A new method for Quantitative Trait Loci Detection

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A new method for Quantitative Trait Loci Detection

Charles-Elie Rabier, Céline Delmas

To cite this version:

Charles-Elie Rabier, Céline Delmas. A new method for Quantitative Trait Loci Detection. 2010.

�hal-00610615�

A new method for Quantitative Trait Loci detection

Charles-Elie Rabier

Institut de Mathématiques de Toulouse, Toulouse, France.

INRA UR631, Auzeville, France.

Céline Delmas

INRA UR631, Auzeville, France.

Summary. We consider the likelihood ratio test (LRT) process related to the test of the ab- sence of QTL on the interval [0, T ] representing a chromosome (a QTL denotes a quantitative trait locus, i.e. a gene with quantitative effect on a trait). We give the asymptotic distribution of this LRT process under the general alternative that there exist m QTL on [0, T ]. This theo- retical result allows us to propose to estimate the number of QTL and their positions using the LASSO. Our method does not require the choice of cofactors contrary to Composite Interval Mapping (CIM). Besides, our method is not affected by interactions.

Keywords: Gaussian process, Likelihood Ratio Test, Mixture models, Nuisance parameters present only under the alternative, QTL detection, χ

²

process.

1. Introduction

Westudyabakrosspopulation:

A × (A × B)

^,where

A

^and

B

^{arepurelyhomozygouslines}

andweaddresstheproblemofdetetingQuantitativeTraitLoi,so-alledQTL(genesinu-

eningaquantitativetraitwhihisabletobemeasured)onagivenhromosome. Thetrait

isobservedon

n

individuals(progenies)andwedenoteby

Y

j

, j = 1, ..., n

^,theobservations, whih wewill assumetobeindependentandidentially distributed (iid). Themehanism

ofgenetis,ormorepreiselyofmeiosis,impliesthat amongthetwohromosomesofeah

individual,oneispurely inheritedfrom

A

^{whiletheother(the}reombined"one),onsists ofpartsoriginatedfrom

A

^{andpartsoriginatedfrom}

B

^,duetorossing-overs.TheHaldane (1919)modelling assumesthat rossoversourasa Poisson proess. Using the Haldane

(1919)distane and modelling, eah hromosome will berepresented bya segment

[0, T ]

^.

Thedistane on

[0, T ]

^{isalledthegenetidistane(whihismeasuredinMorgans).}

Inafamous artile,Landerand Botstein(1989)proposed,withthehelp of genetimark-

ers,to santhe hromosome,performingalikelihood ratiotest (LRT)of theabsene ofa

QTL at every loation

t ∈ [0, T ]

^{. It leadsto alikelihood ratiotest} proess"

Λ

n

(.)

^{, and}

thenanaturalstatistiisthesupremumof suhaproess. This methodisalledinterval

mapping". There have been many papers related to the supremum of the LRT proess.

Forexample,weanmentionFeingoldandal.(1993),ChurhillandDoerge(1994),Rebaï

andal.(1994), Rebaïand al.(1995), Ciero(1998), Piepho(2001),Chang and al.(2009),

Rabier(2010).

Theproblem is that onsideringthe supremumof theproessasatest statisti isappro-

priatewhenthereisonlyoneQTLonthehromosomebutitbeomesinappropriatewhen

there areseveral QTL loatedon thehromosome. Besides, generallygenetiists haveno

a more general approah has to be onsidered. When multiple QTL our on the same

hromosome,theyaetsimultanouslytheLRTproess. Forinstane,whentwoQTLare

loatedintwodierentmarkerintervallosebutnotadjaent,apeakisoftenfoundbetween

thesetwomarkerinterval: itisaghostQTL(MartinezandCurnow(1992)). Jansen(1993)

andZeng(1994)proposedindependentlytheCompositeIntervalMapping",whihonsists

inombiningintervalmappingontwoankingmarkersandmultipleregressionanalysison

othermarkers(Wuand al.(2007)). This way,theQTLnotloatedin themarkerinterval

testeddo notaet anymorethe LRTproess. Their eetsare removeddue to multiple

regressionanalysis. Howewer, thehoie of markersasofator isveryompliated. It is

stillanopenquestiontoday. Untilnow,therehasbeennomathematialproofwhihould

helpusonhowtohoosethesetofmarkersrigorously. Inthisontext,theaimofourpaper

istoproposeanalternativetoCompositeIntervalMapping",thatistosayanewmethod

whihdoesnotrequirethehoieofofators.

Asmentionedbefore,inRabier(2010),theauthorssupposethatthereisnomorethanone

QTLonthehromosome(itis loatedat

t

^⋆

∈ [0, T ]

^{). Theyshowthat theLRTproess is}

asymptotiallythesquareofanonlinearinterpolatedproess"entered under

H

0 ^{(ie. no}

QTLonthehromosome)andunentered ofameanfuntion under thealternative. This

meanfuntiondependsontheQTLeet anditsloation

t

^{⋆. Inthispaper,wegeneralize}

theseresultstothegeneralalternativethat thereexist

m

^QTLon

[0, T ]

^at

t

^⋆₁

, · · · , t

^⋆_m ^with

additiveeets

q

1

, · · · , q

m^.

Themain dierenesbetweenthealternativeofonlyoneQTLandthegeneralalternative,

isinthedistributionofthetrait

Y

^{. WhenthereisonlyoneQTLat}

t

^⋆

∈ [0, T ]

^,thetrait

Y

^,

onditionallytoinformationbroughtbygenetimarkersloatedonthehromosome,obeys

toamixture modelwithknownweights:

p(t

^⋆

)f

(µ+q,σ)

(.) + { 1 − p(t

^⋆

) } f

(µ−q,σ)

(.)

⁽¹⁾

where

f

(µ,σ)

(.)

^{denotesaGaussiandensitywithmean}

µ

^andvariane

σ

^2.

(µ, q, σ)

^arethe

unknownparameters.

When there are

m

^QTL segregating, the distribution of the trait

Y

^{, is a mixture of}

2

^m

omponentsoftheform:

2^m

X

α=1

w

α

f

(Mα,σ)

(.)

wherethe

w

α^sandthe

M

α^{sare knownfuntions oftheunknownparameters}

µ

^,

m

^,

t

^⋆₁^{, ...,}

t

^⋆_m^,

q

1^,...,

q

m^.

Inthisontext,weshowthatunderthegeneralalternative,theLRTproessisstillasymp-

totially the square of anon linear interpolated proess". Howewer, the mean funtion

depends this time onthe numberof QTL,their positions andtheir eets. This theoret-

ialresult allowsus to propose a newmethod to estimate the number of QTL and their

positions using theLASSO.Note that in this paper,asin Broman andSpeed(2002), the

fous is mainly onthe estimation of thenumberof QTL andtheir positions, rather than

ontheestimation oftheQTLeets. Nevertheless,theeetsanbeobtainedeasilywith

themethodthatwepropose.

Theoriginalityofourpaperistwofold. First,withourasymptoti studyofthe LRTpro-

essunderthegeneralalternative,wearenowabletoexplainmathematiallysomestrange

betweentwotrueQTL.Seondly,theoriginalityisinthefatthatweproposeanewmethod

tondQTL.Ourmethodisveryeasytoimplementanddoesnotrequirethehoieofmark-

ersas ofators whih is amajor drawbak of Composite Interval Mapping. Besides, we

provethat our method is not aeted by interations. With the help of simulateddata,

weshowthat ourmethod performs better thantheCompositeIntervalMappingwhihis

largelyused in thegeneti ommunity. Werefer to thebook ofVan derVaart (1998)for

elementofasymptotistatistisusedin proofs.

2. Model and Notations

Thehromosomeisthesegment

[0, T ]

^.

K

^{genetimarkersareloatedonthehromosome,}

oneat eah extremity.

t

1

= 0 < t

2

< ... < t

K

= T

^{are theloations ofthemarkers. The}

genomeinformation"at

t

^{willbedenoted}

X (t)

^{. TheHaldane(1919)model,whihassumes}

that rossoversouras aPoissonproess, anbewrittenmathematially : let

N (t)

^bea

standardPoisson proess,thelawof

X(t)

^{is 1}₂

(δ

1

+ δ

₋1

)

^and

X(t) = ( − 1)

^N(t)

X (t

1

)

^{. The}

Haldane(1919)funtion

r : [0, T]

²

7−→

0,

¹₂

issuh as:

r(t, t

^′

) = P (X (t)X(t

^′

) = − 1) = P ( | N (t) − N (t

^′

) |

^odd

) = 1

2 (1 − e

⁻²

|

^t−t′

| )

¯

r(t, t

^′

)

^{willbethefuntion equalto}

1 − r(t, t

^′

)

^.

r(t, t

^′

)

^denotestheprobabilityof reombinationbetweentwoloi(ie. positions)loatedat

t

^and

t

^′.

r(t, t ¯

^′

)

^{denotestheabseneof}reombination. Notethatareombinationoursif thereisanoddnumberofrossoversbetweenthetwoloi.

Weareinterestedinaquantitativetrait

Y

^{whihisaetedbyseveralQTLloatedonthe}

hromosome.

m

^{willrefertothenumberofQTLand}

q

s^{totheQTLeetofthesthQTL.}

Itsposition will bealled

t

^⋆_s^{. Weimpose}

0 < t

^⋆₁

< ... < t

^⋆_m

< T

^{and wewillsupposethat}

theQTL eets areadditives and there is no interation betweenthem. In this ontext,

thequantitativetrait

Y

^veries:

Y = µ +

m

X

s=1

X(t

^⋆_s

) q

s

+ σε

where

ε

^{isaGaussian whitenoise.}

Besides, the genome information"is available only at loations of geneti markers, that

is to say at

t

1

, t

2

, ..., t

K^{. We denote by}

X

j

(t)

^{the value of the variable}

X (t)

^{for the jth}

observation. So, in fat, our observation on eah individual is

(Y

j

, X

j

(t

1

), ..., X

j

(t

K

))

^.

Theseobservationsaresupposed tobeiid.

3. LRT process under the alternative of only one QTL located on [0, T ] (Rabier (2010))

Before etablishing the general result of this paper, we rst should fous on the work of

Rabier (2010), that is to say the ase where there is only one QTL lying on

[0, T ]

^(ie.

m = 1

^{). It will be agood wayto introdue the LRT proess and will make thereading}

of our paper easier. In order to sum up this previous work, we will onsider the same

elementsand notationsused bytheauthors. Assaid previously, theauthors fous onthe

hromosome, performing a likelihood ratio test (LRT) of the absene of a QTLat every

loation

t ∈ [0, T ]

^.

Weonsider values ofthe parameter

t

^{that are distint ofthe markerspositions, and the}

resultwillbeprolongedbyontinuityat themarkerspositions. For

t ∈ [t

1

, t

K

] \ T

_K where

T

_K

= { t

1

, ..., t

K

}

^,wedene

t

^ℓand

t

^ras:

t

^ℓ

= sup { t

k

∈ T

_k

: t

k

< t } , t

^r

= inf { t

k

∈ T

_k

: t < t

k

}

Inotherwords,

t

^{belongsto theMarker}interval"

(t

^ℓ

, t

^r

)

^{. Wedene}

p(t)

^theweightsuh

as

p(t) = P

X (t) = 1

X(t

^ℓ

), X(t

^r

)

^.

BytheBayesrule,

p(t) = Q

^1,1_t

1

X(t^ℓ)=1

1

X(t^r)=1

+ Q

^1,_t⁻¹

1

X(t^ℓ)=1

1

X(t^r)=−1

+ Q

⁻_t^1,1

1

X(t^ℓ)=−1

1

X(t^r)=1

+ Q

⁻_t^1,−1

1

X(t^ℓ)=−1

1

X(t^r)=−1 ⁽²⁾

where:

Q

^1,1_t

= r(t ¯

^ℓ

, t) ¯ r(t, t

^r

)

¯

r(t

^ℓ

, t

^r

) , Q

^1,_t⁻¹

= r(t ¯

^ℓ

, t) r(t, t

^r

) r(t

^ℓ

, t

^r

) Q

⁻_t^1,−1

= 1 − Q

^1,1_t ^and

Q

⁻_t^1,1

= 1 − Q

^1,_t⁻¹

Let

θ = (q, µ, σ)

^{betheparameterofthemodelat}

t

^xedand

θ

0

= (0, µ, σ)

^thetruevalue

of the parameterunder

H

0^{. The likelihood of the triplet}

Y, X(t

^ℓ

), X (t

^r

)

with respet

tothemeasure

λ ⊗ N ⊗ N

^,

λ

^{beingtheLebesguemeasure,}

N

^{theountymeasureon}

N

, is

∀ t ∈ [t

^ℓ

, t

^r

]

^:

L(θ, t) =

p(t)f

(µ+q,σ)

(y) + { 1 − p(t) } f

(µ−q,σ)

(y)

g(t)

⁽³⁾

where

g(t)

^isafuntion independentof

θ

^.

Thelikelihood

L

n

(θ, t)

^for

n

observationsisobtainedbytheprodutof

n

^{termsasabove.}

θ ˆ = (ˆ q, µ, ˆ σ) ˆ

^{willbethemaximumlikelihoodestimator(MLE)of}

θ

^.

Under

H

0^{,there is noQTLlyingon theinterval}

[0, T ]

^{. Besides,under}

H

1^{, it issupposed}

thatthere isonlyoneloationwhere theQTLlies(ie.

m = 1

^{). Inorder todealwiththis}

alternative, theloation ofthe QTL,

t

^{⋆ (}

t

^⋆

∈ [0, T ]

^{),has to beadded in thedenition of}

H

1^{. So,the}alternativehypothesis anbewritten :

H

at^⋆

:

^{theQTLisloatedattheposition}

t

^⋆witheet

q = a/ √

n

^where

a ∈ R

^⋆ "

In this ontext, the authors show that the LRT proess,

Λ

n

(.)

^{, onvergesweakly to the}

square of a non linear interpolated proess". It means that the LRT statistis at eah

pointaneasilybededuedfromtheWaldorsorestatistisalulatedatmarkerspositions.

Besides, this non linear interpolated proess" is entered under

H

0 ^{and unentered of a}

meanfuntion

m

t^⋆

(t)

^under

H

at^{⋆. ThismeanfuntiondependsontheloationoftheQTL}

t

^{⋆,thepositiontested}

t

^{andtheparameter}

a

^{linkedtotheQTLeet. Itisalsoanonlinear}

interpolatedfontion" (sameinterpolation astheproess). Then,sinethey supposethat

thereisonlyoneQTLon

[0, T ]

^{,theauthorshavealoseformula(duetothe}interpolation) toomputethesupremumof

Λ

n

(.)

^.

4. LRT process under the general alternative of m QTL on [0, T ]

Inthe previousSetion, it has been supposed that there wasonly one QTLlying on the

interval

[0, T ]

^{. As aonsequene,thetest statistiused wasanaturalstatisti, that isto}

say the supremum of the proess. The interest is now on studying the same proess as

previously,

Λ

n

(.)

^{,butunderthepreseneofseveralQTLontheinterval}

[0, T ]

^{. Inthisase,}

thegoalisnotto performatestanymore,buttobeabletorunamodelseletioninorder

toestimatethenumberofQTLandtheirloations.

Letdenote

~t

^{⋆ thequantityreferingto theloationsof theQTL.}

H

_a~t⋆ ^{willbethefollowing}

assumption:

H

_a~t⋆^{: there are}

m

^QTLloatedrespetivelyat

t

^⋆₁^,...,

t

^⋆_m ^andwitheet

q

1

=

^√a1_n^,...,

q

m

=

^√am_n ^where

(a

1

, ..., a

m

) ∈ R

^m⋆"

WeremindthatwesupposethattheQTLeetsareadditivesandthatthereisnointera-

tionbetweenthem. Wewillonsidervalues

t

^,

t

^⋆₁^,...,

t

^⋆_m^{oftheparametersthat aredistint}

of the markers positions, and the result will be prolonged by ontinuity at the markers

positions.

4.1. Results

TheoremWith the previousdenednotations,

S

n

(.) ⇒ Z

^⋆

(.) , Λ

n

(.)

^F.d.

→ { Z

^⋆

(.) }

²

asn tendstoinnity,under

H

0 ^and

H

_a~t⋆ ^where:

• S

n

(.)

^{is thesoreproessfor}

n

observations

• ⇒

^{isthe weak onvergeneand F.d.}

→

^{isthe onvergeneof}nite-dimensional distribu- tions

• Z

^⋆

(.)

^{isaGaussian proesswith unitvariane.}

• Z

^⋆

(.)

^{isthe ontinuousandthe non linear} interpolatedproess"suhas:

Z

^⋆

(t) =

α(t) Z

^⋆

(t

^ℓ

) + β(t) Z

^⋆

(t

^r

) / r

E h

{ 2p(t) − 1 }

²

i

The meanfuntion of

Z

^⋆

(.)

^:

•

^under

H

0^,

m(t) = 0

•

^under

H

_a~t⋆^,

m

~t^⋆

(t) =

α(t) m

~t^⋆

(t

^ℓ

) + β(t) m

~t^⋆

(t

^r

) / r

E h

{ 2p(t) − 1 }

²

i

Thedierent quantitiesare:

α(t) = Q

^1,1_t

+ Q

^1,_t⁻¹

− 1, β(t) = Q

^1,1_t

− Q

^1,_t⁻¹

,

^Cov

Z(t

^ℓ

), Z(t

^r

) = e

^{−2(tr−tℓ)}

m

~t^⋆

(t

^ℓ

) =

m

X

s=1

a

s

e

⁻²

|

^t⋆s−tℓ

| / σ , m

~t^⋆

(t

^r

) =

m

X

s=1

a

s

e

^{−2|tr−t⋆s|}

/ σ ,

and

E h

{ 2p(t) − 1 }

²

i

= { α(t) }

²

+ { β(t) }

²

+ 2 α(t) β(t)e

^{−2(tr−tℓ)}

.

TheproofisgiveninSetion 7.1.

4.2. Illustration of the theorem and of the Ghost QTL phenomenon

0 20 40 60 80 100

−1.8

−1.6

−1.4

−1.2

−1

−0.8

−0.6

−0.4

−0.2 0

t(cM)

Z*(t)

0 20 40 60 80 100

0 0.5 1 1.5 2 2.5 3

t(cM)

( Z*(t) )

2

Proess

Z

^⋆

(.)

^Proess

{ Z

^⋆

(.) }

²

Fig. 1. A path under H

0

of the processes Z

^⋆

(.) and {Z

^⋆

(.)}

²

(T = 100cM, 6 markers equally spaced

every 20cM)

0 20 30 40 60 70 80 100 0.5

1 1.5 2 2.5 3 3.5 4 4.5 5 5.5

t(cM)

t*1=70cM and a 1=4 t*1=30cM and a

1=4 t*1=70cM and a

1=6

0 20 30 40 50 60 70 80 100 3

3.5 4 4.5 5 5.5 6 6.5 7 7.5 8

t(cM)

a2=4 a2=6

m = 1 m = 2

^,

t

^⋆₁

= 30

^M,

t

^⋆₂

= 70

^M,

a

1

= 4

Fig. 2. Mean function m

~t^⋆

(t) as a function of the number m of QTL, their positions t

^⋆s

, and the

parameters a

s

linked to the QTL effects (T = 100cM, 6 markers equally spaced every 20cM)

0 20 40 60 80 100 1.5

2 2.5 3 3.5 4 4.5 5 5.5 6

t(cM)

Z*(t)

a2=4 a2=6

0 20 40 60 80 100

0 5 10 15 20 25 30 35

t(cM)

( Z*(t) )

2

a2=4 a2=6

Proess

Z

^⋆

(.)

^Proess

{ Z

^⋆

(.) }

²

Fig. 3. Same path of Z

^⋆

(.) and {Z

^⋆

(.)}

²

as under H

0

but under H

_a~t⋆

(m = 2, t

^⋆1

= 30cM, t

^⋆2

= 70cM,

a

1

= 4, T = 100cM, 6 markers equally spaced every 20cM)

In order to illustrate the theorem, we will onsider a geneti map whih onsists of

a hromosome of size

T = 100

^{M with}

6

^{markers equally spaed every}

20

^{M. Figure 1}

refersto theabsene of QTLon thehromosome. On theleft-side, a pathof theproess

Z

^⋆

(.)

^is represented under

H

0^{. As there is not any QTL, it orresponds only to noise.}

Besides, we an observe the interpolation obtained between geneti markers. The same

pathorrespondingtotheproess

{ Z

^⋆

(.) }

^{2 hasbeenaddedontheright-side: in genetis,}

we all this path "a likelihood prole". It is usually this path that we obtain when we

analyzedata. Note that manyauthors, insteadof omputing theproess

Λ

n

(.)

^{, fous on}

theLOD proess,

LOD

n

(.)

^where

LOD

n

(.) = Λ

n

(.)/ { 2 log(10) }

^.

Figure 2 represents the signal. On the left-side, we present some mean funtions

m

~t^⋆

(t)

whenonly oneQTL(

m = 1

^{)is loated onthehromosome. As expeted, the supremum}

ofthese interpolatedfuntions is obtainedatthe loationofthe QTL.Besides, thelarger

theQTLeetis,thestrongerthesignalis. Ontheright-side,thefousison

m

~t^⋆

(t)

^when

m = 2

^{. Aording to the theorem,}

m

~t^⋆

(t)

^{is obtained by summing the mean funtions}

orrespondingto the ase

m = 1

^{. As aonsequene,thefuntions}

m

~t^⋆

(t)

^{of the graphof}

theright-sideareeasilyobtainedfromthoseofthegraphoftheleft-side. Let'sfousonthe

urveinsolidline. ThetwoQTLareloatedrespetivelyat

t

^⋆₁

= 30

^Mand

t

^⋆₂

= 70

^M.So,

themarkerinterval(

40

^M,

60

^{M) isadjaenttothe twomarkerintervalswhere theQTL}

areloated. Asaresult,wean observeonthegraphthat thebiggestpeakis obtainedin

theinterval(

40

^M,

60

^{M)andthatthesupremumisobtainedin themiddleof thismarker}

interval, at

50

^{M. Note that it is obtainedexatlyat}

50

^{M sine we onsider exatlythe}

same eet (

a

1

= a

2

= 4

^{) and that there is symmetry due to the loation of the QTL}

andthelength ofthehromosome. Ifnowweonsider alargereet fortheseond QTL

(

a

2

= 6

^)loatedat

t

^⋆₂

= 70

^{M(dashedline),weanobservealmostthesametwopeaksin}

theintervals(

40

^M,

60

^M)and(

80

^M,

100

^{M).Besides,thesupremumofthemeanfuntion}

is obtainedat

52

^{M. It is like abaryenter : someweights are aeted to the QTL asa}

funtionoftheireets,sothesignalandtheloationofthesupremumisaetedbythese

weights.

Figure3istheanalogousofFigure1under thealternativeof

2

^QTLloatedat

t

^⋆₁

= 30

^M

and

t

^⋆₂

= 70

^{M. As in Figure 1, the path of theproess}

Z

^⋆

(.)

^{is on the left-side whereas}

theoneorrespondingto

{ Z

^⋆

(.) }

^2isontheright-side. Aordingto thetheorem, inorder to obtainthe path of

Z

^⋆

(.)

^under

H

_a~t⋆^{, wehave to sum thepath of}

Z

^⋆

(.)

^under

H

0 ^(ie.

the noise), and the mean funtion

m

~t^⋆

(t)

^{(ie. the signal). In other words, the path of}

Z

^⋆

(.)

^under

H

_a~t⋆ ^{hasbeenobtainedbyaddingthepathof}

Z

^⋆

(.)

^{presentedinFigure1and}

themean funtion of the graphof theright-sideof Figure 2. Note that on theright-side

of Figure 3, the likelihood prole (ie. the path of

{ Z

^⋆

(.) }

^{2) haseasily been obtained by}

omputationof thesquare of

Z

^⋆

(.)

^{. We anobservein Figure3that, whenthe eetsof}

thetwoQTLarethesame(ie. thesolidlines),thebiggestpeakisobtainedbetween

40

^M

and

60

^{MwhihisamarkerintervalwherethereisnoQTL:suhapeakisalledaghost}

QTL(MartinezandCurnow(1992)). Itwasexpetedsinethesupremumofthesignalwas

obtainedat

50

^M.

Notethat whenweinreasetheeetoftheseondQTL(ie. thedashedlines),thebiggest

peakis obtainedin themarkerinterval(

60

^M,

80

^{M)whihistheintervalwhihontains}

theseond QTL.Itis dueto thenoisesinethesignalisalmost thesameinthe intervals

(

40

^M,

60

^{M) and (}

60

^M,

80

^{M) whereas the values of}

Z

^⋆

(.)

^{are larger under}

H

0 ^{in the}

markerinterval(

60

^M,

80

^{M)thanintheinterval(}

40

^M,

60

^M).