genetics and genomics of mammalian pigmentary variation

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