Physica Scripta

Phys. Scr. 94 (2019) 125006 (13pp) https://doi.org/10.1088/1402-4896/ab3739

White noise functional integral for

exponentially decaying memory: nucleotide
distribution in bacterial genomes
Renante R Violanda1, Christopher C Bernido1,2,3 and
M Victoria Carpio-Bernido1,2
1
Department of Physics, University of San Carlos, Cebu City 6000, Philippines
2
Research Center for Theoretical Physics, Central Visayan Institute Foundation, Jagna, Bohol 6308,
Philippines

E-mail: cbernido.cvif@gmail.com

Received 5 March 2019, revised 22 July 2019

Accepted for publication 31 July 2019
Published 11 September 2019

Abstract
We utilize a stochastic functional integral approach that forms a natural framework for analyzing
ubiquitous complex sequences of fluctuations with underlying non-Markovian stochastic process
beyond fractional Brownian motion. We demonstrate how Hida white noise calculus, guided by
mean square deviation (MSD) analysis of empirical data, allows derivation of single nucleotide
occurrence probability distributions for whole genomes of four significant species of bacteria:
(a) freshwater cyanobacteria Synechococcus elongatus PCC7942, 2.7 Mbp, (b) marine
cyanobacteria Prochlorococcus marinus subsp. marinus str. CCMP1375, 1.8 Mbp,
(c) pathogenic bacteria Staphylococcus aureus subsp. aureus NCTC 8325, 2.8 Mbp, and
(d) Staphylococcus aureus ILRI Eymole1/1, 2.9 Mbp. Here, the stochastic variable is chosen
to represent separation distances between succeeding identical single nucleotides where distance
is defined as the number of steps through intervening bases. The stochastic parameter set takes
values of nucleotide occurrence count along the genome length. The probability density function
(PDF) is derived in closed form for the associated stochastic process with exponentially damped
memory kernel, and is shown to satisfy a modified diffusion equation with a parameter-
dependent diffusion coefficient. The PDF yields an analytical result for MSDs that match
empirical plots, showing a rising nonlinear curve that flattens to a plateau starting close to 1 kb,
similar to restricted diffusion. The plots exhibit compliance with Chargaff’s second parity rule
for nucleotides. The same PDF describes occurrences of single nucleotides adenine, guanine,
cytosine, and thymine for all four bacterial genomes considered.
Keywords: non-Markovian stochastic process, white noise calculus, DNA sequence, S.
elongatus PCC7942, P. marinus subsp. marinus str. CCMP1375, S. aureus subsp. aureus NCTC
8325, S. aureus ILRI Eymole1/1

(Some figures may appear in colour only in the online journal)

1. Introduction nucleotides that make up the DNA [1–3]. To determine the

The evolution of a species arising from mutations, genetic
drift, and adaptation to environmental changes, among others,
is recorded in changes that occur in the sequence of
3
Author to whom any correspondence should be addressed.
diversity or similarity of species at the DNA level, the gen-
ome can be viewed as a collection of molecules, or nucleo-
tides, interacting with each other that form a highly structured
DNA sequence that encodes information. In this paper, we
extract physical information from this highly organized col-
lection of molecules using stochastic analysis which has been

0031-8949/19/125006+13$33.00 1 © 2019 IOP Publishing Ltd Printed in the UK

Phys. Scr. 94 (2019) 125006
used in physics to understand many biopolymers. We use the
Hida white noise functional integral [4] which is an especially
natural framework for treating stochastic processes with var-
ious forms of memory kernels and probability measure weight
functions [5, 6]. The functional integral approach which is
basically a Green function integral approach readily yields the
probability density function (PDF) in closed form. With the
PDF, significant physical quantities could then be derived
such as moments, variances, correlations and first passage
times.
Here we demonstrate that the Hida white noise integral
approach technique is handy for investigating genomes or
sections thereof. Various stochastic and computational mod-
els have been used to reveal patterns in DNA sequences not
only to test similarities or differences between species, but
more importantly to understand how information is encoded
in a genome [7–15]. However, it remains a tedious endeavor
to distill information from the complexity of differences in
nucleotide distributions along genomes and alleles even for
the same species. In this work, we focus on the location and
variable separation distances between two nearest-neighbor
identical single nucleotides in the whole genome of four
bacterial species: (a) freshwater cyanobacteria Synechococcus
elongatus PCC7942, (b) marine cyanobacteria Prochlorococcus
marinus subsp. marinus str. CCMP1375, 1.8 Mb, (c) pathogenic
bacteria Staphylococcus aureus subsp. aureus NCTC 8325, 2.8
Mb, and (d) Staphylococcus aureus ILRI Eymole1/1, 2.9 Mb.
The unicellular cyanobacteria S. elongatus has been studied as a
cyanobacterial clock [3, 16] for exhibiting circadian rhythms and
has recently been shown to protect rats from heart attacks aided
by its photosynthetic ability [17]. S. elongatus PCC7942 has
a length of approximately 2700 000 bp with a GC content of
55.5%. The marine cyanobacteria Prochlorococcus plays an
important role in the global carbon balance [18]. P. marinus
subsp. marinus str. CCMP1375 has 1751 080 bp with 1882
coding genes and 94 non-coding genes. Common infections
are caused by the pathogenic bacteria S. aureus. Moreover,
S. aureus subsp. aureus NCTC 8325 is an exemplar for strains
used in genetic manipulation. S. aureus ILRI Eymole1/1 has
2874 302 bp with a GC-content of 32.88% [19].
We investigate, in particular, the distribution of a given
nucleotide in a DNA sequence. Mean square displacement
(MSD) analysis for the fluctuations in distribution of single
nucleotides along the bacterial genomes lends insight for the
choice of underlying stochastic process for the system. The
genome-wide patterns in MSD plots generated deviate from
linearity pointing to non-Markovian stochasticity. Evaluation
of the expectation of the constrained stochastic variable over
Hida white noise probability measure yields analytical results
for the MSD that match empirical plots, showing a rising
nonlinear curve that flattens to a plateau starting close to 1 kb,
and following Chargaff’s second parity rule for nucleotides.
The same PDF describes occurrences of single nucleotides
adenine (A), guanine (G), cytosine (C), and thymine (T) for
all four bacterial genomes considered.
In section 2, we present relevant essential points of the
stochastic integral approach for processes with memory using
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R R Violanda et al
Figure 1. Distances between adjacent adenine A nucleotides are
marked xi with i = 1, 2,¼, N - 1, where N is the total number of
adenines in a genome. Distances are determined by the number of
steps through intervening non-adenine nucleotides such
that, x1 = 4, x2 = 2, x3 = 5.
Hida white noise calculus [4]. Note that, in the literature,
noise may refer to random fluctuations of a signal. In this
paper, the term white noise does not refer to noise external to
the system. We use the term white noise as a mathematical
description [4] of the fluctuating separation distances between
similar nucleotides in a DNA sequence. For the bacterial
species considered, the behavior of the fluctuating nucleotide
separation distances turns out to be aptly characterized by a
stochastic white noise model with memory which provides
new insight into how a specific nucleotide is distributed in a
genome. This is followed by section 3 on the bacterial gen-
ome data, sources, and computational work done for
empirical MSD analysis. Sections 4 and 5 present the main
results and discussion, respectively.
2. White noise functional integral approach
In terms of the Hida white noise variable w (s ), defined as the
derivative of ordinary Brownian motion B (s ), i.e. w (s ) =
dB (s ) /ds [4], we will consider the stochastic process given
by
L ⎡ b ⎤
x (L ) = x 0 + bc ò0 exp ⎢ - (L - s) ⎥ w (s) ds ,
⎣ 2 ⎦
(1 )
where, b , c > 0 are constants. The stochastic variable x (L )
represents fluctuating separation distances between succeed-
ing identical single nucleotides where distance is defined in
terms of steps through the intervening bases as shown in
figure 1.
The stochastic parameter set takes values of nucleotide
occurrences along the whole genome length, typically over a
million base pairs, so that we take 0  s  L with
L = N - 1, where N is the total number of the single
nucleotide present in the genome strand. In equation (1),
exp [-(b /2)(L - s )] is a memory kernel characteristic of the
system. The initial value of the process is fixed at x 0. How-
ever, from equation (1), we see that the fluctuating variable
can take any value in the domain when the parameter takes
the value, s = L. We thus introduce the constraint fixing the
endpoint x (L ) = xL , using the Donsker delta functional,
d (x (L ) - xL ), the stochastic distributional analog of the
Dirac delta function [20–22]. The delta functional constraint
takes as nonvanishing paths only those with terminal values at
the specified point xL . The PDF P (xL , L; x 0 , 0) for fluctua-
tions ending at xL with initial value at x 0 is the expectation
P (xL , L; x 0, 0) = ò d (x (L ) - xL ) dm (w ). (2 )
Phys. Scr. 94 (2019) 125006 R R Violanda et al

Figure 2. Separation distances between a nucleotide base and the identical single nucleotide immediately preceding it for S. elongatus
PCC7942. The occurrence number n is the nth nucleotide base of the same type encountered in the DNA sequence.

In equation (2), dm (w ) = Nw exp ⎡⎣ -(1 /2) ò w (t )2dt ⎤⎦ d¥w,
is the Gaussian white noise probability measure where the
exponential is responsible for the Gaussian fall-off and Nw is a
normalization factor [4]. The dm (w ) is defined by the char-
acteristic functional
We now write, e (s ) = k bc exp [-(b /2)(L - s )], e Î S (),
and integration over dm (w ) can be done using the characteristic
functional equation (3). With equation (5), the PDF can then be
written as
1 +¥

⎡ L ⎤ ⎡ 1 L ⎤
P (xL , L; x 0, 0) =
2p ò-¥ exp {ik [x 0 - xL ]}

òS¢ () exp ⎢i

⎣ ò0 w (s) e (s) ds⎥ dm (w ) = exp ⎢ -
⎦ ⎣ 2 ò0 e 2 d s⎥ ,
⎦ ⎧ 1 L ⎫
(3 )
´ exp ⎨ - k 2bc
⎩ 2 ò0 exp [ - b (L - s)] ds⎬ dk.
⎭
(6 )

where e (s ) Î S () with the Gel’fand triple, S () Ì L2 () Ì We also remark that it is the pairing between the dual spaces
S ¢ (). Here S (), L2 (), and S ¢ () are the Schwartz space through the triple S () Ì L2 () Ì S ¢ (), defined as the
of test functions, the Hilbert space of square integrable bilinear extension of the inner product on L2, that facilitates the
functions, and the space of tempered distributions, respec- treatment of memory functions in the stochastic integral. In
tively [4]. equation (6), the integral over dk is a Gaussian integral which
To evaluate equation (2), we write the Donsker delta yields
functional in terms of its Fourier representation to get 1
P (xL , L; x 0, 0) =
1 +¥ 2pc [1 - exp ( - bL )]
P (xL , L; x 0, 0) =
2p ò ò-¥ exp {ik [x (L ) - xL ]} dk dm (w ).
⎧ - (xL - x 0 )2 ⎫
(4 ) ´ exp ⎨ ⎬, (7 )
⎩ 2c [1 - exp ( - bL )] ⎭
Using equation (1) for x (L ) we have
where integration over ds has been carried out. The PDF of
+¥
1 equation (7) can be shown to satisfy a modified diffusion
P (xL , L; x 0, 0) =
2p -¥ ò
dk exp {ik [x 0 - xL ]}
equation with a parameter-dependent diffusion coefficient similar
⎧ L ⎡ b ⎤ ⎫ to other stochastic processes with memory [23].
ò
´ exp ⎨ik bc
⎩ 0
ò
exp ⎢ - (L - s) ⎥ w (s) ds⎬ dm (w ).
⎣ 2 ⎦ ⎭ With equation (7), the MSD can be calculated,
(5 ) MSD = á (x - á xñ)2 ñ, where brackets á¼ñ denote an average.

3
Phys. Scr. 94 (2019) 125006
Figure 3. A magnified view of figure 2 for the 400th–500th identical single nucleotide occurring in the DNA sequence of S. elongatus
PCC7942.
This leads to
MSD = c [1 - exp ( - bL )]. (8 )
For the genomic analysis, it is convenient to uniformly shift
the graph of MSD versus L for equation (8) without changing
its shape by adding a constant interval such as (a - c ) > 0.
In particular, we have, MSDa = MSD + (a - c ), where the
shifted MSDa can then be written as
MSDa = a - c e-bL . (9 )
Equations (7) and (9) are the key relations that we apply to the
bacterial genomes.
We note that the stochastic process and corresponding
MSD, equation (8), discussed in this paper have some simi-
larity with the direct tempering model of Meerschaert and
Sabzikar [24, 25] as discussed in reference [24]. The differ-
ence lies in that the starting point, (equation (64), in [24]) is
Mandelbrot’s definition of fractional Brownian motion where
an exponential truncation factor, exp [-l (t - t ¢)], is added
with l as the truncation parameter. For l  0 the classical
fractional Brownian motion is obtained. In the long time limit
t  l-1 and H = 1 /2, the MSD, equation (69) of [24],
reduces to the form, (s 2 /l )(1 - e-lt) which is then similar
to equation (8) above for c = s 2 /l and b = l. It is observed
that the Meerschaert and Sabzikar model does not lead to
ordinary Brownian motion for H = 1 /2 due to the added
exponential factor, exp [-l (t - t ¢ )]. Note that time t in [24]
corresponds to our occurrence number L.
4
R R Violanda et al
3. Data and methods
DNA sequences were obtained from the National Center for
Biotechnology Information (www.ncbi.nlm.nih.gov) for the
whole genomes of: (a) Synechococcus elongatus PCC7942,
2.7 Mb, (b) Prochlorococcus marinus subsp. marinus str.
CCMP1375, 1.8 Mb, (c) Staphylococcus aureus subsp. aur-
eus NCTC 8325, 2.8 Mb, and (d) Staphylococcus aureus ILRI
Eymole1/1, 2.9 Mb. For a given genome, separation dis-
tances between adjacent identical single nucleotides were
evaluated with the distances determined by the number of
intervening nucleotides as depicted in figure 1. The varying
distances generate a graph with high density of fluctuations as
shown in figure 2 of section 4 (Results). The numbers in the
horizontal axis of figure 2 are the sequential occurrences of
the selected single nucleotide such as adenine A along the
length of the genome. The same procedure is done for single
nucleotides G, C, and T for each bacterial genome.
To compute the empirical MSD, any given nucleotide in
the circular DNA sequence of a bacteria, say G, can be taken
as starting point corresponding to s = 0. One then evaluates,
á [x (s + Ds ) - x (s )]2 ñ, with s taking successively increasing
values of occurrence numbers. The first point in the empirical
MSD plot is for Ds = 1, i.e. nearest-neighbor G nucleotides.
The second MSD point is for Ds = 2 which takes the dif-
ference of values for two next-to-nearest nucleotide G, and so
on for increasing values of Ds. The MSD of the separation
Phys. Scr. 94 (2019) 125006 R R Violanda et al

Figure 4. MSD for T, A, G, and C nucleotide bases of S. elongatus PCC7942. Empirical MSD (blue dots); theoretical fit (red curve) given by
equation (9).

Table 1. Values of parameters in equation (9) that give a good match Table 2. Values of parameters in equation (9) that give a good match
between theoretical MSD (red curve, figure 4) and genome-based between theoretical MSD (red curve, figure 5) and genome-based
MSD (blue dots, figure 4) for S. elongatus PCC7942. MSD (blue dots, figure 5) for P. marinus subsp. marinus str.
CCMP1375.
Base T Base A Base G Base C
Base T Base A Base G Base C
a 32.2 31.85 16.63 16.69
b 0.003 54 0.003 32 0.003 12 0.002 75 a 15.82 15.59 53.92 53.93
c 0.62 0.59 0.24 0.27 b 0.002 96 0.004 24 0.007 12 0.008 33
c 0.18 0.19 1.28 1.15

distances is then generated for each nucleotide in the whole

genome as shown in figures 4–7 of the following Section.
4. Results
4.1. Synechococcus elongatus PCC7942
Following the procedure for determining distances between
similar nucleotides depicted in figure 1, the results for the
varying distances between two successive T nucleotides in the
genome of S. elongatus PCC7942 are shown in figure 2. The
occurrence number is the number of times a T nucleotide is
encountered sequentially as one runs along the length of a
genome. Hence, the ninth T nucleotide encountered in a
sequence is assigned an occurrence number of 9. Similar
graphs for distance versus occurrence number for nucleotides
G, A, and C are also shown in figure 2. A magnified view of
the fluctuating values of separation distances versus occur-
rence number is shown in figure 3.
The MSD for the fluctuating separation distances
(figures 2 and 3) of nucleotides A, G, C, and T for S. elon-
gatus PCC7942 are shown in figure 4. Note how the best fit
curve MSD coincides with the analytical MSD (red curve in
figure 4) given by equation (9) for parameter values given in
table 1.
4.2. Prochlorococcus marinus subsp. marinus str. CCMP1375
Following the same procedure as with S. elongatus, we obtain
the MSD of the separation distances for nucleotides A, G, C,

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Phys. Scr. 94 (2019) 125006 R R Violanda et al

Figure 5. MSD for T, A, G, and C nucleotide bases of P. marinus subsp. marinus str. CCMP1375. Empirical MSD (blue dots); theoretical fit
(red curve) given by equation (9).

Table 3. Values of parameters in equation (9) that give a good match ILRI Eymole1/1 are plotted with parameter values given in
between theoretical MSD (red curve, figure 6) and genome-based table 4. The MSD plots are shown in figure 7.
MSD (blue dots, figure 6) for S. aureus subsp. aureus NCTC 8325.
Base T Base A Base G Base C
a 12.63 13.30 65.05 63.82
b 0.0027 0.001 59 0.002 46 0.002 16 5. Discussion
c 0.18 0.19 0.89 0.90
As shown in figures 4–7, a good match between theoretical
and genome-based MSD is obtained for each of the four
bacterial genomes. This indicates that varying separation
and T for the genome of P. marinus subsp. marinus str. distances between neighboring nucleotides of the same type
CCMP1375, with parameter values in table 2. The MSD plots
are described by a non-Markovian stochastic process char-
are shown in figure 5.
acterized by equations (7)–(9). The theoretical MSD calcu-
lated as an ensemble average closely matches the empirically
derived MSD especially at large occurrence numbers (see
4.3. Staphylococcus aureus subsp. aureus NCTC 8325
figures 4–7). Noting that increasing occurrence numbers
The MSD of the separation distances similar to figures 2 and correspond to the role of increasing time for fluctuations
3 for nucleotides A, G, C, and T for the bacterial species S. measured in a time series, one could say that the system is
aureus subsp. aureus NCTC 8325 are obtained for parameter ergodic for large occurrence numbers. For small occurrence
values given in table 3. The corresponding MSD plots are numbers, however, a slight deviation is observed between the
shown in figure 6. theoretical and empirical MSD. A non-ergodic behavior is
therefore manifested for small occurrence numbers, or when a
series of similar nucleotides are relatively close to each other.
4.4. Staphylococcus aureus ILRI Eymole1/1
We now discuss the significance of parameters a, b, and c of
The MSD of the separation distances (similar to figures 2 and equation (9), as well as the PDF obtained for the different
3) for nucleotides A, G, C, and T for the genome of S. aureus genomes.

6
Phys. Scr. 94 (2019) 125006 R R Violanda et al

Figure 6. MSD for A, G, C, and T nucleotide bases of S. aureus subsp. aureus NCTC 8325. Empirical MSD (blue dots); theoretical fit (red
curve) given by equation (9).

Table 4. Values of parameters in equation (9) that give a good match PDF and MSD, equations (7) and (8), respectively, i.e.
between theoretical MSD (red curve, figure 7) and genome-based exp (-bL ) » 1 - bL + (b 2L2 /2!)+¼, one sees that the
MSD (blue dots, figure 7) for S. aureus ILRI Eymole1/1. stochastic process approaches the mathematical form of
Base T Base A Base G Base C ordinary Brownian motion when, b  1. The only physical
difference is that the ‘step length’ or distances between suc-
a 12.42 13.54 70.46 58.61 ceeding similar nucleotides can vary (see, also, figure 9). Note
b 0.002 89 0.001 79 0.002 53 0.001 92
that here, L is the occurrence number which corresponds to
c 0.20 0.19 0.93 0.92
time T in discussions of Brownian fluctuations.

5.2. Chargaff’s second parity rule

5.1. Memory parameter
For the four species of bacteria considered, the difference
Although occurrence distances of all nucleotides considered between parameters a and c, i.e. (a - c ), can be used to test
are influenced by the same memory function of the form the second parity rule of Chargaff [26]. This parity rule states
exp [-b (L - s ) /2], as shown in equation (1), the effect of that for a single DNA strand, the frequency of appearance of
the memory function differs with values of b > 0 ranging nucleotide A is equal to that of T, and the same holds for the
from 0.001 59 to 0.008 33 (see tables 1–4). Smaller values of frequency of appearance of C which is equal to that of G.
b diminishes memory effects. This may be seen by expanding Specifically, for a given genome (see, tables 1–4), whenever
the memory function, i.e. the parameters (a - c ) of A and T have approximately the
b b2 same values, then Chargaff’s second rule applies. The same
exp [ - b (L - s) / 2] = 1 - (L - s) + (L - s)2 situation holds for G and C. Explicitly, consider table 1 for S.
2 8
elongatus PCC7942 for which values of (a - c ) are sum-
b3
- (L - s)3 + O (b 4) +¼ , (10) marized in table 5. The corresponding graph of MSD versus
48 occurrence number for S. elongatus PCC7942 is shown in
where terms with higher powers of b are negligible figure 8 where the frequency of appearance of A is closely
with b  1. The b may then be referred to as a memory matched by T as reflected in their MSD. The MSD of G and C
parameter. Likewise, by expanding the exponential in the likewise imply similar frequencies of appearance.

7
Phys. Scr. 94 (2019) 125006
Figure 7. MSD for A, G, C, and T nucleotide bases of S._aureus ILRI Eymole1/1. Empirical MSD (blue dots); theoretical fit (red curve)
given by equation (9).
Table 5. Chargaff’s second parity rule may be verified if (a–c) for A
and T have approximately the same values. The same holds for G
and C.
S. elongatus PCC7942 T A G C
(a–c) 31.58 31.26 16.39 16.42
5.3. MSD for large occurrence numbers
As observed in figures 4–7, the MSD plateaus at a roughly
horizontal line as occurrence numbers become large. This
behavior is similar to confined or restricted diffusion (see, e.g.
[27]). The approximate MSD values at large occurrence
numbers when the graph becomes approximately flat are
given by parameter a as summarized in table 6. We can also
compare the genome-based MSD with an MSD arising from
purely random arrangement of the four nucleotides. This is
shown in figure 9 and reflected in table 6 for comparison. As
expected, the genomic nucleotide sequence is far from
random.
We note that the randomly distributed A, G, C, and T of
figure 9 do not represent an MSD typical of ordinary Brow-
nian motion. In the usual Brownian motion, or random walk,
the step lengths are normally equal although directions are
unpredictable. In figure 9, the distances between similar
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R R Violanda et al
nucleotides, or ‘step lengths,’ can be very different from each
other.
5.4. Probability density function
We could also extract information from the probability of
occurrence of a given nucleotide from the PDF. This may be
illustrated in figure 10 where empirical and theoretical graphs
(equation (7)) of the PDF are shown as a function of (x - x 0 )
and the occurrence number L.
Both empirical and theoretical graphs in figure 10 show a
peak at x = x 0. Recall that x represents separation distance of
a single nucleotide from an identical nucleotide immediately
preceding it in the sequence (see figure 1). Hence, given any
nucleotide separated by a distance x 0 from the identical
neighboring nucleotide, it is most likely that the fluctuation of
distance values would end up with a nucleotide characterized
by a distance x = x 0 from a nucleotide of the same type
preceding it.
We note that the PDF, equation (7), is a solution of a
modified diffusion equation of the form [6]
¶P (x , s ; x 0, 0) ⎡ bc ⎤ ¶ 2 P (x , s ; x 0 , 0 )
=⎢ ⎥ , (11)
¶s ⎣ 2 exp (bs) ⎦ ¶x 2
with a parameter-dependent diffusion coefficient D(s).
Such kinetic equations are of recent interest due to the wide
Phys. Scr. 94 (2019) 125006 R R Violanda et al

Figure 8. MSD versus occurrence number for nucleotides T (blue), A (red), G (green), and C (black) for S. elongatus PCC7942.

Table 6. MSD values at large occurrence numbers given by parameter a. The last row shows the exact MSD value for randomly placed
nucleotides corresponding to figure 9.
MSD at Large Occurrence Numbers
Base T Base A Base G Base C
S. elongatus PCC7942 32.2 31.85 16.63 16.69
P. marinus subsp. marinus str. CCMP1375 15.82 15.59 53.92 53.93
S. aureus subsp. aureus NCTC 8325 12.63 13.30 65.05 63.82
S. aureus ILRI Eymole1/1 12.42 13.54 70.46 58.61
Random locations of A, G, C, and T 23 23 23 23

range of geological, biological and chemical phenomena 5.5. Autocorrelation function

where time-dependent diffusion coefficients arise (see, e.g.
[23, 28–31]).
Matching theory with empirical data at the level of their
MSD and PDF does provide a certain level of confidence that
a stochastic model indeed properly describes the experimental
data. We could not exclude the possibility however that other
stochastic models with appropriate approximations and lim-
iting cases such as those considered in [24], could also
describe the same experimental data. It would then be
important to consider other criteria, such as kurtosis or first
passage time properties, to distinguish more precisely and pin
down the correct model for given experimental data.
For a stochastic process described by equation (1), the fluc-
tuations have an autocorrelation function given by,
Rx (L ) = (cN0 /2) exp (-bL /2), where white noise w (s ) has a
power spectral density Sw = (N0 /2), with N0 a constant. We
can then compare this with the autocorrelation based on
empirical data.
Figure 11 shows an example of the autocorrelation function
of the T-base occurrence distance fluctuation of S. elongatus
PCC7942 bacteria, fitted with the theoretical autocorrelation
function (solid red curve). We have normalized the theoretical
autocorrelation function such that at lag L = 0, the Rx (0) = 1.

9
Phys. Scr. 94 (2019) 125006
Figure 9. MSD versus occurrence number for randomly placed T, A, G, and C nucleotide bases. The graph significantly differs from genome-
based MSD of figures 4–8.
Since Rx (L > 0)  1, the graph removes the Rx (0) from the
plot to emphasize the exponential decay. Similar graphs are
exhibited by the other nucleotides of other bacterial species.
In figure 11, a weak but positive correlation for small lag
values is observed with the autocorrelation function dropping
close to zero starting around occurrence number 1000. Note
that occurrence numbers less than 1000 refer to nucleotides
nearer to each other as compared to those with occurrence
numbers beyond 1000 where nucleotides have much larger
separations. Considering that the initial or starting point of the
occurrence number (e.g. the first A in figure 1) could be any
nucleotide in the circular genome of the bacteria, a possible
source for the positive correlation could be a functionally
related group of nucleotides beyond which a drop in corre-
lation may develop. For example, a bacterial gene may consist
of around a thousand or more nucleotides depending on its
function. Moreover an operon, which is a cluster of adjacent
genes with a common control mechanism [32], may also be
responsible for this positive correlation.
6. Conclusion
Predicting patterns in DNA sequences, in general, is made
challenging by the high degree of complexity and variability
of nucleotide combinations in genomes. With the rapid
increase in the number of bacterial genomes being sequenced
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R R Violanda et al
and the challenge of looking for similarities and differences
that cut across diverse bacterial communities [33, 34], a non-
Markovian stochastic process as presented in this paper could
provide a framework and analytical tool for revealing infor-
mation encoded in these complex genome sequences. More-
over, knowing the appropriate PDF and the modified
diffusion equation it obeys provides a novel perspective and
analytical tool. Such stochastic framework may find future
use not only in bacterial taxonomy [33], but also in the design
and synthesis of DNA sequences [35, 36].
Here we note that, in evaluating nucleotide separation
distances, no distinction has been made yet between coding
and non-coding regions of the DNA sequence [9]. Most
bacterial genomes have 10%–20% noncoding DNA. It would
thus be interesting to apply the stochastic functional integral
method to investigate spatial distributions of and correlations
between special clusters in genomic strands. It is of interest to
determine whether trends and relations between motifs will
emerge in MSD plots of spatial distributions of dyads, triads
and tetrads of nucleotides. Nonlinear behavior of the MSD
could shed light on functional separation distances for related
genes clustered together such as an operon. This would be of
immediate consequence to studies of genetic maps and pat-
terns in repeated sequences (see, e.g. [37]) and reserved for
future work. Moreover, applications to other biopolymers can
be explored. For instance, the sequence of amino acids in a
protein and its interaction with a solvent play an important
Phys. Scr. 94 (2019) 125006 R R Violanda et al

Figure 10. Probability density function (PDF) as a function of occurrence number L and distance, x - x 0 , for S. elongatus PCC7942. Top
graph (empirical); bottom graph theoretical, equation (7), for b = 0.003 54; c = 0.62.

role in the crystallization of proteins needed to determine Recent advances in computational analysis [41] could help
protein structures [38–40]. Given a protein, the distribution deal with a sequence of twenty amino acids comprising a
properties of identified residues significant in a crystallization protein instead of sequences of four nucleotides discussed in
process can be investigated using the method in this paper. this paper. Possible reduction could be done if distributions of

11
Phys. Scr. 94 (2019) 125006 R R Violanda et al

Figure 11. Autocorrelation function versus occurrence number for the T-base of S. elongatus PCC7942 (Empirical: blue dots; Theoretical:
solid red curve). The fluctuation shows a weak but positive correlation at small lag values indicating that distance fluctuation is weakly
persistent only for small occurrence numbers.

‘patches’ or clusters [40] rather than single amino acids are
considered.
Acknowledgments
The authors thank Benjamin E Rubin, Rev R Aure, Hyunjin
Shim, and Victor Sojo for helpful discussions. R R V wishes
to acknowledge support from the Commission on Higher
Education.
ORCID iDs
Christopher C Bernido https://orcid.org/0000-0002-
9329-214X
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