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Genetics and genomics of mammalian pigmentary variation. Human Genome Meeting June 3, 2006. Greg Barsh Department of Genetics Stanford University School of Medicine. pleiotropic effects of lethal yellow ( A y ). Biology of Pigmentation and its Applications to disease….

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Genetics and genomics of mammalian pigmentary variation

Genetics and genomics of mammalian pigmentary variation

Human Genome Meeting

June 3, 2006

Greg BarshDepartment of Genetics

Stanford University School of Medicine


Biology of pigmentation and its applications to disease

pleiotropic effects of lethal yellow (Ay)

Biology of Pigmentation and its Applicationsto disease…

MC4R: +/- (siblings) +/+

~4% of individuals with severe childhood-onset obesity (Farooqi et al.)


Melanocyte development and biochemistry

Pigment type switching and genetics


Molecular causes of Mc1r loss-of-function

DG104

red cow

(Klungland, 1995)

DC183

yellow mouse

(Robbins, 1993)

R306ter

Irish Setter

(Newton, 2000)

C33T

red chicken

(Takeuchi, 1996)

S83F

chestnut horse

(Marklunk, 1996)

A240T

red pig

(Kijas, 1998)

R151C

red hair

(Rees, 1997)



Control of pigment distribution by agouti alleles in time and space
Control of pigment distribution by Agouti allelesin time and space

dorsum

1-3 4-6 7-9

days of post-natal hair growth

ventrum

light-bellied Agouti (AW)

Agouti (A)

black-and-tan (at)




Adaptive coloration in Peromyscus (H. Hoekstra)

Sand Hills of Nebraska:"Wide band" Agouti(P. maniculatus)

Santa Rosa Beach Mouse

Perdido Key Beach Mouse

Alabama Beach Mouse

St. Andrew Beach Mouse

Choctawhatchee Beach Mouse

open sand dunes,

lighter sand

increased cover,

darker sand

Coastal dunes and barrier islands (P. polionotus)



Dominance of Agouti alleles in Mice and Dogs (Little, 1969)

Mice

Dogs


X

Black-and-tan

Finnish Lapphund

Black

Finnish Lapphund

(Fawn-colored

Greyhound;

Fawn-colored

Boxer)

(Newfoundland;

Black Labrador;

Dalmation)


The Cornell cross (Lust, Todhunter)

40

16 non-black

16 black


Genome scan: a new black locus (K) in dogs

(Cornell cross)18 animals,155 markers:LOD 8.6 attheta = 0



Genetics of domestic dogs as a model system

Domestication from wolves about 15,000 years ago

Patterns of linkage disequilibrium

(Linblad-Tohet al., 2005)

Large Ne; short LD(like humans)

Establishment of modern breeds about 250 years ago

Small Ne; long LD(like lab mice)

(1) Establish rough subchromosomal position by association within breeds

(2) Fine-map by association across breeds (assuming ancestral allele)



K maps to a gene cluster encoding secreted cysteine-rich proteins

Dog 16 (356 kb)

25kb

Reversion mapping interval (200 kb)

LD mapping interval (9 kb)

widely expressed

expressed in skin

signal peptide

mature peptide

mutated in fawn vs. black


How does the K locus work? proteins

Agouti Mc1r K Phenotype

ay + fawn (k) Pheomelanic

ay+ black (K) Eumelanic

a (lof) + K or k Eumelanic

aye (lof) K or kPheomelanic

K

?

?

K


brindled proteins (kbr) is an allele of the K locus

fawn or red (k)

brindle (kbr)

Black (K)

k < kbr < K


Brindled ( proteinskbr) is a segmental duplication

fawn (k): ancestral allele (wolves, coyotes

Black (K): derivative allele

(~10,000 years ago)

Brindled (kbr):

segmental duplication

(~1000 years ago)


Epigenetic control of brindled stripes proteins

black stripe

yellow stripe


Building blocks for pigment patterns proteins

Agouti

Black (K)


Acknowledgements proteins

Cornell

George LustRory TodhunterMichael Olivier

Saskatchewan

Sheila Schmutz

Harwell

Bruce Cattanach

Chris Kaelin

Sophie Candille

Julie Kerns


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