (progressive cone degeneration) Australian Cattle + Australian Stumpy Tail Cattle Dog, American Cocker Sp. American Eskimo Dog, Chesapeake Bay Retr., Chinese Crested, English Cocker Spaniel, Entlebucher

Sennenhund, Finnischer Lapphund, Kuvasz, Lapponian Herder, Nova Scotia Duck Tolling Retr., Port. Wasserhund, Schwedischer Lapphund, Silky Terrier, Toy- + Zwerpudel

o rcd1 PRA rezessiv (rod-cone Dysplasie Typ I) Irish Setter

o rcd1a PRA rezessiv (rod-cone Dysplasie Typ Ia) Sloughi

o rcd2 PRA rezessiv (rod-cone Dysplasie Typ II) Collie

o Typ A PRA (Photorezeptor Dysplasie / pd PRA) Zw ergschnauzer

o XL-PRA X rezessiv (XL-PRA1, XL-PRA2) Samojede, Siberian Husky (XLPRA1), Mischlinge (XL-PRA2)

Pyruvatdehydrogenase-Phosphatase-Defizienz (PDH, PDP1) Clumber Spaniel, Sussex Spaniel

PLP1 / Proteolipid Protein 1 (Pelizaeus-Merzbacher disease, spastic paraplegia 2, uncomplicated)

Schwere Kombinierte Immundefizienz (SCID autosomal) Jack Russell Terrier

Schwere Kombinierte Immundefizienz (X-SCID) Cardigan Welsh Corgi, Basset

Thrombastenie (Glanzmann Typ I) Pyrenäen-Berghund, Otterhund

von Willebrandkrankheit (vWD) o vWD Typ I Berner Sennenhund, Deutsch Kurzhaar, Schäferhund, Dobermann, Golden Retr., Kerry Blue + Manchester T., Papillon, Pembroke Welsh Corgi, Pudel

o vWDTyp II Deutsch Drahthaar, Deutsch Kurzhaar

o vWD Typ III Kooikerhondje, Scottish Terrier, Sheltland Sheep dog

conclusions

small breeding population

danger for breed-specificrecessive inherited diseases

after cross-breeding/introgression

inherited disease imported