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**I. Stochastic Tunneling in the Neutral Case
**

Richard Durrett

∗

and Stephen Moseley

†

Department of Mathematics, Box 90320,

Duke U., Durham NC 27708-0320

December 15, 2012

Abstract

We consider a multistage cancer model in which cells are arranged in a d-

dimensional integer lattice. Starting with all wild-type cells, we prove results

about the distribution of the ﬁrst time when two neutral mutations have ac-

cumulated in some cell in dimensions d = 2, and 3, extending work done by

Inspired by Komarova (2007) for d = 1.

1 Introduction

The accumulation of mutations is important not only for cancer initiation, pro-

gression, and metastasis, but also for the emergence of acquired resistance against

chemotherapeutics, radiation therapy, or targeted drugs. For this reason there is a

large and growing literature on the waiting time τ

k

until some cell has acquired k

prespeciﬁed mutations. In all the models we consider type i individuals mutate to

type (i + 1) at rate u

i+1

. The dynamics considered are primarily of two types have

most often been studied in multi-type Moran models with a homogeneously mixing

population of constant size. Here we will concentrate on how results change when

one considers a spatial Moran models, and as is the case for much earlier work we

will concentrate on the behavior of τ

2

.

We suppose that cells of type 0 and type 1 have relative ﬁtness 1 and λ. Since we

will only consider the waiting time for the ﬁrst type 2, the relative ﬁtness of type 2’s

is not important. In this work we will consider situation in which λ is so close to 1

that the mutations are essentially neutral. For cancer applications, this is a restrictive

∗

Partially supported by NIH grant 5R01GM096190

†

This work was part of his 2011 Ph.D. thesis in Applied Mathematics at Cornell U.

1

assumption, and it will be removed in the companion paper (part II) by Durrett, Foo

and Leder (2012). However, the current result applies to the important case of tumor

suppressor genes. In this case, when both copies of the gene are inactivated trouble

develops, but while there is one working copy the cell can function normally.

We begin by recalling results for the Moran model in a homogeneously mixing

population of size N. Iwasa, Michor, and Nowak (2004), and Iwasa et al. (2005)

proved:

Theorem 1. In the neutral case, λ = 1, if we assume that

1

√

u

2

N

1

u

1

(1)

and let u

1

, u

2

→0 then we have

P(τ

2

> t/Nu

1

u

1/2

2

) →exp(−t)

The same conclusion holds if |λ −1| u

1/2

2

.

Durrett and Schmidt (2008) applied these ideas to study regulatory sequence evolution

and to expose ﬂaws in Michael Behe’s arguments for intelligent design. Durrett,

Schmidt, and Schweinsberg (2009), see also Schweinsberg (2008), generalized this

result to cover τ

k

.

The conditions in the result may look mysterious but they can be derived by

simple reasoning. Suppose ﬁrst that λ = 1.

(A1) If we start the Moran model with k N type 1’s and the rest type 0, then the

1’s behave like a critical branching process. The time needed for the 1’s to die out is

O(k) and the number of type-1 births before they die out is O(k

2

). Thus we expect

the ﬁrst type 2 to occur in a type 1 family that reaches size k

1

= O(1/

√

u

2

). The

ﬁrst condition in (1) guarantees k

1

N.

(A2) The probability a type-1 mutation creates a family that reaches size 1/

√

u

2

is

√

u

2

. More to the point a simple computation (consider what happens at the ﬁrst

jump) shows that the probability a type-1 family gives rise to a type-2 before it dies

out is ∼

√

u

2

. Once this is done it follows easily that if ρ

2

is the birth time of the

type-1 mutant that ﬁrst gives rise to a type 2 then

P(ρ

2

> t/Nu

1

u

1/2

2

) →exp(−t)

Mutations to type 1 occur at times of a rate Nu

1

Poisson process and with probability

∼

√

u

2

give rise to a type 2. To complete the proof we need to show that τ

2

−ρ

2

ρ

2

,

and for this we need the second condition in (1).

(A3) By the discussion of (A1), the ﬁrst mutation will occur in a family that reaches

a size O(1/

√

u

2

). If |λ −1| u

1/2

2

, then computations with Girsanov’s formula show

2

that (in the limit u

2

→0) the behavior of the Moran model, while it is O(1/

√

u

2

), is

indistinguishable from the case with no drift.

The assumption of a homogeneously mixing cell populations simpliﬁes calculations

considerably, but is not realistic for solid tumors. For this reason, Komarova (2006)

considered a spatial model, which is very similar to one introduced much earlier by

Williams and Bjerknes (1972). Due to work of Bramson and Griﬀeath (1980b, 1981),

the second model is known to probabilists as the biased voter model.

In the usual formulation of the biased voter model each site on the d-dimensional

integer lattice Z

d

can be in state 0 or 1 indicating the presence of a cell with realtive

ﬁtness 1 or λ > 1. Cells give birth at a rate equal to its ﬁtness, and the oﬀspring

replaces a nearest neighbor chosen at random. When λ = 1 this is the voter model

which was introduced independently by Cliﬀord and Sudbury (1973) and Holley and

Liggett (1975). For a summary of what is known see Liggett (1999).

In the biased voter model births drive the process. In Komarova’s version cells

die at rate 1 and are replaced by a copy of a nearest neighbor chosen with probability

proportional to its ﬁtness. A site with n

i

neighbors in state i makes

transitions at rate

0 →1 λn

1

/(λn

1

+ n

0

1 →0 n

0

/(λn

1

+ n

0

In d = 1 if the set of sites in state 1 is an interval [, r] with < r then any site

that can change has n

1

= n

0

= 1 so Komarova’s model is a time change of the biased

voter model. In d ≥ 2 this is not exactly true. However, we are interested in values

of λ = 1+s where s = 0.02 or even less, so we expect the two models to have similar.

In any case, the diﬀerence between the two models is much less than their diﬀerence

from reality, so will choose to study the biased voter, whose duality with branching

coalescing random walk (to be described below) gives us a powerful tool for doing

computations.

Since we want a ﬁnite cell population we will restrict our process to be a subset

of [−L/2, L/2)

d

. Komarova (2006) uses “Dirichlet boundary conditions”, i.e., she

assumes her space is an interval with no cells outside, but this is awkward because

the set of type 1 cells may reach one end of the interval and then no further changes

happen at that end. To avoid this, we will use periodic boundary conditions, i.e., we

consider (Z mod L)

d

. The resulting toroidal geometry is a little strange for studying

cancer. However, using (Z mod L)

d

has the advantage that the space looks the same

seen from any point. Our results will show that for the parameter values the ﬁrst

type 2 will arise when the radius of the set of sites occupied by 1’s is L so the

boundary conditions do not matter.

Let ξ

0

s

be the set of cells equal to 1 in the voter model on Z

d

starting from a single

type 1 at 0, let |ξ

0

s

| be the number of cells in ξ

0

s

, and let

ν

d

= 1 −E exp

_

−u

2

_

T

0

0

|ξ

0

s

| ds

_

(2)

3

be the probability, which depends on the dimension d, that a mutation to type 1 gives

rise to a type 2 before its family dies out, assuming there were no further mutations

to type 1. Since mutations to type 1 in a population of N cells occur at rate Nu

1

this suggests that

P(τ

2

> t) ≈ exp (−Nu

1

ν

d

t) (3)

As we will explain in a moment, ν

d

∼ γ

d

h

d

(u

2

) as u

2

→0 where

h

d

(u) =

_

¸

_

¸

_

u

1/3

d = 1

u

1/2

log

1/2

(1/u) d = 2

u

1/2

d ≥ 3

(4)

and f(u) ∼ g(u) means f(u)/g(u) → 1. To state the result we need one more

deﬁnition:

g

d

(u) =

_

¸

_

¸

_

u

1/3

d = 1

log

−1/2

(1/u) d = 2

1 d ≥ 3

(5)

Theorem 2. In the neutral case, r = 1, if we assume

1

h

d

(u

2

)

N

g

d

(u

2

)

u

1

(6)

then there are constants γ

d

given in (10) and (11) so that as u

1

, u

2

→0

P(τ

2

> t/Nu

1

γ

d

h

d

(u

2

)) →exp(−t)

The same conclusion holds if |λ −1| h

d

(u

2

).

In d = 1 this result was proved by Komarova (2006), see her equation (62) and

assumption (60), then change notation u

1

→u, u

2

→u

1

. See also Komarova (2007).

Note that when d ≥ 3 the order of magnitude of the waiting time and the assumptions

are the same as in Theorem 1. In d = 2 there are logarithmic corrections to the

behavior in Theorem 1, so only in the case of d = 1 (which is relevant to cancer in

the mammary ducts) does space make a substantial change in the waiting time.

The reasons for the conditions in Theorem 2 are the same as in Theorem 1.

(B1) We will see that the mutation to type-2 will occur in a type-1 family that reaches

size k = O(1/h

d

(u

2

)). The left hand assumption in (6) implies that k N, so the

type 2 mutant arises before the 1’s reach ﬁxation.

(B2) Let ρ

2

be the time of the ﬁrst type 1 mutation that leads to a type 2. Since

mutations to type 1 occur at rate Nu

1

and lead to a type 2 with probability ν

d

, it is

easy to see that

P(ρ

2

> t) ≈ exp(−Nu

1

ν

d

t)

4

so to prove the result we need to show that with high probability τ

2

−ρ

2

ρ

2

, and

this is guaranteed by the right-hand assumption in (6).

(B3) As in the discussion of Theorem 1, once we know that the mutation to type-2

will occur in a type-1 family that reaches size k = O(1/h

d

(u

2

)), it follows that if

|λ−1| h

d

(u

2

) then (in the limit u

2

→0) the behavior of the random walk is, while

it is O(1/h

d

(u

2

)), indistinguishable from the case with no drift.

2 Proof, part I: Ideas

Let T

k

be the ﬁrst time |ξ

0

t

| = k. Let

a

n

=

_

¸

_

¸

_

n

2

d = 1

2nlog n d = 2

n d ≥ 3

Let β

2

= π and for d ≥ 3 let β

d

be the probability two simple random walks started

at 0 and e

1

= (1, 0, . . . 0) never hit. The key is to the proof of Theorem 2 is

Lemma 1. Let ξ

0

t

be the unbiased voter model (i.e., λ = 1) starting from a single

occupied site.

_

|ξ

0

Tn+ant|

n

¸

¸

¸

¸

¸

T

n

< ∞

_

⇒(X

t

|X

0

= ) (7)

where ⇒indicates convergence in distribution of the stochastic processes and the limit

has

dX

t

=

_

√

2 dB

t

d = 1

√

2β

d

X

t

dB

t

d ≥ 2

where B

t

is a one dimensional Brownian motion. In d = 1 the process is stopped

when it hits 0. In d ≥ 2, 0 is an exit boundary so we don’t need to stop the process.

In the homogeneously mixing case the limit is dX

t

=

√

2X

t

dB

t

.

Proof. The one dimensional case is easy because the boundary of ξ

0

t

always has size 2

when |ξ

0

t

| > 0, and hence |ξ

0

t

| is a symmetric simple random walk that jumps at rate

2. Sawyer (1979) and Bramson and Griﬀeath (1980a) were the ﬁrst to study the size

of |ξ

0

t

|, but here we need the more sophisticated result of Bramson, Cox, and LeGall

(2001), which gives the result quoted above.

In d ≥ 2 when |ξ

0

t

| = k the boundary could be as large as 2dk for isolated points,

or as small as Ck

(d−1)/d

for a solid ball. The right answer lies in between these two

5

extremes, but is much closer to the upper bound. As we will explain in more detail

later, (7) holds because when |ξ

0

t

| = k and k is large then

the size of the boundary is ∼

_

2dβ

d

k d ≥ 3

4β

2

k/ log k d = 2.

(8)

Let ν

d

be the probability deﬁned in (2) ignoring mutations to type 2 that occur

before T

n

. |ξ

0

t

| is a martingale, so using the P

1

to denote the law of the voter model

starting from one occupied site P

1

(T

n

< ∞) = 1/n and using (7)

ν

d

≈

1

n

·

_

1 −E

exp

_

−na

n

u

2

_

T

0

0

X

s

ds

__

(9)

where T

0

= min{t : X

t

= 0}, and E

**is the expected value for (X
**

t

|X

0

= ). We have

na

n

=

_

¸

_

¸

_

n

3

d = 1

2n

2

log n d = 2

n

2

d ≥ 3

so if we set n = 1/h

d

(u

2

) then na

n

u

2

→1 and using (9) gives

ν

d

≈ h

d

(u

2

) ·

_

_

1 −E

exp

_

−

_

T

0

0

X

s

ds

_

_

_

Thus the type-2 mutation will occur in a family that reaches sizes O(1/h

d

(u

2

)), and

we must assume 1/h

d

(u

2

) N.

If we ignore the time to reach 1/h

d

(u

2

), the time needed to generate the type-2

mutation is, by (7),

a(1/h

d

(u

2

)) ∼

_

¸

_

¸

_

u

−2/3

2

d = 1

2u

−1/2

2

log

1/2

(1/u

2

) d = 2

u

−1/2

2

d ≥ 3

Thus for (B2) we need a(1/h

d

(u

2

)) 1/Nu

1

h

d

(u

2

), which means N g

d

(u

2

)/u

1

The next order of business is to compute γ

d

. Stochastic calculus (or calculations

with inﬁnitesimal generators) tells us that

v(x) = E

x

exp

_

−

_

T

0

0

X

s

ds

_

is the unique function on [0, ∞) with values in [0, 1], v(0) = 1 and

v

−xv = 0 in d = 1 β

d

xv

−xv = 0 in d ≥ 2

6

In d = 1 all solutions have the form:

v(x) = αAi(x) + βBi(x)

where Ai and Bi are Airy functions

Ai(x) =

1

π

_

∞

0

cos

_

t

3

3

+ xt

_

dt

Bi(x) =

1

π

_

∞

0

exp

_

−

t

3

3

+ xt

_

+ sin

_

t

3

3

+ xt

_

dt.

See, e.g., http://en.wikipedia.org/wiki/Airy_function for this and other facts

we need. Since Bi is unbounded and Ai is decreasing on [0, ∞), we take β = 0 and

set α = 3

2/3

Γ(2/3) to satisfy the boundary condition, v(0) = 1. Letting → 0 we

conclude that

γ

1

= −αAi

(0) = 3

1/3

Γ(2/3)/Γ(1/3) (10)

In d ≥ 2, v(x) = exp(−β

−1/2

d

x), and we have

γ

d

= β

−1/2

d

(11)

3 Proof part II: missing details for λ = 1

In the previous section we have calculated the probability ν

d

that a type 1 family

reaches size /h

d

(u

2

) and then gives rise to a type 2. To let →0 and prove Theorem

2 we need to consider the possibility of a mutation to type 2 in a family that (i) never

reaches size n, or (ii) will reach n but hasn’t yet. To have a convenient name we will

call these small families. Families of the ﬁrst kind arise at rate Nu

1

(1 − 1/n) and

families of the second kind arise at rate Nu

1

/n. We will now calculate the expected

rate at which type-2’s are born from these small families. In the proof of Theorem 2,

we will let →0 slowly as n →∞ so we can and will assume n →∞.

Consider the voter model ξ

0

t

starting from a single 1 at the origin at time 0. Let

V

k

be the total time spent at level k, i.e., |{t : |ξ

0

t

| = k}|, let N

k

be the total number

of returns to level k before leaving the interval (0, n), and let q(k) the rate jumps

occur at level k. As the reader will see, q(k) is the only quantity that depends on

dimension.

E

1

__

T

0

0

|ξ

0

s

| ds T

0

< T

n

_

= E

1

_

n

k=1

kV

k

T

0

< T

n

_

= E

1

_

n

k=1

kN

k

q(k)

T

0

< T

n

_

=

n

k=1

¯

P

1

(T

k

< ∞)

¯

P

k

(T

+

k

> T

0

)

k

q(k)

(12)

7

where T

+

k

= min{n ≥ 1 : X

n

= k} and the bar indicates conditioning on T

0

< T

n

. A

similar argument shows that

E

1

__

Tn

0

|ξ

0

s

| ds T

n

< T

0

_

=

n

k=1

1

ˆ

P

k

(T

+

k

> T

n

)

k

q(k)

(13)

where the hat indicates conditioning on T

n

< T

0

.

The three conditional probabilities we need can be computed using facts about

simple random walk that follow from the fact that it is a martingale.

¯

P

1

(T

k

< ∞) =

P

1

(T

k

< ∞)P

k

(T

0

< T

n

)

P

1

(T

0

< T

n

)

=

(1/k)(1 −k/n)

(1 −1/n)

(14)

For the next two we note that the ﬁrst step has to be in the correct direction for these

events to happen.

¯

P

k

(T

+

k

> T

0

) =

(1/2)(1/k)

(1 −k/n)

(15)

ˆ

P

k

(T

+

k

> T

n

) =

(1/2)(

1

n−k

)

(k/n)

(16)

Thus the expected total man-hours

_

T

0

0

|ξ

0

s

| ds for a family that will die out before

reaching size n is

∼

2

(1 −1/n)

n

k=1

(1 −k/n)

2

k

q(k)

(17)

And in families that have yet to reach size n

2

n

n

k=1

(n −k)

k

2

q(k)

(18)

The next result shows that the contribution of small families are indeed negligible.

Note that in all three cases the order of magnitude of the contributions from small

families is the same as the overall rate, but contains a constant that →0 as →0.

Lemma 2. The expected total man-hours in small families is

≤

_

¸

_

¸

_

Nu

1

u

1/3

2

·

2

4

d = 1

Nu

1

u

1/2

2

log

1/2

(1/u

2

) ·

7

24β

2

d = 2

Nu

1

u

1/2

2

·

2dβ

d

d ≥ 3

Proof. In one dimension, q(k) = 2. The sum in (17) is dominated by

_

n

0

(1 −x/n)

2

x dx =

1

(n)

2

_

n

0

y

2

(n −y) dy =

(n)

2

12

.

8

Thus, families of the ﬁrst kind produce type 2’s at rate ≤ Nu

1

u

2

(n)

2

/12. The

expression in (18) is dominated by

2

n

_

n

0

(n −x)x

2

dx =

(n)

3

6

.

Thus, families of the second kind produce type-2’s at rate ≤ Nu

1

u

2

(n)

2

/6. Adding

the last two conclusions gives the result for d = 1.

In dimensions d ≥ 3, the rate of jumps when |ξ

0

t

| = k depends on the set ξ

0

t

.

However, Cox, Durrett, and Perkins (2000) have shown that when k is large the jump

rate is close to 2dβ

d

k with high probability, see (I1) on page 202 and consult the

deﬁnitions on pages 186 and 196. The intuition behind this result is that the voter

model is dual to a collection of coalescing random walks, so neighbors of points in

ξ

0

t

will be occupied with probability ≈ β

d

, the probability that the genealogies of the

two sites never coalesce. Using q(k) = 2dβ

d

k, (17) becomes

1

dβ

d

n

k=1

(1 −k/n)

2

The sum is bounded above by the integral

_

n

0

(1 −x/n)

2

dx =

n

3

,

so with our choice of n = u

−1/2

2

, families of the ﬁrst kind produce type 2’s at rate

bounded above by Nu

1

u

1/2

2

/(3dβ

d

). Using q(k) = 2dβ

d

k, (18) becomes

1

dβ

d

n

n

k=1

(n −k)k

The sum is bounded above by the integral

_

n

0

(n −x)x dx =

(n)

3

6

.

Thus, families of the second kind produce type-2’s at rate ≤ Nu

1

u

1/2

2

/(6dβ

d

). Adding

the last two conclusions gives the result for d ≥ 3.

In dimension d = 2, the recurrence of random walks implies that when |ξ

0

t

| = k

is large neighbors of points in ξ

0

t

will be occupied with probability close to 1. In

this case the result of Cox, Durrett, and Perkins (2000) implies that when k is large

q(k) ≈ 4β

2

k/ log k with high probability, and (17) becomes

1

2β

2

n

k=1

(1 −k/n)

2

log k

9

Each term in the sum is bounded above by log(n), so the sum is less than n log n.

Since n = u

−1/2

2

log

−1/2

(1/u

2

), families of the ﬁrst kind produce type 2’s at rate

bounded above by

Nu

1

u

2

·

1

2β

2

n log(n) = Nu

1

u

2

·

1

2β

2

u

−1/2

2

log

−1/2

(1/u

2

) ·

1

2

log(1/u

2

)

=

4β

2

Nu

1

u

1/2

2

log

1/2

(1/u

2

)

Taking q(k) ≈ 4β

2

k/ log k, (18) becomes

1

2β

2

n

_

n

k=1

(n −k)k log k

_

The sum is bounded above by

_

n

0

(n −x)x log(n) dx ≤

(n)

3

6

log(n)

Thus families of the second kind produce type 2’s at rate bounded above by

Nu

1

u

2

n

·

1

2β

2

n

·

(n)

3

6

log(n) =

1

12β

2

Nu

1

u

2

· n log(n)

=

24β

2

Nu

1

u

1/2

2

log

1/2

(1/u

2

)

Adding the last two conclusions gives the result for d = 2 and completes the proof.

4 Proof part III: Almost neutral mutations

In the biased voter model, whose law we denote by P

λ

, jumps occur at rate 2 + λ

times the size of the boundary. To compensate for this we need to run the unbiased

(λ = 1) voter at rate (2 +λ)/2. If we do this, call the resulting law

˜

P

0

, and let ω

T

is

a realization of ξ

0

t

run up to time T then the Radon-Nikodym derivative

dP

λ

d

˜

P

0

(ω

T

) =

_

2λ

λ + 1

_

n

+

_

2

λ + 1

_

n

−

where n

+

and n

−

are the number of up jumps in ω

t

when 0 ≤ t ≤ T.

If max

t≤T

|ξ

0

t

| = O(K) then the diﬀerence 0 ≤ n

+

−n

−

= O(K). Since under

˜

P

0

,

|ξ

0

t

| is a time change of simple random walk, we see that the total number of jumps

n

+

+ n

−

= O(K

2

). Taking K = 1/h

d

(u

2

) and assuming |λ −1| h

d

(u

2

), when u

2

is

small the Radon Nikodym derivative is

=

_

1 +

λ −1

λ + 1

_

n

+

_

1 −

λ −1

λ + 1

_

n

−

=

_

1 +

λ −1

λ + 1

_

n

+

−n

−

_

1 −

(λ −1)

2

(λ + 1)

2

_

n

+

+n

−

≈ 1

10

The last result implies that Lemma 7 extends to almost neutral mutations, and

the computations in Section 2 are valid. To extend the part of the proof in Section 3,

we need to check that (14)–(16) are true asymptotically for almost neutral mutations.

To do this we recall that if a < x < b

P

λ

x

(T

b

< T

a

) =

θ

x

−θ

a

θ

b

−θ

a

where θ = 1/λ (19)

When 0 ≤ a < x ≤ b = O(1/h

d

(u

2

)) and |λ −1| h

d

(u

2

) we have

P

λ

x

(T

b

< T

a

) ≈

x −a

b −a

.

To show that the sums come out the same we need the following uniform version

which follows from (19). If |λ −1|h

d

(u

2

) →0 the for any C ﬁxed

sup

0≤−a,b≤C/h

d

(u

2

)

¸

¸

¸

¸

P

0

(T

b

< T

a

)

−a/(b −a)

−1

¸

¸

¸

¸

→0

References

Bramson, M., Cox T., Le Gall J. (2001) Super-Brownian Limits of Voter Model Clus-

ters. Ann. Probab. 29, 1001–1032

Bramson, M., and Griﬀeath, D. (1980a) Asymptotics for interacting particle systems

on Z

d

. Z. Wahrscheinlichkeitstheorie verw. Gebiete. 53, 183–196

Bramson, M., and Griﬀeath, D. (1980b) On the Williams-Bjerknes tumour growth

model. II. Math. Proc. Camb. Phil. Soc. 88, 339–357

Bramson, M., and Griﬀeath, D. (1981) On the Williams-Bjerknes tumour growth

model. I. Ann. Probab. 9, 173–185

Cliﬀord, P., and Sudbury, A. (1973) A model for spatial conﬂict. Biometrika. 60,

581–588

Cox, J.T., Durrett, R., and Perkins, E.A. (2000) Rescaled voter models converge to

super-Brownian motion. Ann. Probab. 28, 185–234

Durrett, R., Foo, J., and Leder, K. (2012) Spatial Moran models, II. Tumor growth

and progression.

Durrett, R., and Schmidt, D. (2008) Waiting for two mutations: with applications to

regulatory sequence evolution and the limits of Darwinian evolution. Genetics. 180,

1501–1509

Durrett, R., Schmidt, D., and Schweinsberg, J. (2009). A waiting time problem arising

from the study of multi-stage carcinogenesis. Ann. Appl. Probab. 19, 676–718

11

Holley, R. A., and Liggett, T. M. (1975) Ergodic theorems for weakly interacting

inﬁnite systems and the voter model. Ann. Probab. 3, 643–663.

Iwasa, Y., Michor, F. and Nowak, M.A. (2004) Stochastic tunnels in evolutionary

dynamics. Genetics. 166, 1571–1579

Iwasa, Y., Michor, F., Komarova, N.L., and Nowak, M.A. (2005) Population genetics

of tumor suppressor genes. J. Theor. Biol. 233, 15–23

Komarova, N.L. (2006) Spatial stochastic models of cancer initiation and progression.

Bull. Math. Biol. 68, 1573–1599

Komarova, N.L. (2007) Loss and gain-of-function mutations in cancer: Mass action-

action, sptail and hierarchical models. J. Stat. Phys. 128, 413–448

Komarova, N.L., Sengupta, A., and Nowak, M.A. (2003) Mutation-selection networks

of cancer initiation: tumor suppressor genes and chromosomal instability. J. Theor.

Biol. 223, 433–450

Liggett, T.M. (1999) Stochastic interacting systems: contact, voter and exclusion pro-

cesses. Springer, New York.

Nowak, M. A., 2006 Evolutionary Dynamics: Exploring the Equations of Life. Belknap

Press, Cambridge, MA

Sawyer, S. (1979) A limit theorem for patch sizes in a selectively-neutral migration

model. J. Appl. Probab. 16, 482–495

Schweinsberg, J. (2008) The waiting time for m mutations. Electron. J. Probab. 13,

1442–1478

Williams, T., and Bjerknes, R. (1972) Stochastic model for abnormal clone spread

through epithelial basal layer. Nature. 235, 19–21

12

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