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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 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

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  1. Genetics and genomics of mammalian pigmentary variation Human Genome Meeting June 3, 2006 Greg BarshDepartment of Genetics Stanford University School of Medicine

  2. 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.)

  3. Melanocyte development and biochemistry Pigment type switching and genetics

  4. 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)

  5. What causes pigmentation patterns? Arctic Lemming

  6. 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)

  7. Regional promoters give rise to pigment patterns

  8. Reversal of an inverted duplication in the AW to A mutation

  9. 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)

  10. Pigment type-switching in other animals

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

  12. X Black-and-tan Finnish Lapphund Black Finnish Lapphund (Fawn-colored Greyhound; Fawn-colored Boxer) (Newfoundland; Black Labrador; Dalmation)

  13. The Cornell cross (Lust, Todhunter) 40 16 non-black 16 black

  14. Genome scan: a new black locus (K) in dogs (Cornell cross)18 animals,155 markers:LOD 8.6 attheta = 0

  15. Epistasis instead of dominance Mice Dogs

  16. 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)

  17. Single dogs for association study

  18. 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

  19. How does the K locus work? 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

  20. brindled (kbr) is an allele of the K locus fawn or red (k) brindle (kbr) Black (K) k < kbr < K

  21. Brindled (kbr) 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)

  22. Epigenetic control of brindled stripes black stripe yellow stripe

  23. Building blocks for pigment patterns Agouti Black (K)

  24. Acknowledgements Cornell George LustRory TodhunterMichael Olivier Saskatchewan Sheila Schmutz Harwell Bruce Cattanach Chris Kaelin Sophie Candille Julie Kerns

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