eye color - stanford university color eyes occur infrequently in populations outside of europe the...

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

The Internet, 2012

Western Asia, especially Afghanistan, Lebanon, Iran, Iraq, Syria, and Jordan.

Wikipedia, 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'%$09-.%'B%4-1#(*(CD<:!"#$%&% E +1#6=*."%+)'A(D69"*!"#$%&% E )-77*."%0-11'A

F$,)4%!"#$%8%%GHHI

!"#$%&'($)*+,$-.%$'%/0-%&'1')2%%!"-)-%3'-.%*$%&'4-%5)'42

• 6"-%!"#$%& #(7%'!&(# '8%-,4-1#(*( #(7%9"-'4-1#(*( *(%$"-%',$-)%1#0-)%'8%$"-%*)*.%7-$-)4*(-.%0',)%-0-%:'1');

)<-'91-%=*$"%*!'+,'-.#/#',*-,0,1 >+)'=(?%"#@-%4')-%4-1#(*(%*(%A-(-)#1B%#(7%4')-%-,4-1#*( :'49#)-7%$'%9"-'4-1#(*(;)<-'91-%=*$"%/(23&,'-.#/#',*-,0,1->+1,-B%A)--(?%"#@-%1-..%4-1#(*(%'@-)#11B%#(7%4')-%9"-'4-1#(*( :'49#)-7%$'%-,4-1#(*(;%%/0-.%#)-%+1,-%#(7%A)--(B%)#$"-)%$"#(%)-7%#(7%0-11'=B%7,-%$'%1*A"$%.:#$$-)*(A%'88%'8%9)'$-*(.%*(%$"-%-0-;%%)C4%&,'",*(!&,5-.#/#',*-,0,1->"#D-1?%#)-%-..-($*#110%.'4-="-)-%*(%+-$=--(;%%

E$,)4%!"#$%B%FGGH

!"#$"%&'(')%*+'%,(-./-'0%#(%12'%3./.+4%%

567+8%!"#$%9%%:;;<

OCA2 and HERC2 are Major Genes in Eye Color Determination

OCA2 HERC2

UCSC Genome Browser, May 2012

OCA2 and HERC2 interact to modulate production of pigments

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


rs1448485 OCA2 GT 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 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

Predicted Structure

OCA2 Controls Pigmentation Production

• Highest association SNPs are located in first intron:

• 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

• rs1800407: Arg419Gln (AG). p-val < 0.001

• Favors Green/Hazel

Duffy et al., 2007

ModBase, 2010

Predicted Structure

Rebbeck et al., 2002

HERC2 SNPs Associated with Eye Color


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


rs2346050 HERC2 CT Kayser et al., 2008


rs1667394 HERC2 CT Kayser et al., 2008;Sulem et al., 2008;Sturm et al., 2008;Sulem et al., 2007


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*> !"#$%#3KK93L$%@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

I J&/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

I D)/&/#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++

LMEN

MONP,PEN

Other SNPs Associated with Eye Color


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., 2003Larsson et al., 2011

Iris Color Pattern: Crypt Frequency

Larsson et al., 2011

• 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.

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.

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.

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.

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.

eye color - stanford university color eyes occur infrequently in populations outside of europe the...

Documents