Post on 31-Dec-2015
Genetics and genomics of mammalian pigmentary variation
Greg BarshDepartment of
Genetics
Stanford University School of Medicine
Human Genome Meeting
June 3, 2006
Biology of Pigmentation and its Applicationsto disease…
pleiotropic effects of lethal yellow (Ay)
MC4R: +/- (siblings) +/+
~4% of individuals with severe childhood-onset obesity (Farooqi et al.)
Melanocyte development and biochemistry Pigment type switching and genetics
C33Tred chicken
(Takeuchi, 1996)
S83Fchestnut horse
(Marklunk, 1996)
R151Cred hair(Rees, 1997)
A240Tred pig
(Kijas, 1998)
G104red cow
(Klungland, 1995)C183
yellow mouse(Robbins, 1993)
R306terIrish Setter
(Newton, 2000)
Molecular causes of Mc1r loss-of-function
What causes pigmentation patterns?
Arctic Lemming
Control of pigment distribution by Agouti alleles
in time and space
days of post-natal hair growth
1-3 4-6 7-9
dorsum
ventrum
light-bellied Agouti (AW)
Agouti (A) black-and-tan (at)
Regional promoters give rise to pigment patterns
Reversal of an inverted duplication in the AW to A mutation
Adaptive coloration in Peromyscus (H. Hoekstra)
Sand Hills of Nebraska:"Wide band" Agouti(P. maniculatus)
Coastal dunes and barrier islands (P. polionotus)
St. Andrew Beach Mouse
Santa Rosa Beach Mouse Perdido Key Beach Mouse Alabama Beach Mouse
Choctawhatchee Beach Mouse
open sand dunes,
lighter sand
increased cover,darker sand
Pigment type-switching in other animals
Dominance of Agouti alleles in Mice and Dogs (Little, 1969)
Mice Dogs
Black-and-tanFinnish Lapphund
X
(Fawn-coloredGreyhound;
Fawn-coloredBoxer)
(Newfoundland;Black Labrador;
Dalmation)
BlackFinnish Lapphund
16 non-black 16 black
40
The Cornell cross (Lust, Todhunter)
Genome scan: a new black locus (K) in dogs
(Cornell cross)18 animals,155 markers:LOD 8.6 attheta = 0
Epistasis instead of dominance
Mice Dogs
Genetics of domestic dogs as a model systemDomestication from wolves
about 15,000 years ago
Establishment of modern breeds about 250 years ago
Large Ne; short LD(like humans)
Small Ne; long LD(like lab mice)
Patterns of linkage disequilibrium(Linblad-Tohet al., 2005)
(1) Establish rough subchromosomal position by association within breeds
(2) Fine-map by association across breeds (assuming ancestral allele)
Single dogs for association study
Breeds Fawn R/R Brindle B/- Black K/-Boxers (Am. and E.) 63 107Great Danes 74 45 54Greyhounds 4 7 4Basenjis 21 15 8Afghan 1 1 4Akitas 33 15Bulldogs 30 28Bullmastiffs 25 11Mastiffs 12 7Whippets 3 8Poodle 1 3German Shephard 7 3Puli 2 3Sharpei 3 5Labs 3 10Rottweiler 10Doberman 13American Stafforshire Bull Terrier 3Dalmatian 6Curly Coated Retriever 5Field Spaniel 5Flat Coated Retriever 4Portuguese Water Dog 4German Shorthair Pointer 5German Wirehair Pointer 5Large Munsterlander 3Total 305 247 131
Reversion mapping interval (200 kb)
K maps to a gene cluster encoding secreted cysteine-rich proteins
25kb
Dog 16 (356 kb)
expressed in skin widely expressed
signal peptide mature peptide
mutated in fawn vs. black
LD mapping interval (9 kb)
How does the K locus work? Agouti Mc1r K Phenotype
ay + fawn (k) Pheomelanic
ay + black (K) Eumelanic
a (lof) + K or k Eumelanic
ay e (lof) K or k Pheomelanic
K
K ?
?
brindled (kbr) is an allele of the K locus
fawn or red (k) Black (K)brindle (kbr)
k < kbr < K
fawn (k): ancestral allele (wolves, coyotes
Brindled (kbr) is a segmental duplication
Black (K): derivative allele(~10,000 years ago)
Brindled (kbr): segmental duplication(~1000 years ago)
Epigenetic control of brindled stripes
black stripe
yellow stripe
Building blocks for pigment patterns
Agouti
Black (K)
Acknowledgements
Julie KernsSophie Candille
Chris Kaelin
Cornell
George LustRory TodhunterMichael Olivier
Saskatchewan
Sheila Schmutz
Harwell
Bruce Cattanach