Ataxia in Kelpiesmembers.iinet.net.au/~wkc/AtaxiaSlideSummary.pdf · Working Kelpies Alan Wilton,...
Transcript of Ataxia in Kelpiesmembers.iinet.net.au/~wkc/AtaxiaSlideSummary.pdf · Working Kelpies Alan Wilton,...
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Ataxia in
Working Kelpies
Alan Wilton, Jeremy Shearman, Bill Ballard
School of Biochemistry and Molecular Genetics
University of New South Wales
Aim
! identify the genetic defect causing
cerebellar abiotrophy, ataxia
! find the ONE base in 2,500,000,000
of the dog genome
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How
! Linkage grant application
! ~$70,000 p.a.
! funding from WKC
!$8,000 p.a.
! in kind contributions
" personnel
" samples
Tools
! samples from affected
! samples from relatives
! samples from controls
! dog genome sequence
! information from model organisms
with ataxias (eg human)
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Dog Gene Mapping
! Reasons for identifying dog disease genes
!dog health
"many genetic diseases
!model for human genetic diseases
!identification of gene function
!understanding of development
Dog Gene Mapping
! Human is a good model for dog diseases
! human genome advanced
! many disease genes identified
" make good candidates for dog diseases
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Humans as models
Dog Gene Mapping
! Breeding structures
! dogs similar to most domestic animals
" take a champion dog
" breed from it widely
" line breeding -! breeding related animals (with selection)
" results in identity-by-descent
" homozygosity of autosomal recessive defects
" genetic disease
! been estimated we each carry ~5 gene defects
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Same defective copy of geneinherited from common ancestor
Dog Gene Mapping
! each breed is an isolated population
! different, independent defects
! ~300 breeds
! many genetic diseases
! some will be rare in human
" such orphan diseases difficult to identify in man
" dogs make good models for human disease
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Two approaches
! Candidate gene
! find a gene you think is likely to be “it”
! test it.
! Whole genome mapping
! look everywhere
! narrow down possible locations
! the look at candidates
Mice as models
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Other dogs asmodels
Dog Gene Mapping
! Need good coverage of the genome
with informative loci
! microsatellites
"DNA fingerprinting
"Paternity testing
! used in locating the disease gene
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DogMapping
needsPedigrees
Dog Chromosomes
39 pairs
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Genetic RH HumanRed markers common to both maps
Dogs
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Dog Breeding
! High use of champion dogs
! inbreeding
! reveal genetic defects carried as harmless
recessive alleles in ancestor
! often defective alleles identical-by-descent
!inherited from common ancestor
! pedigrees can get quite complicated
!many multiple matings
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Research
! Locating markers close to disease
!need pedigrees with several affecteds
!need lots of markers to test
!examine inheritance of disease allele and markers
! Like looking for needle in haystack
!need test 300 markers to cover all possibilities
!need large pedigree with many affected to provelinkage
Microsatellites on ABI377
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Parentage Test
DAM
SIRE
PUP
Research - Positional cloning
! once location is known
!start search for disease gene itself
!examine known genes in region
!identify new genes in region to test
!find new markers in region
" test new markers on pedigrees for closeness
!can discover gene based only on position
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Affecteds only approach
! modern technology advancing fast
! microarrays
! can test 20,000 sites at one time
! for $500 per animal
! 10 affecteds + 10 controls
! look for regions where no variation
in affecteds