Citation: Jacek Banasiak, Aleksandra Falkiewicz. A singular limit for an age structured mutation problem[J]. Mathematical Biosciences and Engineering, 2017, 14(1): 17-30. doi: 10.3934/mbe.2017002
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An important problem related to mutations is to understand how a particular trait spreads in a population. One of the simplest ways to model this is to describe the change in the sizes of subpopulations having this trait. It can be done by the standard balancing argument: the rate of change of the number of, say, cells with a particular genome
u′0=a0u0+d1u1,u′1=a1u1+d2u2,u′n=anun+bn−1un−1+dn+1un+1,n≥2, | (1) |
where
It is clear that, in principle, jumps between arbitrary populations can occur and thus there is no need to restrict our attention to tridiagonal matrices. We can consider a general model
u′=Lu, | (2) |
where
At the same time it is recognized that the cells have their own vital dynamics that should be taken into account if a more detailed model of the evolution of the whole population is to be built. Also, the mutations can be divided into various groups. Here, we distinguish two types of mutations: those that are due to the replication errors and occur when the cell divides, and others, due to external factors (mutagenes), that may happen at any moment of the cell's life cycle. This results in a model of the form
∂tu(x,t)+V∂xu(x,t)=−Mu(x,t)+Ru(x,t),x∈(0,1),t≥0,u(x,0)=˚u(x),u(0,t)=Ku(1,t), | (3) |
where we consider a population of cells described by their density
The main objective of this paper is to determine under what conditions can solutions to (3) be approximated by the solutions of (2). There could be several ways to approach this problem and the answer may be not unique. Our approach is to assume that the maturation velocities are very large or, in other words, the cells divide many times in the reference unit of time, while the deaths and mutations due to external causes remain at fixed, independent of the maturation velocity, levels. To balance the fact that there is a large number of cell divisions in the unit time, we assume that the daughter cells have a tendency to be of the same genotype as the mother (see e.g. [18,p. 19]), which is represented by splitting the boundary operator as
∂tuϵ(x,t)+ϵ−1V∂xuϵ(x,t)=−Muϵ(x,t)+Ruϵ(x,t),x∈(0,1),t≥0,uϵ(x,0)=˚u(x),uϵ(0,t)=(I+ϵB)uϵ(1,t), | (4) |
where
∂tuϵ(x,t)+ϵ−1V∂xuϵ(x,t)=0,x∈(0,1),t≥0,uϵ(x,0)=˚u(x),uϵ(0,t)=(I+ϵB)uϵ(1,t). | (5) |
We will be working in
0<vmin≤vj≤vmax<+∞,j∈N. | (6) |
If
The paper is organized as follows. In Section 2 we show the convergence of the resolvents of (4) as
Lemma 2.1. The operators
Proof. We begin with
In the general case, we rewrite the main formulae from the proof of [5,Theorem 3.1], specified for (5). First, we solve
λϵuϵ,j+vj∂xuϵ,j=ϵfj,j∈N,x∈(0,1), | (7) |
with
uϵ(x)=Eϵλ(x)cϵ+ϵV−11∫0Eϵλ(x−s)f(s)ds, | (8) |
where
(I−(I+ϵB)Eϵλ(1))cϵ=ϵ(I+ϵB)V−11∫0Eϵλ(1−s)f(s)ds. | (9) |
If
Since
∑j∈Ncϵ,j=∑j∈N(1+ϵbj)e−ϵλvjcϵ,j+ϵ∑j∈N1+ϵbjvj1∫0eϵλvj(s−1)fj(s)ds, | (10) |
where
‖uϵ‖v=1λ∑j∈Ncϵ,je−ϵλvjbj+ϵλ∑j∈Nbjvj1∫0eϵλvj(s−1)fj(s)ds+1λ‖f‖v, | (11) |
see [5,Theorem 3.1] for details. The case when
Using, for instance, the proof given in [3,Theorem 3.39], a densely defined resolvent positive operator
‖λnR(λ,S)nx‖≤c−1‖R(0,S)‖‖x‖=c−1‖R(ω,T)‖‖x‖,λ>0. | (12) |
Hence, we have to show that
‖(I−(I+ϵB)Eϵλ(1))−1‖≤∞∑n=0(1+ϵ‖B‖)ne−ϵλnvmax≤∞∑n=0eϵ‖B‖ne−ϵλnvmax=11−eϵ(‖B‖−v−1maxλ), | (13) |
provided
Next, using l'Hôspital's rule, we find
limϵ→0+ϵ1−eϵ(‖B‖−v−1maxλ)=1v−1maxλ−‖B‖ |
and hence
‖cϵ‖=ϵ‖(I−(I+ϵB)Eϵλ(1))−1(I+ϵB)V−11∫0Eϵλ(1−s)f(s)ds‖≤L2‖f‖ | (14) |
for some constant
‖R(ω,A0,ϵ)‖≤L. | (15) |
Then, using (11), the equivalence of the norms
‖R(λ,A0,ϵ)n‖≤M(λ−ω)n | (16) |
for some constant
‖etA0,ϵ‖≤Meωt |
with constants
The result for
Now let us pass to the question of the convergence of the resolvents. We introduce the projection operator
Pf=1∫0f(s)ds=(1∫0f1(s)ds,…,1∫0fn(s)ds,…). | (17) |
Theorem 2.2. If
limϵ→0+R(λ,Aϵ)=R(λ,VB+Q)P. | (18) |
in the uniform operator topology.
Proof. By the previous proof, the resolvent of
[R(λ,A0,ϵ)f](x)=Eϵλ(x)cϵ+ϵV−11∫0Eϵλ(x−s)f(s)ds,λ>vmax‖B‖, | (19) |
where
cϵ=ϵ(I−(I+ϵB)Eϵλ(1))−1(I+ϵB)V−11∫0Eϵλ(1−s)f(s)ds. | (20) |
We observe that for any
Eϵλ(α)=I+ϵR0(α)=I−ϵλαV−1+ϵ2R1(α), | (21) |
where, using the integral form of the reminders, we find
‖R0(α)‖≤λαvmax‖R1(α)‖≤λ2α22v2max. |
First we see that
‖ϵV−11∫0Eϵλ(x−s)f(s)ds‖≤ϵ‖V−1‖1∫0‖1∫0(e−λϵ(x−s)vjfj(s))j∈Nds‖dx≤ϵ‖V−1‖1∫01∫0‖f(s)‖dsdx≤ϵ‖V−1‖‖f‖ |
and hence the last term in (19) converges to zero as
Next, using the second equality in (21) with
ϵ(I−(I+ϵB)Eϵλ(1))−1=ϵ(I−(I+ϵB)(I−ϵλV−1+ϵ2R1))−1=(λV−1−B−ϵR1+ϵλBV−1−ϵ2BR1)−1. |
Since
limϵ→0+ϵ(I−(I+ϵB)Eϵλ(1))−1=(λ−VB)−1V. | (22) |
Next, using the first equation in (21) we see that
‖1∫0Eϵλ(1−s)f(s)ds−1∫0f(s)ds‖≤ϵ‖f‖1∫0‖R0(1−s)‖ds≤ϵλ‖f‖vmax1∫0(1−s)ds=ϵλ‖f‖2vmax. |
Thus
limϵ→0+cϵ=(λ−VB)−11∫0f(s)ds. | (23) |
Finally, treating
‖Eϵλ(x)c−c‖=1∫0‖(Eϵλ(x)−I)c‖dx≤ϵ‖c‖1∫0‖R0(x)‖dx≤ϵλ2vmax‖c‖. |
This actually shows that the operators converge in the uniform operator norm. Combining all estimates and using the projection operator
limϵ→0+R(λ,A0,ϵ)=(λ−VB)−1P. | (24) |
From (16) and (15) we have, in particular,
‖R(λ,A0,ϵ)‖≤‖R(ω,A0,ϵ)‖c(λ−ω)≤Lω(λ−ω). | (25) |
for some fixed
‖(QR(λ,A0,ϵ))n‖≤‖Q‖nLnωn(λ−ω)n. |
Hence, for
R(λ,Aϵ)=R(λ,A0,ϵ)∞∑n=1(QR(λ,A0,ϵ))n | (26) |
and the series converges uniformly in
limϵ→0+R(λ,Aϵ)=R(λ,VB)P∞∑n=1(QR(λ,VB)P)n=R(λ,VB+Q)P. |
Corollary 1. If
limϵ→0+etAϵ˚u=et(VB+Q)˚u | (27) |
almost uniformly (that is, uniformly on compact subsets) on
Proof. According to the version of the Trotter-Kato approximation theorem given in [9,Theorem 8.4.3], if the resolvents of the generators of an equibounded family of semigroups (strongly) converge to an operator
This result is not very satisfactory. In asymptotic theory, [6,7,10], the convergence obtained in Corollary 1 is referred to as the regular convergence. However, typically it is possible to extend the convergence to initial data from the whole space, albeit at the cost of losing the convergence at t = 0; or adding necessary initial or boundary layers. The following example shows that this is impossible to achieve in our context. Consider the scalar problem
∂tuϵ(x,t)+ϵ−1∂xuϵ(x,t)=0,x∈(0,1),t≥0,uϵ(x,0)=˚u(x),uϵ(0,t)=(1+ϵb)uϵ(1,t), |
where
uϵ(x,t)={(1+ϵb)⌊te⌋+1˚u(x+⌊te⌋+1−te)for0≤x≤te−⌊te⌋,(1+ϵb)⌊te⌋˚u(x+⌊te⌋−te)forte−⌊te⌋≤x≤1. | (28) |
Then
limϵ→0+(1+ϵb)n=limϵ→0+((1+ϵb)1ϵb)⌊t/ϵ⌋ϵb=ebt, |
where we used
limϵ→0+⌊tϵ⌋ϵ=t. | (29) |
The above is obvious for
nn+1≤⌊te⌋ϵt≤1 |
and
At the same time, let us consider
u1k(x,1)=(1+1kb)k˚u(x),0≤x≤1, |
while for
u22k+1(x,1)={(1+22k+1b)k+1˚u(x+12)for0≤x<12,(1+22k+1b)k˚u(x−12)for12≤x≤1. |
From this it follows that
limk→∞eA0,1k˚u=eb˚u |
and
limk→∞eA0,22k+1˚u=eb˚v |
in
limϵ→0+etA0,ϵ˚u=ebt˚u, |
provided
As demonstrated in Section 3, we should not expect the convergence of
limϵ→0+PetAϵ˚u=etHP˚u | (30) |
hold for some some matrix
In this section we shall focus on problem (5) and adopt the assumption from [17] that the speeds
∃v∈R∀j∈Nvvj=lj∈N. | (31) |
In our interpretation of the model, this corresponds to the situation that the maturation times
Condition (31) allows the problem to be transformed into an analogous problem with unit velocities. Such a transformation appeared in [17] (and in a more detailed version in [20]) in the context of transport on networks and thus, even though (5) is not necessarily related to the network transport, see [4], its interpretation as a network problem allows for a better description of the construction.
Using the graph theoretical terminology, we identify the
To proceed with the construction, first we re-scale time as
T+ϵC=(T100…0…⋮⋱⋮⋮⋮⋮0…Tj…0…⋮⋮⋮⋱⋮…)+ϵ(C11…C1j…⋮⋮⋱⋮Cj1…Cjj…⋮⋮⋮⋮). |
Here,
Tj=(00…0110…00⋮⋮⋮⋮000…10),Cij=(00…0bij00…00⋮⋮⋮⋮000…00). |
Summarizing, we converted (5) into
∂tυϵ(x,t)+ϵ−1v∂xvϵ(x,t)=0,x∈(0,1),t≥0,vϵ(x,0)=˚v(x),vϵ(0,t)=(T+ϵC)vϵ(1,t). | (32) |
Since (32) has the same structure as (5), there is a semigroup
To be more precise, the above construction defines an operator
ϕj,s(y)=fj|[s−1lj,slj)(s+y−1lj). | (33) |
It is easy to see that the inverse
fj(x)=ϕj,s(ljx+1−s),x∈[s−1lj,slj),s∈{1,…,lj},j∈N. | (34) |
By direct calculation, see also [20],
etA0,ϵf=S−1etvA0,ϵSf,f∈X. | (35) |
The motivation behind (35), see [13] and [20,Proposition 4.5.1], is the fact that for any
(etvA0,ϵφ)(x)=(T+ϵC)nφ(n+x−vte),n∈N,0≤n+x−vte<1, | (36) |
with
Let
(T+ϵC)l=I+ϵ˜C+ϵ2D, | (37) |
where
˜C=l∑i=0Tl−1−iCTi. |
For any
The next result is not strictly necessary but it relates operators on
Proposition 1. For
(λv−l−1˜C)−1ΠPMφ=S(λ−VB)−1PNS−1φ, | (38) |
where
Π=l−1l−1∑i=0Ti. | (39) |
Proof. The estimate (13) carries over to this case by (35), which also gives
R(λ,vA0,ϵ)φ=SR(λ,A0,ϵ)S−1φ,φ∈X,λ>vmax‖B‖, | (40) |
and, by Theorem 2.2 and the continuity of
limϵ→0+R(λ,vA0,ϵ)φ=S(λ−VB)−1PNS−1φ. | (41) |
To find the limit resolvent in terms of
cϵ=ϵ(I−(T+ϵC)Eϵλ(1))−1(T+ϵC)1∫0Eϵλ(1−s)f(s)ds, | (42) |
where here
(I−(T+ϵC)Eϵλ(1))−1=∞∑k=0e−ϵλv−1k(T+ϵC)k=l−1∑i=0(T+ϵC)i(∞∑j=0(T+ϵC)lje−ϵλv−1(lj+i))=∞∑j=0(I+ϵ˜C+ϵ2D)jEϵlλ(j)(l−1∑i=0(T+ϵC)ie−ϵλv−1i). |
Hence, as in (22) with
limϵ→0+ϵ(I−(T+ϵC)Eϵλ(1))−1=(λ−vl−1˜C)−1(l−1l−1∑i=0Ti)=(λ−vl−1˜C)−1Π. |
Since
Πj=l−1l−1∑j=0Tij=l−1jlj−1∑j=0Tij |
amounts to
Πjvj=1lj(lj∑r=1υj,r,…,lj∑r=1υj,r). | (43) |
Then the operator
Now, proceeding as in the proof of Theorem 2.2, we find
limϵ→0+R(λ,vA0,ϵ)φ=(λ−vl−1˜C)−1(l−1l−1∑i=0Ti)1∫0φ(s)ds=(λ−vl−1˜C)−1ΠPMφ, |
where we used
(l−1∑i=0Ti)T=l−1∑i=0Ti, | (44) |
by periodicity. This, combined with (40), ends the proof.
Using (43) and (34), we see that
PNS−1φ=1∫0[S−1φ](x)dx=(l−1jlj∑s=11∫0ϕj,s(y)dy)j∈N=S−1ΠPMφ. | (45) |
Theorem 4.1. For any
limϵ→0+PNetA0,ϵf=etVBPNf. | (46) |
Proof. Let us write
f=PNf+f−PNf=PNf+w, |
where
By Corollary 1 and the continuity of
limϵ→0+PN[etA0,ϵPNf]=PNetVBPNf=etVBPNf. |
Hence, by linearity, it suffices to show that
limϵ→0+PN[etA0,ϵw]=0, | (47) |
provided
PN[etA0,ϵf]=PNS−1[etvA0,ϵSf]=S−1ΠPM[etvA0,ϵSf],f∈X. | (48) |
Further, for
PMetvA0,ϵφ=(T+ϵC)nvtϵ−n+1∫0φ(n+x−vtϵ)dx+(T+ϵC)n−11∫vtϵ−n+1φ(n−1+x−vtϵ)dx, | (49) |
hence, by (44),
ΠPMetvA0,ϵφ=Π(T+ϵC)n−11∫0φ(z)dz+ϵΠC(T+ϵC)n−11∫n−vtϵφ(z)dz. |
Let us denote
Π(T+ϵC)n−1=1ll−1∑j=0Tj(T+ϵC)n−1=1ll−1∑j=0((T+ϵC)n−1+j−ϵRj(T+ϵC)n−1)=1ll−1∑j=0((T+ϵC)n−1(Tj+ϵRj)−ϵRj(T+ϵC)n−1)=(T+ϵC)n−1Π+ϵ((T+ϵC)n−1R−R(T+ϵC)n−1), | (50) |
where
limϵ→0ΠPMetvA0,ϵSw=limϵ→0ϵΠC(T+ϵC)n−11∫n−vtϵSw(z)dzxx+limϵ→0ϵ((T+ϵC)n−1R−R(T+ϵC)n−1)PMSw=0, |
which proves (47).
The authors are indebted to Professor Adam Bobrowski for taking interest in the paper, suggesting corrections to its early version and many stimulating discussions.
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