Fixation patterns in simple choice reflect
optimal information sampling.

ZK[KF ZIN FZ\OIS K
Ltxktt{z |ktto~z€ tz€ty|wo ms{tmo ~oqwomt
{|ttykw tzq{~yktt{z €ky|wtzr
L~ono~tmv Ikwwk�k� OJ
4*.Fz�{zt{ Zkzrow5.\s{yk� S1M~tqqt�s�4.6
4Jo|k~�yoz� {qW��ms{w{r�. W~tzmo �{z]zt�o~�t��. W~tzmo �{z.Uo� Qo~�o�. ]zt�on [�k�o� {qFyo~tmk.
5Jo|k~�yoz� �{qN�ykzt�to� kzn[{mtkw [mtozmo� kznI{y|�� k�t{z kznUo�~kw [���oy �.Ikwtq{~zt kOz��t���o
{q\omsz{w{ r�.Wk�knozk. Ikwtq{~zt k.]zt�on [�k�o� {qFyo~tmk. 6Jo|k~�yo z�{qI{y|��o~ [mtozmo.
W~tzmo� {z]zt�o~�t��. W~tzmo� {z.Uo� Qo~�o�. ]zt�on [�k�o� {qFyo~tmk
*q~onmkww k�k�E|~tzm o�{z1on�
Fl€t~kmt
[ty|wo ms{tmo� *o1r1. ok�tzr kzk||wo ��1kz{~kzro+ k~oykno l�tz�or~k�tzr z{t�� o�tnozmo
�sk�t��ky|won {�o~ �tyo kzntzqw�ozmon l��t��kw k��oz�t{z? k�k~o��w�. qw�m��k�t{z� tz�t��kw
k��oz�t{z mkzkqqom� ms{tmo�1 G���sk� no�o~ytzo� �sk� t�qt�k�on kzn�sozD \{knn~o�� �st�
}�o��t{z. �oy{now �sonomt�t{z |~{mo�� q{~�ty|wo ms{tmo k�kztzq{~yk�t{z �ky|wtzr |~{l/
woy. kznk||~{�tyk�o �so{|�tykw �ky|wtzr |{wtm�1 _oqtzn�sk�t�t�{|�tykw �{�ky|wo q~{y
{|�t{z� �s{�o �kw�o o��tyk�o� k~ol{�s strs kzn�zmo~�ktz1 L�~�so~y{~o. �so{|�tykw |{wtm�
|~{�tno� k~ok�{zklwo kmm{�z� {qqt�k�t{z� kznms{tmo� tzltzk~� kzn�~tzk~� �ty|wo ms{tmo.
k��oww k��sontqqo~ozmo� lo��ooz �so��{mk�o�1 V�o~kww. �so~o��w�� �s{� �sk��soqt�k�t{z
|~{mo�� n�~tzr �ty|wo ms{tmo t�tzqw�ozmon n�zkytmkww� l��so�kw�o o��tyk�o� m{y|��on
n�~tzr �sonomt�t{z |~{mo��. tzkykzzo~ m{z�t��oz� �t�s {|�tykw tzq{~yk�t{z �ky|wtzr1
F��s{~ ��yyk~�
FzÞ €�|o~yk~vo� €s{||o~ t€qkytwtk~ Ðt�s �so|~{lwoy {qms{{€tzr lo�Ðooz k€ykww z�y/
lo~{qt�oy€1 K�oz �so€o �€ty|wo ms{tmo€� mkzlomskwwozrtzr lomk�€o Ðosk�o �{�stzv
kl{�� �so{|�t{z€ �{no�o~ytzo Ðstms {zoÐowtvoy{€�. kzn Ðomkz)� �stzv kl{�� kww{q
�soy k�{zmo1 \st€ ~kt€o€ k}�o€�t{z> Ðsk� €s{�wn Ðo�stzv kl{��Œkzn q{~s{Ð w{zr
€s{�wn Ðo�stzvŒloq{~o ykvtzr knomt€t{zD _oq{~ykwtþo �st€}�o€�t{z k€kztzq{~yk�t{z
€ky|wtzr |~{lwoy. kzn tnoz�tqÞ kz{|�tykw €{w��t{z1 Vl€o~�tzr Ðsk� |o{|wo w{{v k�Ðstwo
ykvtzr ms{tmo€. Ðoqtzn �sk� ykzÞ {q�sovoÞ|k��o~z€ tz�sot~ oÞoqtðk�t{z€ k~om{z€t€�oz�
Ðt�s {|�tykw tzq{~yk�t{z €ky|wtzr1
Oz�~{n�m�t{z
I{z€tno~ �so|~{lwoy€ qkmon lÞkntzo~ k�kl�qqo� �klwo {~k€s{||o~ k�k€�|o~yk~vo� €sowq1
\soÞ k~o|~o€oz�on Ðt�s kz�ylo~ {q{|�t{z€ kzn y�€� o�kw�k�o �soy �z�tw �soÞ tnoz�tqÞ �so
y{€� no€t~klwo {zo1 Fmoz�~kw }�o€�t{z tz|€Þms{w{rÞ kzn zo�~{€mtozmo t€�{�zno~€�kzn �so
kwr{~t�sy€. {~m{y|��k�t{zkw |~{mo€€o€. lostzn �so€o mkz{ztmkw €ty|wo ms{tmo€1
WSV[ I{y|��k�t{zk wGt{w{r� �s��|�>2 2n{t1{~r243146 ;42u{�~zkw1| mlt1433<<:6 Tk~ms 5:.5354 425=k4444444444
k4444444444
k4444444444
k4444444444
k4444444444
OPEN ACCESS
It�k�t{z> Ikwwk�k� L.Zkzrow F.M~tqqt�s� \S*5354+
Lt�k�t{z |k��o~z� tz�ty|wo ms{tmo ~oqwom� {|�tykw
tzq{~yk�t{z �ky|wtzr1 WS{[ I{y|�� Gt{w4;*6+>
o433<<:61 s��|�>22n {t1{~r243146;42u {�~zkw1
|mlt1433<<:6
Knt�{~> [�oqkz{ Wkwytz�o ~t.Km{wo U{~yk wo
[�|o~to�~ o.LZFUIK
Zomot�on> F�r��� 63.5353
Fmmo|�on> Tk~ms 43.5354
W�lwt�son> Tk~ms 5:.5354
Woo~ Zo�to� Nt��{~�> WSV[ ~om{rzt�o ��so
lozoqt�� {q�~kz�|k~ ozm� tz�so|oo~ ~o�to�
|~{mo��? �so~oq{~o. �oozklwo �so|�lwtmk�t{z {q
kww{q�som{z�oz� {q|oo~ ~o�to� kznk��s{~
~o�|{z�o �kw{zr�tno qtzkw. |�lwt�son k~�tmwo�1 \so
ont�{~tkw st��{~� {q�st�k~�tmwo t�k�ktwklwo so~o>
s��|�>22n{t1{ ~r243146;42u{ �~zkw1|mlt 1433<<:6
I{|�~trs�> ©5354 Ikwwk�k� o�kw1\st�t�kz{|oz
kmmo�� k~�tmwo nt��~tl��on �zno~ �so�o~y� {q�so
I~ok�t�o I{yy{z� F��~tl��t{z Stmoz�o. �stms
|o~yt�� �z~o��~tm�o n��o.nt��~tl� �t{z.kzn
~o|~{n�m�t{z tzkz�yont�y. |~{�tnon �so{~trtzkw
k��s{~ kzn�{�~mo k~om~ont�on1
Jk�k F�ktwkltwt� �[�k�oyoz�> \sonk�kkznkzkw��t�
m{no mkzloq{�zn {zMt�s�l> s��|�>22rt�s� l1m{y2
q~onmkwwk�k �2{|�tykw/qt �k�t{z�/�ty|w o/ms{tmo1
L�zntzr> \st�~o�ok~ms �k���||{~�on l�kr~kz�
q~{y Lkmol{{v Zokwt�� Skl� k�k~non �{\M
W~o�t{�€ Ð{~v sk€o€�klwt€son �Ð{ty|{~�kz� qok��~o€ {q�so|~{mo€€o€ �zno~wÞtzr €ty|wo
�kw�o/lk€on ms{tmo€1 Lt~€�. ms{tmo€ kzn ~okm�t{z �tyo€ k~oÐoww oð|wktzon lÞtzq{~yk�t{z €ky/
|wtzr y{now€ wtvo�sontqq�€t{z nomt€t{z y{now *JJT+ d4˘6f kzn �sowokvÞ m{y|o�tzr kmm�y�/
wk�{~ y{now d7.9f1Oz�so€o y{now€. tznt�tn�kw€ k~otzt�tkwwÞ �zmo~�ktz kl{�� �sono€t~kltwt�Þ {q
okms {|�t{z. l���soÞ ~omot�o z{t€Þ €trzkw€ kl{�� �so{|�t{z€) �kw�o€ �sk� �soÞ tz�or~k�o {�o~
�tyo �{q{~y y{~o kmm�~k�o o€�tyk�o€1 Fmoz�~kw tz€trs� {q�so€o y{now€ t€�sk� €ky|wtzr tzq{~/
yk�t{z kl{�� �zvz{Ðz €�luom�t�o �kw�o€ t€kmoz�~kw qok��~o {q€ty|wo ms{tmo1 [om{zn. �t€�kw
k��oz�t{z kqqom�€ �sonomt€t{z/ykvtzr |~{mo€€1 Oz|k~�tm�wk~. t�oy€ �sk� k~oqtðk�on w{zro~ k~o
y{~o wtvowÞ �{loms{€oz d:˘46f. �zwo€€ �soÞ k~ok�o~€t�o. tzÐstms mk€o �soÞ k~oms{€ozlessq~o/
}�oz�wÞ d;.47f1 \so€o qtzntzr€ sk�o looz oð|wktzon lÞ�soF��oz�t{zkw J~tq� Jtqq�€t{z T{now
*kJJT+. tzÐstms �so�kw�o €ky|wo€ {q�soqtðk�on t�oy k~o{�o~/Ðotrs�on ~owk�t�o �{�s{€o {q
�zqtðk�on {zo€ *{~o}�t�kwoz�wÞ tz�soltzk~Þ mk€o. nt€m{�z�tzr �sotzqw�ozmo {q�so�zk��oznon
t�oy {z�son~tq� ~k�o+ d=.43.45.46f1 [ood49. 4:fq{~~o�toÐ€1
\so€o tz€trs�€ ~kt€o kzty|{~�kz� }�o€�t{z> _sk� no�o~ytzo€ Ðsk� t€qtðk�on kzn Ðsoz n�~/
tzr�sonomt€t{z |~{mo€€D W~o�t{�€ Ð{~v sk€q{m�€on {z�Ð{l~{kn mwk€€o€ {q�so{~to€1 Vzo
mwk€€ €�rro€�€ �sk� nomt€t{z€ kzn qtðk�t{z€ k~on~t�oz lÞ€o|k~k�o |~{mo€€o€. €{�sk� qtðk�t{z€
kqqom� s{Ð tzq{~yk�t{z kl{�� �kw�o€ t€€ky|won kzn tz�or~k�on. l��z{��so{�so~ ÐkÞ k~{�zn1
Oz�st€�toÐ. kw�s{�rs qtðk�t{z€ mkzloy{n�wk�on lÞqok��~o€ wtvo�t€�kw €kwtozmÞ {~€|k�tkw w{mk/
�t{z. �soÞ k~ok€€�yon �{lotzno|oznoz� {q�so€�k�o {q�sonomt€t{z |~{mo€€1 \st€ t€�soq~kyo/
Ð{~v lostzn �sokJJT d=.43.45fkzn ~owk�on y{now€ d4;˘4=f1
Fz{�so~ mwk€€ {q�so{~to€ oð|w{~o€ �sotnok �sk� �sonomt€t{z |~{mo€€ kqqom�€ qtðk�t{z€. o€|o/
mtkwwÞ kq�o~ €{yo tzq{~yk�t{z kl{�� �so{|�t{z€) �kw�o€ sk€looz kmm�y�wk�on1 Kðky|wo€ {q�st€
mwk€€ tzmw�no �soMkþo Ik€mkno T{now d:f.kzoð�oz€t{z {q�sokJJT tzÐstms {|�t{z€ Ðt�s
y{~o kmm�y�wk�on o�tnozmo tz�sot~ qk�{~ k~oy{~o wtvowÞ �{loqtðk�on d53f. kzn kGkÞo€tkz
€ky|wtzr y{now tzÐstms {|�t{z€ Ðt�s wo€€mo~�ktz o€�tyk�o€ k~oy{~o wtvowÞ �{loqtðk�on d54f1
N{Ðo�o~. �so€o y{now€ sk�o z{�m{z€tno~on s{Ð �zmo~�ktz�Þ kzn �kw�o ytrs� tz�o~km�. z{~
sk�o �soÞ m{z€tno~on �so{|�tykwt�Þ {q�so|{€t�on qtðk�t{z |~{mo€€ *kw�s{�rs €ood55˘57f q{~
€�ms kzkwÞ€o€ tz€ty|wtqton €o��tzr€+1
Zo€ok~ms {zoÞoy{�oyoz�€ tz�so|o~mo|��kw n{yktz €�rro€�€ k�st~n |{€€tltwt�Þ> �sk� qtðk/
�t{z€ k~ono|w{Þon �{€ky|wo tzq{~yk�t{z {|�tykwwÞ tz{~no~ �{ykvo �solo€� ms{tmo1 W~o�t{�€
Ð{~v tz�t€t{z sk€€s{Ðz �sk� qtðk�t{z€ k~or�tnon �{w{mk�t{z€ �sk� |~{�tno �€oq�w tzq{~yk�t{z
q{~|o~q{~ytzr k�k€v. kzn {q�oz tzÐkÞ€ �sk� k~om{z€t€�oz� Ðt�s {|�tykw €ky|wtzr d59f1 L{~
oðky|wo. tz�t€�kw €ok~ms *o1r1. qtzntzr kzjT)tzkqtown {qjU€)+ |o{|wo qtðk�o {zk~ok€ y{€�
wtvowÞ �{m{z�ktz �so�k~ro� d5:. 5;f? tz|o~mo|��kw nt€m~tytzk�t{z |~{lwoy€. |o{|wo knk|� �sot~
~owk�t�o qtðk�t{z �tyo �{�so�k~ro�€) z{t€o wo�ow€ d5<. 5=f? kzn tzzk��~kwt€�tm �k€v/q~oo �toÐtzr.
qtðk�t{z€ k~on~kÐz �{k~ok€ �sk� sk�o strs �GkÞo€tkz €�~|~t€o�. t1o1.k~ok€ Ðso~o yokztzrq�w
tzq{~yk�t{z t€y{€� wtvowÞ �{loq{�zn d63f1 \so |~{|o~�to€ {qqtðk�t{z€ tz�so€o �Þ|o€ {q�k€v€
k~omk|��~on lÞ{|�tykw €ky|wtzr y{now€ �sk� ykðtytþo oð|om�on tzq{~yk�t{z rktz d59. 64f1
N{Ðo�o~. �so€o y{now€ sk�o z{�looz k||wton tz�som{z�oð� {q�kw�o/lk€on nomt€t{z ykvtzr.
kzn �s�€ �sooð�oz� �{Ðstms qtðk�t{z |k��o~z€ n�~tzr €ty|wo ms{tmo€ k~om{z€t€�oz� Ðt�s {|�t/
ykw tzq{~yk�t{z €ky|wtzr t€kz{|oz }�o€�t{z1
Oz�st€|k|o~. Ðon~kÐ �so€o �s~okn€ �{ro�so~ lÞnoqtztzr ky{now {q{|�tykw tzq{~yk�t{z
€ky|wtzr tzmkz{ztmkw €ty|wo ms{tmo �k€v€ kzn tz�o€�trk�tzr �sooð�oz� �{Ðstms t�kmm{�z�€ q{~
qtðk�t{z |k��o~z€ kzn �sot~ ~owk�t{z �{ms{tmo€1 Ozk�kw�o/lk€on ms{tmo. {|�tykw tzq{~yk�t{z
€ky|wtzr ~o}�t~o€ ykðtytþtzr �sontqqo~ozmo lo�Ðooz �so�kw�o {q�soms{€oz t�oy kzn �so
m{€� {qkm}�t~tzr �sotzq{~yk�t{z zoonon �{ykvo �soms{tmo1 V�~ y{now �s�€ qkww€ tz�{ kl~{kn
mwk€€ {qy{now€ �sk� oð�ozn mwk€€tmkw ~k�t{zkw y{now€ {qom{z{ytm ms{tmo d65. 66f�{knnt�t{zkwwÞ
kmm{�z� q{~m{z€�~ktz�€ ty|{€on lÞwtyt�on m{rzt�t�o ~o€{�~mo€ d67˘6=f1 N{Ðo�o~. k€t€m{y/
y{z tz�st€k||~{kms. Ðo€�{| €s{~� {q€|omtqÞtzr kq�wwkwr{~t�sytm y{now {q€ty|wo ms{tmo1
PLOS COMP UTATIONAL  BIOLOGYLt�k�t{z |k��o~z� tz�ty|wo ms{tmo ~oqwom� {|�tykw tzq{~yk�t {z�ky|wtzr
WSV[ I{y|��k�t{zk wGt{w{r� �s��|�>2 2n{t1{~r243146 ;42u{�~zkw1| mlt1433<<:6 Tk~ms 5:.5354 525=*s��|�>22~o�o k~ms1ql1m{ y2mk�or{~�2k �ryoz�on/
~okwt��/�t~��k w/~okwt��2+ kznkr~kz� q~{y �soUVTO[
L{�znk�t{z *s��|�>22z{y t�q{�znk�t{z1 ms2+k�k~non
�{FZ1\soq�zno~� sknz{~{wotz���n� no�trz.
nk�km{wwom�t{z kznkzkw��t� .nomt�t{z �{|�lwt�s. {~
|~o|k~k�t{z {q�soykz��m~t|�1
I{y|o�tzr tz�o~o��� >\sok��s{~� sk�o nomwk~on
�sk�z{m{y|o�tzr tz�o~o��� o�t��1
Oz€�okn. Ðok€v�{Ðsk� oð�oz� |o{|wo)€ qtðk�t{z€ k~om{z€t€�oz� Ðt�s {|�tykw tzq{~yk�t{z €ky/
|wtzr. Ðt�s{�� €|omtqÞtzr s{Ð �sol~ktz km��kwwÞ ty|woyoz�€ kz{|�tykw €ky|wtzr |{wtmÞ1
Kð|w{~tzr kz{|�tykw tzq{~yk�t{z €ky|wtzr y{now {qqtðk�t{z€ tz€ty|wo ms{tmo t€�€oq�w q{~
€o�o~kw ~ok€{z€1 Lt~€�. €tzmo qtðk�t{z€ mkzkqqom� ms{tmo€. �zno~€�kzntzr Ðsk� n~t�o€ �soqtðk�t{z
|~{mo€€ mkz|~{�tno m~t�tmkw tz€trs� tz�{ �so€{�~mo€ {qyt€�kvo€ kzn ltk€o€ tznomt€t{z/ykvtzr1
Oz|k~�tm�wk~. �sooð�oz� �{Ðstms losk�t{~€ mkzlomsk~km�o~tþon k€yt€�kvo€ no|ozn€ {z�so
oð�oz� �{Ðstms qtðk�t{z€ €ky|wo tzq{~yk�t{z €�l/{|�tykwwÞ1 [om{zn. €ty|wo ms{tmo kwr{~t�sy€
wtvo�soJJT sk�o looz €s{Ðz �{ty|woyoz� {|�tykw GkÞo€tkz tzq{~yk�t{z |~{mo€€tzr Ðsoz
�sonomt€t{z/ykvo~ ~omot�o€ �so€kyo ky{�z� {qtzq{~yk�t{z kl{�� kww{|�t{z€ k��so€kyo ~k�o
d73˘7:f. kzn �st€t€{q�oz �toÐon k€kzoð|wkzk�t{z q{~ÐsÞ �sol~ktz �€o€ �so€o kwr{~t�sy€ tz
�soqt~€� |wkmo1 Ozm{z�~k€�. �so{|�tykw kwr{~t�sy Ðsoz �sonomt€t{z/ykvo~ y�€� €ky|wo tzq{~/
yk�t{z €owom�t�owÞ t€�zvz{Ðz1 \st~n. rt�oz �sol{nÞ {qo�tnozmo €s{Ðtzr �sk� qtðk�t{z€ k~o
no|w{Þon {|�tykwwÞ tz|o~mo|��kw nomt€t{z ykvtzr. t�t€tz�o~o€�tzr �{k€vtq�so€kyo s{wn€ q{~
�kw�o/lk€on nomt€t{z€1 Mt�oz �sk� €�ms |~{lwoy€ k~omsk~km�o~tþon lÞl{�s kntqqo~oz� {luom�t�o
q�zm�t{z *ykðtytþtzr k€mkwk~ �kw�o ~k�so~ �skz kmm�~kmÞ+ kzn kntqqo~oz� €{�~mo {qtzq{~yk/
�t{z *o1r1. €ky|wtzr q~{y yoy{~Þ d7;˘7=f ~k�so~ �skz q~{y kz{t€Þ �t€�kw €�ty�w�€+. t�t€qk~
q~{y mwok~ �sk� {|�tykw tzq{~yk�t{z €ky|wtzr y{now€ Ðtww€�tww|~{�tno kr{{n kmm{�z� {qqtðk/
�t{z€ tz�st€€o��tzr1
G�twntzr {z�so|~o�t{�€ wt�o~k��~o. {�~y{now k€€�yo€ �sk� �sonomt€t{z ykvo~ o€�tyk�o€
�so�kw�o {qokms t�oy tz�soms{tmo €o�lk€on {zk€o}�ozmo {qz{t€Þ €ky|wo€ {q�sot�oy€) �~�o
�kw�o€1 _oknnt�t{zkwwÞ k€€�yo �sk� �so€o €ky|wo€ mkz{zwÞ lo{l�ktzon q~{y �sok��oznon
t�oy. kzn �sk� t�t€m{€�wÞ �{�kvo €ky|wo€ kzn �{€Ðt�ms qtðk�t{z w{mk�t{z€1 \st€ €o�€�|k€o}�oz/
�tkwnomt€t{z |~{lwoy> k�okms y{yoz� �sonomt€t{z ykvo~ y�€� nomtno Ðso�so~ �{voo| €ky/
|wtzr. kzn tq€{.Ðstms t�oy �{€ky|wo q~{y1 [tzmo �soy{now n{o€ z{�sk�o k�~km�klwo
kzkwÞ�tmkw €{w��t{z. tz{~no~ �{€{w�o t�kzn �kvo t��{�sonk�k. Ðok||~{ðtyk�o �so{|�tykw €{w�/
�t{z �€tzr �{{w€ q~{y yo�k~ok€{ztzr tzk~�tqtmtkw tz�owwtrozmo d93˘96f1
_om{y|k~o �so{|�tykw qtðk�t{z |{wtmÞ �{s�ykz qtðk�t{z |k��o~z€ tz�Ð{tzqw�oz�tkw
ltzk~Þ kzn �~tzk~Þ ms{tmo nk�k€o�€ d=.43f1 _oqtzn �sk� �soy{now mk|��~o€ ykzÞ |~o�t{�€wÞ
tnoz�tqton |k��o~z€ tz�soqtðk�t{z nk�k. tzmw�ntzr �sooqqom�€ {q|~o�t{�€ qtðk�t{z �tyo d54f kzn
t�oy �kw�o d4;. 53.55f1 Ozknnt�t{z. �soy{now ykvo€ €o�o~kw z{�ow |~ontm�t{z€ kl{�� �sontqqo~/
ozmo€ tzqtðk�t{z€ lo�Ðooz ltzk~Þ kzn �~tzk~Þ ms{tmo€ kzn kl{�� qtðk�t{z n�~k�t{z€. Ðstms k~o
m{z€t€�oz� Ðt�s �sonk�k1 LtzkwwÞ. Ðotnoz�tqÞ km~t�tmkw ~{wo {q�so|~t{~ nt€�~tl��t{z tz|~{n�m/
tzr�somwk€€tm oqqom�€ {qk��oz�t{z {zms{tmo d;.=.43.47f1 V�o~kww. �so~o€�w�€ €s{Ð �sk� �soqtðk/
�t{z |~{mo€€ n�~tzr €ty|wo ms{tmo t€tzqw�ozmon lÞ�so�kw�o o€�tyk�o€ m{y|��on n�~tzr �so
nomt€t{z |~{mo€€. tzkykzzo~ m{z€t€�oz� Ðt�s {|�tykw tzq{~yk�t{z €ky|wtzr1
T{now
[o}�oz�tkw €ky|wtzr y{now
_om{z€tno~ €ty|wo ms{tmo |~{lwoy€ tzÐstms knomt€t{z ykvo~ *JT+ t€|~o€oz�on Ðt�s k€o�
{qt�oy€ *o1r1. €zkmv€+ kzn y�€� ms{{€o {zo1 Kkms t�oyit€k€€{mtk�on Ðt�s €{yo �~�o l��
�zvz{Ðz �kw�o.u*i+.�so��twt�Þ �sk� �soJT Ð{�wn rktz lÞms{{€tzr t�1L{ww{Ðtzr |~o�t{�€
Ð{~v d4.=.73.75˘7:. 97f. Ðok€€�yo �sk� �soJT tzq{~y€ so~ms{tmo lÞm{wwom�tzr z{t€Þ
€ky|wo€ {q�sot�oy€) �~�o �kw�o€. okms |~{�tntzr k€ykww ky{�z� {qtzq{~yk�t{z. l��tzm�~/
~tzr k€ykww m{€�1 \so JT tz�or~k�o€ �so€ky|wo€ tz�{ |{€�o~t{~ lowtoq€ kl{�� okms t�oy)€
�kw�o. ms{{€tzr �sot�oy Ðt�s ykðtykw |{€�o~t{~ yokz Ðsoz €so�o~ytzk�o€ �so€ky|wtzr
|~{mo€€1
PLOS COMP UTATIONAL  BIOLOGYLt�k�t{z |k��o~z� tz�ty|wo ms{tmo ~oqwom� {|�tykw tzq{~yk�t {z�ky|wtzr
WSV[ I{y|��k�t{zk wGt{w{r� �s��|�>2 2n{t1{~r243146 ;42u{�~zkw1| mlt1433<<:6 Tk~ms 5:.5354 625=
F€tww�€�~k�on tzLtr4.Ðoy{now k��oz�t{z lÞk€€�ytzr �sk� �soJT mkz{zwÞ €ky|wo q~{y
{zot�oy k�okms �tyo |{tz�. �sot�oy €sot€qtðk�tzr {z1\st€ €o�€�|kq�znkyoz�kw |~{lwoy>
N{Ð €s{�wn €sokww{mk�o qtðk�t{z€ tz{~no~ �{ykvo r{{n nomt€t{z€ Ðt�s{�� tzm�~~tzr �{{
y�ms m{€�D [|omtqtmkwwÞ. k�okms �tyo |{tz�. �soJT y�€� nomtno Ðso�so~ �{€owom� kz{|�t{z {~
m{z�tz�o €ky|wtzr. kzn tz�sowk��o~ mk€o. €soy�€� kw€{ nomtno Ðstms t�oy �{€ky|wo q~{y1
Oy|{~�kz�wÞ. €somkzz{� €ty|wÞ kww{mk�o so~k��oz�t{z �{�sot�oy Ðt�s �sostrso€� �~�o �kw�o
lomk�€o €son{o€ z{�vz{Ð �so�~�o �kw�o€1 Zk�so~. €soy�€� nomtno Ðstms t�oy �{k��ozn �{
lk€on {zso~m�~~oz� �kw�o o€�tyk�o€ kzn �sot~ �zmo~�ktz�Þ1
\so JT)€ lowtoq kl{�� �sot�oy �kw�o€ k��tyott€no€m~tlon lÞk€o�{qMk�€€tkz€. {zoq{~
okms t�oy. Ðt�s yokz€ wi
tkzn |~omt€t{z€ �i
t*�so |~omt€t{z t€�sotz�o~€o {q�so�k~tkzmo+1
\so€o o€�tyk�on �kw�o nt€�~tl��t{z€ k~otzt�tkwtþon �{�soJT)€ |~t{~ lowtoq kl{�� �sont€�~tl�/
�t{z {q�kw�o€ tz�sooz�t~{zyoz�1 \sk� t€.€sok€€�yo€ �sk�ui�Gaussian�wC�~9kzn m{z€o/
}�oz�wÞ €o�€wi
6�wkzn�i
6�~9q{~kwwi1_oq�~�so~ nt€m�€€ �soty|{~�kz� ~{wo {q�so|~t{~
low{Ð1
_oy{now �som{z�~{w {qk��oz�t{z k€�so€owom�t{z {qm{rzt�t�o {|o~k�t{z€. ct.�sk� €|omtqÞ
ot�so~ kzt�oy �{€ky|wo. {~�so�o~ytzk�t{z {q€ky|wtzr1 Oq�soJT Ðt€so€ �{€ky|wo q~{y
t�oyck��tyo/€�o| t.€so€owom�€ctBckzn ~omot�o€ k€trzkw
xt�GaussianucC~9
xC 4
Ðso~ou*c+t€�sounknown �~�o �kw�o {q�sot�oy lotzr €ky|won. kzn~9
xt€kq~oo |k~kyo�o~ €|om/
tqÞtzr �soky{�z� {qz{t€o tzokms €trzkw1 \so lowtoq €�k�o t€�soz �|nk�on tzkmm{~nkzmo Ðt�s
Ltr41[ky|wtzr kzn lowtoq �|nk�tzr tz�soltzk~Þ ms{tmo �k€v1 \so �{|~{Ð €s{Ð€ �sooð|o~tyo z�kw nt€|wkÞ. Ðt�s �soqtðk�on t�oy noz{�on lÞ�sooÞo
€Þyl{w1 \so l{��{y �Ð{~{Ð€ no|tm� �soqt~€� qoÐ€�o|€ {q�so€ky|wtzr kzn lowtoq �|nk�tzr |~{mo€€1 \so nomt€t{z ykvo~)€ lowtoq€ kl{�� �so�kw�o {qokms
t�oy k~onoz{�on lÞ�soMk�€€tkz |~{lkltwt�Þ noz€t�Þ m�~�o€1 \so �~�o �kw�o€ {qokms t�oy *nk€son wtzo€+ k~o€ky|won q~{y €�kznk~n z{~ykw nt€�~tl��t {z€?
�st€t€mk|��~on tz�sonomt€t{z ykvo~)€ tzt�tkw lowtoq €�k�o *qt~€� m{w�yz +1K�o~Þ �tyo €�o|.t.�sonomt€t{z ykvo~ qtðk�o€ {zo{q�sot�oy€ kzn~omot�o€ kz{t€Þ
€ky|wo kl{�� �so�~�o �kw�o {q�sk� t�oy *xtyk~v€+ 1[so�soz �|nk�o€ so~lowtoq kl{�� �so�kw�o {q�soqtðk�on t�oy �€tzr GkÞo€tkz �|nk�tzr *€stq� q~{y wtrs�
�{nk~v m�~�o+1 \so lowtoq€ q{~�so�zqtðk�on t�oy k~oz{��|nk�on1 \so |~{mo€€ ~o|ok�€ okms �tyo €�o| �z�tw �sonomt€t{z ykvo~ �o~ytzk�o €€ky|wtzr. k�
Ðstms |{tz� €soms{{€o€ �sot�oy Ðt�s ykðtykw |{€�o~t {~yokz1
s��|�>22n {t1{~r243146;4 2u{�~zkw1|mlt143 3<<:61r334
PLOS COMP UTATIONAL  BIOLOGYLt�k�t{z |k��o~z� tz�ty|wo ms{tmo ~oqwom� {|�tykw tzq{~yk�t {z�ky|wtzr
WSV[ I{y|��k�t{zk wGt{w{r� �s��|�>2 2n{t1{~r243146 ;42u{�~zkw1| mlt1433<<:6 Tk~ms 5:.5354 725=
GkÞo€tkz tzqo~ozmo>
�c
t7�c
t~9
x
wc
t7~9
xxt�c
twc
t
�c
t7
�i
t7�i
tand wi
t7wi
tfori=cB5
\so m{rzt�t�o m{€� {qokms €�o| {q€ky|wtzr kzn �|nk�tzr t€rt�oz lÞkq~oo |k~kyo�o~. γ€ky|wo 1
_oknnt�t{zkwwÞ ty|{€o k€Ðt�mstzr m{€�. γ€Ðt�ms .�sk� �soJT tzm�~€ Ðsozo�o~ €so€ky|wo€
q~{y kzt�oy {�so~ �skz �so{zo€ky|won {z�sowk€��tyo€�o| *t1o1. ykvo€ k€kmmkno �{kntqqo~/
oz�t�oy+1 \s�€. �som{€� {q€ky|wtzr t€
costctqsample1ct=ct7qswitchB 6
U{�o �sk� �soy{now tzmw�no€ �so€|omtkw mk€o tzÐstms �so~o k~oz{€Ðt�mstzr m{€�€
*γ€Ðt�ms B3+1
Ozknnt�t{z �{ms{{€tzr kzt�oy �{€ky|wo. �soJT mkzkw€{ nomtno �{€�{| €ky|wtzr kzn
ms{{€o �sot�oy Ðt�s �sostrso€� oð|om�on �kw�o1 Oz�st€mk€o. €so€owom�€ctBG1O�q{ww{Ð€ �sk� tq
�soms{tmo t€ykno k��tyo €�o|T*t1o1.cTBG+�soms{€oz t�oy t€i�argmaxiwi
T1\so JT)€
�{�kw |kÞ{qq {zk€tzrwo nomt€t{z t€rt�oz lÞ>
payoffui�
��±�
utilityof
chosenitemdT7
t7costctB
����������±���������
cognitivecost7
V|�tykw |{wtmÞ
_ok€€�yo �sk� �sonomt€t{z€ kl{�� Ðso~o �{qtðk�o kzn Ðsoz �{€�{| €ky|wtzr k~oykno {|�t/
ykwwÞ. €�luom� �{�sotzq{~yk�t{zkw m{z€�~ktz�€ no€m~tlon tz�so|~o�t{�€ €om�t{z1 L{~ykwwÞ. Ðo
k€€�yo �sk� �soctk~o€owom�on lÞkzoptimalpolicy1 F|{wtmÞ €owom�€ �sozoð� m{rzt�t�o {|o~k/
�t{z �{oðom��o.ct.rt�oz �som�~~oz� lowtoq €�k�o. *μt.λt+?t�t€{|�tykw tqt�€owom�€cttzkÐkÞ �sk�
ykðtytþo€ �sooð|om�k�t{z {qK}71N{Ð mkzÐotnoz�tqÞ €�ms k|{wtmÞD W~{lwoy€ {q�st€vtzn
sk�o looz oð|w{~on tz�sok~�tqtmtkw tz�owwtrozmo wt�o~k��~o {z~k�t{zkw yo�k~ok€{ztzr d93. 94f1
\s�€. Ðomk€� �soy{now no€m~tlon kl{�o k€kyo�kwo�ow Tk~v{� nomt€t{z |~{mo€€ d95f. kzn
tnoz�tqÞ kzok~/{|�tykw |{wtmÞ �€tzr k~omoz�wÞ no�ow{|on yo�s{n �sk� sk€looz €s{Ðz �{
kmsto�o €�~{zr |o~q{~ykzmo {zk~owk�on |~{lwoy d96f1 Ozkmm{~nkzmo Ðt�s |k€� Ð{~v y{nowtzr
|o{|wo)€ ms{tmo€ d99f kzn qtðk�t{z€ d53. 54f. Ðok€€�yo �sk� |o{|wo q{ww{Ð k€{q�ykð |{wtmÞ tz
€owom�tzr okms m{rzt�t�o {|o~k�t{z lÞ€ky|wtzr q~{y kG{w�þykzz nt€�~tl��t{z lk€on {z�sot~
o€�tyk�on �kw�o€1 \s�€. �sot~ ms{tmo€ {qm{rzt�t�o {|o~k�t{z€ k~or�tnon lÞ�so{|�tykw |{wtmÞ.
l��€�luom� �{€{yo z{t€o1 [ooTo�s{n€ q{~no�ktw€1
_sk� n{o€ {|�tykw k��oz�t{z kww{mk�t{z w{{v wtvoD Oz{~no~ �{|~{�tno kztz��t�t�o �zno~/
€�kzntzr. Ðoq{m�€ {z�Ð{ voÞ|~{|o~�to€ {qlowtoq €�k�o€> *4+�zmo~�ktz�Þ kl{�� �so�~�o �kw�o€
kzn *5+ntqqo~ozmo€ tz�so�kw�o o€�tyk�o€1 Ltr5F€s{Ð€ �so|~{lkltwt�Þ {q�so{|�tykw |{wtmÞ
*q{~ ky{now Ðt�s |k~kyo�o~€ qt��{s�ykz nk�k+ €ky|wtzr kzt�oy k€kq�zm�t{z {q�so€o �Ð{
ntyoz€t{z€ *yk~rtzkwtþtzr {�o~ �so{�so~ ntyoz€t{z€ kmm{~ntzr �{�sot~ |~{lkltwt�Þ {q{mm�~/
~tzr tz€ty�wk�on �~tkw€+1 _o€oo�sk� �so{|�tykw |{wtmÞ �ozn€ �{qtðk�o {zt�oy€ �sk� k~o
PLOS COMP UTATIONAL  BIOLOGYLt�k�t{z |k��o~z� tz�ty|wo ms{tmo ~oqwom� {|�tykw tzq{~yk�t {z�ky|wtzr
WSV[ I{y|��k�t{zk wGt{w{r� �s��|�>2 2n{t1{~r243146 ;42u{�~zkw1| mlt1433<<:6 Tk~ms 5:.5354 925=
�zmo~�ktz kzn sk�o o€�tyk�on �kw�o€ €tytwk~ �{�so{�so~ t�oy€1 Oz�somk€o {q�~tzk~ÞŒl��
z{�ltzk~ÞŒms{tmo. Ðoknnt�t{zkwwÞ €ook€�k~v k€Þyyo�~Þ tz�sooqqom� {q~owk�t�o o€�tyk�on
�kw�o1 _stwo �so|{wtmÞ t€wtvowÞ �{€ky|wo q~{y kzt�oy Ðs{€o �kw�o t€€�l€�kz�tkwwÞ strso~
�skz �som{y|o�t�{~€. t�t€�zwtvowÞ �{€ky|wo q~{y kzt�oy Ðt�s �kw�o Ðoww low{Ð1 Oz
Ltr51V|�tykw qtðk�t{z |{wtmÞ1 *F+W~{lkltwt �Þ{qqtðk�tzr {zt�oy 4k€kq�zm�t{z {q�so|~omt€t{z {qt�€�kw�o o€�tyk� o.λ*4+.kzn �soyokz
{qt�€~owk�t�o �kw�o o€�tyk� o.μ*4+−yokz*μ*5+.μ*6++1\so sok� yk| noz{�o€ �so|~{lkltwt�Þ {qqtðk�tzr t�oy 4k€{||{€on �{qtðk�tzr {zo{q�so
{�so~ t�oy€ {~�o~ytzk�t zr�so€ky|wtz r|~{mo€€1 *G+Oww�€�~k �t{z {q�so�kw�o {q€ky|wtzr1 Kkms |kzow €s{Ð€ klowtoq €�k�o q{~�~tzk~Þ ms{tmo1
\so m�~�o€ no|tm� �soo€�tyk�on lowtoq€ q{~okms t�oy)€ �kw�o. kzn �so€sknon ~ort{z€ €s{Ð �so|~{lkltwt�Þ �sk� �sot�oy)€ �~�o �kw�o t€strso~
�skz �som�~~oz� lo€� �kw�o o€�tyk�o1 \st€ |~{lkltwt�Þ m{~~owk�o€ €�~{zrwÞ Ðt�s �so�kw�o {q€ky|wtzr �sot�oy lomk�€o €ky|wtzr t€{zwÞ
�kw�klwo tqt�mskzro €�soms{tmo *�so q�ww�kw�o {q€ky|wtzr knnt�t{zkww Þno|ozn€ {z�so€tþo{q�so|{�oz�tkw rktz tz�kw�o. k€Ðoww k€�som{€�
{qq���~o €ky|wo€ kzn �so|{€€tltwt�Þ {q€ky|wtzr {�so~ t�oy€+1 Ozokms mk€o. t�t€y{~o �kw�klwo �{€ky|wo �so{~kzro t�oy �skz �so|�~|wo
t�oy lomk�€o ot�so~ *�{|+ t�€�kw�o t€y{~o �zmo~�ktz. {~*l{��{y+ t�€�kw�o t€mw{€o~ �{�sowokntzr �kw�o1
s��|�>22n {t1{~r243146;42u {�~zkw1|m lt1433<<:61 r335
PLOS COMP UTATIONAL  BIOLOGYLt�k�t{z |k��o~z� tz�ty|wo ms{tmo ~oqwom� {|�tykw tzq{~yk�t {z�ky|wtzr
WSV[ I{y|��k�t{zk wGt{w{r� �s��|�>2 2n{t1{~r243146 ;42u{�~zkw1| mlt1433<<:6 Tk~ms 5:.5354 :25=
|k~�tm�wk~. �so|{wtmÞ sk€k€�~{zr |~oqo~ozmo �{€ky|wo q~{y �sot�oy€ Ðt�s lo€� {~€om{zn/
lo€� �kw�o o€�tyk�o€1
\{€ooÐsÞ �st€t€{|�tykw. z{�o �sk� €ky|wtzr t€{zwÞ �kw�klwo tz€{qk~ k€t�kqqom�€ ms{tmo.
kzn �sk� �soms{€oz t�oy t€�so{zoÐt�s ykðtykw o€�tyk�on �kw�o Ðsoz €ky|wtzr €�{|€1 \s�€.
�so{|�tykw |{wtmÞ rozo~kwwÞ qtðk�o€ {z�sot�oy q{~Ðstms rk�so~tzr y{~o o�tnozmo t€y{€�
wtvowÞ �{mskzro Ðstms t�oy sk€ykðtykw oð|om�on �kw�o1 \so~o k~o�Ð{ÐkÞ€ q{~�st€�{sk|/
|oz> ot�so~ �so�kw�o {q�som�~~oz� lo€� t�oy t€~on�mon low{Ð �so€om{zn/lo€� t�oy. {~�so
�kw�o {q€{yo kw�o~zk�t�o t�oy t€tzm~ok€on kl{�o �solo€� t�oy1 \so q{~yo~ mkz{zwÞ sk||oz lÞ
€ky|wtzr �solo€� t�oy. kzn �sowk��o~ t€ceterisparibus y{€� wtvowÞ �{{mm�~ lÞ€ky|wtzr �so€om/
{zn/lo€� t�oy lomk�€o t�t€mw{€o~ �{�so�{||{€t�t{z �skz �so�st~n/lo€� t�oy t€*Ltr 5Gl{�/
�{y+1 N{Ðo�o~. tq�zmo~�ktz�Þ t€y�ms r~ok�o~ q{~�so�st~n/lo€� t�oy. �st€mkz{��Ðotrs �so
wk~ro~ ntqqo~ozmo tzo€�tyk�on �kw�o *Ltr 5G�{|+1 [ood55f q{~ky{~o q{~ykw u�€�tqtmk�t{z q{~
�kw�o/nt~om�on k��oz�t{z tzk€ty|wtqton z{z/nÞzkytm mk€o1
\so |~t{~ nt€�~tl��t{z
Zomkww �sk� �sotzt�tkw lowtoq kl{�� okms t�oy)€ �kw�o t€€o��{�soJT)€ |~t{~ lowtoq kl{�� �sont€/
�~tl��t{z {q�kw�o€ tz�sooz�t~{zyoz�? �sk� t€wi
6�wkzn�i
6�~91\st€ m{~~o€|{zn€ �{�so
JT k€€�ytzr �sk� okms t�oy)€ �kw�o t€n~kÐz q~{y k|~t{~ nt€�~tl��t{z {q�~�o �kw�o€ rt�oz lÞ
ui�Gaussian�wC�~91\st€ k€€�y|�t{z t€|wk�€tlwo tq�st€t€�sokm��kw nt€�~tl��t{z {qt�oy€
�sk� �soJT ozm{�z�o~€. kzn €sot€kGkÞo€tkz wok~zo~ Ðt�s €�qqtmtoz� oð|o~tozmo tz�som{z�oð�
�zno~ €��nÞ1 N{Ðo�o~. rt�oz �sk� �so€o y{now€ k~o�Þ|tmkwwÞ �€on �{€��nÞ ms{tmo€ ykno tz�so
m{z�oð� {qkzoð|o~tyoz� *k€Ðon{so~o+. �soJT ytrs� z{�sk�o wok~zon �sooðkm� |~t{~ nt€/
�~tl��t{z k�Ð{~v1 F€k~o€�w�. Ðoy�€� m{z€tno~ �so|{€€tltwt�Þ �sk� €sosk€kbiasedprior1
Oz{~no~ �{tz�o€�trk�o �so~{wo {q�so|~t{~ {z�soy{now |~ontm�t{z€. Ðok€€�yo �sk� t�
�kvo€ �soq{~y {qkMk�€€tkz nt€�~tl��t{z Ðt�s kyokz kzn €�kznk~n no�tk�t{z ~owk�on �{�so
km��kw oy|t~tmkw nt€�~tl��t{z k€q{ww{Ð€>
�wj�meanratings
�~stdratingsB9
No~o. yokz*~k�tzr€+ noz{�o€ �soyokz �kw�o ~k�tzr€ {qkwwt�oy€. Ðstms |~{�tno tzno|oznoz�
kzn �zltk€on yok€�~o€ {q�so�~�o �kw�o {q�sot�oy€ *m{y|��on km~{€€ �~tkw€ tzl{�s oð|o~t/
yoz�€+. kzn αt€kq~oo |k~kyo�o~ �sk� €|omtqto€ �soky{�z� {qltk€ tz�so|~t{~ *αB3m{~~o/
€|{zn€ �{k€�~{zr ltk€ kzn αB4m{~~o€|{zn€ �{z{ltk€+1 F€k~o€�w�. �soJT sk€m{~~om�
lowtoq€ kl{�� �so|~t{~ �k~tkzmo. l��t€kww{Ðon �{sk�o kltk€on lowtoq kl{�� �so|~t{~ yokz1
\st€ mk€o m{�wn k~t€o. q{~oðky|wo. tq�sok�o~kro �~�o �kw�o {q�sot�oy€ �€on tz�sooð|o~tyoz�
ntqqo~€ q~{y �sok�o~kro t�oy �sk� �soJT ozm{�z�o~€ tzso~nktwÞ wtqo1
T{now qt��tzr
_ok||wÞ �soy{now �{�Ð{tzqw�oz�tkw €ty|wo ms{tmo nk�k€o�€> kltzk~Þ q{{n ms{tmo �k€v d=fkzn
k�~tzk~Þ q{{n ms{tmo �k€v d43f1 Ozokms €��nÞ. |k~�tmt|kz�€ qt~€� |~{�tnon wtvtzr/~k�tzr€ q{~;3
€zkmv t�oy€ {zk/43�{43€mkwo. Ðstms k~o�€on k€kztzno|oznoz� yok€�~o {q�sot�oy€) �~�o
�kw�o€1 \soÞ �soz ykno 433ms{tmo€ ky{zr t�oy€ �sk� �soÞ skn~k�on |{€t�t�owÞ. Ðstwo �sow{mk/
�t{z {q�sot~ qtðk�t{z€ Ðk€y{zt�{~on k�k~k�o {q93Nþ1[oo[4F||ozntð q{~y{~o no�ktw€ {z
�sooð|o~tyoz�€1
\so y{now sk€qt�oq~oo |k~kyo�o~€> �so€�kznk~n no�tk�t{z {q�so€ky|wtzr nt€�~tl��t{z σx.
�som{€� |o~€ky|wo γ€ky|wo .�som{€� {q€Ðt�mstzr k��oz�t{z γ€Ðt�ms .�so|~t{~ ltk€ α.kzn �so
tz�o~€o �oy|o~k��~o {q�so€{q�ykð |{wtmÞ �€on �{€owom� m{rzt�t�o {|o~k�t{z€. β1\st€ wk€�
PLOS COMP UTATIONAL  BIOLOGYLt�k�t{z |k��o~z� tz�ty|wo ms{tmo ~oqwom� {|�tykw tzq{~yk�t {z�ky|wtzr
WSV[ I{y|��k�t{zk wGt{w{r� �s��|�>2 2n{t1{~r243146 ;42u{�~zkw1| mlt1433<<:6 Tk~ms 5:.5354 ;25=
|k~kyo�o~ m{z�~{w€ �soky{�z� {qz{t€o tz�soqtðk�t{z nomt€t{z€1 Oz{~no~ �{qt��soy{now. Ðo
zoon �{ykvo kzk€€�y|�t{z kl{�� �so�tyo �sk� t��kvo€ �{km}�t~o okms €ky|wo. Ðstms Ðo�kvo
�{lo433y€1U{�o. s{Ðo�o~. �sk� �st€ms{tmo t€z{�ty|{~�kz�> mskzrtzr �sok€€�yon n�~k�t{z
wokn€ �{kmskzro tz�soqt��on |k~kyo�o~€. l��z{�tz�so}�kwt�k�t�o y{now |~ontm�t{z€1
_o�€okzk||~{ðtyk�o ykðty�y wtvowts{{n yo�s{n �{qt��so€o |k~kyo�o~€ �{ms{tmo kzn
qtðk�t{z nk�k. Ðstms t€no€m~tlon tz�soTo�s{n€ €om�t{z1 Oy|{~�kz�wÞ. €tzmo �so€kyo y{now
mkzlok||wton �{U/t�oy ms{tmo€. Ðoqt�km{yy{z €o�{q|k~kyo�o~€ u{tz�wÞ �{�so|{{won nk�k
tzl{�s nk�k€o�€1 \s�€. kzÞntqqo~ozmo€ tzy{now |~ontm�t{z€ lo�Ðooz ltzk~Þ kzn �~tzk~Þ
ms{tmo€ k~oapriori |~ontm�t{z€ ~o€�w�tzr q~{y �so€�~�m��~o {q�soy{now. kzn z{�ntqqo~ozmo€
tz�so|k~kyo�o~€ �€on �{oð|wktz �so�Ð{�Þ|o€ {qms{tmo€1 _oo€�tyk�o �so|k~kyo�o~€ �€tzr
{zwÞ �soo�oz �~tkw€. kzn �soz €ty�wk�o �soy{now tz{nn �~tkw€ tz{~no~ �{m{y|k~o �soy{now
|~ontm�t{z€ Ðt�s �so{l€o~�on |k��o~z€ {��/{q/€ky|wo1 Gomk�€o �so|{wtmÞ {|�tytþk�t{z kzn
wtvowts{{n o€�tyk�t{z yo�s{n€ �sk� Ðo�€ok~o€�{msk€�tm. Ðont€|wkÞ €ty�wk�t{z€ �€tzr �so63
�{||o~q{~ytzr |k~kyo�o~ m{zqtr�~k�t{z€ �{rt�o k€oz€o {q�so�zmo~�ktz�Þ tz�so|~ontm�t{z€1
\so |k~kyo�o~ o€�tyk�o€ Ðo~o *yokz±€�n+σxB51:3±3154:. αB319<4±3144<. γ€Ðt�ms B
3133==9±31334. γ€ky|wo B31336;6±31334. kzn βB6:7±<415 F€oð|wktzon tz�soTo�s{n€. �so
�zt�€ {q�so€o |k~kyo�o~ o€�tyk�o€ k~o€�kznk~n no�tk�t{z€ {q�kw�o *t1o1.�~+1
Oz{~no~ �{oð|w{~o �so~{wo {q�so|~t{~. Ðokw€{ qt��o~€t{z€ {q�soy{now tzÐstms �so|~t{~
ltk€ �o~y Ðk€qtðon �{ αB3{~ αB41\so q{~yo~ m{~~o€|{zn€ �{k€�~{zrwÞ ltk€on |~t{~ kzn
�sowk��o~ m{~~o€|{zn€ �{km{y|wo�owÞ �zltk€on |~t{~1 L{~ αB3.�soqt��on |k~kyo�o~€ Ðo~o
σxB614:±3173=. γ€Ðt�ms B3133<;9±31335. γ€ky|wo B313364=±31334. kzn βB65:±<4151 L{~ α
B4.�soÞ Ðo~oσxB51::±315;5. γ€Ðt�ms B31344<±31335. γ€ky|wo B313393:±31334. kzn βB
66313±=;1=1
Fww�soqtr�~o€ low{Ð k~olk€on {zy{now qt�€o€�tyk�on k��sor~{�| wo�ow {z�so|{{won
nk�k1 N{Ðo�o~. q{~m{y|wo�ozo€€ Ðokw€{ qt��soy{now €o|k~k�owÞ q{~okms tznt�tn�kw. kzn
~o|{~� �so€o qt�€tz[5F||ozntð1 _okw€{ mk~~Þ {��k�kwtnk�t{z {q{�~y{now qt��tzr k||~{kms
tz[4F||ozntð1
Zo��w��
_oz{Ð tz�o€�trk�o �sooð�oz� �{Ðstms �so|~ontm�t{z€ {q�soy{now. qt��on {z�soo�oz �~tkw€.
k~oklwo �{kmm{�z� q{~{l€o~�on ms{tmo. ~okm�t{z �tyo kzn qtðk�t{z |k��o~z€ tz�so{��/{q/€ky/
|wo{nn �~tkw€1
Gk€tm |€Þms{yo�~tm€
_olortz lÞw{{vtzr k�lk€tm |€Þms{yo�~tm |k��o~z€1 Ltr6Fm{y|k~o€ �soms{tmo m�~�o€ |~o/
ntm�on lÞ�soy{now Ðt�s �sokm��kw {l€o~�on ms{tmo€. €o|k~k�owÞ q{~�somk€o {qltzk~Þ kzn �~tz/
k~Þms{tmo1 O�€s{Ð€ �sk� �soy{now mk|��~o€ Ðoww �sotzqw�ozmo {q�sot�oy€) �~�o �kw�o€ *k€
yok€�~on lÞwtvtzr ~k�tzr€+ {zms{tmo1
Ltr6G|w{�€ �sont€�~tl��t{z {q�{�kw qtðk�t{z �tyo€1 \st€ yok€�~o t€€tytwk~ �{~okm�t{z �tyo
oðmo|� �sk� t�oðmw�no€ �tyo z{�€|oz� qtðk�tzr {z{zo{q�sot�oy€1 _o�€o�{�kw qtðk�t{z �tyo
tz€�okn {q~okm�t{z �tyo lomk�€o �soy{now n{o€ z{�kmm{�z� q{~�sotzt�tkw qtðk�t{z wk�ozmÞ z{~
�so�tyo €|oz� €kmmkntzr lo�Ðooz t�oy€ *kw�s{�rs t�n{o€ kmm{�z� q{~�so{||{~��zt�Þ m{€� {q
�sk� �tyo. �s~{�rs �so γ€ky|wo |k~kyo�o~+1 F€€s{Ðz tz�soqtr�~o. �soy{now |~{�tno€ k~ok€{z/
klwo }�kwt�k�t�o kmm{�z� {q�sont€�~tl��t{z€. kw�s{�rs t��zno~|~ontm�€ �soy{no tz�somk€o {q
�Ð{t�oy€ kzn �so€voÐ tzl{�s mk€o€1
Ltr6I€s{Ð€ �so~owk�t{z€st| lo�Ðooz �{�kw qtðk�t{z �tyo kzn �~tkw ntqqtm�w�Þ. k€yok€�~on
lÞ�so~owk�t�o wtvtzr ~k�tzr {q�solo€� t�oy1 _oqtzn �sk� �soy{now |~{�tno€ k~ok€{zklwo
kmm{�z� {qs{Ð �{�kw qtðk�t{z �tyo mskzro€ Ðt�s ntqqtm�w�Þ1 \st€ |~ontm�t{z q{ww{Ð€ q~{y �so
PLOS COMP UTATIONAL  BIOLOGYLt�k�t{z |k��o~z� tz�ty|wo ms{tmo ~oqwom� {|�tykw tzq{~yk�t {z�ky|wtzr
WSV[ I{y|��k�t{zk wGt{w{r� �s��|�>2 2n{t1{~r243146 ;42u{�~zkw1| mlt1433<<:6 Tk~ms 5:.5354 <25=
qkm��sk� qoÐo~ €ky|wo€ k~ozomo€€k~Þ �{no�om� kwk~ro ntqqo~ozmo �skz �{ot�so~ no�om� k€ykww
ntqqo~ozmo {~no�o~ytzo �sk� �sontqqo~ozmo t€€ykww oz{�rs �{lo�zty|{~�kz�1 N{Ðo�o~. �so
y{now oðstlt�€ m{z€tno~klwo �k~tk�t{z tz�so|~ontm�on tz�o~mo|� kzn €�l€�kz�tkwwÞ {�o~|~ontm�€
�{�kw qtðk�t{z �tyo tzntqqtm�w� �~tzk~Þ ms{tmo€1
LtzkwwÞ. Ltr6J€s{Ð€ �so~owk�t{z€st| lo�Ðooz �{�kw qtðk�t{z �tyo kzn �sok�o~kro ~k�tzr {q
kww�sot�oy€ tz�soms{tmo €o�1\st€ �{�o~kww �kw�o oqqom�� sk€looz oy|sk€tþon tz~omoz�
~o€ok~ms d46. 4:flomk�€o t�t€m{z€t€�oz� Ðt�s y�w�t|wtmk�t�o k��oz�t{z Ðotrs�tzr *k€tz�so
kJJT+ l��z{�kzknnt�t�o l{{€�tzr y{now *o1r1. d44f+1 GkÞo€tkz �|nk�tzr ~o€�w�€ tzkq{~y {q
y�w�t|wtmk�t�o Ðotrs�tzr *€|omtqtmkwwÞ. ksÞ|o~l{wtm q�zm�t{z. m1q1d47f+. kzn �s�€ {�~y{now kw€{
|~ontm�€ �st€|k��o~z1 [�~|~t€tzrwÞ. Ðon{z{�€oo€�~{zr o�tnozmo q{~�so{�o~kww �kw�o oqqom� tz
�sonk�k€o�€ Ðom{z€tno~. l��Ðoz{�o �sk� �sooqqom� sk€looz q{�zn ~{l�€�wÞ tz€o�o~kw {�so~
nk�k€o�€ d46. 9:˘9=f1 U{�o �sk�. tz�soltzk~Þ mk€o. �so|~ontm�on {�o~kww �kw�o oqqom� t€€Þyyo�/
~tmk~{�zn �so|~t{~ yokz? �sk� t€.ms{tmo€ lo�Ðooz �Ð{�o~Þ lknt�oy€ Ðtwwkw€{ loykno
}�tmvwÞ1 Oznoon. Ðt�s kz�zltk€on/|~t{~. �soy{now |~ontm�€ kztz�o~�on/] ~owk�t{z€st| k~{�zn
�so|~t{~ yokz1
[o�o~kw knnt�t{zkw |k��o~z€ tzLtr6k~oÐ{~�s strswtrs�tzr1 Lt~€�. kww�soy{now€ ykvo €tytwk~
kzn ~ok€{zklwo |~ontm�t{z€ {q�so|€Þms{yo�~tm ms{tmo m�~�o kzn qtðk�t{z �tyo nt€�~tl��t{z€1
[om{zn. �soy{now€ Ðt�s €{yo |~t{~ ltk€ |~{�tno klo��o~ kmm{�z� {q�soqtðk�t{z �tyo m�~�o€ tz
ltzk~Þ ms{tmo �skz �so�zltk€on y{now. kzn }�kwt�k�t�owÞ €tytwk~ |~ontm�t{z€ �{�sokJJT1
Ltr61Gk€tm |€Þms{yo� ~tm€1 Kkms |kzow m{y|k~o€ s�ykz nk�k *lwkmv+ kzn y{now |~ontm�t{z€ q{~ltzk~Þ ms{tmo *woq�. �Ð{n{�€+ kzn �~tzk~Þ ms{tmo *~trs�. �s~oo n{�€+1
\so yktz y{now |~ontm�t{z€ k~o€s{Ðz tz|�~|wo1 \so ~o€�~tm�on y{now |~ontm�t{z€ q{~�somk€o {qkstrswÞ ltk€on |~t{~ yokz *αB3+k~o€s{Ðz tzlw�o? �somk€o {qk
strswÞ �zltk€ on|~t{~ yokz *αB4+t€€s{Ðz tz|tzv1 \so€o m{w{~€ Ðo~o ms{€oz �{tww�€�~k�o �sk� �soyktz y{now qkww€ lo�Ðooz �so€o �Ð{oð�~oy o€1\so kJJT
|~ontm�t{z€ k~o€s{Ðz tznk€son r~ooz1 K~~{~ lk~€ *s�ykz+ kzn €sknon ~ort{z€ *y{now+ tzntmk�o =9& m{zqtnoz motz�o~�kw€ m{y|��on lÞ43.333 l{{�€�~k| €ky|wo€ *�so
y{now m{zqtnoz motz�o~�kw€ k~o{q�oz �{{€ykww �{lo�t€tlwo+1 U{�o �sk� �soyo�s{n �€on �{m{y|��o kzn o€�tyk�o �soy{now |k~kyo �o~€t€z{t€Þ1 \{|~{�tno k€oz€o {q
�sooqqom� {q�st€z{t€o {z�soyktz y{now |~ontm�t{z€ .Ðono|tm� �so|~ontm�t{z€ {q�so�st~�Þ lo€�/qt��tzr |k~kyo�o~ m{zqtr�~k�t{z€ 1Kkms wtrs� |�~|wo wtzono|tm�€ �so
|~ontm�t{z€ q{~{zo{q�s{€o |k~kyo �o~€. Ðso~ok€ �sonk~vo~ |�~|wo wtzo€s{Ð€ �soyokz |~ontm�t{z1 Oz{~no~ �{voo| �so|w{� wortlwo. {zwÞ �soyokz |~ontm�t{z€ {q�so
ltk€on |~t{~€ y{now€ k~o€s{Ðz1 *F+Is{tmo |~{lkltw t�Þk€kq�zm�t{z {q~owk�t�o ~k�tzr1 *G+Ro~zow noz€t�Þ o€�tyk�t{z q{~�sont€�~tl��t{z {q�{�kw qtðk�t{z �tyo1
Y�k~�two €*59&. 93&. kzn ;9& }�kz�two€ +q{~�sonk�k. kJJT kzn yktz y{now |~ontm�t{z€ k~o€s{Ðz k��sol{��{y1 *I+\{�kw qtðk�t{z �tyo k€kq�zm�t{z {q�so~owk�t�o
~k�tzr {q�sostrso€� ~k�on t�oy1 *J+\{�kw qtðk�t{z �tyo k€kq�zm�t{z {q�soyokz {qkww�sot�oy ~k�tzr€ *{�o~kww �kw�o+1
s��|�>22n {t1{~r243146;4 2u{�~zkw1|mlt143 3<<:61r336
PLOS COMP UTATIONAL  BIOLOGYLt�k�t{z |k��o~z� tz�ty|wo ms{tmo ~oqwom� {|�tykw tzq{~yk�t {z�ky|wtzr
WSV[ I{y|��k�t{zk wGt{w{r� �s��|�>2 2n{t1{~r243146 ;42u{�~zkw1| mlt1433<<:6 Tk~ms 5:.5354 =25=
LtzkwwÞ. no€|t�o �€tzr km{yy{z €o�{q|k~kyo�o~€. kww�soy{now€ mk|��~o Ðoww �sontqqo~ozmo€
lo�Ðooz ltzk~Þ kzn �~tzk~Þ ms{tmo1
Gk€tm qtðk�t{z |~{|o~�to€
_ozoð� m{y|k~o �so|~ontm�on kzn {l€o~�on qtðk�t{z |k��o~z€1 Fz{l€o~�on �qtðk�t{z� ~oqo~€
�{km{z�tr�{�€ €|kz {q�tyo n�~tzr Ðstms k|k~�tmt|kz� w{{v€ k��so€kyo t�oy1 F|~ontm�on
y{now qtðk�t{z ~oqo~€ �{km{z�tz�{�€ €o}�ozmo {q€ky|wo€ �kvoz q~{y {zot�oy1
Ltr7F€s{Ð€ �sont€�~tl��t{z {q�soz�ylo~ {qqtðk�t{z€ km~{€€ �~tkw€1 \so y{now/|~ontm�on
nt€�~tl��t{z t€~ok€{zklwÞ €tytwk~ �{�so{l€o~�on nk�k1 N{Ðo�o~. tz�so�Ð{/t�oy mk€o. �so
y{now t€y{~o wtvowÞ �{ykvo {zwÞ {zoqtðk�t{z. €�rro€�tzr �sk� |o{|wo sk�o k�oznozmÞ �{qtðk�o
l{�s t�oy€ k�wok€� {zmo �sk� �soy{now n{o€ z{�mk|��~o1
Ltr7G€s{Ð€ �so~owk�t{z€st| lo�Ðooz �so�{�kw z�ylo~ {qqtðk�t{z€ kzn nomt€t{z ntqqtm�w�Þ1
_oqtzn �sk� �soy{now mk|��~o€ �so~owk�t{z€st| lo�Ðooz ntqqtm�w�Þ kzn �soz�ylo~ {qqtðk/
�t{z€ ~ok€{zklwÞ Ðoww. Ðt�s �so€kyo mk�ok�€ k€q{~Ltr6G1
\so {~trtzkw ltzk~Þ kzn �~tzk~Þ ms{tmo |k|o~€ d=.43f{l€o~�on k€Þ€�oyk�tm mskzro tzqtðk/
�t{z n�~k�t{z€ {�o~ �som{�~€o {q�so�~tkw. k€€s{Ðz tzLtr7I1Fw�s{�rs �soy{now �ozn€ �{
�zno~|~ontm� �son�~k�t{z {q�soqt~€� �Ð{qtðk�t{z€ tz�so�s~oo/t�oy mk€o. t�mk|��~o€ Ðoww �s~oo
voÞ|k��o~z€> *k+�soqtzkw qtðk�t{z t€€s{~�o~. *l+wk�o~ *l�� z{z/qtzkw+ qtðk�t{z€ k~ow{zro~ kzn
*m+qtðk�t{z€ k~o€�l€�kz�tkwwÞ w{zro~ tz�so�Ð{/t�oy mk€o1 \so qtzkw |~ontm�t{z t€o€|omtkwwÞ
€�~tvtzr rt�oz �sk� �soy{now �€o€ �so€kyo €o�{qqt��on |k~kyo�o~€ q{~l{�s nk�k€o�€1 \so
y{now |~ontm�€ €s{~�o~ qtzkw qtðk�t{z€ lomk�€o �soÞ k~om��{qqÐsoz kms{tmo t€ykno d=.43f1
\so y{now |~ontm�€ �so{�so~ |k��o~z€ lomk�€o y{~o o�tnozmo t€zoonon �{kw�o~ lowtoq€ Ðsoz
�sot~ |~omt€t{z t€kw~oknÞ strs? �st€{mm�~€ wk�otz�so�~tkw. o€|omtkwwÞ tz�so�Ð{/t�oy mk€o Ðso~o
€ky|wo€ k~o€|wt� lo�Ðooz qoÐo~ t�oy€1
Ltr7kw€{ €s{Ð€ �sk� �soyktz y{now |~{�tno€ ky{~o kmm�~k�o kmm{�z� �skz �sokJJT {q
s{Ð �soz�ylo~ {qqtðk�t{z€ mskzro€ Ðt�s �~tkw ntqqtm�w�Þ. kzn {qs{Ð qtðk�t{z n�~k�t{z o�{w�o€
Ltr71Gk€tm qtðk�t{z |k��o~z€ 1*F+Nt€�{r~ky {qz�ylo~ {qqtðk�t{z€ tzk�~tkw1 *G+U�ylo~ {qqtðk�t{z€ k€kq�zm�t{ z{qnomt€t{z ntqqtm�w�Þ. k€yok€�~on lÞ
�so~owk�t�o ~k�tzr {q�solo€� t�oy1 *I+J�~k�t{z {qqtðk�t{z lÞqtðk�t{z z�ylo~1 Ltzkw qtðk�t{z€ k~ooðmw�non q~{y kwwl���sowk€�ltz1 [ooLtr6q{~y{~o
no�ktw€1
s��|�>22n {t1{~r243146;4 2u{�~zkw1|mlt143 3<<:61r337
PLOS COMP UTATIONAL  BIOLOGYLt�k�t{z |k��o~z� tz�ty|wo ms{tmo ~oqwom� {|�tykw tzq{~yk�t {z�ky|wtzr
WSV[ I{y|��k�t{zk wGt{w{r� �s��|�>2 2n{t1{~r243146 ;42u{�~zkw1| mlt1433<<:6 Tk~ms 5:.5354 4325=
{�o~ �som{�~€o {qk�~tkw1 Vzo ntqqtm�w�Þ tzykvtzr �st€m{y|k~t€{z t€�sk� �sokJJT k€€�yo€
�sk� z{z/qtzkw qtðk�t{z n�~k�t{z€ k~o€ky|won q~{y �so{l€o~�on oy|t~tmkw nt€�~tl��t{z. m{znt/
�t{zkw {zkz�ylo~ {q{l€o~�klwo �k~tklwo€. kzn �s�€ �sokmm�~kmÞ {qt�€|~ontm�t{z€ ~ork~ntzr
qtðk�t{z n�~k�t{z kzn qtðk�t{z z�ylo~ no|ozn€ {z�sono�ktw€ {q�st€€ky|wtzr1 \{ykðtytþo
m{y|k~kltwt�Þ Ðt�s �sooðt€�tzr wt�o~k��~o. so~o Ðo�€o�so€kyo yo�s{n€ k€tz�so{~trtzkw
ty|woyoz�k�t{z€ d=.43f1
]zmo~�ktz�Þ/nt~om�on k��oz�t{z
F€Ðosk�o €ooz. {zo{q�sovoÞn~t�o~€ {qqtðk�t{z€ tz�so{|�tykw |{wtmÞ t€�zmo~�ktz�Þ kl{��
�sot�oy€) �kw�o€1 [|omtqtmkwwÞ. lomk�€o �so|~omt€t{z {q�so|{€�o~t{~€ tzm~ok€o€ wtzok~wÞ Ðt�s �so
z�ylo~ {q€ky|wo€. �soy{now |~ontm�€ �sk�. {�so~ �stzr€ lotzr o}�kw. qtðk�t{z€ €s{�wn r{�{
t�oy€ �sk� sk�o ~omot�on wo€€m�y�wk�t�o qtðk�t{z �tyo1 N{Ðo�o~. �sontqqo~ozmo tz|~omt€t{z
y�€� lowk~ro oz{�rs �{u�€�tqÞ |kÞtzr �so€Ðt�mstzr m{€�1 Oz�st€€om�t{z Ðooð|w{~o €{yo {q
�soqtðk�t{z |k��o~z€ k€€{mtk�on Ðt�s �st€yomskzt€y1
Ltr9Fno|tm�€ �sont€�~tl��t{z {q~owk�t�o m�y�wk�t�o qtðk�t{z �tyo k��solortzztzr {qk
zoÐ qtðk�t{z. €�k~�tzr Ðt�s �so€om{zn qtðk�t{z1 \sk� t€.k��so{z€o� {qokms qtðk�t{z. Ðok€v
s{Ð y�ms �tyo sk€kw~oknÞ looz €|oz� qtðk�tzr �sozoÐwÞ qtðk�on t�oy. m{y|k~on �{�so{�so~
t�oy€1 Ozl{�s mk€o€. �sokm��kw kzn |~ontm�on nt€�~tl��t{z€ k~omoz�o~on low{Ð þo~{. €{�sk�
t�oy€ �ozn �{loqtðk�on Ðsoz �soÞ sk�o ~omot�on wo€€qtðk�t{z �tyo �skz �so{�so~ t�oy€1 Fnnt/
�t{zkwwÞ. �soy{now m{~~om�wÞ |~ontm�€ �sow{Ðo~ y{no kzn qk��o~ woq��ktwtz�so�Ð{/t�oy mk€o1
U{�o. s{Ðo�o~. �sk� k|�~owÞ yomskztmkw oqqom� mkzkmm{�z� q{~�st€lk€tm |k��o~z> �sot�oy
�sk� t€m�~~oz�wÞ qtðk�on Ðtww{zk�o~kro sk�o ~omot�on �soy{€� qtðk�t{z �tyo. l��t�mkzz{� lo
�so�k~ro� {qkzoÐ qtðk�t{z. Ðstms n~t�o€ n{Ðz �soqtðk�t{z kn�kz�kro {qzoÐwÞ qtðk�on t�oy€1
L{~�st€~ok€{z. t�t€�€oq�w �{w{{v q�~�so~ k��so�s~oo/t�oy mk€o. Ðstms kqq{~n€ k€�~{zro~ �o€�
{q�zmo~�ktz�Þ/nt~om�on k��oz�t{z1 Oz�st€mk€o. �so�k~ro� {qokms zoÐ qtðk�t{z *oðmw�ntzr �so
qt~€�+ y�€� lo{zo{q�so�Ð{t�oy€ �sk� k~oz{�m�~~oz�wÞ qtðk�on1 \s�€. m{y|k~tzr �som�y�wk/
�t�oqtðk�t{z �tyo€ q{~�so€o t�oy€ k�{tn€ �so|~o�t{�€ m{zq{�zn1 Ltr9G�s�€ |w{�€ �sont€�~tl�/
�t{z {qqtðk�t{z �tyo q{~�soqtðk�on t�oy ytz�€ �sk� {q�sot�oy Ðstms m{�wn sk�o looz qtðk�on
l��Ðk€z{�1 _o€ook€tytwk~ |k��o~z �{Ltr9F*~trs�+ tzl{�s �sonk�k kzn y{now |~ontm�t{z€1
\st€ €�rro€�€ �sk� �zmo~�ktz�Þ t€z{�€ty|wÞ n~t�tzr �sonomt€t{z �{ykvo k€kmmkno. l��t€kw€{
tzqw�ozmtzr �sow{mk�t{z {q�sk� €kmmkno1
Ltr9Ioð|w{~o€ �st€q�~�so~ lÞw{{vtzr k��sow{mk�t{z {qzoÐ qtðk�t{z€ tz�so�s~oo/t�oy
mk€o. k€kq�zm�t{z {q�sontqqo~ozmo tzm�y�wk�t�o qtðk�t{z �tyo lo�Ðooz �so�Ð{|{€€tlwo qtðk/
�t{z �k~ro�€1 Fw�s{�rs �soy{~o/|~o�t{�€wÞ/qtðk�o nt�oy t€kwÐkÞ€ wo€€wtvowÞ �{loqtðk�on. �so
Ltr91]zmo~�ktz� Þ/nt~om�on k��oz�t{z 1*F+Jt€�~tl��t{z {qqtðk�t{z kn�kz�kro {q�soqtðk�on t�oy. m{y|��on k��solortzztzr {qokms zoÐ qtðk�t{z1 Ltðk�t{z
kn�kz�kro t€noqtzon k€�som�y�w k�t�o qtðk�t{z �tyo �{�sot�oy ytz�€ �soyokz m�y�wk �t�oqtðk�t{z �tyo �{�so{�so~ t�oy*€+1 Lt~€� qtðk�t{z€ k~ooðmw�non tz
�st€|w{�1 *G+[tytwk~ �{F.oðmo|� �sk� Ðom{y|k~o �soqtðk�t{z kn�kz�kro lo�Ðooz �soqtðk�on t�oy kzn �so{�so~ t�oy �sk� m{�wn sk�o looz qtðk�on l��Ðk€
z{�1 Lt~€� kzn €om{zn qtðk�t{z€ k~ooðmw�non tz�st€|w{�1 *I+\so |~{lkltwt�Þ �sk� �sot�oy Ðt�s r~ok�o~ kw�o~zk�t�o qtðk�t{z kn�kz�kro t€qtðk�on. k€kq�zm�t{z
{q�sk� kn�kz�kro 1[ooLtr6q{~y{~o no�ktw€1
s��|�>22n {t1{~r243146;4 2u{�~zkw1|mlt143 3<<:61r339
PLOS COMP UTATIONAL  BIOLOGYLt�k�t{z |k��o~z� tz�ty|wo ms{tmo ~oqwom� {|�tykw tzq{~yk�t {z�ky|wtzr
WSV[ I{y|��k�t{zk wGt{w{r� �s��|�>2 2n{t1{~r243146 ;42u{�~zkw1| mlt1433<<:6 Tk~ms 5:.5354 4425=
|~{lkltwt�Þ {q€�ms kqtðk�t{z km��kwwÞincreases k€t�€qtðk�t{z kn�kz�kro r~{Ð€1 \st€ m{�z�o~tz/
��t�t�o y{now |~ontm�t{z ~o€�w�€ q~{y �som{y|o�tzr oqqom�€ {q�kw�o kzn �zmo~�ktz�Þ {zk��oz/
�t{z1 [tzmo t�oy€ Ðt�s strs o€�tyk�on �kw�o k~oqtðk�on y{~o. kzt�oy �sk� sk€looz qtðk�on
y�ms wo€€�skz �so{�so~€ t€wtvowÞ �{sk�o kw{Ðo~ o€�tyk�on �kw�o. kzn t€�so~oq{~o wo€€wtvowÞ �{
~omot�o y{~o qtðk�t{z€1 N{Ðo�o~. Ðo€oo�sk� �so|~ontm�on oqqom� t€y�ms €�~{zro~ �skz �so
{l€o~�on oqqom�. kzn �sk� �sokJJT y{now |~{�tno€ klo��o~ kmm{�z� {q�st€|k��o~z �skz {�~
yktz y{now1 N{Ðo�o~. z{�o �sk� �sokmm�~kmÞ {q�st€qt�q{ww{Ð€ q~{y �soqkm��sk� �sokJJT
€ky|wo€ qtðk�t{z w{mk�t{z€ kzn n�~k�t{z€ q~{y �sooy|t~tmkw nt€�~tl��t{z. m{znt�t{zon {z�so
|~o�t{�€ �s~oo qtðk�t{z w{mk�t{z€ kzn �sot�oy ~k�tzr€1
^kw�o/nt~om�on k��oz�t{z
F€om{zn voÞn~t�o~ {qk��oz�t{z tz�so{|�tykw |{wtmÞ t€o€�tyk�on �kw�o. Ðstms nt~om�€ qtðk/
�t{z€ �{�sotwot�oy€ Ðt�s �sostrso€� |{€�o~t{~ yokz€1 F€tww�€�~k�on tzLtr5F.�st€ty|wto€
�sk� qtðk�t{z w{mk�t{z€ €s{�wn lo€oz€t�t�o �{~owk�t�o o€�tyk�on �kw�o€ tz�so�~tzk~Þ l��z{�tz
�soltzk~Þ mk€o1
Fw�s{�rs Ðomkzz{� nt~om�wÞ yok€�~o �so|k~�tmt|kz�€) o�{w�tzr �kw�o o€�tyk�o€. Ðomkz�€o
�sowtvtzr ~k�tzr€ k€k|~{ðÞ q{~�soy lomk�€o strso~/~k�on t�oy€ Ðtww�ozn �{~o€�w� tzstrso~
�kw�o o€�tyk�o€1 ]€tzr �st€tnok. Ltr:F€s{Ð€ �so|~{|{~�t{z {qqtðk�t{z �tyo no�{�on �{�so
woq�t�oy k€kq�zm�t{z {qt�€~owk�t�o ~k�tzr1 L{m�€tzr qt~€� {z�so�s~oo/t�oy mk€o. l{�s �so
y{now kzn nk�k €s{Ð k€�~{zr �oznozmÞ �{€|ozn y{~o �tyo qtðk�tzr {zstrso~ ~k�on t�oy€
*Ðstms k~o�so~oq{~o wtvowÞ �{sk�o strso~ o€�tyk�on �kw�o€+1 Oz�so�Ð{t�oy mk€o. �soy{now
€ty�wk�t{z€ €s{Ð k€ykwwo~ l��kw€{ |{€t�t�o oqqom�1 \st€ t€m{�z�o~tz��t�t�o €tzmo �soy{now
|~ontm�€ �sk� tz�so�Ð{/t�oy mk€o qtðk�t{z w{mk�t{z€ k~otz€oz€t�t�o �{�so€trz {q�so~owk�t�o
�kw�o o€�tyk�o€ *Ltr 5F+1 N{Ðo�o~. �so|k��o~z wtvowÞ k~t€o€ n�o�{�so�oznozmÞ �{qtðk�o wk€�{z
�soms{€oz t�oy *€oo Ltr;Flow{Ð+1
Ltr:1^kw�o/nt~o m�on k��oz�t{z1 *F+W~{|{~�t{ z{q�tyo qtðk�tzr �sowoq�t�oy k€kq�zm�t{ z{qt�€~owk�t�o ~k�tzr1 *G+Lt~€� qtðk�t{z n�~k�t{z k€kq�zm�t{z {q
�so~k�tzr {q�soqt~€�/qtðk�o nt�oy1 *I+W~{lkltwt� Þ{qqtðk�tz r�sow{Ðo€� ~k�on t�oy k€kq�zm�t{z {q�som�y�wk�t�o qtðk�t{z �tyo �{kzÞ{q�sot�oy€1 *J+
W~{lkltwt �Þ�sk� �soq{�~�s qtðk�t{z t€�{�soqt~€�/qtðk�on t�oy k€kq�zm�t{ z{q�sontqqo~ozmo tz~k�tzr lo�Ðooz �sk� t�oy kzn�so€om{zn/q tðk�on t�oy1 *K+
W~{lkltwt �Þ�sk� �so�st~n qtðk�t{z t€�{�soqt~€� qtðk�on t�oy k€kq�zm�t{z {qt�€~k�tzr1 [ooLtr6q{~y{~o no�ktw€1
s��|�>22n {t1{~r243146;4 2u{�~zkw1|mlt143 3<<:61r33:
PLOS COMP UTATIONAL  BIOLOGYLt�k�t{z |k��o~z� tz�ty|wo ms{tmo ~oqwom� {|�tykw tzq{~yk�t {z�ky|wtzr
WSV[ I{y|��k�t{zk wGt{w{r� �s��|�>2 2n{t1{~r243146 ;42u{�~zkw1| mlt1433<<:6 Tk~ms 5:.5354 4525=
Ltr:G|~{�tno€ kzkw�o~zk�t�o �o€��sk� k�{tn€ m{zq{�zn€ k€€{mtk�on Ðt�s �soqtzkw qtðk�t{z1
O�€s{Ð€ �son�~k�t{z {q�soqt~€� qtðk�t{z. Ðstms t€~k~owÞ qtzkw. k€kq�zm�t{z {q�so~k�tzr {q�so
qt~€� qtðk�on t�oy1 Oz�so�s~oo/t�oy mk€o. l{�s �soy{now kzn nk�k €s{Ð w{zro~ tzt�tkw qtðk�t{z€
�{strs/~k�on t�oy€. kw�s{�rs �soy{now €Þ€�oyk�tmkwwÞ �zno~|~ontm�€ �soyokz qt~€� qtðk�t{z
n�~k�t{z1 \st€ |~ontm�t{z q{ww{Ð€ q~{y �soqkm��sk�. �zno~ �so{|�tykw |{wtmÞ. qtðk�t{z€ k~o�o~/
ytzk�on Ðsoz �soqtðk�on t�oy)€ o€�tyk�on �kw�o qkww€ {��{q�so�{|�Ð{*low{Ð þo~{ q{~�so
qt~€� qtðk�t{z+? �sostrso~ �so�~�o �kw�o {q�sot�oy. �sowo€€wtvowÞ �st€t€�{sk||oz1 Oz�so�Ð{/
t�oy mk€o. s{Ðo�o~. �soy{now |~ontm�€ �sk� qt~€� qtðk�t{z n�~k�t{z €s{�wn lowk~rowÞ tz€oz€t�t�o
�{o€�tyk�on �kw�o? strswÞ �kw�klwo t�oy€ km��kwwÞ ~omot�o €wtrs�wÞshorter qtðk�t{z€ lomk�€o �so€o
t�oy€ k~oy{~o wtvowÞ �{rozo~k�o oð�~oyowÞ |{€t�t�o €ky|wo€ �sk� ~o€�w� tz�o~ytzk�tzr �soqt~€�
qtðk�t{z kzn tyyontk�owÞ ms{{€tzr �soqtðk�on t�oy1 I{z€t€�oz� Ðt�s �st€|~ontm�t{z. s�ykz€
€s{Ð wt��wo o�tnozmo q{~w{zro~ qt~€� qtðk�t{z€ �{strs/~k�on t�oy€ tz�soltzk~Þ mk€o1
W~o�t{�€ Ð{~v sk€€�rro€�on �sk� k��oz�t{z ykÞ lont~om�wÞ tzqw�ozmon lÞ�so�~�o �kw�o {q
�sot�oy€ d4;. 4<.:3f1 Oz{�~y{now. s{Ðo�o~. k��oz�t{z t€n~t�oz {zwÞ lÞ�sotz�o~zkw �kw�o o€�t/
yk�o€ rozo~k�on n�~tzr �sonomt€t{z ykvtzr |~{mo€€1 \{nt€�tzr�t€s lo�Ðooz �so€o �Ð{
kmm{�z�€. Ðozoon kÐkÞ �{nt€€{mtk�o o€�tyk�on �kw�o q~{y �~�o �kw�o1 Vzo ÐkÞ �{n{�st€t€lÞ
w{{vtzr k��so�tyo m{�~€o {qk��oz�t{z1 Kk~wÞ tz�sonomt€t{z ykvtzr |~{mo€€. o€�tyk�on �kw�o€
Ðtwwlo{zwÞ ÐokvwÞ ~owk�on �{�~�o �kw�o1 N{Ðo�o~. Ðt�s �tyo �so�kw�o o€�tyk�o€ lom{yo
tzm~ok€tzrwÞ kmm�~k�o kzn �s�€ y{~o mw{€owÞ m{~~owk�o Ðt�s �~�o �kw�o1 \s�€. tq�sonomt€t{z
ykvo~ kwÐkÞ€ k��ozn€ �{�sot�oy€ Ðt�s strsestimated �kw�o. €so€s{�wn lotzm~ok€tzrwÞ wtvowÞ
�{k��ozn �{t�oy€ Ðt�s strstrue �kw�o k€�so�~tkw |~{r~o€€o€1 Ltr:I€s{Ð€ �so|~{lkltwt�Þ {q
qtðk�tzr {z�soÐ{~€� t�oy k€kq�zm�t{z {q�som�y�wk�t�o qtðk�t{z �tyo �{kzÞ{q�sot�oy€1 Oz
l{�s �so�Ð{/ kzn �s~oo/t�oy mk€o€. �so|~{lkltwt�Þ lortz€ zok~ mskzmo1 Oz�so�s~oo/t�oy mk€o.
s{Ðo�o~. �so|~{lkltwt�Þ }�tmvwÞ qkww€1 \st€ t€m{z€t€�oz� Ðt�s ky{now tzÐstms k��oz�t{z t€
n~t�oz lÞo€�tyk�on �kw�o ~k�so~ �skz �kw�o t�€owq1
Ltr;1Is{tmo ltk€o€1 *F+W~{lkltwt�Þ �sk� �sowk€�qtðk�on t�oy t€ms{€oz k€kq�zm�t{z {qt�€~owk�t�o ~k�tzr1 *G+W~{lkltwt�Þ �sk� �sowoq�t�oy t€ms{€oz k€k
q�zm�t{z {qt�€qtzkw qtðk�t{z kn�kz�kro. rt�oz lÞ�{�kw qtðk�t{z �tyo �{�sowoq�t�oy ytz�€ �soyokz �{�kw qtðk�t{z �tyo �{�so{�so~ t�oy*€+1 *I+W~{lkltwt�Þ {q
ms{{€tzr �soqt~€�/€ooz t�oy k€kq�zm�t{z {q�soqt~€�/qtðk�t{ zn�~k�t{z1 [ooLtr6q{~y{~o no�ktw€1
s��|�>22n {t1{~r243146;4 2u{�~zkw1|mlt143 3<<:61r33;
PLOS COMP UTATIONAL  BIOLOGYLt�k�t{z |k��o~z� tz�ty|wo ms{tmo ~oqwom� {|�tykw tzq{~yk�t {z�ky|wtzr
WSV[ I{y|��k�t{zk wGt{w{r� �s��|�>2 2n{t1{~r243146 ;42u{�~zkw1| mlt1433<<:6 Tk~ms 5:.5354 4625=
\so y{now ykvo€ o�oz €�k~vo~ |~ontm�t{z€ tz�so�s~oo/t�oy mk€o1 Lt~€�. �kvo kww�~tkw€ tz
Ðstms �sonomt€t{z/ykvo~ €ky|wo€ q~{y ntqqo~oz� t�oy€ n�~tzr �soqt~€� �s~oo qtðk�t{z€1 I{z/
€tno~ �soms{tmo {qÐso~o �{no|w{Þ �soq{�~�s qtðk�t{z1 \so y{now |~ontm�€ �sk� �st€qtðk�t{z
€s{�wn lo�{�soqt~€�/qtðk�on t�oy tqt�€|{€�o~t{~ yokz t€wk~ro~ �skz �sk� {q�so€om{zn/qtðk�on
t�oy. kzn �tmo �o~€k1 F€k~o€�w�. �so|~{lkltwt�Þ �sk� �soq{�~�s qtðk�t{z t€k~oqtðk�t{z �{�so
qt~€�/qtðk�on t�oy €s{�wn tzm~ok€o Ðt�s �sontqqo~ozmo tz~k�tzr€ lo�Ðooz �soqt~€�/ kzn €om{zn/
qtðk�on t�oy€1 F€€s{Ðz tzLtr:J.�so{l€o~�on |k��o~z q{ww{Ð€ �soy{now |~ontm�t{z1
LtzkwwÞ. �soy{now ykvo€ k€�~tvtzr |~ontm�t{z ~ork~ntzr �sow{mk�t{z {q�so�st~n qtðk�t{z tz
�so�s~oo/t�oy mk€o1 I{z€tno~ �soms{tmo {qÐso~o �{qtðk�o kq�o~ �soqt~€� �Ð{qtðk�t{z€1 \so
nomt€t{z ykvo~ mkzms{{€o �{qtðk�o {z�sot�oy �sk� €sosk€z{�€ooz Þo�.{~�{~oqtðk�o �so
qt~€�/qtðk�on t�oy1 \so y{now |~ontm�€ k~oqtðk�t{z �{�soqt~€�/€ooz t�oy tql{�s �sk� t�oy kzn
�so€om{zn/€ooz t�oy kw~oknÞ sk�o strs �kw�o o€�tyk�o€ *wok�tzr �so�zqtðk�on t�oy Ðt�s �so
w{Ðo€� �kw�o o€�tyk�o+1 I{z€t€�oz� Ðt�s �st€|~ontm�t{z. Ltr:K€s{Ð€ �sk� �so|~{lkltwt�Þ {q�so
�st~n qtðk�t{z lotzr k~oqtðk�t{z �{�soqt~€�/€ooz t�oy tzm~ok€o€ Ðt�s �sk� t�oy)€ ~k�tzr1 U{�o
�sk� �soy{now Ðt�s αqtðon �{þo~{ *m{~~o€|{zntzr �{k€�~{zr |~t{~ ltk€+. n~kyk�tmkwwÞ {�o~/
|~ontm�€ �sotz�o~mo|�1 \st€ t€lomk�€o �st€y{now r~ok�wÞ �zno~o€�tyk�o€ �so�kw�o {q�soz{�/
Þo�/qtðk�on t�oy1
Ltr:€s{Ð€ �sk� {�~yktz y{now |~{�tno€ klo��o~ |~ontm�t{z {q€{yo qtðk�t{z |k��o~z€.
Ðso~ok€ �sokJJT |~{�tno€ klo��o~ qt�{q{�so~€1 N{Ðo�o~. t�t€ty|{~�kz� �{voo| tzytzn
�sk� Ðso~ok€ {�~y{now |~{�tno€ |~ontm�t{z€ q{~�so€o qtðk�t{z |k��o~z€ lk€on {zqt~€� |~tzmt/
|wo€. �so|~ontm�t{z€ {q�sokJJT q{~�so€o |k��o~z€ k~owk~rowÞ yomskzt€�tm €tzmo �sk� y{now
€ky|wo€ qtðk�t{z w{mk�t{z€ kzn n�~k�t{z€ q~{y �so{l€o~�on oy|t~tmkw nt€�~tl��t{z1 F€k~o€�w�.
t�t€z{�€�~|~t€tzr �sk� Ltr:G€s{Ð€ klo��o~ yk�ms lo�Ðooz �sokJJT kzn �sonk�k €tzmo �so
|~ontm�on n�~k�t{z€ k~o.wt�o~kwwÞ. €ky|won q~{y �so{l€o~�on nk�k m{znt�t{zkw {z�soqt~€� t�oy
~k�tzr1
Is{tmo ltk€o€
W~o�t{�€ Ð{~v sk€q{�zn k€Þ€�oyk�tm |{€t�t�o m{~~owk�t{z lo�Ðooz ~owk�t�o qtðk�t{z �tyo kzn
ms{tmo q{~k||o�t�t�o *t1o1. |{€t�t�owÞ �kwozmon+ t�oy€ d:.;.=.43.47.53f1 Oz|k~�tm�wk~. y{now€
wtvo�sokJJT |~{|{€o �sk� kzoð{roz{�€ {~~kzn{y tzm~ok€o tzqtðk�t{z€ �{Ðk~n€ kzk||o�t/
�t�ot�oy tzm~ok€o �so|~{lkltwt�Þ �sk� t�Ðtwwloms{€oz. Ðstms wokn€ �{k��oz�t{z n~t�oz ms{tmo
ltk€o€1 No~o Ðotz�o€�trk�o Ðso�so~ �so{|�tykw y{now mkzkmm{�z� q{~�so€o �Þ|o€ {qoqqom�€1
Oy|{~�kz�wÞ. tz�so�Þ|o {q{|�tykw qtðk�t{z y{now |~{|{€on so~o. �so~o k~o�Ð{|{�oz�tkw
yomskzt€y€ �s~{�rs Ðstms €�ms m{~~owk�t{z€ mkzoyo~ro1 \so qt~€� t€n~t�oz lÞ�so|~t{~1 Oq
�so|~t{~ yokz t€zork�t�owÞ ltk€on. �soz €ky|wtzr q~{y kzt�oy Ðtww{zk�o~kro tzm~ok€o t�€
o€�tyk�on �kw�o1 \st€ q{ww{Ð€ q~{y �soqkm��sk� €ky|wtzr Ðtwwrozo~kwwÞ y{�o �soo€�tyk�on
�kw�o �{Ðk~n€ �sot�oy)€ �~�o �kw�o. kzn kzork�t�owÞ ltk€on |~t{~ ty|wto€ �sk� �sotzt�tkw �kw�o
o€�tyk�o t€rozo~kwwÞ wo€€�skz �so�~�o �kw�o1 \so €om{zn yomskzt€y. Ðstms t€{zwÞ |~o€oz� tz
�~tzk~Þ ms{tmo. t€�so~o€�w� {q�kw�o/nt~om�on k��oz�t{z1 No~o. �somk�€kw nt~om�t{z t€qwt||on.
Ðt�s �kw�o o€�tyk�o€ n~t�tzr qtðk�t{z€ ~k�so~ �skz qtðk�t{z€ n~t�tzr �kw�o o€�tyk�o€1 Oz|k~�tm�/
wk~.t�oy€ Ðt�s strso~ o€�tyk�on �kw�o k~ol{�s y{~o wtvowÞ �{loqtðk�on. kzn y{~o wtvowÞ �{lo
ms{€oz1 \s�€. qtðk�t{z€ kzn ms{tmo k~om{~~owk�on �s~{�rs km{yy{z mk�€o €�~�m��~o1 Oy|{~/
�kz�wÞ. �so�Ð{yomskzt€y€ k~oz{�y���kwwÞ oðmw�€t�o? tzqkm�. {�~y{now |~ontm�€ �sk� l{�s
Ðtwwlotzoqqom� q{~ms{tmo lo�Ðooz y{~o �skz �Ð{t�oy€1
Ltr;F€s{Ð€ �sk� �so~o t€k€tþklwo ms{tmo ltk€ �{Ðk~n€ �sowk€�/€ooz t�oy tzl{�s nk�k€o�€.
k€o�tnozmon lÞ�sor~ok�o~/�skz/mskzmo |~{lkltwt�Þ {qms{{€tzr kzt�oy Ðs{€o �kw�o t€o}�kw
�{�soyokz {q�so{�so~ t�oy€1 V�~ y{now |~{�tno€ k€�~{zr }�kz�t�k�t�o kmm{�z� {q�so|k�/
�o~z tz�~tzk~Þ ms{tmo. l��€�l€�kz�tkwwÞ �zno~|~ontm�€ �sooqqom� tzltzk~Þ ms{tmo1 Oz�o~o€�tzrwÞ.
PLOS COMP UTATIONAL  BIOLOGYLt�k�t{z |k��o~z� tz�ty|wo ms{tmo ~oqwom� {|�tykw tzq{~yk�t {z�ky|wtzr
WSV[ I{y|��k�t{zk wGt{w{r� �s��|�>2 2n{t1{~r243146 ;42u{�~zkw1| mlt1433<<:6 Tk~ms 5:.5354 4725=
t�|~ontm�€ kÐokvo~ oqqom� �skz �sokJJT tz�soltzk~Þ mk€o. l��k€�~{zro~ oqqom� tz�so�~tzk~Þ
mk€o1
\{�zno~€�kzn �st€~o€�w�. t�t€ty|{~�kz� �{�stzv kl{�� �so|~t{~ lowtoq€ ty|wtmt� tz�so
kJJT kzn ~owk�on y{now€ d=.43.53f1 [tzmo �so€o k~oz{�GkÞo€tkz y{now€. �soÞ n{z{�|{€t�
kzoð|wtmt� |~t{~ �sk� t€�soz y{ntqton lÞo�tnozmo1 N{Ðo�o~. �sokJJT mkzlo�toÐon k€kz
k||~{ðtyk�t{z �{kGkÞo€tkz y{now Ðt�s k|~t{~ moz�o~on {zþo~{. k€~oqwom�on lÞ�sotzt�tkw
|{tz� {q�sokmm�y�wk�{~ *þo~{+ kzn �soy�w�t|wtmk�t�o nt€m{�z�tzr *�so o�tnozmo q{~�soz{z/
k��oznon t�oy t€nt€m{�z�on �{Ðk~n€ þo~{+1 \so wk��o~ ~{�rswÞ m{~~o€|{zn€ �{�soGkÞo€tkz ~or/
�wk~tþk�t{z oqqom�. Ðso~otz �so|{€�o~t{~ yokz qkww€ mw{€o~ �{�so|~t{~ yokz Ðsoz �sowtvowt/
s{{n t€Ðokv *w{Ð |~omt€t{z+1 Mt�oz �st€. {�~y{now |~ontm�€ kÐokvo~ oqqom� tz�soltzk~Þ mk€o
lomk�€o t�sk€kÐokvo~ |~t{~ ltk€ *αB319<+ �skz �so{zoty|wtmt� tz�sokJJT *αB3+1V�~
y{now |~ontm�€ k€�~{zro~ oqqom� tz�so�~tzk~Þ mk€o n�o�{�so�kw�o/nt~om�on k��oz�t{z yomsk/
zt€y1 I~t�tmkwwÞ. kw�s{�rs �sokJJT kmm{�z�€ q{~�sooqqom� {qtrue �kw�o {zqtðk�t{z€ *lÞ€ky/
|wtzr q~{y �sooy|t~tmkw qtðk�t{z nt€�~tl��t{z+. {zwÞ �so{|�tykw y{now kmm{�z�€ q{~�sooqqom�€
{qestimated �kw�o1 \s�€. m{znt�t{ztzr {z�~�o �kw�o *k€Ðon{tzLtr;F+ l~okv€ �so�kw�o/
lk€on k��oz�t{z yomskzt€y tz�sokJJT l��z{�tz�so{|�tykw y{now1 LtzkwwÞ. z{�o �sk� �so
{|�tykw y{now Ðt�s αB3|~{�tno€ kr{{n kmm{�z� {q�soltk€ tz�soltzk~Þ mk€o. l��n~kyk�t/
mkwwÞ {�o~|~ontm�€ t�tz�so�~tzk~Þ mk€o1
Ltr;G€s{Ð€ �sk� �sok�o~kro |~{lkltwt�Þ {qms{{€tzr �sowoq�t�oy tzm~ok€o€ €�l€�kz�tkwwÞ
Ðt�s t�€{�o~kww ~owk�t�o qtðk�t{z �tyo1 F€loq{~o. tzm{y|k~t€{z Ðt�s �sokJJT. �so{|�tykw
y{now |~{�tno€ lo��o~ mk|��~o€ �soq�ww€�~ozr�s {q�soltk€ tz�so�~tzk~Þ mk€o. l���zno~|~o/
ntm�€ �sooqqom� tz�soltzk~Þ mk€o1 \so {|�tykw y{now Ðt�s αqtðon �{þo~{ |o~q{~y€ lo€� tz
l{�s mk€o€1 U{�o �sk� �soqt�{q�sokJJT t€z{�k€mw{€o k€q{~€tytwk~ qtr�~o€ tz�so{~trtzkw
|k|o~€ lomk�€o Ðo€ty�wk�o kwwy{now€ Ðt�s �so{l€o~�on ~k�tzr€ *~k�so~ �skz kww|{€€tlwo m{y/
ltzk�t{z {qt�oy ~k�tzr€+ kzn Ðom{z€tno~ kwk~ro~ ~kzro {qqtzkw �tyo kn�kz�kro1 _o~o|wtmk�o
�so{~trtzkw kJJT qtr�~o€ tz[4F||ozntð1
LtzkwwÞ. Ltr;I€s{Ð€ �sk� �so|~{lkltwt�Þ {qms{{€tzr �soqt~€� qtðk�on t�oy tzm~ok€o€ Ðt�s
�son�~k�t{z {q�soqt~€� qtðk�t{z1 Oy|{~�kz�wÞ. �st€qtr�~o €s{Ð€ �sk� �sok��oz�t{z/ms{tmo m{~~o/
wk�t{z mkzz{� looð|wktzon €{wowÞ lÞ�so�oznozmÞ �{ms{{€o �sowk€�/qtðk�on t�oy1 Frktz. kww
q{�~ y{now€ }�kwt�k�t�owÞ mk|��~o �sooqqom�. Ðt�s �k~Þtzr nor~oo€ {q}�kz�t�k�t�o qt�1
Jt�m���t{z
_osk�o l�tw� ky{now {q{|�tykw tzq{~yk�t{z €ky|wtzr n�~tzr €ty|wo ms{tmo tz{~no~ �{
tz�o€�trk�o �sooð�oz� �{Ðstms t�mkz|~{�tno k}�kz�t�k�t�o kmm{�z� {qqtðk�t{z |k��o~z€. kzn
�sot~ ~owk�t{z€st| Ðt�s ms{tmo€. n�~tzr ltzk~Þ kzn �~tzk~Þ nomt€t{z€1 \so y{now t€lk€on {z
|~o�t{�€ Ð{~v €s{Ðtzr �sk� €ty|wo ms{tmo€ k~olk€on {z�so€o}�oz�tkw kmm�y�wk�t{z {qz{t€Þ
�kw�o €ky|wo€ d4.77.:4˘:7f kzn �sk� �so|~{mo€€ t€y{n�wk�on lÞ�t€�kw k��oz�t{z d;.=.43.4;.
53.54.:9f1 N{Ðo�o~. tz€�okn {q|~{|{€tzr k€|omtqtm kwr{~t�sytm y{now {q�soqtðk�t{z kzn
ms{tmo |~{mo€€. k€t€m{yy{z tz�sowt�o~k��~o. {�~q{m�€ sk€looz {zmsk~km�o~tþtzr �so{|�t/
ykw qtðk�t{z |{wtmÞ kzn t�€ty|wtmk�t{z€1 _ol�twn {z|~o�t{�€ Ð{~v {z{|�tykw om{z{ytm
nomt€t{z/ykvtzr tzÐstms €ky|wo€ k~okm}�t~on q{~kww{|�t{z€ k��so€kyo ~k�o d73. 77˘7:f.
kzn oð�ozn t��{�somk€o {qozn{roz{�€ k��oz�t{z. Ðso~o �sonomt€t{z ykvo~ mkzm{z�~{w �so
~k�o {qtzq{~yk�t{z km}�t~on kl{�� okms {|�t{z1 _oq{~ykwtþon �so€owom�t{z {qqtðk�t{z€ k€k
|~{lwoy {qnÞzkytmkwwÞ kww{mk�tzr km{€�wÞ m{rzt�t�o ~o€{�~mo tz{~no~ �{rktz tzq{~yk�t{z
kl{�� �so�kw�o€ {q�sok�ktwklwo {|�t{z€1 So�o~krtzr �{{w€ q~{y yo�k~ok€{ztzr tzk~�tqtmtkw
tz�owwtrozmo d93˘96f. Ðok||~{ðtyk�on �so{|�tykw €{w��t{z �{�st€|~{lwoy. Ðstms �kvo€ �so
q{~y {qk|{wtmÞ �sk� €owom�€ Ðstms t�oy �{qtðk�o k�okms y{yoz� kzn Ðsoz �{�o~ytzk�o �so
nomt€t{z/ykvtzr |~{mo€€1
PLOS COMP UTATIONAL  BIOLOGYLt�k�t{z |k��o~z� tz�ty|wo ms{tmo ~oqwom� {|�tykw tzq{~yk�t {z�ky|wtzr
WSV[ I{y|��k�t{zk wGt{w{r� �s��|�>2 2n{t1{~r243146 ;42u{�~zkw1| mlt1433<<:6 Tk~ms 5:.5354 4925=
_oq{�zn �sk�. no€|t�o t�€€ty|wtmt�Þ. �so{|�tykw y{now kmm{�z�€ q{~ykzÞ voÞqtðk�t{z kzn
ms{tmo |k��o~z€ tz�Ð{tzqw�oz�tkw ltzk~Þ kzn �~tzk~Þ ms{tmo nk�k€o�€ d=.43f1 \so y{now Ðk€
kw€{ klwo �{kmm{�z� q{~€�~tvtzr ntqqo~ozmo€ lo�Ðooz �so�Ð{/ kzn �s~oo/t�oy mk€o€ �€tzr k
m{yy{z €o�{q|k~kyo�o~€ qt��on {��{q€ky|wo1 T{~o ty|{~�kz�wÞ. �so~o€�w�€ |~{�tno o�tnozmo
tzqk�{~ {q�sosÞ|{�so€t€ �sk� �soqtðk�t{z |~{mo€€ t€tzqw�ozmon lÞ�soo�{w�tzr �kw�o o€�tyk�o€.
k�wok€� �{€{yo oð�oz�1 I{z€tno~. q{~oðky|wo. �sotzm~ok€o tzqtðk�t{z n�~k�t{z {�o~ �som{�~€o
{q�so�~tkw €s{Ðz tzLtr7I.�so�oznozmÞ �{o}�k�o qtðk�t{z �tyo km~{€€ t�oy€ *Ltr 9G+. kzn �so
~owk�t{z€st| lo�Ðooz �so~k�tzr {q�soqt~€� qtðk�on t�oy kzn �so|~{lkltwt�Þ {q~o/qtðk�tzr t�*Ltr
:Jkzn :K+1 \so€o oqqom�€ k~ooð|wktzon lÞ{�~y{now. l��k~osk~n �{oð|wktz Ðt�s oð{roz{�€
qtðk�t{z€. {~Ðt�s qtðk�t{z€ �sk� k~om{~~owk�on Ðt�s �so�~�o �kw�o {q�sot�oy€. l��z{�Ðt�s �so
o�{w�tzr �kw�o o€�tyk�o€ *o1r1. k€tzd4;. 4<.::f+1
V|�tykw tzq{~yk�t{z €ky|wtzr y{now€ ykÞ k||ok~ tzk||~{|~tk�o q{~�kw�o/lk€on nomt€t{z/
ykvtzr |~{lwoy€. tzÐstms |o~mo|��kw �zmo~�ktz�Þ kl{�� �sotnoz�t�Þ {q�sontqqo~oz� ms{tmo
t�oy€ *{q�oz strswÞ qkytwtk~ u�zv q{{n€+ t€wtvowÞ ~o€{w�on w{zr loq{~o kms{tmo t€ykno1 \Ð{
qok��~o€ {q�soy{now kyowt{~k�o �st€m{zmo~z1 Lt~€�. �so€ky|wo€ �zno~wÞtzr �kw�o/lk€on nomt/
€t{z€ k~oz{��kvoz q~{y �sooð�o~zkw nt€|wkÞ *k€tz|o~mo|��kw nomt€t{z€+. l��k~otz€�okn roz/
o~k�on tz�o~zkwwÞ. |o~sk|€ lÞ€{yo m{yltzk�t{z {qyoz�kw €ty�wk�t{z kzn yoy{~Þ ~omkww d7;˘
7=f1 [om{zn. �soy{now ykvo€ �soeye-mind k€€�y|�t{z d49. :;f> Ðsk� k|o~€{z t€w{{vtzr k�t€
kr{{n tzntmk�{~ {qÐsk� �soÞ k~o�stzvtzr kl{��1 Oy|{~�kz�wÞ. �so€o k€€�y|�t{z€ ty|wtmt�wÞ
�zno~wto kww€o}�oz�tkw €ky|wtzr y{now€ {q�kw�o/lk€on nomt€t{z/ykvtzr1
V�~ y{now t€z{��soqt~€� �{|~{|{€o �sk� �soqtðk�t{z kzn �kw�o/o€�tyk�t{z |~{mo€€o€ ytrs�
tz�o~km� ~omt|~{mkwwÞ1 N{Ðo�o~. z{|~o�t{�€ y{now€ q�wwÞ mk|��~o �sovoÞmsk~km�o~t€�tm€ {q{|�t/
ykw k��oz�t{z kww{mk�t{z. Ðstms k||ok~ �{lok�wok€� k||~{ðtyk�on tzs�ykz qtðk�t{z losk�t{~1
L{~oðky|wo. �soMkþo Ik€mkno T{now d:f|~{|{€o€ �sk� wk�otzk�~tkw €�luom�€ w{mv/tz qtðk�t{z€
{z�soqk�{~on {|�t{z �z�tw kms{tmo t€ykno. d53f |~{|{€o kzkJJT tzÐstms �so|~{lkltwt�Þ
{qqtðk�tzr kzt�oy t€rt�oz lÞk€{q�ykð {�o~ �soo€�tyk�on �kw�o€. kzn d54f |~{|{€o kGkÞo€tkz
y{now {qltzk~Þ ms{tmo tzÐstms qtðk�t{z€ k~on~t�oz lÞ~owk�t�o �zmo~�ktz�Þ1 Ozm{z�~k€� �{
�so€o y{now€. �so{|�tykw y{now |~ontm�€ �sk� qtðk�t{z€ k~on~t�oz lÞkm{yltzk�t{z {q�soo€�t/
yk�on �zmo~�ktz�Þ kzn ~owk�t�o �kw�o€ �s~{�rs{�� �so�~tkw. kzn �sk� k��oz�t{z t€no�{�on €|omtq/
tmkwwÞ �{�sot�oy€ Ðt�s �so�{|�Ð{�kw�o o€�tyk�o€1 Fw�s{�rs �sonk�k |~o€oz�on so~o €�~{zrwÞ
€�||{~� �soqt~€� |~ontm�t{z. q�~�so~ nk�k k~ozomo€€k~Þ �{nt€�tzr�t€s lo�Ðooz �so�{|/�Ð{ ~�wo
kzn �so€{q�ykð ~�wo {qd53f1
V�~ ~o€�w�€ €son q�~�so~ wtrs� {z�soyomskzt€y€ �zno~wÞtzr �somwk€€tm k��oz�t{z/ms{tmo
m{~~owk�t{z �sk� sk€y{�t�k�on |~o�t{�€ y{now€ {qk��oz�t{z/y{n�wk�on €ty|wo ms{tmo1 Lt~€�.
{�~~o€�w�€ strswtrs� kzty|{~�kz� ~{wo {q|~t{~ lowtoq€ tz€o}�oz�tkw €ky|wtzr y{now€ {q€ty|wo
ms{tmo *m1q1 d:<f+1 Fww|~o�t{�€ y{now€ sk�o k€€�yon k|~t{~ yokz {qþo~{. ot�so~ oð|wtmt�wÞ d54.
:<f{~ty|wtmt�wÞ d=.43.53f1 [�ms k|~t{~ t€zork�t�owÞ ltk€on Ðsoz kww{~y{€� t�oy€ sk�o |{€t/
�t�o�kw�o. k€t€{q�oz �somk€o tzoð|o~tyoz�kw €o��tzr€1 \st€ ltk€ t€m~t�tmkw tzoð|wktztzr �so
mwk€€tm k��oz�t{z/ms{tmo m{~~owk�t{z oqqom�€ lomk�€o t�m~ok�o€ kzo�/|{€t�t�o oqqom� {qk��oz�t{z
{zms{tmo> tq{zolortz€ Ðt�s kz�zno~o€�tyk�o. k��ozntzr �{kzt�oy Ðtww{zk�o~kro tzm~ok€o
t�€o€�tyk�on �kw�o1 N{Ðo�o~. Ðoq{�zn �sk� �solo€� msk~km�o~tþk�t{z {q�soq�wwlosk�t{~ Ðk€
kmsto�on Ðt�s ky{no~k�owÞ ltk€on |~t{~. l{�s tz�o~y€ {q{�~k||~{ðtyk�o wtvowts{{n kzn tz
�soq�ww€o�{qlosk�t{~kw |k��o~z€ tz�so|w{�€1
V�~ ~o€�w�€ kw€{ €�rro€� kz{�so~ *z{� y���kwwÞ oðmw�€t�o+ yomskzt€y lÞÐstms �sok��oz/
�t{z/ms{tmo m{~~owk�t{z mkzoyo~ro> �kw�o/nt~om�on k��oz�t{z1 _oq{�zn �sk� �so{|�tykw
y{now Ðt�s z{|~t{~ ltk€ *αB4+|~ontm�€ kzk��oz�t{z/ms{tmo m{~~owk�t{z tz�so�~tzk~Þ ms{tmo
mk€o1 \st€ t€lomk�€o. m{z�~{wwtzr q{~�~�o �kw�o€. kztzm~ok€o tzo€�tyk�on �kw�o *o1r1. n�o�{
€ky|wo z{t€o+ ykvo€ �soy{now y{~o wtvowÞ �{l{�s qtðk�o kzn ms{{€o kzt�oy1 \st€ m{�wn
|{�oz�tkwwÞ sow| �{~o€{w�o �sonolk�o {�o~ knnt�t�o �€1y�w�t|wtmk�t�o oqqom�€ {qk��oz�t{z {z
PLOS COMP UTATIONAL  BIOLOGYLt�k�t{z |k��o~z� tz�ty|wo ms{tmo ~oqwom� {|�tykw tzq{~yk�t {z�ky|wtzr
WSV[ I{y|��k�t{zk wGt{w{r� �s��|�>2 2n{t1{~r243146 ;42u{�~zkw1| mlt1433<<:6 Tk~ms 5:.5354 4:25=
ms{tmo d44. 46f1 _stwo �so|~t{~/ltk€ yomskzt€y |~ontm�€ ky�w�t|wtmk�t�o oqqom�. �so�kw�o/
nt~om�on k��oz�t{z yomskzt€y |~ontm�€ �sk� qtðk�t{z �tyo kzn ms{tmo Ðtwwlont~om�wÞ ~owk�on *k€
|~ontm�on lÞ�soknnt�t�o y{now+1 Fw�s{�rs Ðontnz{�€oo€�~{zr o�tnozmo q{~�kw�o/nt~om�on
k��oz�t{z tz�soltzk~Þ nk�k€o�. €�ms kltk€ sk€looz €s{Ðz tzoð|wtmt� tzq{~yk�t{z rk�so~tzr
€o��tzr€ d:=f kzn m{�wn lok�Ð{~v tz{�so~ ltzk~Þ ms{tmo €o��tzr€1
V�~ Ð{~v y{€� mw{€owÞ ~owk�o€ �{�Ð{~omoz� wtzo€ {qÐ{~v {z{|�tykw tzq{~yk�t{z €ky|wtzr
q{~€ty|wo ms{tmo1 Lt~€�. No�lo~� kzn _{{nq{~n d;3. ;4fm{z€tno~ €o}�oz�tkw €ky|wtzr y{now€
lk€on {z~k�t{zkw tzk��oz�t{z1 \soÞ no~t�o {|�tykw €ky|wtzr €�~k�orto€ �zno~ strswÞ rozo~kw
tzq{~yk�t{z/�so{~o�tm m{z€�~ktz�€. kzn o€�klwt€s €o�o~kw tz�o~o€�tzr |~{|o~�to€ {q{|�tykw €ky/
|wtzr. €�ms k€�som{znt�t{z€ �zno~ Ðstms �soo�tnozmo kmm�y�wk�t{z Ðtww~o€oylwo ku�y| {~
kntqq�€t{z |~{mo€€1 Oz�sot~ q~kyoÐ{~v. �sonomt€t{z ykvo~ ms{{€o€. k�okms �tyo |{tz�. kz
k~lt�~k~Þ information structure. �so|~{lkltwt�Þ {q|~{n�mtzr okms |{€€tlwo €trzkw �zno~ ntqqo~/
oz��~�o €�k�o€ {q�soÐ{~wn1 Ozm{z�~k€�. Ðo€|omtqÞ k�o~Þ €ykww €o�{qtzq{~yk�t{z €�~�m��~o€.
okms {qÐstms m{~~o€|{zn€ �{€ky|wtzr kz{t€Þ o€�tyk�o {q{zot�oy)€ �kw�o *K}4+1\st€ zk��/
~kwwÞ k€€{mtk�o€ okms tzq{~yk�t{z €�~�m��~o Ðt�s qtðk�tzr {z{zo{q�sot�oy€. kww{Ðtzr �€�{
m{y|k~o y{now |~ontm�t{z€ �{s�ykz qtðk�t{z |k��o~z€1 _so�so~ s�ykz k��oz�t{z y{~o
mw{€owÞ ~o€oylwo€ qwoðtlwo m{z€�~�m�t{z {qnÞzkytm tzq{~yk�t{z €�~�m��~o€. {~€owom�t{z q~{y k
€ykww €o�{qqtðon tzq{~yk�t{z €�~�m��~o€ t€kztz�o~o€�tzr }�o€�t{z q{~q���~o ~o€ok~ms1
Ozk€om{zn wtzo{qÐ{~v. m{zm�~~oz� �{{�~{Ðz. Qkzr. [sk~yk. kzn J~�r{Ðt�€ms d:<f
no�ow{| ky{now {q{|�tykw tzq{~yk�t{z €ky|wtzr q{~ltzk~Þ ms{tmo Ðt�s �so€kyo GkÞo€tkz
€�~�m��~o k€{�~y{now kzn m{y|k~o �sot~ |~ontm�t{z€ �{s�ykz losk�t{~ tz�so€kyo ltzk~Þ
ms{tmo nk�k€o� �sk� Ðo�€od=f1\so~o k~o�s~oo ty|{~�kz� ntqqo~ozmo€ lo�Ðooz �so€��nto€1 Lt~€�.
�soÞ m{z€tno~ �so|{€€tltwt�Þ �sk� €ky|wo€ mkzkw€{ lon~kÐz tz|k~kwwow q{~�so�zk��oznon
t�oy. l��Ðt�s strso~ �k~tkzmo1 N{Ðo�o~. �soÞ qtzn �sk� ky{now tzÐstms kwy{€� z{tzq{~yk/
�t{z t€km}�t~on q{~�so�zk��oznon t�oy qt�€�sonk�k lo€�. m{z€t€�oz� Ðt�s �sok€€�y|�t{z€ {q
{�~y{now1 [om{zn. �soÞ �€onÞzkytm |~{r~kyytzr �{tnoz�tqÞ �so{|�tykw k��oz�t{z |{wtmÞ
kwy{€� oðkm�wÞ1 \st€ kww{Ð€ �soy �{y{~o kmm�~k�owÞ msk~km�o~tþo �~�wÞ {|�tykw k��oz�t{z kww{mk/
�t{z1 N{Ðo�o~. nÞzkytm |~{r~kyytzr t€tz�~km�klwo q{~y{~o �skz �Ð{t�oy€. n�o�{�som�~€o
{qntyoz€t{zkwt�Þ1 \s�€. �soÞ m{�wn z{�m{z€tno~ �~tzk~Þ ms{tmo. Ðstms t€{q€|omtkw tz�o~o€�
lomk�€o {zwÞ �st€mk€o ykvo€ �kw�o/nt~om�on k��oz�t{z {|�tykw. kzn q{~mo€ �sonomt€t{z/ykvo~
�{nomtno Ðstms {q�so�zk��oznon t�oy€ �{qtðk�o zoð�. ~k�so~ �skz €ty|wÞ Ðsoz �{€Ðt�ms �{
�so{�so~ t�oy1 \st~n. �soÞ k€€�yon *q{ww{Ðtzr |~o�t{�€ Ð{~v+ �sk� �so|~t{~ yokz t€þo~{1 Oz
m{z�~k€�. lÞ�k~Þtzr �so|~t{~. Ðo€s{Ð �sk� kw�s{�rs kltk€on |~t{~ t€zoonon �{kmm{�z� q{~
�sok��oz�t{z/ms{tmo m{~~owk�t{z tzltzk~Þ ms{tmo. �sonk�k t€lo€� oð|wktzon lÞky{now Ðt�s
{zwÞ ky{no~k�owÞ ltk€on |~t{~ yokz. kl{�� skwqÐkÞ lo�Ðooz þo~{ kzn �sooy|t~tmkw yokz1
_omkzkw€{ n~kÐ tz€trs�€ q~{y �sooy|t~tmkw |k��o~z€ �sk� �soy{now qktw€ �{mk|��~o1 \so€o
yt€yk�mso€ €�rro€� �sk� �soy{now. Ðstms Ðk€no€trzon �{lok€€ty|wo k€|{€€tlwo. t€yt€€tzr
m~t�tmkw m{y|{zoz�€ �sk� €s{�wn looð|w{~on tzq���~o Ð{~v1 L{~oðky|wo. �so�zno~|~ontm�t{z
{qqtðk�t{z n�~k�t{z€ ok~wÞ tz�so�~tkw m{�wn loknn~o€€on lÞy{~o ~okwt€�tm m{z€�~ktz�€ {z�so
qtðk�t{z |~{mo€€ €�ms k€tzstlt�t{z {q~o��~z. kzn �so{�o~|~ontm�t{z {q�so|~{|{~�t{z {q€tz/
rwo/qtðk�t{z �~tkw€ tz�so�Ð{/t�oy mk€o m{�wn looð|wktzon Ðt�s �zmo~�ktz�Þ k�o~€t{z1 Fw�s{�rs
z{�tww�€�~k�on so~o. �soy{now)€ kmm�~kmÞ m{�wn loq�~�so~ ty|~{�on lÞtzmw�ntzr l{��{y/�|
tzqw�ozmo€ {zqtðk�t{z€ *o1r1. €|k�tkw {~€kwtozmÞ ltk€o€ d4<. ;5f+1
_stwo Ðosk�o q{m�€on {zk��oz�t{z tz€ty|wo ms{tmo. {�so~ €��nto€ sk�o oð|w{~on �so~{wo
{qk��oz�t{z tzy{~o m{y|wtmk�on y�w�t/k��~tl��o ms{tmo€ d9.;6˘<5f1 U{zo {q�so€o €��nto€
sk�o mk~~ton {��kq�wwmsk~km�o~tþk�t{z {q�so{|�tykw €ky|wtzr |~{mo€€ {~s{Ð t�m{y|k~o€ �{
{l€o~�on qtðk�t{z |k��o~z€. kw�s{�rs €ood<6. <7fq{~€{yo ~owk�on ~o€�w�€1 Kð�ozntzr �soyo�s/
{n€tz�st€|k|o~ �{�sk� ty|{~�kz� mk€o t€k|~t{~t�Þ q{~q���~o Ð{~v1 LtzkwwÞ. tzm{z�~k€� �{
ykzÞ €o}�oz�tkw €ky|wtzr y{now€. {�~y{now t€z{�tz�oznon k€klt{w{rtmkwwÞ |wk�€tlwo |~{mo€€
PLOS COMP UTATIONAL  BIOLOGYLt�k�t{z |k��o~z� tz�ty|wo ms{tmo ~oqwom� {|�tykw tzq{~yk�t {z�ky|wtzr
WSV[ I{y|��k�t{zk wGt{w{r� �s��|�>2 2n{t1{~r243146 ;42u{�~zkw1| mlt1433<<:6 Tk~ms 5:.5354 4;25=
y{now {qs{Ð �sol~ktz km��kwwÞ ykvo€ nomt€t{z€1 Kð|w{~tzr s{Ð �sol~ktz ytrs� k||~{ðtyk�o
�so{|�tykw €ky|wtzr |{wtmÞ |~o€oz�on so~o. kzn kw€{ s{Ð {|�tykw €ky|wtzr ytrs� mskzro
�zno~ kmm�y�wk�t{z yomskzt€y€ €�ms k€nomkÞ kzn tzstlt�t{z t€kz{�so~ |~t{~t�Þ q{~q���~o
Ð{~v1
To�s{n�
\so y{now Ðk€ty|woyoz�on tz�soQ�wtk |~{r~kyytzr wkzr�kro d<9f1 \so m{no mkzloq{�zn
k�s��|€>22rt�s�l1m{y2q~onmkwwkÐkÞ2{ |�tykw/qtðk�t{z€/€ty|wo/ms{tm o1
F��oz�t{z kww{mk�t{z k€kyo�kwo�ow Tk~v{� nomt€t{z |~{mo€€
\{msk~km�o~tþo {|�tykw k��oz�t{z kww{mk�t{z tz{�~y{now. Ðomk€� �soy{now k€kyo�kwo�ow
Tk~v{� nomt€t{z |~{mo€€ *TJW+ d95f1 Stvo k€�kznk~n TJW. kyo�kwo�ow TJW t€noqtzon lÞk
€o�{q€�k�o€. k€o�{qkm�t{z€. k�~kz€t�t{z q�zm�t{z rt�tzr �so|~{lkltwt�Þ {qy{�tzr �{okms €�k�o
lÞoðom��tzr krt�oz km�t{z tzkrt�oz €�k�o. kzn k~oÐk~n q�zm�t{z rt�tzr �sotyyontk�o ��twt�Þ
rktzon lÞoðom��tzr krt�oz km�t{z tzkrt�oz €�k�o1 Ozkyo�kwo�ow TJW. �so€�k�o€.B.m{~~o/
€|{zn �{lowtoq€ *yoz�kw €�k�o€+. kzn �sokm�t{z€.C.m{~~o€|{zn �{m{y|��k�t{z€ *m{rzt�t�o
{|o~k�t{z€+1 N{Ðo�o~. q{~ykwwÞ. t�t€tnoz�tmkw �{kzTJW. kzn mkzlotz�o~|~o�on k€€�ms1
Oz{�~y{now. klowtoq €�k�o.b9B.m{~~o€|{zn€ �{k€o�{q|{€�o~t{~ nt€�~tl��t{z€ {�o~ okms
t�oy)€ �kw�o1 Gomk�€o �sont€�~tl��t{z€ k~oMk�€€tkz. �solowtoq mkzlo~o|~o€oz�on lÞ�Ð{�om/
�{~€.μkzn λ.�sk� €|omtqÞ �soyokz kzn |~omt€t{z {qokms nt€�~tl��t{z1 \sk� t€
puiybGaussianuiCwiC7
�iE
\{y{now �so€Ðt�mstzr m{€�. �solowtoq €�k�o y�€� kw€{ ozm{no �som�~~oz�wÞ k��oznon t�oy. t1o1.
�sot�oy €ky|won wk€�*�kvtzr kz�ww �kw�o.�.tz�sotzt�tkw lowtoq+1 \s�€. klowtoq t€k��|wobtB
*μt.λt.wk€�t+1\so ntyoz€t{zkwt�Þ {q�solowtoq €|kmo t€5N-4Ðso~oNt€�soz�ylo~ {qt�oy€1
Fm{y|��k�t{z. c9C.m{~~o€|{zn€ �{€ky|wtzr kzt�oy)€ �kw�o kzn �|nk�tzr �som{~~o/
€|{zntzr o€�tyk�on �kw�o nt€�~tl��t{z1 \so~o k~oN€�ms m{y|��k�t{z€. {zoq{~okms t�oy1
Fnnt�t{zkwwÞ. kwwyo�kwo�ow TJW€ sk�o k€|omtkw m{y|��k�t{z.G�sk� �o~ytzk�o€ �som{y|��k/
�t{z |~{mo€€ *tz{�~mk€o. €ky|wtzr+ kzn €owom�€ kz{|�tykw oð�o~zkw km�t{z rt�oz �som�~~oz�
lowtoq €�k�o *tz{�~mk€o. ms{{€tzr �sot�oy Ðt�s ykðtykw |{€�o~t{~ yokz+1
\so yo�kwo�ow �~kz€t�t{z q�zm�t{z no€m~tlo€ s{Ð m{y|��k�t{z€ �|nk�o lowtoq€1 Oz{�~
y{now. �st€m{~~o€|{zn€ �{�so€ky|wtzr kzn GkÞo€tkz lowtoq �|nk�tzr |~{mon�~o €|omtqton tz
K}5.Ðstms Ðo~o|~{n�mo so~o q{~�so~okno~)€ m{z�oztozmo1 U{�o �sk� Ðoknnt�t{zkwwÞ ykvo
oð|wtmt� �so�k~tklwo �sk� �~kmv€ �so|~o�t{�€wÞ €ky|won t�oy1 Mt�oz �som�~~oz� lowtoq.btB*μt.
λt.wk€�t+.kzn m{y|��k�t{z. c.�sozoð� lowtoq €�k�o.bt-4B*μt-4.λt-4.wk€�t-4+.t€€ky|won q~{y
�soq{ww{Ðtzr rozo~k�t�o |~{mo€€>
xt�GaussianucC~9
x
�c
t7�c
t~9
x
wc
t7~9
xxt�c
twc
t
�c
t7
�i
t7�i
tand wi
t7wi
tfori=cB
lastt7c:
PLOS COMP UTATIONAL  BIOLOGYLt�k�t{z |k��o~z� tz�ty|wo ms{tmo ~oqwom� {|�tykw tzq{~yk�t {z�ky|wtzr
WSV[ I{y|��k�t{zk wGt{w{r� �s��|�>2 2n{t1{~r243146 ;42u{�~zkw1| mlt1433<<:6 Tk~ms 5:.5354 4<25=
LtzkwwÞ. �soyo�kwo�ow ~oÐk~n q�zm�t{z tzm{~|{~k�o€ l{�s �som{€� {qm{y|��k�t{z kzn �so
��twt�Þ {q�soms{€oz km�t{z1 \so yo�kwo�ow ~oÐk~n q{~€ky|wtzr t€noqtzon
RbtCctcostbtCctqsample7lastt=�kct=lasttqswitchB
\sk� t€.�som{€� {q€ky|wtzr tzmw�no€ kqtðon m{€�. γ€ky|wo .k€Ðoww k€kzknnt�t{zkw €Ðt�mstzr
m{€�. γ€Ðt�ms .�sk� t€|ktn Ðsoz €ky|wtzr q~{y kntqqo~oz� t�oy �skz �sk� €ky|won {z�sowk€�
�tyo €�o|1 _ok€€�yo �sk� �st€m{€� t€z{�|ktn q{~�soqt~€� qtðk�t{z? s{Ðo�o~. �st€k€€�y|�t{z
sk€z{oqqom� {z�so{|�tykw |{wtmÞ q{~~ok€{zklwo |k~kyo�o~ �kw�o€1 \so km�t{z ��twt�Þ t€�so
�~�o �kw�o {q�soms{€oz t�oy. t1o1.ui�
TÐso~oi�
Targmax
iwi
T1\so yo�kwo�ow ~oÐk~n q{~�so
�o~ytzk�t{z m{y|��k�t{z.G.t€�sooð|om�k�t{z {q�st€�kw�o1 Gomk�€o Ðok€€�yo kmm�~k�o |~t/
{~€kzn GkÞo€tkz lowtoq �|nk�tzr. �st€oð|om�k�t{z mkzlo�kvoz Ðt�s ~o€|om� �{�sokroz�)€ {Ðz
lowtoq€ d95f. ~o€�w�tzr tz
RbtCGEui�
Tybtmax
iwi
tB
V|�tykw yo�kwo�ow |{wtmÞ
\so €{w��t{z �{kyo�kwo�ow TJW �kvo€ �soq{~y {qkTk~v{� |{wtmÞ.π.�sk� €�{msk€�tmkwwÞ
€owom�€ Ðstms m{y|��k�t{z �{�kvo zoð� rt�oz �som�~~oz� lowtoq €�k�o1 L{~ykwwÞ. ct+π*bt+1\so
{|�tykw yo�kwo�ow |{wtmÞ.π�.t€�so{zo�sk� ykðtytþo€ oð|om�on �{�kw yo�kwo�ow ~oÐk~n.
{�argmax
{EdT
tRbtCctyct�{bt& ’
B
Zo|wkmtzr RÐt�s t�€noqtzt�t{z. Ðo€oo�sk� �st€~o}�t~o€ €�~tvtzr klkwkzmo lo�Ðooz �so
oð|om�on �kw�o {q�soms{€oz t�oy kzn �som{y|��k�t{zkw m{€� {q�so€ky|wo€ �sk� tzq{~yon �so
ms{tmo.
{�argmax
{Emax
iwi
TdT7
tcostbtCctyct�{bt& ’
B
\sk� t€.{zoÐt€so€ �{km}�t~o kmm�~k�o lowtoq€ �sk� €�||{~� €owom�tzr kstrs/�kw�o t�oy. Ðstwo k�
�so€kyo �tyo ytztytþtzr �som{€� {q�so€ky|wo€ zomo€€k~Þ �{k��ktz �s{€o lowtoq€1 \st€ €�r/
ro€�€ k€�~k�orÞ q{~€owom�tzr m{y|��k�t{z€ {|�tykwwÞ1 L{~okms t�oy. o€�tyk�o s{Ð y�ms {zo)€
nomt€t{z Ð{�wn ty|~{�o tq{zo€ky|won q~{y t�*kzn �soz m{z�tz�on €ky|wtzr {|�tykwwÞ+1 [�l/
�~km� q~{y �st€z�ylo~ �som{€� {q�kvtzr �so€ky|wo *kzn kw€{ �soo€�tyk�on m{€� {q�soq���~o
€ky|wo€+1 U{Ð tnoz�tqÞ �sot�oy q{~Ðstms �st€�kw�o t€ykðtykw1 Oqt�t€|{€t�t�o. t�t€{|�tykw �{
�kvo kz{�so~ €ky|wo q{~�st€t�oy? {�so~Ðt€o. t�t€{|�tykw �{€�{| €ky|wtzr kzn ykvo k
nomt€t{z1
\st€ lk€tm w{rtm t€q{~ykwtþon tz~k�t{zkw yo�k~ok€{ztzr k€�sovalueofcomputation *^VI+
d94f1 L{~ykwwÞ. ^VI*b.c+t€noqtzon k€�sooð|om�on tzm~ok€o tz�{�kw yo�kwo�ow ~oÐk~n tq{zo
oðom��o€ k€tzrwo m{y|��k�t{z. c.kzn m{z�tz�o€ {|�tykwwÞ ~k�so~ �skz ykvtzr kms{tmo tyyo/
ntk�owÞ *t1o1. oðom��tzrG+>
VOCbtCcRbtCcEdT
t6t7Rbt6Cct6yct6�{�bt6& ’
RbCGB
PLOS COMP UTATIONAL  BIOLOGYLt�k�t{z |k��o~z� tz�ty|wo ms{tmo ~oqwom� {|�tykw tzq{~yk�t {z�ky|wtzr
WSV[ I{y|��k�t{zk wGt{w{r� �s��|�>2 2n{t1{~r243146 ;42u{�~zkw1| mlt1433<<:6 Tk~ms 5:.5354 4=25=
Oz{�~y{now. �st€mkzlo~oÐ~t��oz
VOCbtCccostbtCcEmax
iwi
TdT7
t6t7costbt6Cct6yct6�{�bt6& ’
max
iwi
tB
\sk� t€.�so^VI q{~€ky|wtzr krt�oz t�oy tz€{yo lowtoq €�k�o t€�sooð|om�on ty|~{�oyoz� tz
�so�kw�o {q�soms{€oz t�oy *~k�so~ �skz ykvtzr kms{tmo lk€on {z�som�~~oz� lowtoq+ ytz�€
�som{€� {q€ky|wtzr �sk� t�oy kzn �sooð|om�on m{€� {qkwwq���~o €ky|wo€1
_omkz�soz noqtzo �so{|�tykw |{wtmÞ k€€owom�tzr m{y|��k�t{z€ Ðt�s ykðtykw ^VI>
{�b�Uniformargmax
cVOCbCcB
L{~�s{€o qkytwtk~ Ðt�s ~otzq{~moyoz� wok~ztzr. �st€~om�~€t�o u{tz� noqtzt�t{z {qπ�kzn ^VI t€
oðkm�wÞ kzkw{r{�€ �{�sou{tz� noqtzt�t{z {q�so{|�tykw |{wtmÞ Ðt�s �so€�k�o/km�t{z �kw�o q�zm/
�t{z.Qd<:f1 Oznoon. ^VI*b.c+BQ*b.c+−R*b.G+1
LtzkwwÞ. lÞnoqtzt�t{z. ^VI*b.G+B3q{~kwwb1\s�€. �so{|�tykw |{wtmÞ �o~ytzk�o€ €ky|wtzr
Ðsoz z{m{y|��k�t{z sk€k|{€t�t�o ^VI1
F||~{ðtyk�tzr �so{|�tykw |{wtmÞ
L{~€ykww nt€m~o�o lowtoq €|kmo€. �so{|�tykw yo�kwo�ow |{wtmÞ mkzlom{y|��on oðkm�wÞ �€tzr
€�kznk~n nÞzkytm |~{r~kyytzr yo�s{n€ €�ms k€�kw�o t�o~k�t{z {~lkmvÐk~n€ tzn�m�t{z d<;f1
\so€o yo�s{n€ mkzkw€{ lok||wton �{w{Ð/ntyoz€t{zkw. m{z�tz�{�€ lowtoq €|kmo€ lÞqt~€� nt€m~o/
�tþtzr �so€|kmo {zkr~tn d79f. kzn �st€k||~{kms sk€~omoz�wÞ looz �€on �{msk~km�o~tþo �so
{|�tykw qtðk�t{z |{wtmÞ tzltzk~Þ ms{tmo d:<f1 ]zq{~��zk�owÞ. �so€o yo�s{n€ k~otzqok€tlwo tz
�so�~tzk~Þ ms{tmo mk€o. €tzmo �solowtoq €|kmo sk€€tðm{z�tz�{�€ ntyoz€t{z€1 Oz€�okn. Ðo
k||~{ðtyk�o �so{|�tykw |{wtmÞ lÞoð�ozntzr �soyo�s{n |~{|{€on tzd96f1 \st€ yo�s{n t€
lk€on {zkzk||~{ðtyk�t{z {q�so^VI k€kwtzok~ m{yltzk�t{z {qqok��~o€.
rVOCbCcCww7VOImyopicbCcw9VOIitembCcw:VOIfullbcostcw;C;
q{~kwwc=G.Ðt�srVOCbCGCwVOCbCG61
_ol~toqwÞ noqtzo �soqok��~o€ so~o. kzn |~{�tno q�wwno~t�k�t{z€ tz[4F||ozntð1 \so ^VO
�o~y€ }�kz�tqÞ �sovalueofinformation d<<f �sk� ytrs� lorktzon lÞntqqo~oz� knnt�t{zkw m{y/
|��k�t{z€1 U{�o �sk� �so^VO t€ntqqo~oz� q~{y �so^VI lomk�€o �sowk��o~ tzmw�no€ �som{€�€ {q
m{y|��k�t{z k€Ðoww k€t�€lozoqt�€1 Ozrozo~kw. �so^VO t€noqtzon k€�sooð|om�on ty|~{�oyoz�
tz�so��twt�Þ {q�sokm�t{z €owom�on lk€on {zknnt�t{zkw tzq{~yk�t{z ~k�so~ �skz �som�~~oz�
lowtoq €�k�o>E~bybR~bCGRbCG. Ðso~o ~bt€ksÞ|{�so�tmkw q���~o lowtoq tzÐstms �sotzq{~/
yk�t{z sk€looz rktzon. �sont€�~tl��t{z {qÐstms no|ozn€ {z�som�~~oz� lowtoq1
^VO yÞ{|tm *b.c+noz{�o€ �sooð|om�on ty|~{�oyoz� tzms{tmo ��twt�Þ q~{y n~kÐtzr {zoknnt/
�t{zkw €ky|wo q~{y t�oycloq{~o ykvtzr kms{tmo. k€{||{€on �{ykvtzr kms{tmo tyyontk�owÞ
lk€on {z�som�~~oz� lowtoq.b1^VO t�oy*b.c+noz{�o€ �sooð|om�on ty|~{�oyoz� q~{y wok~ztzr
�so�~�o �kw�o {qt�oyc.kzn �soz ms{{€tzr �solo€� t�oy lk€on {z�sk� tzq{~yk�t{z1 LtzkwwÞ.
^VO q�ww*b+noz{�o€ �soty|~{�oyoz� q~{y wok~ztzr �so�~�o �kw�o {qo�o~Þ t�oy kzn �soz ykv/
tzrkz{|�tykw ms{tmo lk€on {z�sk� m{y|wo�o tzq{~yk�t{z1
\{ro�so~. �so€o �s~oo qok��~o€ k||~{ðtyk�o �sooð|om�on �kw�o {qtzq{~yk�t{z �sk� m{�wn lo
rktzon lÞ�so*�zvz{Ðz+ €o}�ozmo {qq���~o €ky|wo€1 Oy|{~�kz�wÞ. �st€�~�o �kw�o {qtzq{~yk/
�t{z kwÐkÞ€ wto€lo�Ðooz �sow{Ðo~ l{�zn {q^VO yÞ{|tm kzn �so�||o~ l{�zn {q^VO q�ww*€oo Ltr
Jtz[4F||ozntð+. ty|wÞtzr �sk� �so�~�o ^VO t€km{z�oð m{yltzk�t{z {q�so€o �Ð{�o~y€1
U{�o. s{Ðo�o~. �sk� �soÐotrs�€ {z�st€m{yltzk�t{z k~oz{�m{z€�kz� km~{€€ lowtoq€. k€
PLOS COMP UTATIONAL  BIOLOGYLt�k�t{z |k��o~z� tz�ty|wo ms{tmo ~oqwom� {|�tykw tzq{~yk�t {z�ky|wtzr
WSV[ I{y|��k�t{zk wGt{w{r� �s��|�>2 2n{t1{~r243146 ;42u{�~zkw1| mlt1433<<:6 Tk~ms 5:.5354 5325=
k€€�yon tz{�~k||~{ðtyk�t{z1 \s�€. tzmw�ntzr �so^VO t�oy�o~y. ty|~{�o€ �sokmm�~kmÞ {q
�sok||~{ðtyk�t{z. lÞ|~{�tntzr kztz�o~yontk�o �kw�o lo�Ðooz �so�Ð{oð�~oyo€1 LtzkwwÞ. �so
wk€��Ð{�o~y€ tzK};k||~{ðtyk�o �som{€� {qm{y|��k�t{z> m{€�*c+ t€�som{€� {qmk~~Þtzr {��
m{y|��k�t{z ckznw7k||~{ðtyk�o€ �sooð|om�on q���~o m{€�€ tzm�~~on �zno~ �so{|�tykw |{w/
tmÞ1Fw�s{�rs ykðtytþtzrrVOCbCcCwtnoz�tqto€ �so|{wtmÞ Ðt�s �solo€� |o~q{~ykzmo. t�t€
�zwtvowÞ �sk� s�ykz€ ykvo k��oz�t{zkw nomt€t{z€ �€tzr €�ms |o~qom� kzn z{t€owo€€ ykðtytþk/
�t{z1 \s�€. Ðok€€�yo �sk� m{y|��k�t{z€ k~oms{€oz �€tzr kG{w�þykzz *€{q�ykð+ nt€�~tl��t{z
d99f rt�oz lÞ
{cybCwCk5exptkrVOCbCcCwuC
Ðso~o �sotz�o~€o �oy|o~k��~o. β.t€kq~oo |k~kyo�o~ �sk� m{z�~{w€ �sonor~oo {qz{t€o1 U{�o
�sk� m{y|��k�t{z €owom�t{z t€q�wwÞ ~kzn{y Ðsoz βB3kzn lom{yo€ no�o~ytzt€�tm k€ β%71
\{tnoz�tqÞ �soÐotrs�€ �€on tz�sok||~{ðtyk�t{z. Ðoqt~€� k€€�yo �sk�wi�3kznw4-w5
-w6B4.€tzmow4>6qok��~o€ q{~y km{z�oð m{yltzk�t{z kznw7mk|��~o€ �soz{z/zork�t�o
q���~o m{€�1 W~o�t{�€ Ð{~v d96f �€on GkÞo€tkz {|�tytþk�t{z �{tnoz�tqÞ �soÐotrs�€ Ðt�stz �st€
€|kmo �sk� ykðtytþo �{�kw oð|om�on yo�kwo�ow ~oÐk~n1 N{Ðo�o~. Ðoq{�zn �sk� {q�oz kwk~ro
k~ok {qÐotrs� €|kmo ~o€�w�on tzoð�~oyowÞ €tytwk~ |o~q{~ykzmo. no€|t�o tzn�mtzr losk�t{~kwwÞ
nt€�tzm� |{wtmto€1 W~km�tmkwwÞ. �st€ykvo€ tnoz�tqÞtzr k�zt}�o {|�tykw |{wtmÞ mskwwozrtzr. kzn
�so{~o�tmkwwÞ ÐoÐ{�wn z{�oð|om� kww|k~�tmt|kz�€ �{q{ww{Ð k€tzrwo �zt}�o |{wtmÞ Ðsoz �so~o t€
kÐtno |wk�ok� {qstrs/|o~q{~ytzr |{wtmto€1 \{knn~o€€ �st€. Ðotz€�okn tnoz�tqÞ k€o�{qzok~/
{|�tykw |{wtmto€ kzn k€€�yo �sk� s�ykz losk�t{~ Ðtwwm{zq{~y �{�sokrr~ork�o losk�t{~ {q
�st€€o�1
\{tnoz�tqÞ �st€€o�{qzok~/{|�tykw |{wtmto€. Ðok||wÞ kyo�s{n lk€on {z]||o~ I{zqtnozmo
G{�zn *]IG+ lkznt� kwr{~t�sy€ d<=f1 _olortz lÞ€ky|wtzr <333 Ðotrs� �om�{~€ �{~{�rswÞ
�ztq{~ywÞ �two�so€|kmo {q|{€€tlwo Ðotrs�€1 I{zm~o�owÞ. Ðont�tno k�s~oo/ntyoz€t{zkw sÞ|o~/
m�lo tz�{ <33B536o}�kw/€tþo l{ðo€ kzn €ky|wo k|{tz� �ztq{~ywÞ q~{y okms l{ð1 \so qt~€�
�Ð{ntyoz€t{z€ k~ol{�znon tz*3.4+kzn k~o�€on �{|~{n�mow4>6�€tzr �soq{ww{Ðtzr �~tmv>
So�x4kznx5lo�sow{Ðo~ kzn strso~ {q�so�Ð{€ky|won �kw�o€1 _o�soz noqtzow4>6Bdx4.
x5−x4.4−x5f1Oqx4kznx5k~o�ztq{~ywÞ €ky|won q~{y *3.4+.kzn tznoon �soÞ k~o.�soz �st€
|~{n�mo€ w4>6�ztq{~ywÞ €ky|won q~{y �so6/€ty|woð1 \so �st~n ntyoz€t{z |~{n�mo€ �so
q���~o m{€� Ðotrs�? Ðo€o�w7Bx6�ykðm{€� Ðso~o ykðm{€� t€�sow{Ðo€� m{€� q{~Ðstms z{m{y/
|��k�t{z sk€|{€t�t�orVOC tz�sotzt�tkw lowtoq €�k�o1 _o�soz €ty�wk�o 433nomt€t{z �~tkw€ q{~
okms {q�so~o€�w�tzr |{wtmto€. |~{�tntzr klk€owtzo wo�ow {q|o~q{~ykzmo1 ]€tzr �so€o €ty�wk/
�t{z€. Ðom{y|��o kz�||o~ m{zqtnozmo l{�zn {qokms |{wtmÞ)€ |o~q{~ykzmo o}�kw �{kwi:k~i.
Ðso~o kwikznk~ik~o�sooy|t~tmkw yokz kzn €�kznk~n no�tk�t{z€ {q�soyo�kwo�ow ~o��~z€ €ky/
|won q{~|{wtmÞi1F€�kznk~n ]IG kwr{~t�sy Ð{�wn �soz €ty�wk�o q~{y �so|{wtmÞ ykðtytþtzr
�st€�kw�o1 N{Ðo�o~. lomk�€o Ðok~otz�o~o€�on tztnoz�tqÞtzr k€o�{q|{wtmto€. Ðotz€�okn €owom�
�so�{|<3*t1o14&{q+|{wtmto€ kzn €ty�wk�o 43knnt�t{zkw �~tkw€ q{~okms. �|nk�tzr kwikznk~iq{~
okms {zo1 _ot�o~k�o �st€€�o| 9333 �tyo€1 LtzkwwÞ. Ðo€owom� �so<3|{wtmto€ Ðt�s �sostrso€�
oð|om�on |o~q{~ykzmo k€{�~msk~km�o~tþk�t{z {q{|�tykw losk�t{~ tz�soyo�kwo�ow TJW1 \{
owtytzk�o �so|{€€tltwt�Þ {qqt��tzr z{t€o tz�so{|�tytþk�t{z |~{mon�~o. Ðo�€o{zo€o�{q|{wt/
mto€�{m{y|��o �sowtvowts{{n {z�so�~ktztzr nk�k kzn ~o/{|�tytþo kzoÐ €o�{q|{wtmto€ �{roz/
o~k�o |w{�€ kzn m{y|��o �sowtvowts{{n {q�so�o€�nk�k1 U{�o �sk� Ðo�€o�sol{ð€ky|wtzr
yo�s{n no€m~tlon tz�so|~o�t{�€ |k~kr~k|s ~k�so~ �skz kno�o~ytzt€�tm w{Ðnt€m~o|kzmÞ €ky/
|wtzr €�~k�orÞ d=3f €{�sk� �so€o�{q|{wtmto€ m{z€tno~on k~oz{�oðkm�wÞ �so€kyo tz�soqt��tzr
kzn o�kw�k�t{z €�kro€1
N{Ð r{{n t€�sok||~{ðtyk�t{z yo�s{nD W~o�t{�€ Ð{~v q{�zn �sk� �st€k||~{kms rozo~k�o€
zok~/{|�tykw |{wtmto€ {zk~owk�on |~{lwoy. Ðt�s Go~z{�wwt/nt€�~tl��on €ky|wo€ kzn z{
PLOS COMP UTATIONAL  BIOLOGYLt�k�t{z |k��o~z� tz�ty|wo ms{tmo ~oqwom� {|�tykw tzq{~yk�t {z�ky|wtzr
WSV[ I{y|��k�t{zk wGt{w{r� �s��|�>2 2n{t1{~r243146 ;42u{�~zkw1| mlt1433<<:6 Tk~ms 5:.5354 5425=
€Ðt�mstzr m{€�€ d96f1 U{�o �sk� tz�somk€o {qGo~z{�wwt €ky|wo€. �solowtoq €|kmo t€nt€m~o�o kzn
�s�€ �so{|�tykw |{wtmÞ mkzlom{y|��on oðkm�wÞ tqkz�||o~ l{�zn t€|wkmon {z�soz�ylo~ {q
m{y|��k�t{z€ �sk� mkzlo|o~q{~yon loq{~o ykvtzr knomt€t{z1 Fw�s{�rs tz�~{n�mtzr €Ðt�ms/
tzrm{€�€ ykvo€ �soyo�k~ok€{ztzr |~{lwoy y{~o mskwwozrtzr �{€{w�o. tz�soGo~z{�wwt mk€o
Ðosk�o q{�zn �sk� �soÞ {zwÞ tzn�mo ky{no€� ~on�m�t{z tz�so|o~q{~ykzmo {q�sok||~{ðtyk/
�t{z yo�s{n ~owk�t�o �{�soq�ww{|�tykw |{wtmÞ. kmsto�tzr =5& {q{|�tykw ~oÐk~n tz�soÐ{~€�
mk€o *€oo [4F||ozntð q{~no�ktw€+1 \st€ €�rro€�€ �sk� �st€yo�s{n t€wtvowÞ �{|~{�tno k~ok€{z/
klwo k||~{ðtyk�t{z �{�so{|�tykw |{wtmÞ tz�soy{now Ðt�s Mk�€€tkz €ky|wo€ �€on so~o. l��k
q�ww�o~tqtmk�t{z {q�st€qkm�t€loÞ{zn �so€m{|o {q�som�~~oz� €��nÞ1
Oy|woyoz�k�t{z {q�so|~t{~
Oz�soyktz �oð�. Ðo€|omtqton �so|~t{~ k€k|~{|o~�Þ {q�sotzt�tkw lowtoq €�k�o1 N{Ðo�o~. q{~
�omsztmkw ~ok€{z€ *tz|k~�tm�wk~. �{~o�€o �so€kyo €o�{q{|�tytþon |{wtmto€ q{~y�w�t|wo �kw�o€
{q α+.t�t€|~oqo~klwo �{|o~q{~y |{wtmÞ {|�tytþk�t{z kzn €ty�wk�t{z tzk€�kznk~ntþon €|kmo. tz
Ðstms �sotzt�tkw lowtoq €�k�o sk€μ3B3kzn λ3B41_o�soz mk|��~o �so|~t{~ {�o~ �so~k�tzr€
{qt�oy€ tz�sooð|o~tyoz� lÞ�~kz€q{~ytzr �so~k�tzr€ tz�{ �st€€�kznk~ntþon €|kmo €�ms �sk�
�so�~kz€q{~yon �kw�o€ k~otz�zt�€ noqtzon lÞ�so|~t{~1 I{zm~o�owÞ. rt�oz kzt�oy ~k�tzrr*i+.
Ðo€o��so�~�o �kw�o �{
uiri�w
�~C <
Ðso~o �wkzn�~noz{�o �so|~t{~ yokz kzn €�kznk~n no�tk�t{z1 T{n�w{ �so~o€�w�kz� mskzro tz
�zt�€ *kww|k~kyo�o~ �kw�o€ k~ont�tnon lÞ�~+.�st€|~{n�mo€ �sooðkm� €kyo losk�t{~ k€�so
zkï�o ty|woyoz�k�t{z. tzÐstms �sotzt�tkw lowtoq t�€owq �k~to€1
\so~o t€{zoz{z/�~t�tkw m{z€o}�ozmo {q�€tzr �st€k||~{kms Ðsoz u{tz�wÞ qt��tzr y�w�t|wo
nk�k€o�€> \so u{tz�wÞ qt�|k~kyo�o~€ k~oo€�tyk�on tz�so€�kznk~ntþon €|kmo. ~k�so~ �skz �so
€|kmo noqtzon lÞ�so~kÐ~k�tzr €mkwo1 F€k~o€�w�. tqÐo�~kz€q{~y �so|k~kyo�o~€ lkmv tz�{ �so
~kÐ~k�tzr €|kmo. �so|k~kyo�o~€ Ðtwwlo€wtrs�wÞ ntqqo~oz� q{~�so�Ð{nk�k€o�€ *o�oz �s{�rs
�soÞ k~otnoz�tmkw tz�so�~kz€q{~yon €|kmo+1 \st€ Ðk€n{zo tz�oz�t{zkwwÞ lomk�€o Ðooð|om�
�sk� �so|k~kyo�o~€ Ðtwwlom{z€t€�oz� tz�som{z�oð�/tzno|oznoz� �zt�€ *t1o1. €�kznk~n no�tk/
�t{z€ {qkztz�o~zkw ��twt�Þ €mkwo+1 N{Ðo�o~. �st€nomt€t{z ��~z€ {���{sk�o zorwtrtlwo ty|km� tz
{�~mk€o lomk�€o �sooy|t~tmkw ~k�tzr nt€�~tl��t{z€ k~o�o~Þ €tytwk~1 [|omtqtmkwwÞ. �sooy|t~tmkw
~k�tzr nt€�~tl��t{z€ k~o*yokz±€�n+ 617=5±51:64 q{~�soltzk~Þ nk�k€o� kzn 715=9±51957 q{~
�so�~tzk~Þ nk�k€o�1 J�o �{�sontqqo~ozmo tz€�kznk~n no�tk�t{z€. kww|k~kyo�o~€ *oðmo|� α.
Ðstms t€z{�kqqom�on+ k~o51:64251957 B41375 �tyo€ wk~ro~ tz�so~kÐ~k�tzr €|kmo q{~�soltzk~Þ
nk�k€o� m{y|k~on �{�so�~tzk~Þ nk�k€o�1 \so ntqqo~ozmo tzoy|t~tmkw yokz€ kqqom�€ �w.Ðstms t€
617=52715=9 B31<46 �tyo€ k€wk~ro tz�soltzk~Þ m{y|k~on �{�~tzk~Þ nk�k€o�1 N{Ðo�o~. rt�oz
{�~tz�o~|~o�k�t{z {q αk€knor~oo {q�|nk�tzr �{Ðk~n€ �sooy|t~tmkw yokz. �st€ntqqo~ozmo t€
k€tz�oznon1
T{now €ty�wk�t{z |~{mon�~o
Mt�oz kyo�kwo�ow TJW kzn |{wtmÞ.π.€ty�wk�tzr kms{tmo �~tkw ky{�z�€ �{~�zztzr k€tzrwo
o|t€{no {q�so|{wtmÞ {z�soyo�kwo�ow TJW1 \{~�zkzo|t€{no. Ðoqt~€� tzt�tkwtþo �solowtoq
€�k�o.b3B*μ3B3. λ3B4.wk€� 3B�+1U{�o �sk� wk€� 3B�tzntmk�o€ �sk� z{t�oy t€qtðk�on k��so
{z€o� {qk�~tkw1
\so kroz� �soz €owom�€ kztzt�tkw m{y|��k�t{z c3+π*b 3+kzn �solowtoq t€�|nk�on kmm{~ntzr
�{�so�~kz€t�t{z nÞzkytm€ *K}:+1U{�o �sk�π*cyb 3+k€€trz€ o}�kw €ky|wtzr |~{lkltwt�Þ �{kww{q
�sot�oy€. €tzmo �so€�luom� €�k~�€ Ðt�s €Þyyo�~tmkw lowtoq€1 \st€ |~{mo€€ ~o|ok�€ �z�tw €{yo
PLOS COMP UTATIONAL  BIOLOGYLt�k�t{z |k��o~z� tz�ty|wo ms{tmo ~oqwom� {|�tykw tzq{~yk�t {z�ky|wtzr
WSV[ I{y|��k�t{zk wGt{w{r� �s��|�>2 2n{t1{~r243146 ;42u{�~zkw1| mlt1433<<:6 Tk~ms 5:.5354 5525=
�tyo €�o|.T.Ðsoz �sokroz� €owom�€ �so�o~ytzk�t{z km�t{z.G1\so |~ontm�on ms{tmo t€�sot�oy
Ðt�s ykðtykw |{€�o~t{~ �kw�o.i�
Targmax
iwi
T1Oz�soo�oz� {qk�to.�soms{tmo t€€ky|won �zt/
q{~ywÞ q~{y �so€o�{qt�oy€ Ðt�s ykðtykw oð|om�on �kw�o tz�soqtzkw lowtoq €�k�o? tz|~km�tmo.
�st€zo�o~ sk||oz€ Ðt�s Ðoww/qt��tzr |k~kyo�o~ �kw�o€1
\{�~kz€wk�o �so€o}�ozmo {qm{y|��k�t{z€ tz�{ kqtðk�t{z €o}�ozmo. Ðok€€�yo �sk� okms
€ky|wo �kvo€ 433y€kzn m{zmk�ozk�o y�w�t|wo m{z�tr�{�€ €ky|wo€ q~{y �so€kyo t�oy tz�{
{zoqtðk�t{z1 \so �oy|{~kw n�~k�t{z {qk€ky|wo t€k~lt�~k~Þ? kw{Ðo~ �kw�o Ð{�wn ~o€�w� tzqtzo~
�oy|{~kw |~ontm�t{z€. l��w{zro~ ~�z�tyo Ðsoz €ty�wk�tzr �soy{now1 Oz�st€ÐkÞ. t�t€�o~Þ
€tytwk~ �{�sodt|k~kyo�o~ �€on tz€ty�wk�tzr ntqq�€t{z nomt€t{z y{now€1 Oy|{~�kz�wÞ �so}�kw/
t�k�t�o |~ontm�t{z€ {q�soy{now k~otz€oz€t�t�o �{�st€|k~kyo�o~ lomk�€oσxkzn γ€ky|wo mkzlo
knu�€�on �{~o€�w� tz�so€kyo ky{�z� {qtzq{~yk�t{z kzn m{€� |o~y€1
_o€ty�wk�o �soy{now q{~�Ð{ntqqo~oz� |�~|{€o€> *4+tnoz�tqÞtzr �so{|�tykw |{wtmÞ kzn
*5+m{y|k~tzr y{now |~ontm�t{z€ �{s�ykz losk�t{~1 Oz�soq{~yo~ mk€o. Ðo~kzn{ywÞ €ky|wo
�so�~�o ��twt�to€ {zokms ��~tkw� t1t1n1 q~{y Mk�€€tkz*3. 4+1\st€ m{~~o€|{zn€ �{�sok€€�y|�t{z
�sk� �soqtðk�t{z |{wtmÞ t€{|�tytþon q{~kzoz�t~{zyoz� tzÐstms �soJT)€ |~t{~ t€kmm�~k�o1
_soz €ty�wk�tzr k€|omtqtm �~tkw q{~m{y|k~t€{z �{s�ykz losk�t{~. �so�~�o �kw�o {qokms
t�oy t€tz€�okn no�o~ytzon lÞ�sowtvtzr ~k�tzr€ q{~�sot�oy€ |~o€oz�on {z�sk� �~tkw. k€€|omt/
qton tzK}<1
T{now |k~kyo�o~ o€�tyk�t{z
\so y{now sk€qt�oq~oo |k~kyo�o~€> �so€�kznk~n no�tk�t{z {q�so€ky|wtzr nt€�~tl��t{z. σx.�so
m{€� |o~€ky|wo. γ€ky|wo .�som{€� {q€Ðt�mstzr k��oz�t{z. γ€Ðt�ms .�sonor~oo {q|~t{~ �|nk�tzr. α.
kzn �sotz�o~€o �oy|o~k��~o {q�soG{w�þykzz |{wtmÞ. β1_oo€�tyk�o k€tzrwo €o�{q|k~kyo�o~€
k��sor~{�| wo�ow �€tzr k||~{ðtyk�o ykðty�y wtvowts{{n o€�tyk�t{z tz�som{yltzon �Ð{/
kzn �s~oo/t�oy nk�k€o�€. �€tzr {zwÞ �soo�oz �~tkw€1
\{l~toqwÞ €�yyk~tþo �soo€�tyk�t{z |~{mon�~o> rt�oz kmkzntnk�o €o�{q|k~kyo�o~ �kw�o€.
Ðom{z€�~�m� �som{~~o€|{zntzr yo�kwo�ow TJW kzn tnoz�tqÞ k€o�{q<3zok~/{|�tykw |{wtmto€
q{~�sk� TJW1 _o�soz k||~{ðtyk�o �sowtvowts{{n {q�sos�ykz qtðk�t{z kzn ms{tmo nk�k
�€tzr €ty�wk�t{z€ q~{y �so{|�tytþon |{wtmto€1 LtzkwwÞ. Ðo|o~q{~y �st€q�ww|~{mon�~o q{~
;3.333 }�k€t/~kzn{ywÞ €ky|won |k~kyo�o~ m{zqtr�~k�t{z€ kzn ~o|{~� �so�{|�st~�Þ m{zqtr�~k/
�t{z€ *�s{€o Ðt�s �sostrso€� wtvowts{{n+ �{rt�o k~{�rs €oz€o {q�so�zmo~�ktz�Þ tz�soy{now
|~ontm�t{z€1 F|k~kyo�o~ ~om{�o~Þ oðo~mt€o *~o|{~�on tz[4F||ozntð+ €�rro€�€ �sk� �st€
yo�s{n. �s{�rs k||~{ðtyk�o. t€€�qqtmtoz� �{tnoz�tqÞ �so|k~kyo�o~€ {q�soy{now Ðt�s qkt~wÞ
strs kmm�~kmÞ1 Gow{Ð. Ðooð|wktz tzno�ktw s{Ð Ðoo€�tyk�o kzn �soz ykðtytþo �sok||~{ðt/
yk�o wtvowts{{n1
\so |~tyk~Þ mskwwozro tzqt��tzr �soy{now t€tzo€�tyk�tzr �sowtvowts{{n q�zm�t{z1 Oz|~tz/
mt|wo. Ðom{�wn €oov �{ykðtytþo �sou{tz� wtvowts{{n {q�so{l€o~�on qtðk�t{z €o}�ozmo€ kzn
ms{tmo€1 N{Ðo�o~. wtvoy{€� €o}�oz�tkw €ky|wtzr y{now€. {�~y{now n{o€ z{�sk�o kzkzkwÞ�tm
wtvowts{{n q�zm�t{z1 Fnnt�t{zkwwÞ. �sostrs ntyoz€t{zkwt�Þ {q�soqtðk�t{z nk�k ykvo€ €�kznk~n
yo�s{n€ q{~k||~{ðtyk�tzr �sowtvowts{{n d=4. =5ftzqok€tlwo1 \s�€. �kvtzr tz€|t~k�t{z q~{y
F||~{ðtyk�o GkÞo€tkz I{y|��k�t{z yo�s{n€ d=6. =7f. Ðok||~{ðtyk�o �sowtvowts{{n lÞm{w/
wk|€tzr �sostrs ntyoz€t{zkw qtðk�t{z nk�k tz�{ q{�~ €�yyk~Þ €�k�t€�tm€> �sotnoz�t�Þ {q�soms{/
€ozt�oy. �soz�ylo~ {qqtðk�t{z€. �so�{�kw qtðk�t{z �tyo. kzn �so|~{|{~�t{z {qqtðk�t{z �tyo
{zokms t�oy1 F€no€m~tlon low{Ð. Ðoo€�tyk�o �sou{tz� wtvowts{{n {q�so€o €�yyk~Þ €�k�t€�tm€
k€k€y{{�son st€�{r~ky {q�so€�k�t€�tm€ tz€ty�wk�on �~tkw€. kzn �soz k||~{ðtyk�o �sowtvowt/
s{{n {qk�~tkw lÞ�sowtvowts{{n {qt�€€�yyk~Þ €�k�t€�tm€1 _ooy|sk€tþo. s{Ðo�o~. �sk� Ðon{
z{��€o�st€k||~{ðtyk�o wtvowts{{n �{o�kw�k�o �so|o~q{~ykzmo {q�soy{now1 Oz€�okn. Ðo
tz�ozn t��{lokykðtykwwÞ |~tzmt|won *kzn ytztykwwÞ ~o€ok~mso~/€|omtqton+ k||~{kms �{
PLOS COMP UTATIONAL  BIOLOGYLt�k�t{z |k��o~z� tz�ty|wo ms{tmo ~oqwom� {|�tykw tzq{~yk�t {z�ky|wtzr
WSV[ I{y|��k�t{zk wGt{w{r� �s��|�>2 2n{t1{~r243146 ;42u{�~zkw1| mlt1433<<:6 Tk~ms 5:.5354 5625=
ms{{€tzr y{now |k~kyo�o~€. rt�oz �sk� m{y|��tzr k�~�o wtvowts{{n t€m{y|��k�t{zkwwÞ
tzqok€tlwo1
Mt�oz k€o�{qzok~/{|�tykw |{wtmto€. Ðoo€�tyk�o �sowtvowts{{n {q�so€�yyk~Þ €�k�t€�tm€ q{~
okms �~tkw �€tzr k€y{{�son st€�{r~ky {q�so€�yyk~Þ €�k�t€�tm€ tz€ty�wk�on �~tkw€1 I~t�tmkwwÞ.
�st€wtvowts{{n t€m{znt�t{zkw {z�so~k�tzr€ q{~�sot�oy tz�sk� �~tkw1 N{Ðo�o~. t�no|ozn€ {zwÞ
{z�so*�z{~no~on+ €o�{q�so€o ~k�tzr€? �s�€. Ðoo€�tyk�o �som{znt�t{zkw wtvowts{{n {zmo q{~
okms €�ms €o�1Mt�oz k€o�{q~k�tzr€. Ðo€ty�wk�o �soy{now :59�tyo€ q{~okms {q�so<3|{wt/
mto€. �€tzr �so~o€�w�tzr 93.333 €ty�wk�t{z€ �{m{z€�~�m� kst€�{r~ky {q�so�~tkw €�yyk~Þ €�k/
�t€�tm€1 \so m{z�tz�{�€ €�k�t€�tm€ *�{�kw kzn |~{|{~�t{z qtðk�t{z �tyo€+ k~oltzzon tz�{ }�tz�two€
*t1o1. qt�oltz€ m{z�ktztzr o}�kw ky{�z�€ {q�sonk�k+ noqtzon lÞ�sont€�~tl��t{z tz�sooð|o~t/
yoz�kw nk�k1 L{~�soqtðk�t{z |~{|{~�t{z€. �so}�tz�two€ k~onoqtzon {z�so~k�tzr ~kzv {q�so
t�oy ~k�so~ �skz �so€|k�tkw w{mk�t{z lomk�€o Ðooð|om� �sont€�~tl��t{z€ �{no|ozn {z~owk�t�o
~k�tzr tz�so�s~oo/t�oy mk€o1 ^kw�o€ {��€tno �sooð|o~tyoz�kw ~kzro k~o|wkmon tz�{ �som{~~o/
€|{zntzr �ktwltz1 [tytwk~wÞ. �~tkw€ Ðt�s qt�o{~y{~o qtðk�t{z€ k~okwwr~{�|on tz�{ {zoltz
*tzmw�ntzr o1r1. €tðkzn €o�oz qtðk�t{z€+ kzn mk€o€ tzÐstms �soy{now |~ontm�€ þo~{ qtðk�t{z€
k~or~{�|on tz�{ �so{zo/qtðk�t{z ltz1 \st€ wk��o~ mk€o m{~~o€|{zn€ �{ms{{€tzr kzt�oy tyyo/
ntk�owÞ Ðt�s{�� o�o~ €ky|wtzr. kzn {mm�~€ ~k~owÞ tzÐoww/qt��tzr tz€�kz�tk�t{z€ {q�soy{now. l��
sk||oz€ q~o}�oz�wÞ Ðsoz γ€ky|wo t€€o��{{strs1 L{~okms €ty�wk�t{z. Ðom{y|��o �soltzzon
€�yyk~Þ €�k�t€�tm€. tnoz�tqÞ �som{~~o€|{zntzr mowwtz�sost€�{r~ky. kzn tzm~ok€o t�€m{�z� lÞ
{zo1 LtzkwwÞ. Ðoz{~ykwtþo �st€st€�{r~ky. ~o€�w�tzr tzkwtvowts{{n {�o~ �so€�yyk~Þ €�k�t€�tm€1
\{m{y|��o �sowtvowts{{n {qk�~tkw.Ldyy+.Ðom{y|��o �soltzzon €�yyk~Þ €�k�t€�tm€ q{~
�so�~tkw kzn w{{v �|�som{~~o€|{zntzr �kw�o tz�soz{~ykwtþon st€�{r~ky q{~�sk� �~tkw)€ ~k�tzr
€o�1
\{kmm{�z� q{~�~tkw€ �sk� k~oz{�Ðoww oð|wktzon lÞ{�~y{now. Ðo�€oknn/n €y{{�stzr.
Ðso~onÐk€ms{€oz tzno|oznoz�wÞ q{~okmsθ�{ykðtytþo �sowtvowts{{n1 \st€ t€o}�t�kwoz� �{
k€€�ytzr kytð��~o lo�Ðooz �sooy|t~tmkw nt€�~tl��t{z kzn k�ztq{~y nt€�~tl��t{z Ðt�s ytð/
tzrÐotrs��1\s�€. �soq�wwk||~{ðtyk�o wtvowts{{n t€
LDyymax
�96C6B<e
d9D�7
C7�Ldyy� �
C
Ðso~oCBN�9N-4t€�so�{�kw z�ylo~ {qmoww€ tz�sost€�{r~ky1 Oy|{~�kz�wÞ. �st€o~~{~ y{now
t€{zwÞ �€on �{k||~{ðtyk�o �sowtvowts{{n? t�t€z{��€on q{~rozo~k�tzr �soy{now |~ontm�t{z€
tz�soqtr�~o€Œtznoon. t�m{�wn z{�lo�€on tz�st€ÐkÞ lomk�€o �soo~~{~ y{now t€noqtzon {�o~
�so€�yyk~Þ €�k�t€�tm€. kzn mkzz{� rozo~k�o q�ww€o}�ozmo€ {qqtðk�t{z€1 \s�€. �so�|k~kyo�o~
€s{�wn lotz�o~|~o�on tz~{�rswÞ �so€kyo ÐkÞ k€�solkznÐtn�s |k~kyo�o~ {qkvo~zow noz€t�Þ
o€�tyk�o d=4f. ~k�so~ �skz k€kzknnt�t{zkw q~oo |k~kyo�o~ {q�soy{now1
_o�soz �€o�st€k||~{ðtyk�o wtvowts{{n q�zm�t{z �{tnoz�tqÞ kykðty�y wtvowts{{n o€�t/
yk�o. kyargmaxLDyy1Gk€on {zykz�kw tz€|om�t{z. Ðotnoz�tqton �so|~{yt€tzr ~ort{z
{q|k~kyo�o~ €|kmo �{loσx9*4.9+. γ€ky|wo9*31334. 3134+. γ€Ðt�ms9*31336. 3136+. kzn β9*433.
933+1 _o�soz ~kzkzknnt�t{zkw }�k€t/~kzn{y €ok~ms {q43.333 |{tz�€ Ðt�stz �st€€|kmo �€tzr
[{l{w w{Ð/nt€m~o|kzmÞ €o}�ozmo€ d=3f1 \st€ k||~{kms sk€looz €s{Ðz �{loy{~o oqqom�t�o
�skz l{�s r~tn €ok~ms kzn ~kzn{y €ok~ms. Ðstwo €�twwkww{Ðtzr q{~yk€€t�o |k~kwwowtþk�t{z d=9f1
U{�o �sk� �so{|�tykw |{wtmÞ n{o€ z{�no|ozn {z αlomk�€o �soJT lowto�o€ so~|~t{~ �{lo
�zltk€on *lÞnoqtzt�t{z+ kzn ykvo€ so~qtðk�t{z nomt€t{z€ kmm{~ntzrwÞ1 \so kw�o~zk�t�o. {|�t/
ytþtzr �so|{wtmÞ m{znt�t{zkw {z α.Ð{�wn ty|wÞ �sk� �soJT t€tz�o~zkwwÞ tzm{z€t€�oz�.
kmm{�z�tzr q{~�soltk€ tzso~qtðk�t{z€ l��z{�tz�so|~t{~ t�€owq1 \s�€. Ðo{|�tytþo α€o|k/
~k�owÞ q~{y �so{�so~ |k~kyo�o~€1 [|omtqtmkwwÞ. Ðom{z€tno~ 43.333 |{€€tlwo tz€�kz�tk�t{z€ {qkww
�so{�so~ |k~kyo�o~€. qtzn {|�tykw |{wtmto€ {zmo q{~okms tz€�kz�tk�t{z. kzn o�kw�k�o �so
PLOS COMP UTATIONAL  BIOLOGYLt�k�t{z |k��o~z� tz�ty|wo ms{tmo ~oqwom� {|�tykw tzq{~yk�t {z�ky|wtzr
WSV[ I{y|��k�t{zk wGt{w{r� �s��|�>2 2n{t1{~r243146 ;42u{�~zkw1| mlt1433<<:6 Tk~ms 5:.5354 5725=
wtvowts{{n q{~€o�oz �kw�o€ {q α?�so€o €o�oz �kw�o€ tzmw�non �so€|omtkw mk€o€ {q3kzn 4k€Ðoww
k€qt�oknnt�t{zkw o�ozwÞ/€|kmon �kw�o€ Ðt�s k~kzn{y {qq€o� *~{�rswÞ mk|��~tzr �sow{Ð/nt€/
m~o|kzmÞ |~{|o~�Þ {q�so[{l{w €o}�ozmo+1
_oq{�zn �sk� �so€�{msk€�tmt�Þ tz�so|{wtmÞ {|�tytþk�t{z kzn wtvowts{{n o€�tyk�t{z m{�/
|won Ðt�s Ðokv tnoz�tqtkltwt�Þ q{~€{yo |k~kyo�o~€ ~o€�w�on tz€wtrs�wÞ ntqqo~oz� ~o€�w�€ Ðsoz
~o/~�zztzr �soq�ww|~{mon�~o? �s�€. �{rt�o k~{�rs €oz€o {q�so�zmo~�ktz�Þ tz�soo€�tyk�o. Ðo
tnoz�tqÞ �so�{|�st~�Þ |k~kyo�o~€. rt�tzr �€l{�s yokz kzn €�kznk~n no�tk�t{z q{~okms |k~ky/
o�o~ kzn �so�{�kw wtvowts{{n1
[�||{~�tzr tzq{~yk�t{z
[4F||ozntð1 [�||woyoz�k~Þ yo�s{n€ kzn ~o€�w�€1 Ozmw�no€ no€m~t|�t{z€ {q�so�k€v€ q{~�so
nk�k€o�€ Ðoy{now. tznt�tn�kw qt��tzr yo�s{n€ kzn €�yyk~Þ {q~o€�w�€. |k~kyo�o~ ~om{�o~Þ
~o€�w�€. kJJT ty|woyoz�k�t{z kzn �kwtnk�t{z. no~t�k�t{z€ q{~�so�kw�o {qtzq{~yk�t{z qok/
��~o€. kzn k�kwtnk�t{z {q�so|{wtmÞ k||~{ðtyk�t{z yo�s{n1
*WJL+
[5F||ozntð1 Oznt�tn�kw qt��tzr ~o€�w�€1 Ozmw�no€ �o~€t{z€ {qkww|w{�€ tz�soyktz �oð�Ðt�s
€o|k~k�o |kzow€ q{~okms |k~�tmt|kz� *tzmw�ntzr y{now |~ontm�t{z€ Ðt�s |k~kyo�o~€ qt��{okms
|k~�tmt|kz�+1
*WJL+
Fmvz{�wonryoz ��
_o�skzv OkzR~kultms q{~st€sow| tz€ty�wk�tzr �sokJJT kzn Gk€�kzV|so�€noz q{~€�r/
ro€�tzr �soyo�s{n q{~oqqtmtoz�wÞ m{y|��tzr ^VO q�ww1
F��s{~ I{z�~tl��t{z�
I{zmo|��kwtþk�t{z> L~ono~tmv IkwwkÐkÞ. Fz�{zt{ Zkzrow. \s{yk€ S1M~tqqt�s€1
Jk�k m�~k�t{z> Fz�{zt{ Zkzrow1
L{~ykw kzkwÞ€t€> L~ono~tmv IkwwkÐkÞ1
L�zntzr km}�t€t�t{z> \s{yk€ S1M~tqqt�s€1
[{q�Ðk~o> L~ono~tmv IkwwkÐkÞ1
[�|o~�t€t{z> Fz�{zt{ Zkzrow. \s{yk€ S1M~tqqt�s€1
^t€�kwtþk�t{z> L~ono~tmv IkwwkÐkÞ1
_~t�tzr ˘{~trtzkw n~kq�> L~ono~tmv IkwwkÐkÞ. Fz�{zt{ Zkzrow1
_~t�tzr ˘~o�toÐ ’ont�tzr> L~ono~tmv IkwwkÐkÞ. Fz�{zt{ Zkzrow. \s{yk€ S1M~tqqt�s€1
Zoqo~ozmo�
41 Zk�mwtqq Z.TmR{{z M1\so ntqq��t{z nomt�t{z y{now> �so{~� kznnk�k q{~��{/ms{tmo nomt�t{z �k�v�1 Uo�/
~kwm{y|��k�t{z 1533<? 53*7+><;6 ˘=551 s��|�>22n{t1{~ r243144: 52zom{153 3<145/3:/7 53
51 Zk�mwtqq Z.[yt�s WS.G~{�z [J.TmR{{z M1Jtqq��t {zJomt�t{z T{now> I�~~oz� O���o� kznNt��{~� 1
\~ozn� tzI{rzt�t� o[mtozmo1 534:? 53*7+>5:3˘ 5<41 s��|�>22n{t1{~ r2431434 :2u1�tm�1534:13 4133;
61 Ttw{�k�wuo�tm T.Tkwyk�n Q.N��s F.R{ms I.Zkzrow F1\so J~tq� Jtqq��t {zT{now mkzkmm{�z� q{~�so
kmm�~km� kzn~okm�t{z �tyo {q�kw�o/lk�on mst{mo� �zno~ strs kznw{��tyo |~o���~o1 Q�nryoz� kzn
Jomt�t{z Tkvtzr1 5343? 9*:+>76;˘7 7=1
71 ]�so~ T.TmIwoww kznQS1\so \tyo I{�~�o {qWo~mo| ��kwIs{tmo> \so Sokv�. I{y|o� tzrFmm�y�wk�{~
T{now1 W��ms{w{rt mkwZo�to�1 5334? 43<*6+>993 ˘9=51 s��|�>22 n{t1{~r243143 6;23366 /5=9a143<16 1993
PLOS COMP UTATIONAL  BIOLOGYLt�k�t{z |k��o~z� tz�ty|wo ms{tmo ~oqwom� {|�tykw tzq{~yk�t {z�ky|wtzr
WSV[ I{y|��k�t{zk wGt{w{r� �s��|�>2 2n{t1{~r243146 ;42u{�~zkw1| mlt1433<<:6 Tk~ms 5:.5354 5925=
91 ]�so~ T.TmIwoww kznQS1S{�� F�o~�t{z kznOzstlt�t{z tzJ�zkytmk wT{now� {qT�w�tkw�o~zk� t�oIs{tmo1
W��ms{w{rt mkwZo�to�1 5337? 444*6+>;9; ˘;:=1 s��|�>22n{t1{~ r2431436 ;23366/5=9a 1444161;9;
:1 [sty{u{ [.[tyt{z I.[sty{u{ K.[msoto~ I1Mk�o ltk� l{�s ~oqwom�� kzntzqw�oz mo�|~oqo~ozm o1Uk��~o
Uo�~{�mtozm o15336? :*45+>464; ˘46551 s��|�>22n{t1{~ r2431436<2z z4493
;1 F~yow RI.Gok�yow F.Zkzrow F1Gtk�tzr [ty|wo Is{tmo� l�Tkzt|�w k�tzr Zowk�t�o ^t��kw F��oz�t{ z1
Q�nryoz� kznJomt�t{ zTkvtzr1 533<? 6*9+>6=:˘7 361
<1 Mwks{w� TM. Zotzr{wn KT1 [�ty�w�� o�|{��~o kznrk�o ltk�> Fq�~�so~ �o��{q�sork�o mk�mkno y{now1
F��oz�t{z. Wo~mo|�t{z ’W��ms{|s�� tm�1533=? ;4*6+>779˘ 7931 s��|�>22n{t1 {~r24316;9<2F WW1;4161 779
=1 R~kultms O.F~yow I.Zkzrow F1^t��kw qt�k�t{z� kzn�som{y|�� k�t{z kznm{y|k~t�{z {q�kw�o tz�ty|wo
ms{tmo1 Uk��~o Uo�~{�mtozmo1 5343? 46*43+>45= 5˘45=<1 s��|�>22n{t1{ ~r2431436<2zz 15:69
431 R~kultms O.Zkzrow F1T�w�tkw�o~ zk�t�o n~tq�/ntqq�� t{zy{now |~ontm�� �so~owk�t{z�s t|lo��ooz �t��kw qt�k/
�t{z� kznms{tmo tz�kw�o/l k�on nomt�t{z�1 W~{moo ntzr� {q�soUk�t{zkw Fmknoy� {q[mtozmo� 15344?
43<*66+>46 <95˘46<9;1 s��|�>22n{t1{~ r243143;62 |zk�1443465< 43<
441 Ik�kzkrs QL._tomvt \^.R{msk~ F.L~kzv TQ1K�o �~kmvtzr kzn|�|tww{yo �~�k~otzntmk�{~� {qnt��{mtk/
lwowk�oz� nomt�t{z |~{mo��o� 1Q{�~zkw {qK�|o~tyo z�kwW��ms{w{r�> Mozo~kw1 5347? 476*7+>47; :˘47<<1
s��|�>22n{t1{~ r2431436 ;2k3369<46
451 \k�k~o� M.Wo~{zk W.Zkzrow F1\so F��oz�t{zkw J~tq� Jtqq��t{z T{now {q[ty|wo Wo~mo|��kw Jomt�t{ z/
Tkvtzr1 L~{z�to~� tzUo�~{�m tozmo1 534;? 441
461 [yt�s [T. R~kultms O1Mk�o Fy|wtqto� ^kw�o tzJomt�t{ zTkvtzr1 W��ms{w{rt mkw[mtozmo1 534=?
63*4+>44:˘ 45<1 s��|�>22 n{t1{~r243144 ;;23=9:; =;:4<<43954
471 F~yow RI.Zkzrow F1Uo�~{om{z {ytm y{now� {qom{z{ytm nomt�t{z ykvtzr> \so ty|km� {qm{y|��k�t{z
�tyo kzno�|o~tozmo {znomt�t{z �kw�o�1 Fyo~tmkz Km{z{ytm Zo�to�1 533<? =<*5+>4:6˘ 4:<1 s��|�>22n{t1
{~r2431459;2 ko~1=<1514:6
491 V~}�tz QS.T�owwo~ S{{�o [1F��oz�t{z kznIs{tmo> FZo�to� {zK�o T{�oy oz�� tzJomt�t{ zTkvtzr1
Fm�k W��ms {w{rtmk1 5346? 477*4+>4=3 ˘53:1 s��|�>22n{t1{~ r2431434: 2u1km�|��153461 3:1336
4:1 R~kultms O1Fmm{�z�tz rq{~F��oz�t{ ztz[o}�oz�tkw [ky|wtzr T{now� {qJomt�t{ zTkvtzr1 I�~~oz� V|tzt{z
tzW��ms{w{r�1 534<? 5=>:˘441
4;1 Mw��s [.[|ov�{~ T[. Zto�vky| Q1^kw�o/lk�on k��oz�t{z kwmk|��~o kqqom�� y�w�t/kw�o~zk �t�onomt�t{z
ykvtzr1 Kwtqo1 534<? ;>o6=:9 =1s��|�>22n{t1{~ r2431;99 72oStqo16=:9=
4<1 \{�kw ZG.T{~ykzz T.R{ms I1[ty�w�kz o{�� y{nowtz r{q�t��kw �kwtozm� kzn�kw�o m{y|��k�t{z
ty|~{�o� |~ontm�t{z� {qom{z{ytm ms{tmo1 W~{moontzr� {q�soUk�t{zkw Fmknoy� {q[mtozmo�1 5346?
443*73+>K 6<9<˘K6<:; 1s��|�>22 n{t1{~r243143 ;62|zk�14 63775=443
4=1 \s{yk� F_. T{w�o~ L.R~kultms O.Noovo~oz NZ. T{s~ WUI1 Mk�o Gtk� Jtqqo~ozmo� Ik|��~o Oznt�tn�k w
Is{tmo Gosk�t{�~1 Uk��~o N�ykz Gosk�t{ �~1534=? 6*:+>:59˘: 691s��|�>22n{t1 {~r2431436<2�7 49:5/34=/
39<7/<
531 Mw��s [.Ro~z U.R{~�ykz zT.^t�kwt IS1^kw�o/Gk �onF��oz�t{ zl��U{�Jt�t�t�o U{~ykwt� k�t{z Ozqw�/
ozmo� Jomt�t{z� �t�s T�w�t|wo Fw�o~zk�t�o� 1Uk��~o N�ykz Gosk�t{ �~15353? 7*:+>:67˘: 791s��|�>22 n{t1
{~r2431436<2 �749:5/353/ 3<55/3
541 [{zr T._kzr a.cskzr N.StQ1W~{km�t�o tzq{~yk�t {z�ky|wtzr tz�kw�o/lk�on nomt�t{z/ ykvtzr>
Jomtntzr �soz kzn�so~o �{�kmmkn o1L~{z�to~� tzN�ykz Uo�~{�m tozmo1 534=? 46*Lol ~�k~�+>4˘43 1
551 [o|�w�onk W.]�so~ T.Jk�to� U.Goz�{z FF.V~�{wo� kW.JoTk~�tz{ G1^t��kw F��oz�t{z T{n�wk�o �
�soOz�or~k� t{z{qM{kw/Zowo�kz� K�tnozmo kznU{�^kw�o1 oStqo1 5353? =>o:3;391 s��|�>22 n{t1{~r2431
;9972oStqo 1:3;39
561 T{~oz{/G{�o Z.Zkyõ �~o�/Z�t� Q.J~�r{�t��m sQ.Nk�noz Gb1No�~t��tm �kznV|�tykw [{w��t{z ��{�so
G~okn�s˘J o|�s Jtwoyyk1 W~{moontzr� {q�soUk�t{zkw Fmknoy� {q[mtozmo�1 5353? 44;*66+>4= ;==˘
4=<3<1
571 Zkyõ �~o�/Z�t� Q.T{~oz{/G{�o Z1V|�tykw Fww{mk�t {z{qLtzt�o [ky|wtzr Ik|km t��tzFmm�y�wk�{~ T{now�
{qT�w�t/Fw� o~zk�t�o Jomt�t{z Tkvtzr1 k~at�>5 435349=; d}/lt{f1 5354?1
591 M{��wtol Q.V�no�o~ Wb1\{�k~n� kzo�~{�mto zmo{qkm�t�o �ky|wtzr kznm�~t{�t��1 Uk��~o Zo�to�� Uo�/
~{�mtozmo1 534<? 4=*45+>;9< ˘;;31 s��|�>22n{t1{~ r2431436 <2�749<6/34</ 33;</3
5:1 Ukuoyztv Q.Mot�wo~ _[1 V|�tykw o�oy{�oyoz� ��~k�orto� tz�t��kw �ok~ms1 Uk��~o1 5339?
767*;364+ >6<;˘6=41 s��|�>2 2n{t1{~r243143 6<2zk��~ o366=3
5;1 Kmv��otz TW1 ^t��kw �ok~ms> F~o�~{�|om�t� o1Q{�~zkw {q^t�t{z1 5344? 44*9+>4˘6: 1
5<1 Ik��o� \I.K�oz� JZ. G{rkm� Z.Tk~�skww QFZ. S�n�tr IQN1 Fnk|�t�o [ky|wtzr {qOzq{~yk�t{ ztzWo~/
mo|��kw Jomt�t{z/Tkv tzr1WSV[ VUK1 5346? <*44+>o;<= =61s��|�>22 n{t1{~r243146 ;42u{�~zkw1| {zo1
33;<==6
5=1 S�n�tr IQ.K�oz� JZ1 Ozq{~yk�t{ zq{~krtzr q{~|o~mo|��kw nomt�t{z�1 Q{�~zkw {qK�|o~tyo z�kwW��ms{w/
{r�> N�ykz Wo~mo|�t{z kznWo~q{~yk zmo1 534;? 76*5+>579˘ 5:71
PLOS COMP UTATIONAL  BIOLOGYLt�k�t{z |k��o~z� tz�ty|wo ms{tmo ~oqwom� {|�tykw tzq{~yk�t {z�ky|wtzr
WSV[ I{y|��k�t{zk wGt{w{r� �s��|�>2 2n{t1{~r243146 ;42u{�~zkw1| mlt1433<<:6 Tk~ms 5:.5354 5:25=
631 O��tS.Gkwnt W1Gk�o�tkz ��~|~t�o k��~km�� s�ykz k��oz�t{z 1^t�t{z Zo�ok~ms1 533=? 7=*43+>45= 9˘463:1
s��|�>22n{t1{~ r2431434 :2u1�t�~o�1533 <13=133;
641 M{��wtol Q.V�no�o~ Wb.S{|o� T.Gk~kzo� F1Ozq{~yk�t{ z/[oovtzr. I�~t{�t�� .kznF��oz�t{z> I{y|� �k/
�t{zkw kznUo�~kw Tomskzt�y� 1\~ozn� tzI{rzt�t� o[mtozmo�1 5346? 4;*44+>9<9 ˘9=61 s��|�>22 n{t1{~r2431
434:2u1�tm�153 4613=133 4
651 [k�kro SQ1\so L{�znk �t{z� {q[�k�t��tm� 1\so L{�znk �t{z� {q[�k�t��tm� 1V�q{~n. Kzrwkzn> Q{sz _two�
’[{z�? 4=971
661 ^{z Uo�ykzz Q.T{~roz��o ~zV1\so{~� {qMkyo� kznKm{z{ytm Gosk�t{ ~1W~tzmo �{z.UQ.][>
W~tzmo�{z ]zt�o~� t��W~o��? 4=771
671 So�t� ZS.N{�o� F.[tzrs [1I{y| ��k�t{zkw Zk�t{zkwt��> Stzvtzr Tomskzt�y kznGosk�t{ ~�s~{�rs
G{�znon ]�twt�� Tk�tyt�k �t{z1 \{|tm� tzI{rzt�t�o [mtozmo1 5347? :*5+>5;=˘6 441s��|�>22n{t1{~ r2431
44442�{| �1453<:
691 M~tqqt�s� \S.Stono~ L.M{{nykz UJ1 Zk�t{zkw ]�o {qI{rzt�t�o Zo�{�~mo�> So�ow� {qFzkw��t� lo��ooz
�soI{y|�� k�t{zkw kzn�soFwr{~t�sytm 1\{|tm� tzI{rzt�t�o [mtozmo1 5349? ;*5+>54;˘5 5=1s��|�>22n{ t1
{~r243144442 �{|�14547 5
6:1 Stono~ L.M~tqqt�s� \S1Zo�{�~mo/Z k�t{zkw Fzkw��t�> ]zno~��kzn tzrN�ykz I{rzt�t{z k��soV|�tykw
]�o {qStyt�on I{y|��k�t{zk wZo�{�~m o�1Gosk�t{~kw kznG~ktz [mtozmo�1 534=?1 WTOJ> 63;47<=3
6;1 Mo~�sy kz[Q.N{~�t�� KQ.\ozozlk�y QG1I{y|��k� t{zkw Zk�t{zkwt��> FI{z�o~rtz rWk~kntry q{~Oz�ow/
wtrozmo tzG~ktz�. Ttzn�. kznTkmstzo�1 [mtozmo1 5349? 67=*:579+1 s��|�>22n{t1 {~r2431445:2� mtozmo1
kkm:3;: WTOJ> 5:4<957:
6<1 [ty� IF1[�tmvtzo�� 1Ik~zorto/Z {mso��o~ I{zqo~oz mo[o~to� {zW�lwtm W{wtm�1 4==<? 7=>64;˘ 69:1
s��|�>22n{t1{~ r2431434 :2[34:;/55 64*==+333 46/9
6=1 Ik|wtz F.Jokz T1Gosk�t{~kw Oy|wtmk�t{z� {qZk�t{zkw Ozk��oz�t{ z�t�s [skzz{z Kz�~{|�1 UGKZ _{~v/
tzrWk|o~1 5346?*F�r� ��+>4˘731
731 G{rkm� Z.G~{�z K.T{oswt� Q.N{wyo� W.I{soz QJ1\so |s��tm� {q{|�tykw nomt�t{z ykvtzr> Fq{~ykw
kzkw��t� {qy{now� {q|o~q{~y kzmo tz��{/kw�o~ zk�t�o q{~mon/ms {tmo �k�v�1 W��ms{w{rt mkwZo�to�1 533:?
446*7+>;33 ˘;:91 s��|�>22 n{t1{~r243143 6;23366 /5=9a144617 1;33
741 T{~oz{/G{�o Z1Jomt�t{z I{zqtnozm okzn]zmo~�ktz�� tzJtqq��t{ zT{now� �t�s Wk~�tkww� I{~~owk �onUo�/
~{zkw Oz�or~k�{~�1 Uo�~kw I{y|��k� t{z15343? 55*;+>4;<: ˘4<441 s��|�>22 n{t1{~r243144 :52zom{15 343145/
3</=63
751 J~�r{�t�� msQ.T{~oz{ /G{�o Z.Is�~mswkz nFR.[sknwo zTU. W{�ro� F1\so I{�� {qFmm�y�wk�tz rK�t/
nozmo tzWo~mo| ��kwJomt�t{z Tkvtzr1 Q{�~zkw {qUo�~{�mtozmo1 5345? 65*44+>6:4 5˘6:5<1 s��|�>22n{t1
{~r243149562 QUK]ZV[IO17 343/441 5345
761 Gt��o~ [.Wk~v N.Gwkzvozl �~rL.Rtolow [Q1Wo~mo|��k wnomt�t{z ykvtzr> n~tq�/ntqq�� t{zy{now t�o}�t�k/
woz��{kGk�o�tkz y{now1 L~{z�to~� tzN�ykz Uo�~{�m tozmo1 5347? <*Lol~�k~ �+>4˘4;1
771 \kutyk [.J~�r{�t��m sQ.W{�ro� F1V|�tykw |{wtm� q{~�kw�o/l k�on nomt�t{z/ ykvtzr1 Uk��~o I{yy�z t/
mk�t{z�1 534:? ;>4˘451
791 \kutyk [.J~�r{�t��m sQ.Wk�ow U.W{�ro� F1V|�tykw |{wtm� q{~y�w�t/kw� o~zk�t�o nomt�t{z�1 Uk��~o Uo�/
~{�mtozmo1 534=? 55*=+>4936 ˘49441 s��|�>22n{t1{~ r2431436 <2�749=6/34=/ 3796/=
7:1 L�nozlo ~rJ.[�~kmv W.[�~�kwomvt \1[|oon. kmm�~km� .kzn�so{|�tykw �tytzr {qms{tmo� 1Fyo~tmkz
Km{z{ytm Zo�to�1 534<? 43<*45+>6: 94˘6:< 71s��|�>22n{t1{~ r2431459;2 ko~153493;7 5
7;1 Gtno~ykz U.Gkvv{�~ F.[s{sky� J1_sk� F~oToy{~to� L{~D \so Nt||{mky |��G~tnro� Wk�� K�|o~t/
ozmo �t�s L���~o Jomt�t{ z�1\~ozn� tzI{rzt�t�o [mtozmo�1 5353? 57*;+>975˘ 99:1 s��|�>22n{t1{~ r2431
434:2u1�tm�153 53137133 7
7<1 Gkvv{�~ F.Wkw{yl{ JQ.c�wlo~lo ~rF.Rkzr bNZ. Zotn F.^o~qkowwto T.o�kw1\so Nt||{mk y|�� [�|/
|{~�� Jowtlo~k �t{zn�~tzr ^kw�o/Gk �onJomt�t{z� 1oStqo1 534=? <>�znoqt zon˘�znoqtzo n1s��|�>22n{t1{~ r2
431;9972 oStqo17:3<3 WTOJ> 645:<7 4=
7=1 _kzr [.Lozr [L.G{~z��o tzF1Tt�tzr yoy{~� kznno�t~o> N{� yoy{~� ~okm�t�k�t{ z��||{~�� nowtlo~/
k�t�o nomt�t{z/ ykvtzr1 5353?1
931 Tk�so�{z QK1\so Km{z{ytm ^kw�o {qFzkw��t� kznI{y|�� k�t{z1 OKKK \~kz�km�t{z �{z[���oy �[mt/
ozmo kznI�lo~zo�tm�1 4=:<? 7*6+>659˘6 651s��|�>22n{t1{~ r2431443 =2\[[I14= :<163345:
941 Z���oww [._oqkwn K1W~tzmt|wo� {qyo�k~ok�{ ztzr1 F~�tqtmtkw Oz�owwtrozmo1 4==4? 7=*4/6+>6: 4˘6=91 s��|�>22
n{t1{~r243143 4:23337/6;3 5*=4+=334 9/I
951 Nk� U.Z���oww [.\{w|tz J.[sty{z� [K1[owom�tzr I{y|��k �t{z�> \so{~� kznF||wtmk�t{z� 1Oz>W~{/
moontzr �{q�so\�oz��/Ktr s�sI{zqo~ozmo {z]zmo~�ktz�� tzF~�tqtmtkw Oz�owwtr ozmo1 ]FO)451 F~wtzr�{z.
^t~rtztk. ][F> F]FO W~o��? 53451 |167:˘6991
961 Ikwwk�k� L.M�w[.R~�oro~ W.M~tqqt�s� \S.Stono~ L1Sok~ztzr �{�owom� m{y|��k �t{z�1 Oz>]zmo~� ktz�� tz
F~�tqtmtkw Oz�owwtrozm o>W~{moontzr� {q�so\st~��/L{ �~�s I{zqo~ozmo ?534<1
PLOS COMP UTATIONAL  BIOLOGYLt�k�t{z |k��o~z� tz�ty|wo ms{tmo ~oqwom� {|�tykw tzq{~yk�t {z�ky|wtzr
WSV[ I{y|��k�t{zk wGt{w{r� �s��|�>2 2n{t1{~r243146 ;42u{�~zkw1| mlt1433<<:6 Tk~ms 5:.5354 5;25=
971 M{wn QO.[sknwoz TU1 Gkzl�~t�y�� kzn �soG~ktz> Jom{ntz r�soZowk�t{z�s t|lo��ooz [oz�{~� [�t/
y�wt. Jomt�t{z �.kzn Zo�k~n1 Uo�~{z1 5335? 6:*5+>5==˘ 63<1 s��|�>22n{t 1{~r2431434 :2[3<=:/:5;6 *35+
33=;4/:
991 TmLknnoz J1Km{z{ytm ms{tmo�1 Fyo~tmkz Km{z{ytm Zo�to�1 5334? =4*6+>694˘ 6;<1 s��|�>22n{t1{~ r2431
459;2ko~1=41 61694
9:1 L~{Æyo~ Z.Jokz _{wq IR.[sozsk� F1M{kw I{zr~�o zm�J{ytzk�o� Zo�k~n ^kw�o tzFmm{�z�tz rq{~
Gosk�t{~kw kznUo�~kw I{~~owk�o� {q^kw�o/Gk�o nJomt�t{z/T kvtzr1 Uk��~o I{yy�ztm k�t{z�1 534=?
43*4+>4˘44 1
9;1 N�z� S\.R{wwtzr U.[{w�kzt F._{{w~tms T_. Z��s�{~ �sTL[. Gos~oz� \KQ1 Tomskzt�y� ]zno~w�tz r
I{~�tmkw Fm�t�t�� n�~tzr ^kw�o/M� tnon Is{tmo1 Uk��~o Uo�~{�m tozmo1 5345? 49*6+>7;3˘ 7;:1 s��|�>22n{t1
{~r2431436<2 zz1634;
9<1 W{wkzõ �kZ.R~kultms O.M~�o�ms {�T.Z�qq II1 Uo�~kw V�mtwwk�t{z� kzn[�zms~{zt�k �t{zJtqqo~oz�tk ww�
[�||{~� K�tnozmo Fmm�y�wk�t{ ztzWo~mo|��k wkzn^kw�o/Gk�o nJomt�t{z Tkvtzr1 Uo�~{z1 5347?
<5*6+>;3=˘ ;531 s��|�>22 n{t1{~r243143 4:2u1zo�~{z1 53471361347
9=1 Wt~~{zo F.F�kl N.Nk�noz Gb.[�kqq{~n \.Tk~�skww QFZ1 K�tnozmo q{~�so[|oon˘^kw �o\~kno/{qq>
N�ykz kznT{zvo� Jomt�t{z Tkvtzr O�Tkrzt��n o[oz�t�t�o1 Jomt�t{z1 534<? 9*5+>45=˘4 751s��|�>22
n{t1{~r243143 6;2nom33333;9
:31 Fzno~�{z GF1\so k��oz�t{z sklt�> N{� ~o�k~n wok~ztzr �sk|o� k��oz�t{zkw �owom�t{z1 Fzzkw� {q�soUo�
b{~v Fmknoy� {q[mtozmo�1 534:? 46:=*4+>57 ˘6=1 s��|�>22 n{t1{~r243144 442z�k�145= 9;
:41 Zk�mwtqq Z1F�so{~� {qyoy{~� ~o�~to�kw1 W��ms{w{rt mkwZo�to�1 4=;<? <9*5+>9=˘4 3<1s��|�>22n{t1{~ r2431
436;23366/5 =9a1<9 1519=
:51 \o{n{~o� m�FZ.]�so~ T1Jt�oz�kzrwt zrJomt�t{ zT{now�> L~{y Ozno|oz nozmo �{I{y|o� t�t{z1 W��/
ms{w{rtmk wZo�to�1 5346? 453*4+>4˘6 <1s��|�>22n{t1{~ r2431436 ;2k3363;;:
:61 G��oyo�o~ QZ.\{�z�o znQ\1Jomt�t{ zLtown \so{~�> FJ�zkyt m/I{rzt�t�o F||~{kms �{Jomt�t{z Tkv/
tzrtzkz]zmo~�ktz Kz�t~{zy oz�1W��ms{w{rt mkwZo�to�1 4==6? 433*6+>765 ˘79=1 s��|�>22n{t1{~ r2431
436;23366/5 =9a143 3161765
:71 N{wyo� _Z. \~�olw {{nQ[.Nok�sm{� oF1Fzo� q~kyo�{~v q{~y{nowtz rnomt�t{z� kl{�� mskzrtz r
tzq{~yk�t {z>\so Wtomo�t�o Stzok~ Gkwwt��tm Fmm�y�wk�{~ y{now1 I{rzt�t�o |��ms{w{r�1 534:? <9>4˘5=1
s��|�>22n{t1{~ r2431434 :2u1m{r|��m s153491441335
:91 [yt�s [T. R~kultms O1F��oz�t{ zkznIs{tmo km~{�� J{yktz�1 Q{�~zkw {qK�|o~tyo z�kwW��ms{w{r� Moz/
o~kw1 534<? 47;*45+>4< 43˘4<5 :1s��|�>22n{t1{~ r2431436 ;2�ro33337<5
::1 [�{utć N.V~}�tz QS.Jk�kz W.J{wkz ZQ.[|oovozl~tz vT1]zmo~�ktz�� tzwok~ztzr. ms{tmo. kzn�t��kw
qt�k�t{z1 W~{moontzr� {q�soUk�t{zkw Fmknoy� {q[mtozmo� {q�so]zt�on [�k�o� {qFyo~tmk1 5353?
44;*:+>65= 4˘66331 s��|�>22 n{t1{~r243143 ;62|zk�14 =4467<44;
:;1 Q��� TF. Ik~|oz�o ~WF1K�o Lt�k�t{z� kznI{rzt�t� oW~{mo��o�1 I{rzt�t�o W��ms{w{r� 14=;:?1 s��|�>22
n{t1{~r243143 4:23343/35< 9*;:+=334 9/6
:<1 Qkzr F.[sk~yk Z.J~�r{�t��ms Q1V|�tykw |{wtm� q{~k��oz�t{z /y{n�wk�on nomt�t{z� o�|wktz� s�ykz qt�/
k�t{z losk�t{ ~1Gt{Zat�1 5353?1
:=1 N�z� S\.Z��wonro ZG.Tkwkwk�ovo~ k_TU. Rozzo~wo� [_. J{wkz ZQ1F||~{kms/t zn�mon ltk�o� tz
s�ykz tzq{~yk�t{z �ky|wtzr1 WSV[ Gt{w{r�1 534:? 47*44+>o53 33:6<1 s��|�>22n{t1{~ r243146; 42u{�~zkw1
|lt{15333:6<
;31 No�lo~� G._{{nq{~n T1Zk�t{zkw Ozk��oz�t{z �t�s [o}�oz�tkw Ozq{~yk�t{ z[ky|wtzr1 _{~vtzr Wk|o~1
534;? |14˘4741
;41 Nolo~� G._{{nq{~n T1Zk�t{zkw Ozk��oz�t{z _soz Jomt�t{z� \kvo \tyo1 Q{�~zkw {qIsoytm kwOzq{~yk/
�t{zkznT{nowtz r1534=? 96*=+>4:<= ˘4:==1
;51 O��tS.R{ms I1F[kwtozm �/Gk�on [ok~ms Tomskzt�y q{~V�o~� kznI{�o~� [stq�� {q^t��kw F��oz�t{ z1
^t�t{z Zo�ok~ms 15333? 73*43+>47< =˘493:1
;61 Z{o ZT. G��oyo�o~ QZ.\{�z�ozn Q\1T�w�tkw�o~ zk�t�o nomt�t{z qtown �so{~�> Fn�zkytm m{zzom�t{z t��
y{now {qnomt�t{z ykvtzr1 W��ms {w{rtmkw Zo�to�1 5334? 43<*5+>6;3 ˘6=51 s��|�>22n{t1 {~r2431436;23 366/
5=9a143<15 16;3
;71 U{r�mst \.[�o�k~� U1T�w�tkw�o~zk� t�onomt�t{z l��ky|wtzr> Fy{now {qnomt�t{z ykvtzr m{z��~ktzo n
l�|~{mo�� nk�k1 W��ms{w{rt mkwZo�to�1 534<? 459*7+>945 ˘9771 s��|�>22n{t1{~ r2431436;2~o� 3333435
;91 Z���{ QK.J{�so~ GF1[�~k�orto� q{~T�w�tk��~t l��o Gtzk~� Is{tmo1 Q{�~zkw {qK�|o~tyoz�k wW��ms{ w{r�
Sok~ztzr. Toy{~�. kznI{rzt�t{z1 4=<6? =*7+>:;:˘: =:1s��|�>22n{t1{~ r2431436 ;235;</;6=6 1=171:;:
;:1 \~�olw{{n Q[.G~{�z [J.Nok�sm{�o F1\so T�w�tk��~t l��o Stzok~ Gkwwt��tm Fmm�y�wk�{~ T{now {qI{z�o��
Kqqom�� tzT�w�tkw�o~ zk�t�o Is{tmo1 W��ms{w{rt mkwZo�to�1 5347? 454*5+>4;= ˘5391 s��|�>22n{t1{~ r2431
436;2k336: 46;
PLOS COMP UTATIONAL  BIOLOGYLt�k�t{z |k��o~z� tz�ty|wo ms{tmo ~oqwom� {|�tykw tzq{~yk�t {z�ky|wtzr
WSV[ I{y|��k�t{zk wGt{w{r� �s��|�>2 2n{t1{~r243146 ;42u{�~zkw1| mlt1433<<:6 Tk~ms 5:.5354 5<25=
;;1 Go~v{�t��m sUFQ. [msotlosozzo G.Zto�vky| Q1Ztr{~{��w� �o��tzr y�w�tkw�o~ zk�t�o nomt�t{z qtown �so/
{~�krktz�� ~kzn{y ��twt�� y{now�1 Q{�~zkw {qK�|o~tyo z�kwW��ms{w{r�> Mozo~kw1 5347? 476*6+>466 4˘
467<1 s��|�>22n {t1{~r2431436 ;2k33694 9=
;<1 Lt�so~ M1Fzk��oz�t{z kwn~tq�ntqq��t{z y{now {�o~ ltzk~�/k� �~tl��o ms{tmo1 I{rzt�t{z1 534;? 4:<>67˘791
s��|�>22n{t1{~ r2431434 :2u1m{rzt�t {z1534;13:133;
;=1 R~kultms O.S�J.Ikyo~o~ I.Zkzrow F1\so F��oz�t{zkw J~tq�/Jtqq�� t{zT{now K��ozn� �{[ty|wo W�~/
msk�tzr Jomt�t{z� 1L~{z�to~� tzW��ms{w{r� 15345? 61
<31 _o��l~{{ vF.�kznozG{�ms Z.TkÆkÆ��kÆQO.N{qykz� S.Wk|kn{|o�~ kvtJ.I{{w� Z.o�kw1J{|kytzo |~{/
y{�o� m{rzt�t�o oqq{~� l�ltk�tzr �solozoqt�� �o~��� m{��� {qm{rzt�t�o �{~v1 [mtozmo1 5353? 6:;
*:7<7+>46: 5˘46::1 s��|�>22 n{t1{~r243144 5:2�mtozm o1kk�9<=4 WTOJ> 654=6659
<41 [st[_. _onow T.Wto�o~� L1Ozq{~yk�t{ zkm}�t�t�t{z n�~tzr {zwtzo nomt�t{z ykvtzr> Fy{now/l k�on
o�|w{~k�t{z ��tzr o�o/�~kmvtz rnk�k1 Tkzkroyoz �[mtozmo1 5346? 9=*9+>433= ˘435:1 s��|�>22n{t1 {~r2431
45<;2yz�m 1445314:59
<51 Tkz{sk~ [M. N��ktz T1F��oz�t{z k�L{~krtzr q{~Ozq{~yk�t{ zkzn^kw�o1 L~{z�to~� tzN�ykz Uo�~{�m t/
ozmo1 5346? ;*U{�oylo~ +>4˘4:1
<61 Mklkt� a.Sktl�{z J.T{w{mso M._otzlo ~r[1I{��w� Ozq{~yk�t{ zFm}�t�t�t{ z>K�|o~tyoz �kwFzkw��t� {q
kG{�znonw� Zk�t{zkw T{now1 Fyo~tmkz Km{z{ytm Zo�to�1 533:? =:*7+*7+>4376˘43 :<1s��|�>22n{t1{~ r2
431459;2 3335<5<3:;; =7:<977
<71 bkzr S.\{�ltk V.JoQ{zr TM1 Fl{�znon ~k�t{zkwt�� y{now {qtzq{~yk�t {z�ok~ms kznms{tmo tz|~oqo~/
ozmo yok��~oy oz�1Q{�~zkw {qTk~vo�tzr Zo�ok ~ms15349? 95*5+>4::˘ 4<61 s��|�>2 2n{t1{~r243149 3=2uy~1
46135<<
<91 Go�kz�{z Q.Knowyk zF.Rk~|tz�vt [.[sks ^G1Q�wtk> Fq~o�s k||~{kms �{z�yo~tmkw m{y|��tzr1 [OFT
~o�to�1 534;? 9=*4+>:9˘= <1s��|�>22 n{t1{~r243144 6;24743 33:;4
<:1 [���{z Z[.Gk~�{ FM1 Zotzq{~moyoz �wok~ztzr> Fztz�~{n�m �t{z1 TO\ |~o��? 534<1
<;1 Ikwwk�k� L.Stono~ L.Jk� W.M�w[.R~�oro~ WT. M~tqqt�s� \S1F~o�{�~mo/~k �t{zkw kzkw��t� {qs�ykz
|wkzztzr1 Oz>W~{moontzr� {q�so73�s Fzz�kw I{zqo~oz mo{q�soI{rzt�t�o [mtozmo [{mto��1 F���tz. \a>
I{rzt�t�o [mtozmo [{mto��? 534<1
<<1 N{�k~n ZF1Ozq{~yk�t{ z�kw�o �so{~�1 OKKK \~kz�km� t{z� {z����oy� �mtozmo kznm�lo~zo�tm� 14=::?
5*4+>55˘5: 1s��|�>22n{t1 {~r2431443=2\[ [I14=::16 333;7
<=1 F�o~ W.Io�k/Gtk zmst U.Lt�mso~ W1Ltzt�o/ �tyo kzkw��t� {q�soy�w�tk~yo nlkznt� |~{lwoy1 Tkmstzo
wok~ztzr1 5335? 7;*5/6+>56 9˘59:1
=31 [{l{w) OT1Vz�sont��~tl��t{z {q|{tz�� tzkm�lo kzn�sok||~{�t yk�o o�kw�k�t{ z{qtz�or~kw� 1cs�~zkw
^�mst�wt�ow) z{tTk�oyk�tv ttTk�oy k�tmso�v{t Lt�tvt1 4=:;? ;*7+>;<7˘< 351
=41 \�~zo~ GT. [ono~lo~ rWG1FMozo~kwt�o n.Stvowts{ {n/L~oo To�s{n q{~W{��o~t {~K��tyk�t{z1 W��ms{/
z{ytm G�wwo�tz kznZo�to�1 5347? 54*5+>55;˘ 5931 s��|�>22n{t1 {~r24316;9<2� 46756/346/ 3963/3
=51 �kzV|so�� nozG.Fmo~lt S.Tk_Q1 ]zltk� onkznKqqtmtoz� S{r/Stv owts{{n K��tyk�t{z �t�s Oz�o~�o
Gtz{ytkw [ky|wtz r1k~at�>533436 =<9dm�.}/lt{. ��k�f1 5353?1
=61 [�zzåvo~ T.G��o��{ FM. U�yytzoz K.I{~kzno ~Q.L{wwT.Jo��ty{� I1F||~{�tyk� oGk�o�tkz I{y/
|��k�t{z1 WSV[ I{y|�� k�t{zkw Gt{w{r�1 5346? =*4+>o4335 <361 s��|�>22n{t1{~ r243146; 42u{�~zkw1|mlt 1
4335<36
=71 I�twwo �~�R.Gw�y TMG. Mkrrt{��t VK. L~kzm �{t�V1F||~{� tyk�o Gk�o�tkz I{y|��k� t{z*FGI+ tzW~km/
�tmo1 \~ozn� tzKm{w{r� ’K�{w��t{z1 5343? 59*;+>743˘ 74<1 s��|�>22n{t1{~ r2431434 :2u1�~oo1534313 71334
=91 Go~r��~k Q.Gozrt{ b1Zkzn{y �ok~ms q{~s�|o~/|k~k yo�o~ {|�tyt�k�t{z 1Q{�~zkw {qykmstzo wok~ztzr
~o�ok~ms 15345? 46*Lol+>5<4 ˘6391
PLOS COMP UTATIONAL  BIOLOGYLt�k�t{z |k��o~z� tz�ty|wo ms{tmo ~oqwom� {|�tykw tzq{~yk�t {z�ky|wtzr
WSV[ I{y|��k�t{zk wGt{w{r� �s��|�>2 2n{t1{~r243146 ;42u{�~zkw1| mlt1433<<:6 Tk~ms 5:.5354 5=25=

Frederick Callaway
Antonio Rangel
Thomas L
Griffiths