Mapping regulatory variants influencing complex traits at single-base pair resolution


It is increasingly recognized that the majority of causative variants underlying inherited predisposition to common complex diseases, agriculturally important phenotypes and fitness traits in natural populations are regulatory variants (as opposed to coding variants).  One of the specialties of the UAG has been the identification of such regulatory variants at single-base pair resolution using forward genetic approaches, i.e. by applying various fine-mapping strategies.  We have applied these methods both in livestock and in humans.  One of the striking features is that regulatory variants seem to often affect silencers.
 
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Association mapping of inflammatory bowel disease loci to single variant resolution. Huang H*,  Fang M*, Jostins L*, Umicevic Mirkov M, Boucher G, Anderson CA, Andersen V, Cleynen I, Cortes A,  Crins F, D'Amato M,  Deffontaine V, Dmitrieva J, Docampo E, Elansary M, Kai-How Farh K, Franke A,  Gori A-S, Goyette P, Halfvarson, Haritunians T, Knight J, Lawrance IC, Lees CW,  Louis E, Mariman R, Meuwissen T,  Mni M, Momozawa Y, Parkes M, Spain SL,  Theatre E, Trynka G, Satsangi J, van Sommeren S, Vermeire S, Xavier RJ, IIBDGC, Weersma R, Duerr RH, Mathew CG, Rioux JD, McGovern DPB, Cho JH,  Georges M#, Daly M#, Barrett JC.# *co-first, #co-senior.  Nature 547: 173-178 (2017).
 
Variants modulating the expression of a chromosome domain encompassing PLAG1 influence bovine stature. Karim L, Takeda H, Lin L, Druet T, Arias JAC, Baurain D, Cambisano N, Davis SR, Farnir F, Grisart B, Harris BL, Keehan MD, Littlejohn MD, Spelman RJ, Georges M, Coppieters W.   Nature Genetics 43: 405-413 (2011)
 
A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep. Clop A, Marcq F, Takeda H, Pirottin D, Tordoir X, Bibé B, Bouix J, Caiment F, Elsen JM, Eychenne F, Larzul C, Laville E, Meish F, Milenkovic D, Tobin J, Charlier C, Georges M.  Nature Genetics 38:813-818 (2006)
  

A regulatory mutation in IGF2 causes a major QTL effect on muscle growth in the pig. Van Laere AS, Nguyen M, Braunschweig M, Nezer C, Collette C, Moreau L, Archibald AL, Haley CS, Buys N, Tally M, Andersson G, Georges M, Andersson L. Nature 425:832-836 (2003).

Mosaicism of Solid Gold supports the causality of a noncoding A-to-G transition in the determinism of the callipyge phenotype.
Smit M, Segers K, Carrascosa LG, Shay T, Baraldi F, Gyapay G, Snowder G, Georges M, Cockett N, Charlier C. Genetics 163:453-456 (2003).

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