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Mutation-sele tion models solved exa tly

with methods of statisti al me hani s

Ellen Baake
Zoologis hes Institut
Universitat M
un hen
Luisenstr. 14
D-80333 M
un hen
email: baakezi.biologie.uni-muen
phone: (+49) 89 5902 327
FAX: (+49) 89 5902 474
Holger Wagner
Max-Plan k-Institut f
ur Biophysikalis he Chemie
Am Faberg 11
D-37077 G
phone: (+49) 551-2011306
FAX: (+49) 551-2011089
July 19, 2001 

address for proofs.



We re onsider deterministi models of mutation and sele tion a ting on populations of sequen es,
or, equivalently, multilo us systems with omplete linkage. Exa t analyti al results on erning
su h systems are few, and we present re ent and new ones obtained with the help of methods
from quantum statisti al me hani s.
We onsider a ontinuous-time model for an in

nite population of haploids (or diploids
without dominan e), with N sites ea h, two states per site, symmetri mutation, and arbitrary

tness fun tion. We show that this model is exa tly equivalent to a so- alled Ising quantum
hain. In this pi ture,

and mutation to a temperature-like parameter.tness orresponds to the intera tion energy of spins. The highly elaborate methods of statisti al me hani s allow one to .

These in lude quadrati .nd exa t solutions for nontrivial examples.

The latter is a .tness fun tions. as well as `Onsager's lands ape'.

tness fun tion whi h aptures some essential features of mole ular evolution. and the varian e in . We investigate the mean number of mutations. ompensatory mutations and at ridges. the mutation load. like neutrality.

1 Introdu tion Models of mutation and sele tion as the only evolutionary for es (i.tness under mutationsele tion balan e. examples. a ting on a population of in. whi h o urs in some. This also yields some insight into the `error threshold' phenomenon. but not all.e.

see Burger (1998) or Burger (2000). as well as multilo us models with omplete linkage. this is not so in the multilo us ase. omplete linkage serves as an important referen e ase for the evaluation of re ombination e e ts. for review. Where absen e of re ombination is adequate for one-lo us models. but even here.nite size. without re ombination and migration) have been onsidered in very di erent ontexts. there is a long tradition of one-lo us K -allele models. depending on what the unit of sele tion is supposed to be. A mole ular variant of one-lo us K -alleles models is obtained when the alleles are identi. In lassi al population geneti s.

ed with sequen es. Deterministi mutationsele tion models based on sequen es (as opposed to the sto hasti models for . and an appropriate mutation model is formulated.

nite populations. whi h will not be our on ern here) were .

Li (1987). these models are. 1994.. Due to the sequential stru ture of the `alleles' involved. similar models have also been onsidered in mole ular population geneti s. sequen e spa e models have arisen and evolved independently and only later (Higgs. 1995) been identi. see Eigen et al. Baake. (A tually. O'Brien (1985). e. at the same time. More re ently.rst onsidered in the ontext of prebioti evolution.g. 1989). equivalent to multilo us models with omplete linkage. and be ame known under the name of sequen e spa e models (for review.

and many results were dupli ated ( onvergent evolution)). Depending on the ontext. As a onsequen e.ed with mutation-sele tion models of population geneti s. di erent mutation models and . a spe ial terminology was reated (divergent evolution).

mutation is usually assumed unidire tional at every site (from wild-type to mutant). symmetri mutation at every nu leotide site is more adequate.tness fun tions have been used. on the other hand. As to the . In multilo us models. In the sequen e ontext.

with a unique . one ommon mode of sele tion is dire tional (we will not onsider stabilizing sele tion here).tness fun tion.

ttest genotype and .

tness a 2 .

or a step fun tion (trun ation sele reasing fun tion of the number of deleterious mutations. Charlesworth. In multilo us models. Kimura & Maruyama. The prototype . Kondrashov 1988). e. this is often a quadrati or Gaussian ( f. 1990). 1966.

one type has a sele tive advantage over all others. i.e.tness fun tion of sequen e spa e models has a single sharp peak. whi h are equally un.

t. This is an extreme ase of trun ation sele tion whi h seems highly arti.

see the dis ussion in Charlesworth (1990). Most of them are related to aspe ts of mutation-sele tion balan e: How many mutations (relative to the wildtype) do individuals arry on average? What is the mutation load. the loss in .e. ial from the biologi al point of view. The questions addressed with both types of models are fairly similar. i.

tness aused by the produ tion of maladapted individuals due to mutation. under various .

tness s hemes? How large is the geneti variation within the population? The interest in the mutation load lies in its signi.

From the theoreti al point of view. or a weighty fa tor in nature. reprodu e without re ombination. the mutation load at equilibrium equals the genomi mutation rate. genome sizes. an e for the evolution of mutation rates. and mutation is unidire tional at every site. for review. and re ombination. In spite of de ades of experimental resear h. see Crow (1993) and Kondrashov (1998). it is still not lear whether the mutation load is a small nuisan e. independently of the . one orner stone is the well-known Haldane Prin iple: If organisms are haploid or diploid without dominan e.

for other mutation s hemes. this is still true to .tness fun tion.

The e e t of epistasis in this ase was analyzed in the lassi al paper by Kimura & Maruyama (1966) and. However. or with re ombination. For quadrati . 1998). by Charlesworth (1990) and Higgs (1994). this is no longer true in diploids with dominan e. 1966.rst order in the mutation rate (Kimura & Maruyama. Burger. more re ently.

but vaguely. diminishing returns) epistasis enhan es the mutation load (with respe t to the ase without epistasis). ir ums ribed as a riti al mutation rate beyond whi h mutation an no longer be ontrolled by sele tion and leads to geneti degeneration. In the ontext of sequen e spa e models. the general pi ture emerged that positive (i.tness fun tions and various breeding systems. This may be generally.e. synergisti ) epistasis de reases it.e. populations are usually haploid. More spe i. and mu h attention has been paid to the mutation load in the disguise of the error threshold phenomenon. whereas negative (i.

ally. 1) and de. it was originally des ribed for the sharply-peaked lands ape (see Fig.

ned as a riti al mutation rate above whi h the .

Further. Maynard Smith & Szathmary (1995). (1990). Su h a relationship is. see Holland et al. (1998). Su h observations have been taken as eviden e for the existen e of error thresholds.g. In this setting. observed over a large variety of organisms. an inverse relationship between mutation rate and the (maximum) genome size is predi ted.ttest genotype is lost from the population (see Eigen et al. indeed. a threshold mutation rate above whi h the population goes extin t has been observed in mutagenesis experiments with ertain RNA viruses (but not. for organisms with larger genomes). But the argument relies on the unnatural . e. see the re ent survey by Drake et al. (1989) for a review). and Domingo & Holland (1997) for a review. or not so far.

error thresholds may o ur for ertain . in line with the results on mutation loads. This was orroborated by Charlesworth (1990) and Higgs (1994) who noted that. Charlesworth. 1990).tness fun tion assumed. and may therefore be irrelevant (e.g.

tness fun tions with positive epistasis. A similar observation was made by Wiehe (1997). the results obtained. hinge on the assumptions on the . or error thresholds). but are absent if epistasis is negative. Clearly. as well as the on lusions drawn (on the relevan e of mutation loads.

tness fun tions. Sin e .

. 1995) for urrent 3 .tness lands apes are hard to a ess experimentally (but see (Whitlo k et al.

knowledge and approa hes). for large families of . an important ontribution of theory would be to give answers as general as possible.

tness fun tions. the sharply-peaked and quadrati (or the losely related Gaussian) . As noted already.

They all ome from what we would like to all the permutation-invariant family.tness fun tions have been prominent examples. where .

independently of their position in the genome. this fun tion is de reasing. whi h rules out the existen e of ompensatory mutations in the sense that an additional mutation an never re over . Usually.tness is a fun tion of the number of deleterious mutations.

Even these well-established .tness.

tness fun tions are hard to treat. methods of statisti al physi s (whi h. by de. Exa t solutions are rare. The main reason is that the usual tools from dynami al systems theory are inadequate to handle the large numbers of types involved. one relies on approximate or numeri al treatment. Re ently.

1997.nition.. The purpose of the present paper is to make this toolbox (originally published in ondensed form for the physi s ommunity) available to a population geneti readership. Wagner et al. We shall illustrate these methods by ta kling the quadrati . deals with large numbers of parti les) have been employed to arrive at exa t solutions of ertain mutation-sele tion models (Baake et al. 1998).. and to extend the results.

as well as a novel .tness fun tions.

we shall restri t ourselves to .tness lands ape whi h is outside the permutation invariant family. For simpli ity. and allows for ompensatory mutations.

tness s hemes without dominan e. M Vean & Charlesworth.g. 2000) due to its relevan e for mole ular population geneti s. We shall fo us on symmetri mutation sin e it has attra ted mu h re ent interest (e. More general . but is less well explored than the (simpler) unidire tional ase.

we shall dis uss the mutation-sele tion model. In Se tion 2. along with our hoi e of . The arti le is organized as follows.tness fun tions as well as mutation models (in luding asymmetri mutation) will be ta kled in a forth oming publi ation.

tness fun tions. To avoid dupli ation. we shall dis uss multilo us and sequen e spa e models in a uni.

is on erned with the population averages (`observables') whi h we employ to hara terize mutation-sele tion balan e.ed framework. we shall establish the equivalen e between the mutation-sele tion model and a model of quantum statisti al me hani s. Se tion 5 is devoted to the limit of an in. subsuming both types of models under a ommon terminology. Se tion 4. A short interlude. In Se tion 3.

This is performed with a s aling un onventional in the population geneti s literature and provides the key to mu h of our analysis.nite number of sites. In Se tion 6. the method is applied to the .

tness fun tions des ribed in Se tion 2. where most of our e ort will go into exa t solutions of the quadrati .

1 General onsiderations Haploid genotypes are identi. The results will be dis ussed in Se tion 7. 2 The mutation-sele tion model 2.tness s heme.

ed with linear arrangements of N sites. +1g. Ea h site i is equipped with a variable si whi h may take values from the set f 1. A on.

+1gN .guration (or type) may be denoted by s = s1 s2 : : : sN 2 f 1. In the multilo us ontext. `sites' are identi.

and `+' (or +1) and ` ' (or 1) with `wildtype' and `mutant'. This way. `variables' si with `alleles'. respe tively. s is the on.ed with `lo i'.

guration of one gamete. on. In the mole ular ontext. the orresponding gameti spa e was introdu ed and visualized by Wright (1932).

and we assume the lumping of nu leotides into purines (+) and 4 .gurations are DNA (or RNA) sequen es.

. +1gN is sometimes alled sequen e spa e. (A four-letter alphabet is ta kled in a forth oming paper (Hermisson et al. f.pyrimidines ( ). Although geneti information is . The set f 1. whi h is ommon in mole ular evolution. Swo ord et al. 2000)). (1995) or Li (1997).

Let us now onsider an in. the limit N ! 1 is often appropriate thanks to the large number of sites.nite in prin iple.

+1gN : (1) 0 0 s0 P Here. and use the parallel (or de oupled) mutation-sele tion model (see.nite population of haploids. Crow & Kimura (1970). that is p_s (t) = Rs  R (t) ps (t) + X mss ps (t) . whi h experien e mutation and sele tion. or diploids without dominan e. for example. or Hofbauer (1985)) to des ribe the dynami s of relative frequen ies ps of types s. but no re ombination. s 2 f 1. We shall assume overlapping generations in ontinuous time t. Rs denotes the Malthusian .

and R (t) := s Rs ps (t) is the mean P .tness of type s.

Finally. the dot denotes derivative with respe t to time. with genotypi . instead of haploid genotypes. one has diploid ones. ms s = ms s  0 is the rate at P whi h s mutates to s0 for s0 6= s.tness of the population (note that s ps (t)  1). the matrix (ms s ) is a Markov generator (Rozanov. and mss = s 6=s ms s . If. That is. 1977). Further. ss0 .

absen e of dominan e (in .tnesses Rss .

and the Rs are de. Rss = 12 (Rss + Rs s ). i.e.tness) is assumed.

x may be understood as the ve tor of absolute frequen ies. namely x_ s (t) = Rs xs (t) + X mss xs (t) or x_ (t) = (M + R) x(t) . 1974.  P ps (t) = xs (t)= s xs (t) . and R is the diagonal matrix whi h holds the Rs . with a suitable enumeration of types. xs (t) := ps (t) exp Z t 0  R ( )d . (2) turns Eq. M is the mutation matrix with entries mss . 0 s0 0 (3) where. (1) into a linear system of di erential equations. Moran. 1976) that the transformation 0 0 0 0 0 0 0 0 0 xs (0) := ps (0).ned as Rs := 21 Rss . The latter may be understood as a reprodu tion matrix (we avoid the term `. from whi h the relative frequen ies ps may be retrieved through normalization. It is well-known (Thompson & M Bride.

tness matrix' here sin e this is reserved for the .

tness values of diploid genotypes). This is a onsequen e of the Perron-Frobenius theorem: The equilibrium is given by the eigenve tor belonging to the largest eigenvalue of M + R if supplied with positive sign and orre t normalization.. 5 . i.e.e. Thm. The general solution of the linear system (3) reads 0 0 0  x(t) = exp t(M + R) x(0) : (4) However. solutions of (1) annot leave the positive one. 1990. the system will onverge towards an equilibrium (mutation-sele tion balan e).5). Eq. Due to the usual argument of positive invarian e (Amann. whi h is rarely possible for large numbers of types. some power of it has stri tly positive entries only). xs (t)  0 for all times if xs (0)  0 for all s. f. Moran (1976). (4) remains a somewhat formal expression as long as the matrix exponential is not evaluated expli itly. Sin e the matrix obtained from M by setting its diagonal entries to zero will be assumed to be primitive (i. 16. Thompson & M Bride (1974).

as shown by Hofbauer (1985). both versions display very similar behaviour. (5) 0 has been more popular so far. this is equivalent to weak sele tion and mutation through a res aling of time. This is due to the fa t that the parallel version emerges from the oupled one in the limit of weak sele tion and mutation. however. the mutation-sele tion model with dis rete generations onverges to the parallel version in the limit of short generation times (see the Appendix and Fig. Unlike the parallel model. 4). and others. the oupled mutation-sele tion equation. In a similar way. vss := vs s is the probability of s0 produ ing o spring of type s on P the o asion of a reprodu tion event ( s vss = 1). 0 0 0 2. mutations are oupled to reprodu tion here. `generations') in the oupled one. but proportional to the number of reprodu tion events (and. it was studied in the lassi al ontext by Akin (1979). Here. Hadeler (1981). where reprodu tion and mutation pro eed independently of ea h other.2 Mutation model and . As a onsequen e. the number of mutation events is proportional to time in the parallel version. With an appropriate hoi e of parameters. hen e.In the sequen e spa e ontext. X p_ s (t) = ! vss Rs ps (t) 0 0 s 0 R (t)ps (t) .

tness fun tions Let us now spe ify mutation rates and .

this mutation matrix (plus N times the identity) is primitive.e. every site mutates independently at rate . s0 ) = 1 N. If. in the parallel model (1). We start with mutation be ause the hoi e is straightforward and dealt with qui kly. the number of sites where s and s0 di er. the elements of the mutation matrix read ms s = 0 8 > > <. Clearly.tness fun tions. Note that we have spe i. s = s0 (6) otherwise where D(s0 . s) is the Hamming (or mutational) distan e of s and s0 . We shall restri t ourselves to symmetri mutation at every site. D(s. i. > > : 0.

ed a .

after we have introdu ed the various .xed mutation rate per site. However. We shall dis uss the general issue of s aling in a separate se tion. whi h implies that the overall mutation rate in reases linearly with N . onstant genomi mutation rate (as often assumed in multilo us theory) may be onsidered as well by keeping N onstant and reinterpreting  a ordingly. in line with the mole ular mutation me hanism.

Due to its intuitive appeal.tness fun tions. we shall sometimes use the notion of .

tness lands ape in the way introdu ed by Kau man & Levin (1987) as synonymous with `.

tness fun tion'. i. for the mapping from (geno)types into (individual) .e.

tness values. this is not to be onfused with the mapping from population omposition into mean .

tness. as often referred to as an adaptive lands ape in the sense of Wright (1932). We shall be on erned with two .

tness lands apes. the .

rst of whi h is from the permutation-invariant family. 1. Quadrati .

or the mutational distan e from the referen e genotype. We shall onsider the family of quadrati . the number of sites whi h arry mutations. i.e.tness fun tions: Let `+ + + + + : : : +' be the referen e (mutation free) type and k the number of ` ' sites.

tness fun tions Rk = (ak + 6 2 k) 2N (7) .

where Rk may be understood as de.with parameters a and .

it in .

tness of a type with k mutations. relative to the referen e type (note that Malthusian .

tnesses need only be spe i.

Malthusian . sin e this an els out of Eq.ed up to an additive onstant. (1). in parti ular.

tnesses do not su er from being negative). Quadrati .

tness fun tions provide a good .

by Kimura & Maruyama (1966) to study the e e t of epistasis on mutation-sele tion balan e. so has the orresponding Gaussian . for example. and have been used. 1983).t to the mutation a umulation data in Drosophila (Crow & Simmons.

(We shall. whereas < 0 means diminishing returns (or positive) epistasis. > 0 implies synergisti (or negative) epistasis. in what follows. use the terms of `positive' and `negative' epistasis rather than `diminishing returns' and `synergisti '.tness fun tion as used by Charlesworth (1990). sin e the former do not depend on whether deleterious or bene.

Note that positive urvature of the . ial mutations are onsidered.

tness fun tion ( < 0) is identi.

(2000)).ed with positive epistasis be ause it indu es positive linkage disequilibria. see Phillips et al. With = 0. For a very transparent disse tion of these notions. one has additive . and vi e versa.

i. If Wrightian instead of Malthusian .tness. absen e of epistasis.e. whi h orresponds to independent a tion of sites.

tness is onsidered. one obtains the more familiar multipli ative .

Our de. (81) in the Appendix). Wk = exp(Rk ) = (1 )k . and generations of unit length have been implied (see also Eq.tness s heme. where := 1 exp( a) with a from (7).

Charlesworth. 1990) by the fa tor 1=2N in the s aling of the quadrati term.nition (7) di ers from previous ones (Kimura & Maruyama. While. 1966. for any .

nite N . this may just be understood as the rede.

this issue is deferred to the se tion on s aling.nition of the quadrati oeÆ ient. this point is important to get the s aling right in the limit N ! 1. . Again. for a given fra tion d := k=N of mutated sites. let us only note here that our hoi e ensures that.

tness s ales linearly with N . sin e Rk may be written as Rd = (ad + d2 =2)N . Some on erns have been raised about quadrati .

. with ertain ombinations of a and .tness fun tions sin e.

tness .

whi h is an artifa t introdu ed by the symmetry of the .rst de reases and then rises again with in reasing k.

the . Various remedies are possible. In Charlesworth (1990) and Hermisson et al. (2000). 1990).tness fun tion (Charlesworth.

. 1990. in this limit. Rk is repla ed by its minimum value for k beyond the position of the minimum. there are two bran hes of the equilibrium solution whenever the ..tness fun tion is ut o expli itly. it was observed that the results are very similar whether or not this measure is taken (Charlesworth. We shall see that. We shall adopt a somewhat di erent point of view here whi h is based on the limit N ! 1. at least for most ombinations of the parameters. Hermisson et al.e. 2000). i.

tness fun tion has a se ondary maximum { ea h bran h is derived from one of the maxima (and. For N ! 1. in fa t. the bran h derived from the larger . there is a third bran h derived from the minimum between them).

To make this plausible.tness peak is globally attra ting. even the tiniest symmetry breaking suÆ es to depopulate the `lower' bran h in numeri al simulations ( f. this also holds for large N . irrespe tive of the height (or shape) of a possible se ondary peak. the whole population will . in fa t. 1). onsider the situation without mutation. Then. Fig. To a very good approximation.

provided the .nally arrive at the higher peak. no matter how minute its sele tive advantage.

With mutation. whi h is of order N for the quadrati . some leakage will o ur to the se ond peak. but it will be ome less pronoun ed with in reasing distan e of the peaks.ttest genotype is at all present initially.

the lower peak will be e e tively empty for large N .tness fun tion. Hen e. By utting o the .

Alternatively.tness fun tion. one therefore makes sure that the population is lo ated near the primary maximum (at the wildtype). this may be realized by just `pi king' the orresponding bran h and ignoring an arti.

ial se ond one if 7 .

2. Onsager's lands ape: All lands apes dis ussed so far are in the permutation-invariant family. whether or not the se ondary maximum to whi h it belongs is lower than the primary one.present. They have been standard lands apes in population geneti s sin e large simpli.

permutation invarian e annot seriously be onsidered a reasonable biologi al property. First of all. the fa t that a permutation-invariant fun tion an . However. ations result from this property.

This was pointed out by Phillips et al. (2000). . from within and without the permutation-invariant lass.t the data does not imply that the fun tion is a good des ription of how genes intera t. who further demonstrated that many other models.

whi h. by onstru tion.t the data equally well. as long as the . We go one step further here and also onsider ompensatory mutations. an never o ur in a permutation-invariant model.

tness fun tion is monotoni . As a .

Here.rst attempt to introdu e ompensatory mutations. we borrow from physi s what we would like to all `Onsager's lands ape'. + + + +    + + is the .

ttest type. and the .

tness de.

e. hanges in sign) in the on. it is 2 times the number of `domain walls' (i.

. (8) Note that the .. e.g. .guration. Rs s + + + + + + ++ + + + + ++ + ++ + . 0 4 8 . .

i. the lands ape has a `mirror image' with    as a se ond .e.tness values are invariant under reversal of all signs.

however. we shall just ignore the solution bran h derived from the se ondary maximum. As with quadrati lands apes. This is a valid pro edure for reasons similar to those dis ussed for the quadrati .tness maximum. thus e e ting a uto of the lands ape beyond its minimum.

For . whi h we shall ast in more mathemati al terms here.tness fun tion.

the two symmetri .nite N .

. this eigenve tor be omes asymptoti ally degenerate (the di eren e between the leading and the se ond-largest eigenvalue is of order 1=N ).tness peaks will be equally populated due to the uniqueness and symmetry of the Perron-Frobenius eigenve tor. its omponents hange sign under reversal of signs in the on. however. For N ! 1.e. Sin e the eigenve tor orresponding to the se ond-largest eigenvalue is antisymmetri (i.

guration). any small symmetry breaking (of the lands ape. see also Wagner (1998)). it provides the justi. This is a traditional key to the properties of the physi al system (Yang (1952). At the same time. or of the the initial onditions away from u = 0) are suÆ ient to restri t the population to one of the bran hes.

thus e e ting the (biologi ally reasonable) uto of the lands ape beyond its minimum. The intera tions underlying this . ation to ignore the solution bran h derived from the se ond maximum.

hen e the name of this setting.tness fun tion are those of the well-known Ising model (see the Appendix). of the version solved by Onsager (see Thompson (1972)). As with the quadrati lands ape. there is no justi. more pre isely.

i. However. it bears a few properties whi h may be onsidered typi al of mole ular evolution.e. namely a) a large degree of neutrality. the presen e of on. ation for Onsager's lands ape at the level of geneti intera tions.

gurations with the same .

g. For on.tness (e. +++++ + ++ is sele tively equivalent to + + + + + + + ++).

8 . the degree of neutrality in reases with the distan e from the peak.gurations not too far from the peak. for simple ombinatorial reasons.

there are many ways uphill from + + + + + but only one from + + + + + + + ++).. ) at ridges. i. regions from where immediate improvement is only possible after intermediate steps whi h do not hange .e.g.b) path stru ture: the number of paths uphill dwindles the loser one gets to the peak (e.

+ + + ++ and + + + + + ++.g. but to a hieve an improvement. e. e. the type + + + + ++ allows deterioration in several ways. +++++ + ++ and + + + + + + + ++ before. + + + + + ++. For example.tness. intermediate steps must be a omplished.g. .

There are no stri t lo al maxima. limbing downhill is never required to a ess a higher peak. Judging from models with random assignment of . + + + + + + + + ++ may be rea hed. however. that is. (The relevan e of stri t lo al maxima in mole ular evolution is under debate.nally.

it seems to be hara teristi of high dimensions that there are at ridges onne ting most lo al peaks.tness values to genotypes. ompare Gavrilets (1997). where every site randomly a e ts a number of traits.) d) ompensatory mutations: Fitness is not a monotoni fun tion of the distan e from the referen e genotype. to arrive at + + + + + ++. just as with the popular quadrati . stri t lo al maxima have been found to be rare for most ombinations of parameters in the so- alled multiple quantitative traits model (Taylor & Higgs. for example. It goes without saying that Onsager's lands ape is an unrealisti toy model and has too high a degree of symmetry. Whereas properties a) and b) are shared with the quadrati lands ape. ) and d) rely on the la k of permutation invarian e. But. Similarly. improvement of + + + + + + ++ is possible by introdu ing one further mutation. 2000).

tness fun tion. where we use the following de. it is the symmetries whi h make exa t solutions possible. Onsager's lands ape may be onsidered as displaying positive epistasis.

nition (whi h generalizes the situation for permutation-invariant models): Let R^ k be the average .

and the average is taken over all possible on.tness of types with k ` ' sites.

gurations (not over a population). In line with the de.

or even a t in a ompensatory manner. if R^ k is onvex ( on ave). As a onsequen e. (2000). epistasis is then positive (negative). a larger fra tion of additional mutations either do no further harm. With in reasing distan e from the maximum of Onsager's lands ape.nition in Phillips et al. the average .

tness learly de reases less than linearly as a fun tion of distan e from the .

ttest type. where we shall ome ba k to the olle tion of . This verbal argument will be made pre ise in Se tion 6.

require the physi al on epts of quantum me hani s. Let us start with N = 1. i.tness fun tions and work out solutions for them. we need some ve tor spa e stru ture. as a onsequen e. This equivalen e. First of all. along with its limitations and the relationship with the present approa h. 3 Mutation-sele tion model and quantum hain In 1986. We shall. we need not worry about its mysteries. It is related to the lassi al Ising model des ribed in the Appendix. Leuthausser put forward an exa t equivalen e between a oupled mutation-sele tion model in dis rete time. whi h was established by Baake et al. is dis ussed in the Appendix. and we shall. but exploiting it proved diÆ ult. and the Ising model of lassi al statisti al me hani s. instead. at no stage. work with the equivalen e between the mutation-reprodu tion matrix of the parallel model in ontinuous time. 9 . a single site.e. Let us anti ipate that the equivalen e is a mathemati al one. but now the spins are quantum-me hani al obje ts. (1997). and the Hamiltonian of a so- alled Ising quantum hain. either.

they ip or measure a spin. Let us onsider their a tion on the genotype.. 1)T are the anoni al unit ve tors whi h belong to the homogeneous (i. respe tively. p = (p+ . Sin e p+ + p = 1. One veri. and T denotes transpose. ! 0 1 x := 1 0 1 and z := 0 ! 0 : 1 (9) x and z are known as Pauli's matri es in quantum me hani s. monomorphi ) populations. where e+ := (1. The omposition of a population may then be represented as a ve tor in R2 .e. p )T = p+e+ + p e . 0)T and e = (0.whi h may be + or . p is restri ted to the unit simplex. We now introdu e single-site mutation and reporting operators.

e. assigns . does not hange the variable but reports its sign. x ips the site variable. results in a mutation. 1 the identity matrix. whi h may be used to assign sele tive di eren es: 1 + 1 z .es immediately that x e = e . on the other hand. z e = e : (10) Clearly. i. The matrix z .

e. the linearized parallel mutation-sele tion equation for a single site (i.tness  + 1 to a + site and  1 to a site. in order to be onsistent with the more general indexing to follow. (The subs ript 1 refers to the single site onsidered here. for two types) may be written as x_ (t) = (M + R)x =  x + 1 z + ( )1 x(t): (11) Note that only .) Thus.

tness di eren es (= 21 ) will matter for the .

where  `draws' the population into the 45Æ dire tion. and 1 draws into the horizontal one. The relative strengths of mutation and sele tion determine the dire tion of the ve tor p. see Fig. This is where the physi al pi ture omes in: a quantum-me hani al spin experien ing the ompeting a tion of a transversal .nal. normalized result. 2.

and a longitudinal .eld of strength  in x dire tion.

The strength of the transversal .eld of strength 1 in z dire tion (hen e the symbols for the Pauli matri es). Hen e. is des ribed by the energy operator (or Hamiltonian) H = (x + 1 z ). and a trivial multiple of the identity. the biologi al population orresponds to the quantum-me hani al spin. whi h di ers from our M + R only by a sign.

in the sense that it ountera ts the orientation order of the spins with respe t to the z dire tion.eld () is known as a temperature-like parameter in physi s. This also .

for N sites.ts our intuition of mutation as a randomizing for e. N Now. every type s = s1 : : : sN may be identi.

ed with a unit ve tor es in R2 : es := es1 es2 : : : esN . Correspondingly. and x = s xs es . we an write down the overall mutation operator as M= N X i=1 (ix 10 1): (14) . We now require a mutation operator whi h introdu es a mutation at site i while leaving all other sites un hanged. the required operator is (13) ix := 1| :{z: : 1} x |1 :{z: : 1}. Ch. i ips the i'th site and leaves all others un hanged. P P p and x may be understood as ve tors p = s ps es .2) as a very readable introdu tion.e. 4. (12) where ` ' symbolizes the tensor (or Krone ker) produ t. Bearing in mind that tensor produ ts of operators a t on the sites independently. readers unfamiliar with this formalism may onsult Horn & Johnson (1991. i 1 opies N i opies x i. Hen e.

by abuse of notation.N Note that. we use 1 for the identity on R2 and R2 alike. It is easily veri. sin e there is no danger of onfusion.

every site has its individual ontribution to . ms s as given in (6).ed that the entries of M are. the operator reporting the sign at site i reads iz := 1 : : : 1 z 1 : : : 1 with z  at the i'th position. In the absen e of epistasis. Let us now onstru t reprodu tion operators from single-site reporters. Likewise. indeed.

Malthusian . Thus. independently of P all other sites.tness.

Sites are independent of ea h other.tness is additive. with onstants  and i . the reprodu tion matrix may be written as 0 R = 1 + N X i=1 i iz : (15) This time. the population may be des ribed by a linear arrangement of dire tions (spins). ea h one experien es the ompeting a tion of a longitudinal . Put di erently. and Rs simply reads Rs =  + N i=1 i si . one for ea h site { hen e the name quantum hain.

eld of strength i . and a transversal .

three. Intera tion may involve two. sites intera t. f.eld of strength . If epistasis is in luded. It is easy to see that any . 2. or even more sites. Fig.

whi h has z 's at all sites in I (note that tensor produ ts Q multiply sitewise. (16) may be written more ompa tly as P Q Rs = I I i2I si . the e e t of i2I iz is to multiply the signs reported for sites in I ).tness lands ape may be represented in terms of multiple-site intera tions. as a onsequen e. where I ranges over all subsets of f1. Alternatively.. the operator version of the . i.e. N g. the subs ripts may be olle ted into index sets I . Intera tion between sites i 2 I is Q des ribed by the produ t i2I iz . 2. Let us now re ast this into operator (or matrix) form. 2000). and Eq. : : : . and  = ? . as Rs =  + X i i s i + X i<j ij sisj + X i<j<k ijk sisj sk + (terms up to N th order) : (16) This is known as the Walsh fun tion expansion (Stadler et al. Therefore.

the new terms represent intera tions of the spins with ea h other.tness fun tion (16) reads R= X I I Y i2I iz : (17) In the quantum hain pi ture. as opposed to intera tions with external .

the mutation-reprodu tion matrix is equivalent to the Hamiltonian of an Ising quantum hain. 2. see Fig.elds. Summarizing. with a transversal .

a olle tion of longitudinal .eld whi h orresponds to mutation.

elds whi h orrespond to the additive part of .

and arbitrary spin-spin intera tion whi h orresponds to the epistati part of .tness.

tness. H = (M + R). therefore. the smallest eigenvalue of the Hamiltonian (the ground-state energy) orresponds to the Perron-Frobenius (PF) eigenvalue of the mutation-reprodu tion matrix (the equilibrium mean . More pre isely.

. however.tness). Often.

in the .tness fun tions are not.

rst pla e. de.

We must then determine the intera tions from a . sin e these are not known (see our dis ussion in Se tion 2).ned in terms of su h intera tions.

tness fun tion given otherwise. It is easy to see that i is the average .

averaged over all on.tness ontribution of site i.

1 XY  (18) s R : I = N 2 s i2I i s 11 . in general. ij gives the average ontribution of the orrelation between i and j .gurations. and.

Note that these oeÆ ients may be understood as averages over the on.

in parti ular.guration spa e as opposed to averages over the urrent population.  = ? is the .

tness of a population of random on.

the .e.gurations. i..

tness of a population at mutation equilibrium. We shall often hoose ? = 0 as a onvenient referen e point of the .

tness s ale. The omposition of the .

The latter are based on Wrightian .tness fun tion into intera tion oeÆ ients a ording to (18) is losely related to the de omposition into sele tion oeÆ ients introdu ed by Barton & Turelli (1991).

and the varian e of these quantities. one aims at a few averaged quantities rather than the omplete distribution of genotypes.tness and result from an expansion around any onvenient referen e point (see Turelli & Barton. our point of expansion is a random population (i.e. like the mutation load. In ontrast. although their measurement may be a formidable task in pra ti e. and may therefore hange with time. The mutation load is L(t) := Rmax R (t). 1994). the urrent omposition of the population. 4 Population averages With large numbers of types as involved here. wherefore the I are onstants. the mean number of mutations. a essible to experiment. where Rmax is the largest . at least in prin iple. equidistributed in the type spa e. e...g. We shall subsume them under the name observables be ause they are. ps = 1=2N ).

tness value.e. and max orresponds to the ground state energy of the spin hain (up to a sign). and mention expli itly if equilibrium values.) Unlike the mean . sin e limt!1 R (t) = max. (From now on. are referred to. t ! 1. we shall suppress the notation of time dependen e where there is no danger of onfusion. i. where max is the largest eigenvalue of M + R.. Its equilibrium value is obtained from the physi al pi ture in a straightforward way.

The losest relative is the surplus (or ex ess) of `+' sites. U orresponds to the magnetization of a lassi al Ising system. but it is. the mean mutational distan e from the referen e type has no dire t ounterpart in the physi al pi ture.tness. P P U := s Us ps . but di ers from the orresponding quantum-me hani al quantity (for more on this issue.2). see Se tion 6. of ourse. We shall use U to hara terize the geneti omposition of a population. trivially onverted into the mean number of mutations: If + + +    + is the . where Us := Ni=1 si .

we shall on entrate on the varian e in . the mean mutational distan e is D = (1=2)(N U ). As to the variability of the population.ttest type (whi h will be assumed without loss of generality).

Before embarking on spe i.tness. (19) after all. VR := X s (Rs R )2 ps . this is what sele tion a ts on.


Assuming that the . let us state a fairly general result here.tness fun tions.

tness lands ape is homogeneous in the sense that only n-site intera tions o ur. Rs = for a ertain n. one has X jI j=n I Y i2I VR = 2nR 12 si (20) (21) .e. i.

onsider the hange in mean . To see mutation-sele tion balan e.

tness under sele tion and mutation a ording to (1): d  X R = Rs p_s = dt s X s Rs (Rs R )ps + = VR + X s Rs X X mss ps 0  0 s0 mss ps : (22) 0 0 s 0 Here. the .

rst term represents the in rease of mean .

as familiar from Fisher's Fundamental Theorem.tness due to sele tion. The se ond term is the loss in .

and (20) to obtain X Rs mss = X s mss X 0 0 s I I N X X =  = 0 0 0 Y i2I si ( 1)jfj g\I j I j =1 I N X X 2 j =1 I 3j I Y i2I Y i2I s0i  N s0i = 2nRs : 0 X I I Y i2I s0i  (23) The se ond step re e ts the fa t that mutation at site j of sequen e s0 .tness due to mutation. by ` ipping' s0j . At P P equilibrium. we use (16). (6). hanges Q the sign of those . To evaluate the right-hand side. VR = s Rs s mss ps . therefore.

whi h is re e ted in the last step. the loss in . With (23). summation in (23) is over all sets I whi h ontain j ). Due to homogeneity.tness ontributions I i2I s0i for whi h I ontains j ( onsequently. every set I may be `hit' by n di erent mutations.

the loss in .tness due to mutation be omes X X (24) Rs mss ps = 2nR : 0 s 0 s0 At equilibrium.

tness due to mutation must be balan ed by the gain in .

tness due to sele tion. hen e (21) holds. The homogeneity assumption holds for a number of .

it is a restri tive assumption. in the trivial ase n = 0.tness lands apes.e. it provides some avour of how geneti variation is reated by intera tion of sites. For n > 0. neutral evolution. i. of whi h we shall meet representatives shortly. In general. (Note that. one has Rs   and VR = 0. however. the homogeneity assumption enfor es  = 0. Nevertheless. whi h is no restri tion sin e only .

the limit N ! 1 is employed (and will be used here).tness di eren es matter.) 5 S aling and limits Often. 100 is usually loser to in. First of all. it is a way to make life simpler (and a good one at that. for two reasons. be ause in geneti appli ations.

But even if a . or to make a solution possible at all.nity than to one).

nite-size solution is available. The limit may be performed in various ways. 1979) to 13 . and it is ru ial to get the s aling of the model parameters right.g. Ewens. This is reminis ent of the di usion approximation ( f. the limit is often required to hara terize the behaviour in a lear- ut way (e. to produ e a sharp transition between two regimes instead of just a very steep one).

models of mutation. and drift in . sele tion.

nite populations. where the strengths of mutation and sele tion must s ale inversely with population size to ensure that the di erential equation is a valid approximation of the .

Similarly.nite system. in our in.

s aling of mutation rates and .nite population model.

the solution of the di erential equation onverges to a well-de.tness values should be hosen su h that. for N ! 1.

ned limiting form. the probability distribution of genotypes) annot be expe ted to onverge. sin e one an't . To be more pre ise.e. the solution itself (i.

nd a spa e in whi h this might be possible. What an onverge (at best) is the distribution of quantitative properties of genotypes (su h as the surplus per site). where extensive s aling means that quantities like the mutation rate. The options for the s aling are extensive versus intensive . or .

A standard approa h for mutation-sele tion models is the in. hen e.tness. whereas intensive s aling implies that a quantity is independent of N . are onstant per site (and. proportional to N ). or any of the observables.

where it is further assumed that the deleterious e e t of a mutation is independent of N .nite sites limit N ! 1 under N = onst as introdu ed by Kimura & Maruyama (1966).e. mutation is intensive.. i. and .

and the mutation load s ales intensively. the number of mutated sites per type is approximately Poisson distributed. In this limit.tness is extensive. For additive .

however. we need a limiting pro edure whi h is more generally appli able. For this purpose. Sin e we set out to study mutation-sele tion models without any restri tion to the mutation rates. see the very lear re ent arti le by Johnson (1999). The limit provides meaningful results as long as the mutation rate is so low that only a vanishing fra tion of all sites will arry mutations. and referen es therein.e. of mutation rates and . the Poisson distribution is even exa t. we borrow from the physi al literature the wisdom that. when mutations be ome so frequent that a sizeable fra tion of the sites is a e ted (whi h also implies that sites may be hit more than on e). for systems of statisti al me hani s. It breaks down. extensive s aling of the Hamiltonian (i.tness. as is often assumed in population geneti s.

t) N !1 ! f (y)d!(y. that !N (y. 1gN a value ys 2 I . onvergen e in distribution. Z . onsider a mapping from our type spa e into a ompa t interval I of R whi h asso iates with every element s 2 f 1. for quantum hain examples. as our onvergen e riterion.e.e. with uniform (as opposed to pointwise) onvergen e in t. (1961). To translate this into the biologi al ontext. see Lieb et al. t) on I . the mapping s 7! ys indu es a (time-dependent) probability measure !N (y. 1gN . Let further f (y) be any ontinuous fun tion on I . R R namely f (y)d!N (y. t) onverges towards a limiting measure !(y. i. Bauer 1996). We then demand. the time evolution of the probability distribution on f 1. t). Given p(t). f.tness) is required for a meaningful result in the thermodynami limit. t) in the weak sense (i.


Z (25) f (y)d!(y. t).


= 0: lim sup .


f (y)d!N (y. the mean . t) N !1 t2R+ 0 R Here. ys and f (y) may be arranged su h that f (y)d!N (y.e. t) represents any intensively-s aled observable (i..

the mean surplus.tness. or the varian e in .

one might hoose ys := Us =N with values in [ 1. and f (y) as the mean . for the quadrati lands ape. per site).tness. 1℄. As an example.

andRas f (y) the mean . due to the symmetry. the population averages of Us =N and s1 are the same and equal to the mean P P surplus per site: u := (1=N ) s Us ps = s s1 ps . note that. one ould hoose as ys the fra tion of domain walls in the sequen e. For.tness per site of a sequen e with Us =N = y. For Onsager's lands ape. the alternative hoi e ys = s1 is equivalent. For later use. for permutation-invariant initial onditions.

tness of a sequen e with a fra tion y of domain walls. t) then gives the time evolution 14 . f (y)d!(y. For both lands apes.

of the mean .

tness per site. Eq. (25) then implies that the time evolution of the observable onverges to a well-de.

Wagner et al. 1998.. It an be shown (Wagner.ned limiting form. 1998) that the only meaningful hoi e that a hieves (25) is extensive s aling of both mutation and .

and Eq.tness. (25) indeed holds for the .

Using. provided the initial onditions are ompatible with the symmetries of the lands ape. intensive s aling for both mutation and . whi h does not have a reasonable s aling limit { another of its weaknesses. (25) does not hold for the sharply-peaked lands ape. However. instead.tness lands apes onsidered here.

tness is equivalent to a res aling of ( ontinuous) time. see the dis ussion in Wagner et al. (1998). in the limit.e. dt is repla ed by Ndt. evolution be omes in. i. then.

nitely slow. whereas the absolute number of mutational steps per time unit remains onstant in this limit. This re e ts the fa t that. the loss or gain in .

even though the resulting model has the same equilibrium properties as the all-extensive one. this equilibrium will never be rea hed. As a onsequen e.tness they bring about vanishes. The time evolution of the mean . This is often overlooked sin e only few investigations onsider dynami al aspe ts at all.

tness per site in Onsager's lands ape is illustrated in Fig. 5. for extensive and intensive s aling. These .

gures are modi.

Finally. (1998).ed versions of those given in Wagner (1998) and Wagner et al. where expli it expressions are also derived. the hoi e of extensive mutation together with intensive .

For N ! 1.tness s aling (or vi e versa) is not an option either sin e. hanging N hanges the relative strengths of mutation and sele tion. in this ase. Convergen e of the time evolution a ording to Eq. (25) is immediately lear for additive . the system is dominated solely by mutation. whi h is not what one aims at with a mutation-sele tion model.

tness and all-extensive s aling. where sites are independent. and neither the surplus nor the mean .

they will be removed in the next Se tion. provided initial onditions are the same at all sites.tness per site depend on N at all. even for general .) But. (If there are any doubts about this argument.

tness lands apes. To see this. (22) for the time evolution of the mean . it an be made plausible that the all-extensive s aling is the only one onsistent with similarity of the time evolution in systems with di erent N . onsider the dependen e on N of Eq.

Without mutation. R .tness. But we further demand that R and VR s ale in the same way in a family of models with di erent N (this may be onsidered a re. this elementary version of Fisher's Fundamental Theorem holds for any given model. independently of any s aling onsiderations. (d=dt)R (t) = VR (t).

e. the time s ale both quantities s ale with N ( > 0). as required for similarity of the models within the family. then (d=dt)(R=N  is independent of N .. whi h mimi ks the Fundamental Theorem for the model family): If  ) is of order one. i. Sin e of R=N a hange of the .ned Fisher Property.

tness s ale by a fa tor N hanges R by N . but VR by N 2 . there is only one s aling ompatible with our re.

it is diÆ ult to determine the s aling of VR for a given .ned of Fisher Property. Unfortunately. however.

one has P P d  dt R = VR + s Rs s mss ps . But we an he k for onsisten y with mutation. Clearly. (22). If mutation is present. see Eq. the se ond term on the right-hand side (the hange in .tness fun tion.

tness due to mutation) must also have the same s aling as R . i. Sin e the mixed s alings. and as VR . extensive mutation and intensive .e.

we have to he k if one of the two remaining options is onsistent. Eq.tness and vi e versa. (24) shows that intensive s aling of mutation and . have already been ex luded (sin e they imply a hange in the relative strengths of mutation and sele tion).

tness makes the hange in .

tness due to mutation s ale with 1=N . hen e this s aling is in onsistent. For extensive mutation and extensive . but R is of order one.

this is the only 0 0 0 0 0 15 0 . both R and s Rs s mss ps s ale with N . Therefore.tness. P P on the other hand.

this is the ase for all . It then remains to be he ked (possibly numeri ally) whether onvergen e of the dynami s a tually o urs for a given model. onsistent andidate for s aling.

and the mutation rate per genome. it implies that  is onstant per site. in reases linearly with N . As to (Malthusian) .tness fun tions onsidered in this arti le. If this s aling is to be interpreted in the biologi al pi ture. G := N. (6). as anti ipated in Eq.

extensive s aling implies that the .tness.

tness e e ts of single mutations remain onstant. and the di eren e between the largest and the smallest .

Rmax Rmin. In parti ular. important to stress that it is not required to as ribe any biologi al meaning to the s aling hosen. in reases linearly with N . It is.tness value. as long as we do not aim at omparisons of spe ies (or sequen es) with di erent N . however. there is no point in worrying about mean .

tness be oming in.

nite for N ! 1. It must be kept in mind that any real sequen e is .

and the limit is a te hni al pro ess whi h aims at an approximation of the .nite.

nite system by an in.

This is mu h as with the aforementioned di usion approximation to models of .nite one with very similar properties.

Re apitulating.nite populations. although there is no reason to assume that these for es are weaker in larger populations. with extensive s aling for mutation and . where sele tive di eren es and mutation rates are required to s ale inversely with the population size.

tness. namely per site . the intensively s aled observables.

tness. surplus. and varian e of .

(Note that we use apital letters for extensive quantities and small ones for the orresponding intensive ones. d := D=N  .) The surplus u may be interpreted as mean agreement with +++ : : : + (whi h may be hosen to be the . and We shall therefore work with the quantities r := R=N vR := VR =N . u := U=N  . as well as the orresponding quantities for N ! 1. will onverge in the limit N ! 1. ` = L=N .tness.  .

ttest sequen e without loss of generality). averaged over all sites of the on.

Spe i. and all members of the population.guration.

u = 1 for a pure `wildtype' population. and u = 0 for a population of random on. ally.

gurations. so far. mainly talked about average quantities. Let us anti ipate here that the underlying distributions for r (the . We have.

is binomially distributed with expe tation Np and varian e Np(1 p). i. the varian e per site in . In the same vein. the fra tion of + sites. the distribution of the fra tion of + sites onverges (in the weak sense) to a delta distribution lo ated at p. (1=N )Var(N + ) = p(1 p) for our binomially-distributed N + . no information about the variability of the population may be gained from this limiting distribution alone. Hen e. the number of + sites.. on the other hand. N + =N . point measures in the limit N ! 1. Consequently.tness per site) and u (the surplus per site) will turn out to be delta distributions. This is not surprising in view of the following example: Consider N independent sites whi h read + and with probability p and 1 p. has varian e p(1 p)=N . (21) provides us with independent information about the varian e through vR = VR =N . f (x)d!(x) 6= f (x)d!0 (x). f. in the topology underlying the notion of weak onvergen e R(i. N + . Eq. Then.e. respe tively. However. for some ontinuous fun tion f (x).e. Bauer 1996). Put di erently. probabilityR measures !(x) and !0 (x) are di erent if. the limiting distribution annot be distinguished from a delta distribution.

tness. note that this is di erent from the varian e in .

(21).tness per site. whi h would read VR =N 2 . there is positive varian e as long as the mean . A ording to Eq.

16 .tness is positive (for homogeneous lands apes).

1 Additive .6 Worked examples 6.

To this end. pra ti e the use of mutation-reprodu tion matri es with tensor-produ t stru ture.tness Let us. we re onsider the ase of additive . as a warm-up exer ise whi h does not require any limiting pro edure.

The PN operator i=1 iz adds up the variables at the sites. it assigns the value Us to on. i. In site P P z notation. equivalently (i. or. this may be written as Rs = i si (where = a=2). and thus R = N i=1 i .e. as also ta kled by O'Brien (1985).e. Here.tness. up to the irrelevant onstant term) and to omply with homogeneity. Rk = a(N=2 k). Rk = ak.

Hen e. (Here and in what follows. (26) where Hi := 1 : : : 1 h 1 : : : 1 with the one-site Hamiltonian h := ( x 1) + z (27) in the i'th pla e. we shall work with the de. the mutation-reprodu tion operator may be written as H =M+R= X i (ix 1) + X i iz = X i Hi .guration s.

i = 1. : : : . : : : . vn . j = 1.2 = p 2 + 2  and orresponding eigenve tors v1 = (. n and orresponding eigenve tors v1 . then A B has eigenve tors v i wj with orresponding eigenvalues i j . and an mm matrix B has eigenvalues 1 . : : : . m). : : : .) The one-site Hamiltonian h has eigenvalues p 1. Re alling the spe tral properties of tensor produ ts (if an n  n matrix A (. m and orresponding eigenve tors w1 . : : : . one . + 2 + 2 )T and v2 = 2 + 2 )T . n. wm . : : : . has eigenvalues 1 .nition H = M + R instead ofpthe physi al onvention H = (M + R).

Hen e. Hj ℄ = Hi Hj Hj Hi = 0. at equilibrium. the surplus per site reads p u = h + 1 + h2 = and the mean . i. where k:k1 denotes the one-norm. the PF eigenve tor of H is N v1 . [Hi . they may be diagonalized simultaneously. Note that the tensor produ t stru ture expresses (statisti al) independen e of sites (i. the sites are in linkage equilibrium). with the omponents of v~1 holding the marginal probabilities of + and at every site.e.e. More pre isely.2 with multipli ity 2N 1 ea h. with eigenve tor max = N ( 2 + 2 ). (A similar stru ture pertains in the transfer matrix of the orresponding quasispe ies model. and the spe trum of their sum omposed from that of the one-site Hamiltonian. as exploited by Rums hitzky (1987). where ij is either 1 orp2 for every N site j .) The orresponding stationary distribution is obtained by repla ing v1 by v~1 := v1 =kv 1 k1 .rst observes that Hi has eigenvalues 1. In parti ular. Further. sin e the Hi mutually ommute. H has eigenve tors v i1 v i2 : : : viN with orresponding eigenvalues i1 + : : : + iN .

sin e the lands ape is homogeneous with n = 1.tness per site is p1 h + 1 + h2 r = 1 = u . (28) (29) where we have set h := = . Further. the varian e in .

Not surprisingly.tness (again per site) p is vR = 2 u. Even if we only give the equilibrium properties here. (21). Finally. and allows expli it expressions for the time evolution of the system via (4). the mutation 2 + 2 =  2 =(2 ) + O(3 ). a ording to Eq. this is less than the value  from Haldane's Prin iple. 17 . it is lear that knowledge of the eigensystem is omplete. due to load reads ` = 1 =  + ba k mutations.

given any initial value. the solution pro edure goes through if sites have P di erent e e ts on . Note that. obviously.

i.e.tness. Rs = i i si . but we will not spell this out here (the orresponding situation with unidire tional mutation has been ta kled by Johnson (1999) in the in.

The observables are illustrated in Fig. Not surprisingly. 6. both .nite sites limit).

but never vanish. this is a ompanied by a steady in rease in varian e in .tness and surplus de line smoothly with in reasing mutation rate.

tness. For small . the results are in agreement with the in.

is Poisson distributed with expe tation (and varian e) G=s. and s = 2 is the .nite sites limit whi h predi ts the number of mutated sites. where G = N is the overall mutation rate. N .

Johnson. As a onsequen e. 1999). the mutation load is G.tness e e t per mutation ( f. and the varian e in .

2 Quadrati . namely s2 V ar(N ) = Gs.tness equals the varian e of the mutation load. so the Poisson approximation to the binomial distribution breaks down. and varian e) be ome obvious { they are due to the fa t that a sizeable fra tion of the sites then arries mutations. deviations from the linear in rease (in mutation load. 6. For larger .

tness fun tions We are now ready to embark on quadrati .

tness lands apes with epistasis. instead of Rk = (ak + 2 N k2 ). Again. .

and an additive P onstant is again suppressed. i. Us + 2 N Us2 . where P z P Re alling that i i measures Us of on. = =4.tness may equivalently be expressed as a fun tion of Us .e. Rs = = a=2 =4.

In fa t. no longer independent. (30) shows that every site intera ts with every other site. we obtain the mutation-reprodu tion matrix H =M+R = X i (ix 1) + X i iz + 2N X i. with the same intera tion strength =(2N ) { hen e the name mean . sites are. and. of ourse. ( i iz )2 = i.guration s.j iz jz : (30) For 6= 0. hen e.j iz jz measures Us2 .

eld for su h a setting in physi s. What we need to solve the model is the theory of quantum mean .

1993. we shall follow two parallel approa hes. however.eld systems. 1991). whi h a ts equally and independently at every site. Raggio & Werner. whi h is highly developed (Geris h. and the theory is fairly subtle. but annot prove it rigorously here. this is anything but obvious. 1989. in the limit N ! 1. The . We shall see that. the largest eigenvalue (but not the orresponding eigenve tor) may again be obtained through a one-site Hamiltonian. so that we an make it plausible. In ontrast to the additive ase. refer to the mathemati al literature. instead. To be more pre ise. we must.

Sin e it may seem diÆ ult to the uninitiated. we shall use a se ond route with a more heuristi al ulation.rst one uses the quantum- hain formalism and is mathemati ally rigorous. whi h uses elementary tools only and arrives at the same result. but must be a epted without proof here. Let us set out in the .

is repla ed by a so- alled density matrix % (whi h is self-adjoint. has nonnegative spe trum. the lassi al probability measure !(x) (with R d!(x) = 1). and tr(%) = 1) whi h asso iates with an operator O a real (or omplex) expe tation '(O) via '(O) := tr(O%): (31) 18 . whi h asso iates with a real-valued. ontinuous fun tion f (x) an expe tation R f (x)d!(x). a) Using the quantum statisti al formalism In the quantum-me hani al formalism.rst dire tion.

Weak onvergen e of a probability measure then generalizes to weak onvergen e of a sequen e 'N . see Balian (1991).For a very readable introdu tion. or tr(O%N ) N !1 ! tr(O%1): (32) Here. 'N (O) N !1 ! '1(O) for all O. O must refer to a . Classi al (dis rete) probability distributions are ontained as the spe ial ase of diagonal % (the elements representing the probabilities) and diagonal O (representing the values of the random variable).e. i.

for de. independent of N ).e.xed set of sites (i. Se tion 5). and be ompatible with the symmetries of the system ( f.

%N (t) := exp(tHN ) . tr exp(tHN ) (33) where we have renamed H by HN to emphasize the dependen e on system size. t = . To establish the onne tion with the evolution model. (Our time variable orresponds to minus the inverse temperature. think of O = 1z . i.e. we now identify the density matrix with the (normalized) time-evolution operator.niteness.

f. see Baake et al. of the physi al system. the lassi al magnetization. It may now be shown (Geris h. 1 is a sloppy but self-explaining shorthand notation indi ating that the limiting distribution is a produ t measure. in our system. at equilibrium. then. 1993. (32) is its quantum-me hani al generalization. whereas the mutation rate orresponds to the temperature-like parameter whi h we have met in (11). t ! 1. As an example. (36) is the so- alled self- onsisten y equation. one has m = (v12 v22 )=kv k2 as opposed to u = (v1 v2 )=kv k1 .e. where the Hamiltonian measures the energy of the system. v2 )T of the Hamiltonian h. where the parameter m must be determined su h that (35)  tr z exp(th)  : m(t) = tr exp(th) (36) Eq. the Appendix. (76) and (77). To this end. The quantity m relies on a di erent notion of probability than does u. and a forth oming publi ation. where T is the absolute temperature. quantum-me hani al probabilites are represented by unit ve tors in the two-norm (with omponents vi =kv k2 ). note the formal similarity with the Boltzmann distribution. Eqs. onsider a single-site system with PF eigenve tor v = (v1 . := 1=(kT ). 1991) that (32) holds if %1 is hosen to be exp(th) : (34) %1 := 1 tr exp(th) Here. we have two notions related to temperature: time orresponds to the inverse temperature. the expe tation of the operator z (whi h measures the spin) of a system governed by the Hamiltonian h. the quantum-me hani al magnetization. whereas lassi al probabilities are represented by unit ve tors in the one-norm (with omponents vi =kv k1 . Geometri ally. and k is Boltzmann's onstant.) For more on this subje t. i. We now intend to use the above to determine the behaviour of the system at equilibrium. As before. Note that. It determines m. Indeed. h is the one-site Hamiltonian h =  x + ( + m) z . we need a little interlude to establish that the PF eigenve tor is permutation 19 . Raggio & Werner. 1998. whi h we have termed surplus to avoid ambiguities. 1989.

and may be seen as follows: De. this is true due to the uniqueness of the PF eigenve tor.invariant. Indeed. together with the invarian e of the Hamiltonian under permutations of sites.

ne P P as the operator whi h symmetrizes any given on.

P 2 = P . P := (1=N !) g2SN g. i.guration. Clearly. i. where SN is the set of possible permutations of N sites. sin e both M and R are permutation invariant. Further.e. with + and distributed evenly a ross sites). and hen e exp t(M + R)   P x(0) = exp t(M + R) P 2  x(0) = P exp t(M + R) P x(0): (37) This re e ts the plausible fa t that a population. remains symmetri under the time evolution  de. one has MP = PM. RP = PR. P is idempotent.e. on e symmetrized through the a tion of P (that is.

assume permutation-invarian e for all times to simplify matters. we shall. the PF eigenve tor must be permutation invariant itself. Now. Sin e we only seek to determine the equilibrium behaviour here. and will hold for a symmetri initial ve tor in parti ular. uniqueness of the PF eigenve tor tells us that onvergen e towards it is independent of the initial onditions (if they are in the positive one ex luding the origin). Sin e we know that its time evolution will never leave the symmetri se tor. After this interlude. we now pro eed to determine the leading eigenvalue of HN (or the mean . therefore.ned by exp t(M + R) .

respe tively) to leading order in N . . To this end.tness.

rst observe that. Note further that. appli ation of HN to the proje tor onto its PF eigenve tor yields the largest eigenvalue of HN (times the proje tor). onsideration of two sites is suÆ ient. N 1 HN may be repla ed by O = (1x 1) + 1z + ( =2)1z 2z for all N  2. Therefore: 1   HN %N (t) = tlim lim tr O%N (t) . Now. (33) be omes a proje tor on the PF eigenve tor of HN . %N from Eq. It is easily veri. Due to the stru ture of O and %1 . The key to the evaluation of this expression now lies in the algebrai properties of Pauli's matri es. in the limit t ! 1. (38) !1 N !1 N !1 N where the limiting pro esses t ! 1 and N ! 1 may be inter hanged due to the uniform r = tlim lim !1 tr onvergen e established in (25). One al ulates  1 lim tr O%N (t) N !1 N h   i tr (x 1 1) + z 1 + 2 (z z ) exp(th) exp(th) =   2 tr(exp(th) (39) with h as in (35). due to permutation invarian e and up to a term of order O(N 1 )1.

(40) i. and they anti ommute. We further note that tr(x ) = tr(z ) = 0.. x z z x tr(  ) = tr(  ) = 0: and  (41) With p the help of (41). these operators are involutions. one .e.ed that (x )2 = (z )2 = 1 x z z x   =  .

with the abbreviation  := 2 + ( + m)2 ( is the larger eigenvalue of h).rst al ulates h2 = 2 + ( + m)2 1. Then. evaluation of the exponential series yields  sinh(t) exp(th) = osh(t)1 + x + ( + m)z : (42)  20 .

this be omes m( + m) ( + m)2 + . one arrives at 1 lim tr N !1 N HN %N (t)  =  2 + ( + m) ( + m)2 tanh(t) + tanh(t) 2 : 2  2 (44) In the limit t ! 1.With the help of (41). this leads to  tr exp(th) = 2 osh(t): (43) Plugging (42) and (43) into (39). and observing (41) and (43). (45)  2 2 where we have also used the de.

for t ! 1. the self- onsisten y equation (36) be omes. the mean .nition of  in the form 2 = 2 =  ( + m)2 = . + m + m m= : (46) =p  ( + m)2 + 2 r =  With the above. With similar arguments.

. we hoose the one derived from the relevant maximum (i. As we have dis ussed already in Se tion 2. But   exp(th)=tr exp(th) = exp(th~)=tr exp(th~) (48) for any h~ whi h di ers from h only by a onstant term.tness reads r =  2 m2 . (46) may have multiple solutions. the relevant solution is that solution of (46) whi h is losest to 1 (sin e no solution is larger than one. therefore. Sin e the wildtype is hara terized by m = 1.e.e. alternatively. (47) where m must be determined from the self- onsisten y equation (46). Let us now observe that r di ers from  . work with h~ := h 2  m2 +  1. Re apitulating our derivation. this is simply the largest solution). we note that the one-site Hamiltonian only appeared in the  expression exp(th)=tr exp(th) . i. the leading eigenvalue of h. this orresponds to the hoi e of the energy s ale so that the free energy equals the internal energy of the system at zero temperature (note that t ! 1 orresponds to T ! 0). utting a long derivation short. We may. the determination of the mean . lo ated at the wildtype). However. Therefore. (49) of whi h r in (47) is the leading eigenvalue. i. the entropy vanishes at zero temperature..e. h~ = h + 1. only by the onstant term ( =2)m2 . In physi al terms.

Hi := 1 : : : 1 ~h 1 : : : 1 with h~ in the i'th pla e. however. in analogy with the additive ase. with m the largest solution of (46). max(HN ). is approximated by 1 N max(HN ) = 1 N max X i  Hi + o(1) = max (h~) + o(1): (50) Here. the relationship (50) is stri tly limited to the largest 21 . the largest eigenvalue of the mutation-reprodu tion matrix. In ontrast to the latter.tness boils down to determining the leading eigenvalue of (49). Put di erently.

eigenvalue (sin e it relies on %N proje ting onto the PF eigenve tor of HN for t ! 1) { it does not hold for the remainder of the spe trum. Therefore. we may obtain the mean .

but not for .tness at equilibrium (t ! 1) this way.

so far.nite times. and . We have. drawn on the physi al formalism be ause it an be made mathemati ally rigorous.

.e. i. the equilibrium mean .nally provides an easy-to-use re ipe to al ulate the largest eigenvalue.

tness. For those who . to leading order.

more heuristi manner. regardless of their position. Equivalently. Az ) over all ve tors z with kz k2 = (z . (: . (52) is a large system of 2N equations. see Barton & Shpak (2000) for a re ent appli ation. due to the permutation invarian e of the PF eigenve tor. z ) = 1. one often starts out with this redu ed representation right away. max is obtained by maximizing (z . we shall use another route to arrive at the same result in a less rigorous. however. it may be redu ed to N + 1 equations: it is suÆ ient to spe ify the number of + sites. A tually. Az ) : (z . it may be determined via the Rayleigh oeÆ ient: max(A) = max (z . z ) = 1: (52) Of ourse.nd the derivation diÆ ult. whi h omes down to the eigenvalue equation. sin e the Perron-Frobenius theorem holds). We shall see. and the maximum is taken over all ve tors p in the spa e. and normalization: Az = max z subje t to (z . :) denotes the s alar produ t. z ) (51) Here. that referen e to the larger spa e is essential for . but with the help of elementary tools only. b) Using the Rayleigh oeÆ ient If the largest (in modulus) eigenvalue of a matrix A is real (this is the ase for our H. but. This is a ommon approa h in population geneti s.

nding the leading eigenvalue. we shall perform all steps expli itly. Sin e spe ial emphasis must be put on normalization. starting out from the original variables xs . We shall .

rst lump together all on.

gurations with P k `+' sites. irrespe tive of their position.e. i. yk := s:Ns+ =k xs . where Ns+ again is the number of `+' sites in on.

mk. of whi h there are Nk . it also follows that ky k1 = kxk1 = 1. (55) where mk. Likewise. (53) es : (54) X s:Ns+ =k  bk is the average over all basis ve tors with k `+` sites.k+1yk+1 = max yk .k 1yk 1 + mk.k + Rk )yk + mk. In this representation.k+1 = (k +1). the bk are unit ve tors in the one-norm. the eigenvalue equation (52) reads (mk.k 1 = (N +1 k). This orresponds to the hange in representation x= X where bk := s xs es =   N k 1 N X k=0 yk b k .k = N. mk. sin e k yk = s xs = 1.guration s. and Rk = (N 2k)+ 2 N (N 2k)2 is the . Like the original P P es .

` = 0 for ` 6= k 1. These oeÆ ients may be onsidered as the elements of a tridiagonal matrix (where mk.tness of a type with Ns+ = k. k + 1 is implied). k. 22 .

To this  1 1=2 bk . we now hange the normalization of the bk so that they be ome unit ve tors in the two-norm instead of in the one-norm. Rk ! Rk . ( k . and mkj ! k mkj Nj modi. bk ) = Nk . Performing the orresponding similarity  1=2 1=2 N ) leads to the of the tridiagonal matrix in (55) (i. We therefore hoose k := Nk  1 = 2 as our orthonormal basis (i. k = 0. With zk := Nk yk .j ).In order to keep tra k of the normalization ondition in (52). end. j ) = Æk.e. : : : . we observe that (bk . one then has x = PN PN transform for the elements k=0 yk bk = k=0 zk k .e. N .

Repla ing k=N by  . (N 2N 2k)2  N zk (56) where max is extensive in N . zk by f ( ). we see that f ( ) an only di er from zero if p r =  + 2  (1  ) + (1 2 ) + (1 2 )2 : (58) 2 De. and passing to intensive s aling. one obtains p   (57)  + 2  (1  ) + (1 2 ) + (1 2 )2 f ( ) + o(1) = max f ( ): 2 N Repla ing max =N by r and taking the limit N ! 1. expanding to leading order in N .ed eigenvalue equation in the new basis p p  k(N + 1 k)zk 1 +  (k + 1)(N k)zk+1 + (N 2k) + = maxzk .

one .ning m := 1 2 and demanding that the right-hand side be independent of m (and. Az ) in (51)). hen e. a stationary point of (z .

it is a vast improvement over the original problem. (46) is quarti and an. be solved for all parameter values. But even if one resorts to approximate or numeri al solutions. sin e the eigenvalue problem of a very large matrix boils down to solving this one and only equation. (46) even redu es to a quadrati equation.nally arrives at p  (  +  1 m2 + m + m2 ) = m 2 p m 1 m2 + m + = 0. Eq. In spe ial ases. in prin iple. To be spe i. (59) whi h an elementary al ulation shows to be equivalent to the self- onsisten y equation (46).

> 0 (for this hoi e. . the . let us onsider = 0.

(61) in a ordan e with (47). and m =  1 h .tness fun tion has its minimum at the mutation 2 2 2 2 equilibrium). therefore. all solution bran hes oales e. Then. h)2 . h  1 h > 1. m+ is the largest (and. For h < 1. h  1 m= (60) 0. (46) may be rewritten p as m 2(m + h ) = m (where we have used h := = ). with the solutions m0 = 0. we an also write down the varian e of . Thus. at h = 1. h>1 in agreement with (46). Sin e the lands ape is homogeneous with k = 2 (up to terms of order 1=N whi h do not ontribute in the limit). (p 1 h2 . m0 = 0 is the only one left. relevant) solution. and for h > 1. This leads to ( r = (1 2 0.

tness immediately ( f. h  1 vR = (62) 0. 21): ( 2h 2 (1 h)2 . h > 1: 23 .

So we have .

the al ulation employed here is heuristi . pass to intensive s aling and let N ! 1 to obtain 2 u2 !(u) = r !(u): (63) With r as obtained in Eq. h > 1: (64) This is the limiting probability measure dis ussed in Se tion 5. i. but weak onvergen e was shown expli itly in a somewhat more involved derivation (Wagner et al. an inspe tion of Eq. 1998)). Both . and an be made plausible by more elementary. This s aling omits some details. it follows that (  Æ u (1 h) . it may be used to determine the distribution of genotypes from Eq.e.. in terms of our original variables. (55). but suÆ es to determine the expe tation of u. (61). but less rigorous methods. (64) gives the mean surplus at equilibrium: ( u = 1 h. 6 as a fun tion of h. h  1 !(u) = Æ(u). we have seen that the quantum hain formalism provides a powerful method to determine the leading eigenvalue of the mutation-reprodu tion matrix. Finding that eigenvalue is the primary problem. h > 1: (65) The quantities r. the fa t that a delta peak appears here (instead of a distribution with positive varian e) is a onsequen e of the ` rude' 1=N s aling and weak onvergen e (a tually. Clearly. u and vR are displayed in Fig. So far. h  1 0.. and on e the answer is known. (55). As was noted there. We therefore put u := (2k N )=N and !N (u) := yk in Eq.nally managed to al ulate our observables.

tness and surplus de rease with in reasing mutation rate. whereas the varian e in .

tness .

The de line indi ates that sele tion be omes less and less eÆ ient and .rst in reases and then de reases again.

although there are . at the same time. (Note that. A population at mutation equilibrium also has r = vR = u = 0.nally eases to operate when vR vanishes. r and u vanish.

t genotypes and .

sin e the distribution is lustered very narrowly around u = 0 even for .tness di eren es present in a population of random types. they have vanishing impa t on r and vR in the limit N ! 1.

A ording to the usual de.nite N { hen e. One may therefore speak of an error threshold here: Beyond a riti al mutation rate ( > ). we must be more pre ise here. R = o(N ) and VR = o(N )). and the population loses its geneti stru ture in the sense that it annot be distinguished from a random population. at least not on the basis of the observables onsidered here. mutation an no longer be ountera ted by sele tion. However.

nition. an error threshold is identi.

ed with the mutation rate at whi h the .

with a large number of loselyspa ed . However. this riterion is taylored to the assumption of a sharply-peaked lands ape and need not give meaningful answers in other ases. In the urrent example.ttest type is lost from the population.

the .tness values.

ttest type may be ex eedingly rare even at small mutation rates. although the population is very near to its .

in ontrast to the sharply-peaked lands ape. We therefore require a more generally appli able de.tness optimum. until a onspi uous hange happens at  = . It is seen from Fig. 1 that. the distribution of types moves steadily in the dire tion of more mutations.

nition of error thresholds. and tentatively use the existen e of a nonanalyti point of the mean .

this is also used in physi s to de.tness as a fun tion of .

ne the analogous phenomenon of a phase transition. In the ase just treated. the dis ontinuous se ond 24 .

. Some referen e to the .derivative of r at h = 1 is obvious. and `something qualitatively new happens' beyond this point.e. a point at whi h the fun tion annot be expanded into a Taylor series) means that extrapolation is impossible. In any ase. but we shall see a more subtle example below. a nonanalyti ity (i.

ttest type remains: Our surplus (whi h plays a similar role as an order parameter in physi s) measures the mean agreement with the .

and vanishes at the error threshold. averaged over all sites.ttest genotype. dealt with the ompletely symmetri . and all members of the population. so far. We have.

. approximate solutions are more instru tive than the exa t ones. > 0. i.tness lands ape with positive epistasis. = 0. Let us al ulate the mean . for whi h everything may be written down analyti ally. For other parameters.e.

for the general quadrati .tness to se ond order in the mutation rate.

With m = m(). one obtains through impli it di erentiation of (46) (and with a little help from (Wolfram. 1996)): 1 : (66) m0 () = 0 and m00 () = ( + )2 Using this to expand r from Eq. (47) to se ond order in  yields for the mean .tness fun tion.

tness Mathemati a r = + 2 + 2 + O(3 ): 2( + ) (67) Sin e the referen e genotype has .

positive epistasis ( > 0) redu es the mutation load. one obtains for the mutation load `= 2 + O(3 ): 2( + ) (68) Clearly. whereas negative epistasis ( < 0) in reases it relative to additive .tness rmax = + =2.

tness ( = 0). To make sure that this is not an artifa t of variation in the range of .

let + =2 = . r1  and r0  0.tness values. Then. where r0 (r1 ) refer to the .

tness per site of a type with u = 1 (u = 0). ` =  2=(2( + =2)) + O(3 ). and the interpretation remains un hanged. But we an also extra t the qualitative pi ture for the general quadrati . Then.

with m := sin '. m 2 tan ' = + m . and write the self- onsisten y equation (46) in the form p m 1 or. 6= 0. even without approximation. Let .tness fun tion from a simple graphi al argument based on the self- onsisten y equation.  (69) + sin ' :  (70) = The `rightmost' interse tion of the graphs of the left-hand and right-hand sides of (70) de.

7 for various . and  (but only s enarios of dire tional sele tion are onsidered).. An error threshold o urs if this interse tion vanishes. i.e. if the interse tion on the positive bran h of tan ' eases to exist at some large enough  (the interse tion on the negative bran h may be safely ignored. arti. sin e it belongs to the se ond.nes the relevant equilibrium of the model. . This is depi ted in Fig.

ial peak of the .

e.  < 0. error thresholds exist whenever > 0.tness fun tion). diminishing returns) epistasis ( > 0). for unidire tional mutation. Geometri ally. but additionally. independently of (Charlesworth. in both ases the ondition means that the . In ontrast. 1990). The Figure demonstrates that this requires positive (i.

tness lands ape attains its minimum (i.. the .e.

that 25 .tness gradient vanishes) at positive surplus values.

whi h is lo ated at u = f. one has positive epistasis with the . 7. In the third panel (0 < < ). before the mutation equilibrium. Fig.

and no error threshold. For ompleteness. where the .tness minimum situated at u < 0. let us mention that there is no error threshold in the ase of stabilizing sele tion either.

whi h we ex luded from the Figure sin e we have been on entrating on dire tional sele tion throughout the arti le).1. 6. although we have hosen the setup (in parti ular the s aling) arefully to also allow the analysis of the time evolution of the model.3 Onsager's lands ape As suggested by the verbal des ription in Se tion 2. We have. and will ontinue to. But this is a separate issue and will be deferred to a future publi ation. the .tness maximum is at a surplus value between zero and one (this is the ase < < 0. restri t ourselves to the equilibrium behaviour here.

tness of on.

and w is the number of domain walls in the on. where > 0. up to an irrelevant onstant term) Rs = (N 2w) = k sk sk+1.guration s under OnP sager's lands ape is (again.

We assume y li boundary onditions for onvenien e. i.e.guration. sN +1 = s1 (other boundary onditions would not hange the qualitative behaviour of the solution { so we may go for the simplest ase). This orresponds to a spin system with nearest-neighbour intera tions as .

However.rst solved by Onsager. hen e the name of this setting. thus aiming at intera tions of `logi al' neighbours rather than spatial ones. we have listed a few qualitative properties of this . as well. we might. perform any renumbering of sites. In Se tion 2. it should be noted that the neighbouring relation need not be limited to spatial neighbours.

it was intuitively lear that there is positive epistasis. In parti ular. sin e the fra tion of ompensatory mutations in reases with the distan e from the peak. We shall make this more pre ise now by al ulating r^(u). the average .tness lands ape.

tness of a on.

In a random on. or N + = N (u + 1)=2 `+' sites.guration with surplus u.

between any pair of neighbouring sites. any site reads `+' with probability p = (1+ u)=2. and the expe ted number of domain walls in the on. there is a domain wall with probability 2pq = (1 + u)(1 u)=2.guration with surplus u. and ` ' with probability q = (1 u)=2. Thus.

r^(u) = u2 : (71) That is. but re all that expe tations are additive for sums of random variables. even if these random variables fail to be independent. Chap.guration is w = Npq = N (1 u2 )=2 (of ourse. IX). Therefore. as far as the average . Feller 1968. f. overlapping pairs of sites are not independent.

Onsager's lands ape oin ides with the quadrati .tness of types with surplus s is on erned.

whi h is very well studied ( f. Feller. Let us further remark that the whole distribution of the number of domain walls is easily al ulated. we now hange our strategy. Chap. however. 1968. For the previous lands apes. But we shall see in a moment that the behaviour is not governed by r^(u) alone. sin e no literature on the method is available that is a essible to the typi al theoreti al biologist. the mutation-reprodu tion operator for Onsager's lands ape reads H =M+R= X i (ix 1) + X i iz iz+1 : (72) To solve this model. the solution may be 26 . but we will not pursue this here. sin e the problem translates dire tly into the statisti s of runs in sequen es of Bernoulli trials. we have performed a line-by-line derivation.tness fun tion with = 0 and > 0 (up to a fa tor of 2). P With Rs = k sk sk+1 . II). For Onsager's lands ape.

followed in the famous paper by Lieb et al. To avoid dupli ation. (1961). Starting from expli it expressions for eigenvalues and eigenve tors of H for . we shall therefore not dwell on the derivation here. and there is also a very helpful text available (Thompson. but only summarize the results. Adaptations of this method to the biologi al situation an be found in Wagner et al. (1998). 1972).

e. the limit N ! 1 is performed and yields two symmetri bran hes of equilibria. the ground state energy (i. As a fun tion of h := = . At  = . just as with the orresponding quadrati lands ape.nite N . after whi h there is only one bran h left to survive. the bran hes oales e. mean .

Sin e the lands ape is.  :=  := 1 2 sin2 ( ) d (1 + h)2 2 0 is the omplete ellipti integral of the se ond kind. f. vR ) both have a nonanalyti point at h = 1 (the se ond derivative is dis ontinuous. homogeneous (two-site intera tions only).e. Abramowitz & Stegun (1970). r (and. the phase transition is se ond order in the . Although this is not so obvious. onsequently. (73)  2 where Z =2 q   4h 2 (74) . and E . again.  . one also has vR = 4r..tness per site) is derived to read 2   r = (1 + h)E . i.

the surplus does not orrespond to any physi al property and must be al ulated separately. (1998) and results in (p 1 h. h > 1. Clearly. As in the ase of the quadrati lands ape. at h = 1. h  1 u = (75) 0. the . This was done in Wagner et al.tness variable). for the positive bran h of the solution.

.e. the phase transition is .rst derivative is dis ontinuous (i.

rst order with respe t to the surplus). the nonanalyti ity is more readily diagnosed from this variable than from the mean . hen e.

6. The results are depi ted in Fig. For small mutation rates. the behaviour of mean and varian e in .tness alone.

however. and a phase transition o urs in the sense that the mean . For larger mutation rates. The surplus pre ipitates to zero. there are obvious di eren es.tness is very similar to the orresponding permutation-invariant model.

But there is still appre iable .tness displays a nonanalyti ity.

tness left. This re e ts the fa t that . and the varian e remains very large.

tness is not a fun tion of the number of deleterious mutations when ompensatory mutations are present: Here. we have very .

t on.

gurations (+ + +    +    as an extreme example) whose distan e from the .

and. 5. where the time evolution of the mean . Re all that we have.ttest sequen e is lose to that of a random sequen e. used this system to illustrate the time evolution in the limit N ! 1. they will be present in appre iable amounts. in the `s aling and limits' se tion. at high mutation rates. Let us now ome ba k to this point and refer again to Fig.

onvergen e to equilibrium o urs within an evolutionarily reasonable time span. onvergen e towards the equilibrium be omes in. however. namely a purely wildtype and a fully randomized population. for example. Let us. The time evolution of the varian e of the surplus. whi h we have not dis ussed here. may show a qualitatively di erent behaviour. shows what is alled a ` riti al slowing down': In the vi inity of the riti al point. mention that other observables.tness is depi ted for two di erent (extreme) initial onditions. Clearly.

although the mean .nitely slow (in genotype spa e). and the equilibrium distribution of genotypes will never be rea hed.

tness has long be ome stationary. We only mention this 27 .

the di eren es ranging from subtle to fundamental. 7 Dis ussion There are obvious parallels between the topi s of population geneti s and statisti al physi s: Both deal with a huge number of possible to hint at the ompli ated rearrangements that may go on as a onsequen e of ompensatory mutations. In the realm of mutation-sele tion models. the equivalen e with a lassi al two-dimensional Ising model had been known for . it is an obvious idea to try and apply su h methods to solve problems from population geneti s. a one-to-one orresponden e between biologi al and physi al models is rare. One is therefore interested in a few statisti al properties rather than all the details. see Wagner et al. for more details. However. and there is no way to observe them all. Sin e the mathemati al tools of statisti al physi s are highly developed. (1998).

the translation is one-to-one. nearest neighbour between rows) proved so di erent from those in typi al physi al models that progress along these lines was limited.fteen years (Leuthausser. 1986). and the di tionary reads . The quantum hain pi ture over omes this problem. the surplus di ers from the quantum-me hani al magnetization in a fundamental way. but the intera tions arising in the biologi al model (long-range within rows. Apart from this. in parti ular. but now are must be exer ised to distinguish arefully between quantum-me hani al and lassi al quantities.

tness additive part of .

tness epistati part of .

tness equilibrium mean .

tness mutation mutation rate time error threshold $ $ $ $ $ $ $ $ energy intera tion with longitudinal .

eld within- hain intera tion ground state energy intera tion with transversal .

eld temperature-like parameter inverse temperature phase transition The main bene.

t of the equivalen e is that it makes available the toolbox of quantum statisti al me hani s to al ulate the leading eigenvalue of the mutation-reprodu tion matrix. i.e. the mean .

one obtains the mutation load. Mu h more dire tly. This.tness. gives a ess to the orresponding eigenve tor and the surplus. the mutation load in haploids (or diploids without dominan e) equals the mutation rate if mutation is unidire tional { independently of the ..e. This is nontrivial as soon as one leaves the territory where Haldane's Prin iple holds (i. in turn.

Not surprisingly. For quadrati . but still with haploid. Charlesworth. with symmetri mutation. in parti ular. 1990. independently of epistasis).tness fun tion. symmetri mutation by itself diminishes the mutation load. Higgs. Deviations from Haldane's Prin iple have been investigated in situations with dominan e and various s hemes of sexual reprodu tion but still with unidire tional mutation. the overall pi ture is that positive epistasis enhan es the mutation load. whereas negative epistasis alleviates it (Kimura & Maruyama. 1966. 1994). asexual populations. We have explored the other dire tion here.

tness fun tions with epistasis. we again .

28 . too { f. The same holds true for Onsager's lands ape. Fig.nd that positive (negative) epistasis enhan es (de reases) the mutation load relative to this zero-epistasis referen e ase. 6. whi h exhibits ompensatory mutations but positive epistasis.

A phenomenon losely related to mutation loads is the error threshold. so far. whi h. has no lear- ut de.

nition. but whi h we have tentatively identi.

ed with a nonanalyti point of the mean .

This subsumes various types of behaviour.tness. in the quadrati lands ape with = 0. For example. Onsager's lands ape displays a phase transition whi h is not obvious at the . sele tion eases to operate beyond a riti al mutation rate. in ontrast.

and has been dis ussed from various points of views. there is a nonanalyti point in the limit N ! 1. The existen e of error thresholds has been highly ontroversial. In both ases. The . whi h marks a qualitative hange in the behaviour of the system. but all the more onspi uous at the geneti level.tness level.

rst question is whether su h a phenomenon is observed in experiments. Answers require .

tness measurements at various (arti.

whi h are pra ti ally unfeasible for organisms larger than ba teria. extin tion of the population is observed at in reased levels of mutagenesis (Holland et al. In viruses with small RNA genomes. the main question is whi h . From the theoreti al point of view. the demonstration of a sharp transition would require mu h more pre ise measurements at very losely spa ed mutation rates. Domingo & Holland. ially elevated) mutation rates. whi h is taken as indi ative of an error threshold. might help to larify the pi ture. However. 1990. sin e this would yield a measurement orresponding to our surplus. In lusion of the geneti level.. maybe through DNA hybridization studies with the wildtype. 1997).

7 that a further requirement is that the (lo al) . They further allow the spe ulation that positive epistasis is a ne essary.tness lands apes have error thresholds. Wiehe (1997). The examples investigated in Charlesworth (1990). and the present study demonstrate that error thresholds are not restri ted to the sharply-peaked lands ape. but not suÆ ient ondition for the existen e of an error threshold (we have seen in Fig.

this is due to what is known as universality in physi s (Kadano . the last but hardest question is: What are biologi ally realisti .tness minimum be lo ated at a positive surplus value). Although the models are admittedly rather spe ial. there is no reason to believe that the result is atypi al. 1987). Cardy. 1976. Of ourse.

the hromosome-wide average of the .. 1972) yield data for R^ k .tness lands apes? The lassi al mutation-sele tion experiments (Mukai et al.

the data are ompatible with a quadrati . For the small range of k observed.tness of a genotype with k mutations. permutation-invariant .

The importan e of individual intera tions is orroborated by our results on Onsager's lands ape.tness fun tion Rk with positive epistasis. Further. (2000) to demonstrate that. depending on the state of the remainder of the metaboli network. without a general pi ture emerging so far (Whitlo k et al.. metaboli ontrol theory is used by Phillips et al. detailed mutation experiments have revealed all kinds of epistati intera tions lo ally. 1997). positive and negative epistasis are equally plausible to o ur. as pointed out in Phillips et al. and many of the intera tions tend to an el ea h other when it omes to averages (Elena & Lenski. there is no reason to believe that this fun tion models the lo al intera tions orre tly. with a single gene oding for an enzyme. whi h has the same average . 1995). But. for example. it may be argued on theoreti al grounds that all kinds of intera tions may exist. On the ontrary. (2000).

It is hard to on eive that the . one ru ial question on erns R^ k for larger k than those measured. but displays very di erent behaviour.tness fun tion r^(u) as a quadrati one. Of ourse. But let us return to the Drosophila data.

it will be shown that even onvex regions of the .tness fun tion is on ave throughout. In a forth oming paper.

and to extra t the hara teristi behaviour in an expli it manner. So the ase is not yet losed | not even for Drosophila. The limit N ! 1 was a ru ial tool to simplify the solution of the models. For .tness fun tion may lead to threshold behaviour.

there annot be a nonanalyti point. 29 .nite N .

whi h we used to de.

ne error thresholds. In a large but .

nite system with a quadrati .

the se ond derivative of the mean .tness fun tion. for example.

(61). the limit must be performed in a way whi h guarantees maximum similarity between the behaviour of the . whi h turns into a jump for N ! 1. f. To be on lusive.tness performs a steep but smooth transition from to 0.

nite (biologi al) system and the in.

as de.nitely large (mathemati al) one.

ned in (25). We have seen that this requires extensive s aling of both mutation and .

and gives a ess to observables like the mean and varian e in .tness.

without referen e to the spatial stru ture within the on.tness. whi h involve simple averages over all sites. or the fra tion of mutated sites.

guration. however. Also. These quantities are measureable with high pre ision in physi s and onvey ru ial information about the nature of the phase transition. As we have dis ussed above. If `spatial' aspe ts (like the size of domains) were to be investigated. . Criti al exponents give the power laws of the de ay of a quantity in the vi inity of the riti al point. for example. but exponent 1=2 in Onsager's lands ape. the lo ation of the error threshold (if any) is only measureable with an enormous e ort (if at all). the surplus has exponent 1 in the quadrati lands ape with = 0 and = 1. and pre ise hara terization of the equilibrium for mutation rates in the vi inity of the threshold are virtually impossible. Readers with a physi al ba kground may have wondered why we have not even mentioned riti al exponents. a very di erent approa h would be required.

and hanges the nature of the transition. sin e it shifts error thresholds to smaller mutation rates. For small mutation rates.nite population size would render su h observations meaningless. on the other hand. the behaviour is often very similar to that of the in.

may be in either of two states (or phases). see Wiehe et al. 2000).. (1995). and the parameter regions far from the riti al point are at least as interesting. riti al exponents seem to be less meaningful from the biologi al point of view. 30 . we re ommend Thompson (1972) as a really lu id text. For readers unfamiliar with the matter. At a riti al temperature. parti les are onsidered as lo alized at the verti es of a re tangular latti e pat h.nite population. To on lude. this paper has been mainly on erned with the development of novel methods for the analysis of mutation-sele tion balan e. an ordered one (at low temperature) and a disordered one (at high temperature)1 . It is worth mentioning that these te hniques an also be applied to mutation-sele tion models with more than two states per site (Hermisson et al. we will apply our methods to the general lass of permutation-invariant lands apes and draw more general biologi al on lusions. the phases in question have or do not have spontaneous magnetization. whi h may be 1 More pre isely. We have illustrated these methods by means of sele ted examples. and a phase transition o urs from the ordered into the disordered phase. The intera tion between the parti les tends to align the magneti moments. 8 Appendix: Ising's model (Ferro-)magneti materials. In a forth oming paper. A ording to Ising's model. whereas the thermal movement has a randomizing e e t. like iron. Whi h of them is present depends on the interplay of two `for es'. The lassi al model for the des ription of su h phenomena is the Ising model. whi h in luded ompensatory mutations in one ase. and their magneti moments (or spins) may only assume two dire tions. the latter be omes so strong that the intera tion between the parti les is e e tively over ome. For these reasons.


respe tively. or +1 and 1. there are thus 2MN possible on.ed with `north' and `south'. For a pat h with N olumns and M rows.

1gMN .gurations 2 f+1. Every on.

guration has an energy E ( ). E is a mapping from on.

and depends on the details of the intera tion between the parti les. in thermodynami equilibrium. the probabilities p( ) of the on. It is well-known that.guration spa e to the real numbers.

e.gurations follow the Boltzmann distribution.  . i.

(76) Z where .E ( ) p( ) = .

and T the absolute temperature). and Z is the partition fun tion exp Z := X  . := 1=(kT ) is the inverse temperature (with k being Boltzmann's onstant.

After all. in fa t. as su h. One therefore seeks to al ulate Z on e the model (i. sin e the operation involves di erentiation). but is.e. all ma ros opi properties of the system may be derived from it (in the literal sense indeed.E ( ) : exp (77) The partition fun tion appears just as a normalization fa tor here. a quantity of fundamental importan e. a generating fun tion and. E ( )) is spe i.

but this tends to be a formidable task due to the large number of on.ed.

For two-dimensional systems on a re tangular pat h. the transfer matrix method is appropriate. as long as the intera tions do not span more than two neighbouring rows. The (row-to-row) transfer matrix is a 2N  2N matrix whi h `transports' the distribution of `row on. whi h solves the problem at least formally. It will also provide the link to the evolution model.gurations involved.

To be more spe i. The al ulation of Z for the pat h is then a hieved by starting from the equidistribution at the bottom row.gurations' from one row of the latti e pat h to the next. and summing up the result at the last row. su essive appli ation of the transfer matrix.

let a on. .

guration be de.

ned through its row on.

: : : . Assume that the intera tion energy within a row with on. M (i. si2 . siN ).gurations si := i (s1 . the supers ripts label rows. : : : .e. i = 1. the subs ripts label olumns).

e. and intera tion between the rows is nearest neighbour. where J determines the strength of the intera tions.guration s is given by E (s). every pair of neighbouring spins in the verti al dire tion yields an energy ontribution of Jsij+1 sij . and positive ones from those whi h are di erent. so there are negative energy ontributions from all neighbouring pairs whi h are alike. i. The energy of the whole on.

Thompson. 1972) has elements Ts0s = exp .guration then reads E ( ) = M  X J j =1 N X j +1 j i=1  si si + E (sj ) : (78) The orresponding row-to-row transfer matrix ( f.

J X i  s0i si exp  .

Eq. x(t +  ) = VW x(t) (80) where  denotes the duration of one generation. (80) is obtained through the identi. (3).E (s) : (79) Let us now link the transfer matrix with our mutation-sele tion model. To this end. we onsider a dis rete-time version of Eq.

ations V = exp( M) and 31 W = exp( R): (81) .

the elements of the diagonal matrix W are ws = exp(Rs ) (the well-known relationship between Wrightian and Malthusian .More expli itly.

whi h belong to the quasispe ies model (5).tness.s) . and the elements of V are the mutation probabilities vs s = pD(s . (82) with p = e  sinh( ). Crow & Kimura 1970).s) (1 p)N 0 0 D(s0 . to whi h the transfer matrix approa h was applied in the . f.

This is be ause its elements may be rewritten as  .rst pla e (Leuthausser. 1986). Leuthausser (1986. A tually. 1987) showed that the mutation-reprodu tion matrix VW is exa tly equivalent to the transfer matrix of a two-dimensional Ising model of the type just des ribed.

X 0  (VW )s0 s = p(1 p) N=2  exp s s exp(Rs  ) . (83) 2 j j j  where .

= ln(p=(1 p)). The analogy with (79) is then apparent (note that p(1 p) N=2 is a onstant fa tor independent of the spin on.

This is the line of des ent depi ted in Fig. grandmother-mother-daughter-granddaughter sequen e). 3. whi h is obtained when sequen es are piled on top of ea h other generation-wise (i.e. A line of des ent may now be identi. not in the sense of the oales ent (it does not bifur ate).guration). note that the result is a genealogy in the sense of a single lineage. We have reprodu ed this result here be ause there is a plausible biologi al pi ture behind this equivalen e.

ed with a on.

The intera tions de. and the rows to generations.guration of a two-dimensional Ising latti e pat h. The present time orresponds to the (upper) pat h surfa e. where the olumns orrespond to positions in the sequen e.

Within rows. whi h pro eeds independently at every site.ning this Ising model are anisotropi . These intera tions represent the . intera tions may be very ompli ated and long-ranged|just imagine a protein folding ba k upon itself. on the other hand. and has no memory of previous generations. this orresponds to mutation. They are nearest-neighbour between rows.

e. i.tness lands ape. they de.

ne the mapping from sequen es (i.e. row on.

gurations) into .

tness values. The .

in turn. the intera tions (but not the . Sin e the lands ape is stagnant. orresponds to the intera tion energy within the row.tness of a sequen e.

More pre isely.tness!) are the same for every row. the .

tness lands ape may be de omposed into intera tion oeÆ ients I in the way des ribed in the main text. The intera tion pattern stored in these oeÆ ients may be visualized as in Fig. It may be understood as a re ipe of how to determine the . 3.

In parti ular.tness given the sequen e. This re ipe is the same for every sequen e. hen e the intera tions are identi al in all rows of the latti e. an in. The translation between biologi al and physi al quantities may be ontinued.

nite biologi al population (together with its history) orresponds to an ensemble of Ising on.

gurations. the mutation rate orresponds to a temperature-like parameter ( f. and the error threshold may be identi. (79) and (83)).

over the past ten years. surprisingly few appli ations have made use of it.ed with a phase transition of the system. this equivalen e makes available the highly developed tools of statisti al physi s for use in population geneti s. Apart from the ase of multipli ative . and progress along these lines has been surprisingly sparse. Apart from its intuitive appeal. However.

The reason for the general sparseness of results seems to be that. This may be seen by evaluating the matrix exponentials and writing their produ t in terms of sums of produ ts 32 .tness. After all. in exp( M) exp( R).g. horizontal and verti al intera tions of all orders mix. a few approximate and numeri al studies have exploited the transfer matrix method. e. there are still no lands apes for whi h exa t solutions are available. Tarazona (1992).

and vi e versa. (80) and (81) shrink to zero. as in Fig. 4. mutation and reprodu tion intera tions remain separate in M + R.of Pauli matri es. whi h results in `mutation' (x ) terms whi h are in uen ed by `reprodu tion' terms (z ). But let now  in Eqs. In ontrast. so that the number of generations per unit time goes to in.

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and under a quadrati .Figure aptions Figure 1: Mutation-sele tion balan e in a sharply-peaked lands ape (left).

whi h are equally un.tness fun tion with positive epistasis (right). the referen e type has a sele tive advantage over all others. In the sharply-peaked lands ape.

Shown is the numeri al solution of Eq. i. where k is the number of mutated sites.e. Rk = 1 for k  1. (1) for N = 30. Relative frequen ies pk of on. R0 = 1..t. and sele tive advantage = 0:03 of the favourable type.

gurations with k mutant sites are represented as grey s ales in the plane with k (0  k  30) in the horizontal dire tion.e. For the quadrati . For mutation rates above the error threshold ( ' =N = 0:001). pk = Nk =2N .  (0    0:002) in the verti al dire tion (type freqen ies in rease with darkness of shading). and the mutation rate per site. i. the population is evenly distributed over type  spa e.

and a = 0:002+2  10 6 . whi h orresponds to the Hamiltonian (26) with = 0:001 and = 10 6 (this breaks the symmetry). = 0:004. Rk = (ak + k2 =2N ) with N = 30. until the agreement with the . Here.tness fun tion. the type distribution broadens and moves away from the optimum gradually.

For both .ttest type (i. the surplus) vanishes at  ' = 0:001.e.

tness fun tions. Figure 2: A biologi al population and a olle tion of quantum-me hani al spins may both be identi. this transition be ome sharp in the limit N ! 1.

Left: N = 1. A ve tor in the unit simplex under the ompeting a tions of mutation (at rate ) and sele tion (at rate 1 > 0). and with ea h other. The dashed line indi ates the dire tion of mutation (the transversal .ed N with a ve tor in R2 .

eld). whereas the horizontal dire tion orresponds to sele tion (the longitudinal .

eld). Fitness is de omposed into additive (1 . Right: Chain of length N = 5. 5 ) and epistati (12 . The marginal frequen ies at ea h of the sites may be represented by a ve tor in the unit simplex (the ve tors are drawn to have unit one-norm ea h). 345 ) omponents. : : : . The additive omponents a t separately at the sites (longitudinal .

as does mutation (transversal .eld).

Figure 3: Line of des ent as a two-dimensional.e. Sequen es des ending from ea h other (i. grandmother-mother-daughter) form the rows of the latti e. and the transition from one row to the next is governed by the mutation-reprodu tion matrix VW .eld). The epistati omponents introdu e intera tions within the hain. If the letters of the sequen e are identi. anisotropi Ising model. rows to generations. olumns orrespond to sequen e positions. This way.

every line of des ent orresponds to one possible on.ed with spins.

but are identi al for every row. Intera tions are anisotropi : Intera tions between the rows (dashed) are nearest neighbour and orrespond to mutation. de. as well as their strengths. Intera tions within the rows (solid lines) may be arbitrary and long-range.guration of a twodimensional Ising model. and the transfer matrix takes the role of the mutation-reprodu tion matrix. Their presen e or absen e.

ne the .

The latti e is as in Fig. 3. Figure 4: Short-generation or anisotropi limit.tness lands ape in the sense of a mapping from sequen e spa e into the real numbers. whereas the distan e between olumns remains onstant. with olumns orresponding to sequen e positions and rows to generations. the line of des ent with dis rete 38 . The distan e between rows tends to zero. This way.

Figure 5: Time evolution of the mean . and the lassi al Ising model is repla ed by an Ising quantum hain.generations turns into the parallel mutation-sele tion model in ontinuous time.

and equidistribution of sequen es (u = 0). Top: Extensive s aling of mutation and . The initial onditions are a pure wildtype distribution (u = 1). N = 100 (dashed) and N = 1000 (solid line). Furthermore. any intermediate value on the urve may be taken as initial ondition due to the semigroup property of the ow. respe tively.tness on Onsager's lands ape with = 0:001 and  = 0:00025 for N = 10 (dotted). but illustrates the properties of the s aling. The latter is not meant to be a realisti initial ondition.

tness (as in (6) and (8)) yields uniform onvergen e. even from the most extreme initial ondition. Figure 6: Mean . one has only pointwise onvergen e to zero for every value of t. Bottom: Intensive s aling (obtained through Rs ! Rs =N . Then.  ! =N ) slows evolution down. then onvergen e to equilibrium o urs roughly within 2000 years. If reprodu tion and mutation rates have the unit 1=year.

and varian e in . surplus.tness.

as a fun tion of the mutation rate per site. in the limit N ! 1.tness per site at equilibrium. Dotted: additive .

tness (with = 0:001). solid line: quadrati .

tness fun tion (with = 0. for N = 1000 sites. dashed: Onsager's lands ape (with = 0:001). The parameters are hosen su h that. = 0:002). the intensive quantities translate into the extensive ones R0 = 1 (.

ttest type). R1 ' 0:998 or R1 ' 0:996 (se ondbest type in the ase of additive .

respe tively). or in the ase of quadrati and Onsager lands ape.tness. RN=2 = 0 (randomized genotype). and VR is in the range of 10 3 . Figure 7: Equilibria for the quadrati .

Shown are those ases with a .tness fun tion.

0 < < . < < 0. Upper panels: (intensively-s aled) . 0 < < .tness maximum at the wildtype (dire tional sele tion). From left to right: < < 0.

for small  (dotted) as well as large  (dashed). lower panels: left-hand side of Eq. as a fun tion of '. (70). An error threshold o urs if the interse tion disappears for some large enough . This only happens in the regime < < 0. A bullet indi ates the solution of (70).tness fun tion r (verti al axes) as a fun tion of u (horizontal axes). 39 . (70) (solid line). and right-hand side of Eq.

001 0 0 0 15 30 Figure 1: 40 0 15 30 .002 0.0.001 0.002 0.

− η η 12 345 µ η1 η1 + Figure 2: 41 η2 η3 η4 η5 .

generation position in sequence Figure 3: 42 .

Figure 4: 43 .

5 0 Figure 5: 44 .5 0 0 1000 2000 t 0 10000 20000 t 30000 3000  R 0.0 r @´10-3 D 0.1.

002 Μ 0.0 vR @´10-6 D 0.001 0.003 0 0.1.001 0.001 0.0 r @´10-3 D 0.003 0 0.5 0 1.002 Μ 0.002 Μ 0.5 0 0 0.5 0 Figure 6: 45 .003 1  u 0.

5 0. 0 -1 1 10. 46 0 0 -А4 0 А4 0 -А4 0 А4 0 -А4 Figure 7: 0 А4 -А4 0 А4 . 0 0 -1 1 10.5 0.´10-3 ´10-3 ´10-3 ´10-3 0.5 0 0 0 0 -1 1 10.5 0. 0 -1 1 10.