human genetics + animal models - ruhr-universität bochum · pdf filehuman genetics +...
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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
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
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
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
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
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
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
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
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
● 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
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