Eye Color Arielle Yablonovitch and Ye Henry Li Most People in the World Have Brown Eyes, Except in Europe Wikipedia, 2012 Non-Brown Color Eyes Occur Infrequently in Populations Outside of Europe Western Asia, especially Afghanistan, Lebanon, Iran, Iraq, Syria, and Jordan. Wikipedia, 2012 The Internet, 2012 !"#$%&'&($)*$+&,$-$.)/0'#$1(-), 2',3&453$5#6#,)7*$,#8,9&&:*$&;,#6$5)<#$#"#$7&'&($-*$-6$#8-/0'#$&;$-$*)/0'#$=#6>#')-6 ,(-),?$,3#(#$-(#$-7,4-''"$/-6"$>);;#(#6,$<-()-6,*$,3-,$7&6,()94,#$,&$),@$ .+A#>)- -'&6#$')*,*$BC$.+A*$,3-,$-(#$-**&7)-,#>$D),3$#"#$7&'&(E !"#$%&'($)*+,$-.%$'%/0-%&'1')2%%!"-)-%3'-.%*$% &'4-%5)'42 • /0-%6'1')%*.%7,-%$'%!"#$%&%8%#%9*:4-($%9)'7,6-7%+0%6-11.%*(%0',)%*)*.;%%<-1#(*(%#1.'% 6'($)*+,$-.%$'%.=*(%#(7%"#*)%6'1'); • '()*+&%$+" ,'-./8%'()*+&%$+"0)"#$1"234)*1"&%353,'-.65/8#(7%7*4$89)*!" '$:1*!")$+" ,7;'/3#)-%-(>04-.%*(?'1?-7%*(%9*:4-($%9)'7,6$*'(%*(%'):#(-11-.%% 6#11-7%!"#$%*+*!"+ ;% • @"-)-%#)-%$A'%$09-.%'B%4-1#(*(C D<:!"#$%&% E+1#6=*."%+)'A( D69"*!"#$%&% E)-77*."%0-11'A F$,)4%!"#$%8%%GHHI !"#$%&'($)*+,$-.%$'%/0-%&'1')2%%!"-)-%3'-.%*$% &'4-%5)'42 •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and HERC2 are Major Genes in Eye Color Determination OCA2 HERC2 OCA2 and HERC2 interact to modulate production of pigments UCSC Genome Browser, May 2012 OCA2 SNPs Associated with Eye Color SNPs Gene Allele (major, minor) Paper rs2594935 OCA2 AG Kayser et al., 2008 rs728405 OCA2 AC Kayser et al., 2008 rs6497268 OCA2 AC Duffy 2007 rs11855019 OCA2 AG Duffy 2007 rs1800407 OCA2 CT Sturm et al., 2008 rs3794604 OCA2 CT Kayser et al., 2008 rs1800401 OCA2 GC Rebbeck 2002 rs4778232 OCA2 CT Kayser et al., 2008 rs1448485 OCA2 GT Kayser et al., 2008 rs8024968 OCA2 CT Kayser et al., 2008 rs1597196 OCA2 GT Kayser et al., 2008 rs7179994 OCA2 AG Kayser et al., 2008 rs4778138 OCA2 AG Kayser et al., 2008;Duffy et al., 2007 rs4778241 OCA2 AC Kayser et al., 2008;Eiberg et al., 2008;Duffy et al., 2007 rs7495174 OCA2 AG Kayser et al., 2008;Sulem et al., 2008;Sulem et al., 2007;Duffy et al., 2007 OCA2 Controls Pigmentation Production • Polymorphisms in OCA2 account for Predicted Structure 74% of the variation in human eye color in Europeans. • OCA2 codes for an integral membrane protein called P protein, thought to transport of tyrosine, a precursor of melanin. Duffy et al., 2007 ModBase, 2010 OCA2 Controls Pigmentation Production • Highest association SNPs are located in first intron: Predicted Structure • rs7495174 (AG). p-val = 1.02x10^-61 • Favors blue/green • rs6497268 (AC). p-val = 1.57x10^-96 • Favors blue • rs11855019 (AG). p-val = 4.45 x 10^-54 • Favors blue • Coding region changes also contribute • rs1800401: Arg305Trp. (CT). p-val < 0.001 • Favors brown Rebbeck et al., 2002 • rs1800407: Arg419Gln (AG). p-val < 0.001 Duffy et al., 2007 • Favors Green/Hazel ModBase, 2010 HERC2 SNPs Associated with Eye Color SNPs Gene Allele (major, minor) Paper rs1129038 HERC2 CT Sturm et al., 2008;Eiberg et al., 2008 rs12593929 HERC2 AG Eiberg et al., 2008 rs12913832 HERC2 AG Han et al., 2008;Sturm et al., 2008;Eiberg et al., 2008 rs7183877 HERC2 AC Kayser et al., 2008 rs3935591 HERC2 CT Eiberg et al., 2008 rs7170852 HERC2 AT Eiberg et al., 2008 rs8028689 HERC2 CT Kayser et al., 2008 rs8041209 HERC2 GT Kayser et al., 2008 rs2240203 HERC2 CT Eiberg et al., 2008 rs2240202 HERC2 AG Kayser et al., 2008 rs916977 HERC2 CT Kayser et al., 2008;Sturm et al., 2008;Eiberg et al., 2008 rs16950979 HERC2 AG Kayser et al., 2008 rs2346050 HERC2 CT Kayser et al., 2008 rs16950987 HERC2 AG Kayser et al., 2008 rs1667394 HERC2 CT Kayser et al., 2008;Sulem et al., 2008;Sturm et al., 2008;Sulem et al., 2007 rs12592730 HERC2 AG Kayser et al., 2008 rs1635168 HERC2 AC Kayser et al., 2008 !"#$%#&'&$ !"#$%#&'()*+$%+#,-.#!%#/0123#4)*# 056#2)7)*#86+6*'!%$+!)% • &%#!%+*)%#9:#)4#+;6#/0123< • =;!"#)%6#,-.#!"#+;6#')"+#"!>%!4!?$%+#@6+6*'!%$%+#)4#A;6+;6*#5)B#;$C6#D*)A%#)*# %)%ED*)A%#656"<# EFFG##H)"+#7!I675#D*)A%#656" EFJG#H)"+#7!I675#D*)A%#656" EJJG##H)"+#7!I675#%)%ED*)A%#656" 0!D6*> !"#$%#3KK9 3L$%@H6#A6D"!+6 !"#$%#&'&$ !"#$%#&'()*+$%+#,-.#!%#/0123#4)*# 056#2)7)*#86+6*'!%$+!)% • 9)#:6++6*#;6+6*'!%6#+<6#,-."#$%;#<$(7)+5(6"#$"")=!$+6;#>!+<#:7?6#656#=)7)*@# 0!:6*A 6+#$7#(6*4)*'6;#7!%B$A6#$%$75"!"#!%#$#7$*A6#;$%!"< 4$'!75C## • 9<65#4)?%;#$#"!%A76#<$(7)+5(6#!%#+<6#DE#*6A!)%#)4#/6*=3#+<$+#!"#"+*)%A75#$"")=!$+6;# >!+<#:7?6#656"F#!%#+<$+#<$(7)+5(6@#!"##$%(&' $%;#!"#$%#&'&$)<$;#(6*46=+# $"")=$+!)%"C • GHH#:7?6I656;#!%;!J!;?$7"#4*)'#86%'$*B@#$"#>677#$"#H#$%;#3#:7?6I656;#!%;!J!;?$7"# 4*)'#9?*B65#$%;#K)*;$%#*6"(6=+!J675#<$;#+<!"#<$(7)+5(6@#"?AA6"+!%A#$#=)'')%# *+,-./!)0,1213+-)!%#+<6"6#(6)(76C## 0!:6*A !"#$%#3LLM !"#$%#&'&$(!"#$!%&'(#) *+,-.&/#0,1)1!+- • 23!"#4,1)1!+-#4+"1#'!%&'(#)/+"&#5#6 78988#(&)/"#):+ !-#13&#;+/13<&"1#=)/1#+>#13&#?')@%#A&)#/&:!+-9#<3&/&#)#')/:& ):/!@,'1,/&#4!:/)1!+-#1+#;+/13&/-#B,/+=&#<)"#1)%!-: =')@&C • D&')1!E&'(#3!:3#>/&F,&-@(#!-#B,/+=&)-"#1+.)(#",::&"1"# 13&#4,1)1!+-#<)"#"&'&@1&.#>+/#6 G,1#<3(H IJ&/1)!-#&(&#.!"&)"&"9#",@3#)"#&(&#@)-@&/#)-.#):&I/&')1&.#4)@,')/# .&:&-&/)1!+-9#+@@,/#4+/&#>/&F,&-1'(#!-#G',&#&(&"C##23&#!-@/&)"&.#&,4&')-!- !-# .)/%&/#&(&"#4)(#3&'=#=/+1&@1#):)!-"1#13&"&#.!"&)"&"#KL,"1#'!%&#4&')-!-#!-#13&#"%!-# 3&'="#=/+1&@1#!1#>/+4#MN#",-#.)4):&OC ID)/&/#P#4+/&#.&"!/)G'&H##K*/&F,&-@(I.&=&-.&-1#"&'&@1!+-O B!G&/: !"#$%#Q88R !"#$%#&'&$ !"#$%&'()*+,"-.&/012 • 3+)"-"/'+4&4")+56011") "'+&%7+8"/(2"+!"1"&)-.7+9:;9<+="2(/1')&'"=+)1;9>;?@?9A1+ )(%"+&1+&/+"/.&/-")+)"#$%&'0/#+BC39+')&/1-)04'0(/D++E."+FEG+&%%"%"+5&11(-0&'"=+H0'.+ I)(H/+"*"1<+1.(H1+0/-)"&1"=+I0/=0/#+(J+')&/1-)04'0(/+J&-'()1 &/=+0/-)"&1"=+ -.)(2&'0/+%((4+J()2&'0(/+H0'.+'."+BC39+4)(2('")+-(24&)"=+'(+'."+FCG+&%%"%"7+ %"&=0/#+'(+0/-)"&1"=+"K4)"110(/+(J+BC39D++ ,PEN MONP LMEN Other SNPs Associated with Eye Color SNPs Gene Allele (major, minor) Paper rs6058017 ASIP AG Kanetsky et al., 2002;Frudakis et al., 2003 rs4911442 NCOA6 AG Liu 2010 rs10235789 SEMA3A CT Larsson et al., 2011 rs3739070 TRAF3IP1 AC Larsson et al., 2011 rs12896399 on Chr14 GT Eriksson et al., 2010 rs4900109 on Chr14 GT Larsson et al., 2011 rs16891982 SLC45A2 (MATP) CG Han et al., 2008 rs26722 SLC45A2 (MATP) CT Han et al., 2008 rs12203592 IRF4 CT Han et al., 2008 rs1408799 TYRP1 CT Sulem et al., 2008 rs683 TYRP1 AC Frudakis et al., 2003 rs1393350 TYR AG Sulem et al., 2007 rs12896399 SLC24A4 GT Sulem et al., 2008;Han et al., 2008;Sulem et al., 2007 Advanced Topic: Iris Color Pattern Trait Heritability Crypt Frequency 84% Furrows 87% Pigmented Ring 93% Nevi 71% Larsson et al., 2003 Larsson et al., 2011 Iris Color Pattern: Crypt Frequency • rs10235789 (7q21.11) with p-value 2.7e-6 • located in intro 6 of SEMA3A • SEMA3A inhibits migration of neural crest cells that develops into the pupillary membrane, the precursor of anterior border layer and stroma in the iris, where the crypt occurs. Larsson et al., 2011 Iris Color Pattern: Furrow • rs3739070 (2q37.3) with p-value 6.2e-8 • located in coding region of TRAF3IP1 • TRAF3IP1 implicated in neurogenesis, neural migration and synaptogenesis, and may contribute to thickness and density of iris. Larsson et al., 2011 Iris Color Pattern: Pigmentation Ring • rs4900109 (14q32.12) with p-value 2.90e-13 • located in intergenic region upstream of SLC24A4. • SLC24A4 is a pigmentation gene. Larsson et al., 2011 Iris Color Pattern: Nevi • rs11630290 (15q22.31). No validation. • located in HERC1. • HERC1 is distinct from HERC2. Very little known is about HERC1, except it is speculated to be involved in membrane transport processes. Larsson et al., 2011 Eye Color is a Complex Trait • We are just starting to understand eye color determination. • More genes involved in color determination are being discovered. • Eye color is tied to hair and skin color. • The genes involved in eye color determination are important for eye and brain development. • GWAS helps elucidate the important SNPs and genes involved, and paves the way for future molecular and developmental biology studies..