Computational Biology and Chemistry 53 (2014) 84–96

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Orphan and gene related CpG Islands follow power-law-like
distributions in several genomes: Evidence of function-related and
taxonomy-related modes of distribution
Giannis Tsiagkas a , Christoforos Nikolaou b , Yannis Almirantis a, *

Institute of Biosciences and Applications, National Center for Scientific Research “Demokritos”, 15310 Athens, Greece
Computational Genomics Group, Department of Biology, University of Crete, 71409 Heraklion, Greece



Article history:
Available online 16 September 2014

CpG Islands (CGIs) are compositionally defined short genomic stretches, which have been studied in the
human, mouse, chicken and later in several other genomes. Initially, they were assigned the role of
transcriptional regulation of protein-coding genes, especially the house-keeping ones, while more
recently there is found evidence that they are involved in several other functions as well, which might
include regulation of the expression of RNA genes, DNA replication etc. Here, an investigation of their
distributional characteristics in a variety of genomes is undertaken for both whole CGI populations as
well as for CGI subsets that lie away from known genes (gene-unrelated or “orphan” CGIs). In both cases
power-law-like linearity in double logarithmic scale is found. An evolutionary model, initially put
forward for the explanation of a similar pattern found in gene populations is implemented. It includes
segmental duplication events and eliminations of most of the duplicated CGIs, while a moderate rate of
non-duplicated CGI eliminations is also applied in some cases. Simulations reproduce all the main
features of the observed inter-CGI chromosomal size distributions. Our results on power-law-like
linearity found in orphan CGI populations suggest that the observed distributional pattern is
independent of the analogous pattern that protein coding segments were reported to follow. The
power-law-like patterns in the genomic distributions of CGIs described herein are found to be compatible
with several other features of the composition, abundance or functional role of CGIs reported in the
current literature across several genomes, on the basis of the proposed evolutionary model.
ã 2014 Elsevier Ltd. All rights reserved.

Orphan CpG-Islands
CpG dinucleotide
Power-law-like distribution
Genome evolution

1. Introduction
Genomic CpG islands, in which CpG dinucleotides are abundant
and non-methylated, have been initially detected experimentally
and defined as short (hundreds of nucleotides-long) stretches in
vertebrate genomes, thus offered as cleavable sites for mCpGsensitive restriction enzymes (HTF islands, see e.g. Bird, 1986). As
lengthy DNA sequences and whole genomes became progressively
available, sequence-based definitions of CpG Islands (CGIs) and
computational algorithms using a sliding window combined with
threshold values for key quantities were put forward. Thresholds
for sequence-based search of CGIs are considered for: (i) the
minimal island length (Lmin); (ii) the percentage of cytosine and
guanine content (C + G, abbreviated in the following as CG%); and
(iii) the observed over expected frequency of occurrence of the CpG

* Corresponding author. Tel.: +30 2106503619; fax: +30 2106511767.
E-mail address: (Y. Almirantis).
1476-9271/ ã 2014 Elsevier Ltd. All rights reserved.

dinucleotide (CpGo/e). Gardiner-Garden and Frommer (1987)
introduced the first widely used set of thresholds (Lmin = 200 bp,
CG > 50%, CpGo/e > 0.6; to which we will hereafter refer as “relaxed
criteria”; bp stands for ‘base pairs’), while later, Takai and Jones
(2002) used more conservative threshold values, named hereafter
“stringent criteria” (Lmin = 500 bp, CG > 55%, CpGo/e > 0.65). In the
following, these threshold choices will be abridged as G-G&F and
T&J respectively. Alternatively, methods based on the degree of
CpG dinucleotide clustering (Hackenberg et al., 2006; Glass et al.,
2007) and on entropic edge detection (Luque-Escamilla et al.,
2005) have also been introduced. In order to avoid false positives
(e.g. due to high C + G Alu sequences in the human genome),
especially when relaxed criteria are used, repeat-masking is
usually applied before searching for CGIs.
CGIs are widely accepted as markers for the existence of
protein-coding genes, the promoter regions of which are usually
proximal to or overlapping with the islands. Consequently, the
search for CGIs was motivated by the need of detection of yet
unannotated protein coding genes. Therefore, most of the

including biologically plausible steps. Origin of the genomic and epigenomic data The genomes of the following organisms are used in this study: Apis melifera. Bird. Canis familiaris. besides the “standard” G-G&F and T&J threshold sets. (2010) were downloaded from the additional material of this article. when tested numerically. After the systematic search for CGIs in the human and other genomes using the simple sequence criteria described above. as well as. distances between protein-coding segments (PCS) often follow “power-law-like” size distributions in entire chromosomes. the data of Illingworth et al. More recently. The persistence of orphan CGIs’ chromosomal distributions to form power-laws. Power-lawlike distributions are extensively observed and through the proposed model we attempt to extend our understanding of the evolution and function of CGIs.e. full-length gene masking. in human and mouse genome comparisons. Drosophila melanogaster. The CpG depletion of the vertebrate genome is explained on the basis of heavy methylation and the consequent mutation of 5-methylcytosine to thymine. see Antequera and Bird (1993).g. More specifically. Our principal result herein is that CGIs also. Saccharomyces cerevisiae. There is not an unambiguous consensus about what an orphan CpG-Island really is. In previous works (Sellis et al. To what extent the colocalization of CGI and origins of replication is due to a direct causal link or an indirect effect mediated by positional preferences of gene transcription start sites remains.e. This model.2. Genomewide methylation data were not available until] for each of the organisms we have studied. Han and Zhao. CpA excess on the level of DNA methylation) is held. cerevisiae). Such distributions present extended linear regions in log–log scale (see Methods). Later on. Data for coordinates of CGIs derived from the methylation state of the sequence. like the ones found in the CGI chromosomal distributions. (2007) used a method combining a standard sliding window algorithm with available epigenomic data for human chromosomes 21 and 22. we use different distance thresholds from the nearest gene in order to characterize a CGI as orphan. Mus musculus. This lack of methylation on specific locations may be seen as the result either of protection from point-mutations (mutational “cold spots”) or of purifying selection due to functional roles which are fulfilled only if specific compositional traits are preserved in the underlying sequences. 85 Here we investigate the large-scale genomic distribution of CpG Islands in several genomes. for the temporal evolution of genomic components that are subjected to purifying selection. many of which could be functional RNA genes. (2007). (2010) provided a comprehensive list of CGIs in the human and mouse genomes based principally on methylation data. The most important of this work’s observations was that there exist numerous “orphan” CpG Islands (i. principally in order to exclude that the observed power-law-like distributions in whole CGI populations are a mere consequence of similar distributions already known to exist for the inter-genic distances (Sellis and Almirantis. Illingworth and co-workers formulated a hypothesis according to which most of orphan CGIs are related to functional promoters of unknown genes. with flanks of 5 kbp and 2 kbp (thousands of base pairs) at 50 and 30 ends respectively. 2. but the exact proximity relationships between CGI and gene bodies vary according to the study.G. 2011). in some cases. Caenorhabditis elegans. is shown to systematically generate power-law-like size distributions. We have put forward an evolutionary model. verified by the observed increase in TpG and CpA abundances and is extensively discussed in relation to CGIs evolution and function. for more information see later on (sub-Section 2. We used the annotation of these files in order to define the subset of CGIs which may be considered as orphan. when taken alone. 2007. follow power-law-like size distributions. These are retained for long evolutionary time in other species where they remain functional. 2. In the following. several additional choices of sequence composition are also tested and the resulting inter-CGI distances’ distributions are critically presented. after masking for known repeated sequences (for all organisms apart from S. Matsuo et al. Bos taurus. Antequera (2003) and Jabbari and Bernardi (2004). CGIs were shown to often coincide with Origins of Replication (ORIs) thus suggesting their functional roles may extend beyond transcriptional regulation (Cayrou et al. Sellis and Almirantis. The propensity of 5-methylcytosine to quickly mutate to thymine has driven to the conjecture that the methylation is hindered in genomic sequences where CpG frequency is close to the expected one. 2009). 2009. / Computational Biology and Chemistry 53 (2014) 84–96 introduced CGI finding algorithms were judged upon their ability to find CGIs in the proximity of known genes (see e. protein-coding exon) coordinates were downloaded from the FTP site of NIH [ftp. The term has been widely used to denote all CGIs which are not directly involved in the regulation of nearby genes.ncbi. Methods 2.nih.. (2010) are also used alongside with CGI coordinates derived from the implementation of compositional thresholds. in large genomes. 1987. while the same domains largely coincide with Polycomb-binding sites. the independence of CpG deficiency and TpG. (1993). depending on genome sizes. For all studied organisms. Tsiagkas et al.2. Tanay et al. Information about the origin of the genomic sequences used may be found in the supplementary file “genome data”. unclear. These data are used for the sequence-based determination of CGIs. Homo sapiens. Algorithm for the extraction of CGIs coordinates in genomic sequences The algorithm we have used for the localization of CGIs is an implementation of the method described by Takai and Jones .e.g. independently of the method used for their detection. researchers attempted to introduce several forms of epigenomic information.. based on human and chimpanzee genomes’ comparison. e.1. 2012) we have observed that distances between transposable elements (TE) belonging to the same family. A separate study of populations of orphan CGIs is performed. not connected to a known protein-coding gene). Monodelphis domestica. Klimopoulos et al. either studied as entire populations or when only orphan islands are considered. Information about the origin of the genomic coordinates used for masking of transcription start sites (TSS) and of genes may also be found in “genome data”. 2008. 2009).5) and the supplementary file “Supplementary Table”. Additional data for gene or CDS (i. Illingworth et al. The functional character of a CGI is related to the condition that its CpG dinucleotides are predominantly unmethylated. found regions with reduced CpG mutability. Only entire chromosomes are considered. apart from an indication of their functional role and conservation through purifying selection.. where however the opposite position (i. Several or all chromosomes of each genome are studied. as determined by Illingworth et al. CGIs cannot be generally seen as mutational cold spots. by means of the algorithm described in the following sub-Section 2. we have considered. In the cases of human and mouse genomes. can provide valuable insight into the overall organization of genome architecture and the mechanisms under which sequences are attributed with functionality. Gallus gallus. at least in the germ line. Bock et al. as there are converging data that many CGIs in several lineages have been lost when they ceased to be under purifying selection. nonetheless. See Bird (1986). Danio rerio.

long-range correlations extend to several length scales (ideally. (2007) the use (in double-logarithmic plots) of the slope of the cumulative form of the distribution for the estimation of the exponent of the power-law gives much more precise results than the use of the slope of the original one. with symmetric flanks 50 bp upstream and downstream. p(r) is the original spacers’ size distribution. .e. a > 0 When scale-free clustering appears. are randomly positioned in a sequence of equal length. m > 0 2. which are known to have promoters often intersecting with CGIs.1. defined as follows: Z1 PðSÞ ¼ pðrÞdr. The criterion adopted for choosing chromosomes for the study of the distribution of orphan CGIs is to include the chromosome with the most extended linearity for the standard threshold choices G-G&F or T&J. with a linear extent below unity. we cannot speak about “power-laws” but rather about “power-law-like” distributions. for 8 organisms out of the 11 overall studied. Most of this work concerns the human and a few other. taken at random. and one or more chromosomes (taken at random) with a medium E value. / Computational Biology and Chemistry 53 (2014) 84–96 (2002). the threshold values for CGIs detection in the cited literature are mostly determined for the purpose of the localization of new protein-coding genes. CG% and CpGo/e. and several other chromosomes. In finite size collections taken from physical systems. (where s is the size of the bin width) and N*(S) the number of spacers: N ðSÞ ¼ npðSÞ / eaS . Power-laws in size distributions 2. with free to be adjusted thresholds on Lmin. Li (2002). Newman (2005). Original vs. by definition. The intensity of the power-law-like pattern is quantified through the value of the extent (E) of the linear region in double logarithmic scale. The cumulative distribution forms smoother “tails”. For reviews on power-law size distributions. corresponding to the CGIs of the original natural sequence. In such random collections of objects we can approximate the distribution of their sizes with an exponential distribution (like the runs of heads in a coin-tossing experiment). The criterion adopted for choosing chromosomes for the creation of their parameter grids is to include the chromosome with the most extended linearity for the standard threshold choices G-G&F or T&J. 2. or (ii) we masked only around the TSS by adding flanks of 500 bp upstream of the TSS and 100 bp downstream of the TSS. Here. 2. in order to further elaborate on alternative modes of CGI detection.2. Let p(S) be the probability of a spacer having length between S  s/2 and S + s/2. for some chromosomes of the most widely studied genomes. The grid-driven search is done only for a limited number of chromosomes. Tsiagkas et al. where the proposed model is explained) as there appears to be no particular tendency for a unique (universal) exponent m. independent of any binning choice: in a cumulative curve the value of P(S) for length S is not associated with the subset of spacers whose length falls in the same bin. denoted by altG-G&F (for L > 500 bp) and altT&J (for L > 200 bp). Additionally to CGIs genomic distributions. The cumulative form of a power-law size distribution is again a power-law characterized by an exponent (slope) equal to that of the original distribution plus 1 (i.3. The inclusion of these random (surrogate) data sets in the figures allows for a direct visualization of the difference between observed and random distribution patterns.e. 2. (2007) and Stumpf and Porter (2012). because power-laws for the others are found to be rudimentary. with a medium E value. elegans we derived a grid only for one chromosome. In the case of C. This is done in an attempt to determine the threshold values corresponding to functional islands. less affected by statistical fluctuations. but it corresponds to the number of all spacers longer than S. Also provided in the Supplementary Table (see also in the Results and Table 1) are values of E given for the standard G-G&F and T&J threshold sets and for alternative sets for the same values of CG% and CpGo/e. allows for an objective estimation of the linearity trend in each case. or (iv) we followed the TSS masking again. The equations in terms of probabilities Suppose there is a large collection of n objects (in our case spacers between CGIs). 2007) for the sizes of spacers (distances) between CpG Islands. warm-blooded. For small genomes (insects.86 G. and S. we form a two-dimensional “parameter grid” of threshold values for CG% and CpGo/e (around the G-G&F and T&J threshold choices) for either L > 200 bp or L > 500 bp. It is also. each characterized by its length S.. interchanging the minimal length thresholds. which corresponds to a linear graph in a double logarithmic scale: N ðSÞ ¼ npðSÞ / Sz ¼ S1m . for large genomes (actually. This is particularly important for our study (see Section 4 for further details. cumulative size distribution In the present work we use the “complementary cumulative distribution function” (Clauset et al. the inclusion of ten surrogate data distribution curves. which are thus preserved in evolutionary time. Methodology for the search of threshold values for CGIs localization in several genomes As discussed in the introduction. all figures also include a bundle of ten simulated size distributions (continuous lines) where an equal number of markers. These grids are given in the supplementary file “grid”. animal genomes.3. tabulating the used thresholds alongside with the extent (E) of the complementary cumulative inter-CGI distances size distributions. S where N(S) is the number of spacers longer or equal to S. S where. Clauset et al. Although the cumulative form of the distribution may be seen as presenting more “inertia” thus overshadowing local features. as in the original distribution. Neighbor CGIs are merged together and then considered as a unique island. in our case for the whole examined genomic region) and the spacers’ size distributions follow a power-law. i.3.4. if they are separated by less than 100 base pairs and if the extended island they form meets the requirements put by the considered thresholds.5. but with the additional masking of each protein coding segment. all the vertebrates included in our list): (i) either we masked the total length of genes by additionally masking 5 kbp upstream of the start-of-gene (TSS) and 2 kbp downstream of the end-of-gene (TES). Details of the masking procedure In order to define the “orphan” CGI subsets. In all applications the window is sliding per one nucleotide. worm. their properties and alternative forms see Adamic and Huberman (2002). cerevisiae): (iii) we either followed the TSS masking (narrowing the upstream masking to 100 bp) as in (ii). then Z1 NðSÞ ¼ nPðSÞ / ðr1m Þdr / Sm . As it is pointed out by Sims et al. (see in the Discussion). along with every genomic one (see below for details). minus one in absolute value): if p(r) / r1m.

V.70 M.V.37 1.41 – – – M. Alternatively.-5 1.82 2. 256 additional events of non-duplicated CGIs eliminations are also allowed (step iii of the model). 2. Scripts in Perl and programs in FORTRAN used for parsing genomic data files. Here.87 – – – M. as well as the fraction of the TSS-unrelated CGIs (Fig.V.05 1. For genomic and for model-generated size distributions.52 1. In (b) the segmental duplications were 87 (50% of those in (a)) and the final sequence length 22 Mbp. More plots are included in “Supplementary Plots”.88 1.40 1. although the extent of linearity is somewhat reduced. as described in detail in the Methods. 5 are representative of a large number of numerical experiments conducted.6.-5).18 1. Additionally. Tsiagkas et al.15 M.) for all studied chromosomes from each organism.13 – M.01 1.47 0.-5 1. 1.4. chromosomal distributions for the islands determined by Illingworth et al. In these Tables we have included along with the standard parameter sets. Results 3.-5 1. 87 for whole chromosomes from the 11 considered genomes. (2010) based on methylation data are studied and the power-law-like pattern is also found.82 – 1.70 1.38 M. throughout. 1. When a masking procedure is applied in the epigenetically determined CGI collection (for details see Methods. along with the corresponding CGI subsets remaining after gene-masking (non-TSS CGIs.G. G-G&F Large genomes Bos taurus Canis familiaris Danio rerio Gallus gallus Homo sapiens Monodelphis domestica Mus musculus Small genomes Apis melifera Caenorhabditis elegans Drosophila melanogaster Saccharomyces cerevisiae M. with lengths sampled from a uniform distribution not exceeding in size the 5% of the actual length of the simulated sequence. while in Supplementary Table all the studied cases are included.66 – 1.90 1. Simulations using the segmental duplication – CGI loss model Examples of simulations are given in Fig.67 2.-5 – – – – 1. In Fig.4. 2.V. while.V. 2010) not intersecting with TSSs and having a minimal distance of 100 bp from a TSS of the RefSeq annotation. examples of these distributions are presented.49 2. The principal result of this study is that power-law-like distributions of inter-CGIs distances are observed in several cases with linearity extent E > 2.86 1. In Supplementary Table all chromosomes are presented.V. 1 we present examples of the complementary cumulative inter-CGI distances’ size distributions. The full set of epigenetically determined CGI populations and their orphan subsets are presented in the Supplementary Table. the two classes of epigenetically determined CGIs defined above are considered as orphan.89 M.-5 1. 1000 markers (representing CGIs) are randomly inserted in a sequence 2 Mbp long. we observe increase of the extent of linearity when orphan islands are considered instead of the full populations. Standard and alternative threshold values are considered.1.29 1.02 1. the complete sets of epigenetically determined CGI are presented (Fig.42 0.89 1.61 0. the ones we called “alternative” in sub-Section 2.44 1.16 – 1.32 1.67 – – – T&J M. Initially.70 M.V.33 1.04 – M.03 – Epigenetically determined CGIs (complete population) M. (ii) mean values of linearity Extent E for the five more extended power-law incidences (M.79 1.-5 1.59 M.-5 2.26 – 1. which in two instances surpass the three orders of magnitude (in dog chr.-5).03 1. The length reached by the simulated chromosome was 195 Mbp (steps i and ii of the model.V.V.45 M. 1. (ii) mean values of linearity extent E for the five more extended power-law incidences (M.V.74 1. in some chromosomes for each organism.09 M. 21.74 M.34 1. The G-G&F or T&J thresholds values have been used here. 3.51 1.V.58 0.02 1.39 1. 31 and human chr.24 – 1.78 1. We have also performed gene masking and subsequently we studied the spacers’ size distribution for orphan CGIs.V. 5(a–c).V. 3. This filtering is analogous to the case (i) of the previous paragraph.V.50 – 1. In Table 2. computing the presented size distributions and simulating the evolutionary model are available upon request. / Computational Biology and Chemistry 53 (2014) 84–96 We have also checked the existence of power-law-like distributions for the set of epigenetically determined CGIs (Illingworth et al. like the ones found in the orphan CGI populations derived on the basis of compositional criteria.V. We observe that power-law-like distributions are again formed.V. in some instances of masked genomes.54 0.5) the picture remains qualitatively the same. – – – – M. 1. 1.V. 3c and f). We have also attempted a search for the determination of the form of distribution of distances between CGIs using Table 1 (i) Mean values of linearity extent E (M. 1.68 – 1. 173 segmental duplication events occurred.-5 1. 3b and e).V. which have a minimal distance of 5 kbp upstream or 2 kbp downstream of any RefSeq TSS and we name them “TSS-unrelated” in the present text.-5 1. see sub-Section 2. Fig.V. for one chromosome of each organism. This is done in order to test the distribution of CGIs that are unlikely to have any role in the transcriptional regulation of protein coding genes at mediumdistances (and probably spatially linked).08 – – – altG-G&F altT&J M. In Table 1 the following information is included: (i) mean values of linearity extent E (M. In the framework of the present study. Power-law-like distributions of orphan CGIs are widespread. 1. In Table 2 mean values are given for the orphan CGI spacers’ size distribution in the same form with Table 1.-5 – – – – . In (c) the number of segmental duplications is as in (a) and the finally reached length 119 Mbp.V.V. 1.V. After each such event a number of markers (CGIs) equal to 90% of the number of the duplicated ones are eliminated. dealing with the study of masking of threshold-based CGIs. 1.33 M..) for all studied chromosomes from each organism.29 1.01 1.33 1.V. see in the Section 4. These eliminations represent cases of loss of function of ancestral CGIs with a subsequent progressive decomposition.87 1.73 – 1.15 – 1. summary information about non-gene-related epigenetically determined CGIs is also included. In (a). see the Supplementary Table). Chromosomal distributions of CpG-Islands in various genomes In Fig. serving as an additional estimator of the intensity of the appearance of the power-law-like pattern per organism. for the human and mouse genomes.V.56 M.66 1. In Fig. in double logarithmic scale. Simulations presented in Fig.37 1.19 1. circles and diamonds are used respectively. See also the Supplementary Plots. for the same chromosomes as in Fig.59 2. we have formed the subset of Illingworth and co-workers original CGIs. 3a and d).93 – 1. We name these Islands “non-TSS”.79 1. – – – – 1. sub-Section 2.

In the supplementary file “grid” the extents of linearities are presented in the form of grids of thresholds (see Methods) for all the studied cases. [(Fig. GC > 50%.6) or the Takai and Jones. An evolutionary scenario reproducing the observed power-lawlike distributions based on segmental duplications and CGI loss Segmental duplication events occurred continuously in the evolutionary past of virtually all eukaryotes (De Grassi et al. 2008. Logarithms are to base 10. 4. Each sub-plot (a–f) corresponds to a chromosome of one of the examined genomes. Inter-CGI spacers’ complementary cumulative size distributions in whole chromosomes.. 3. . while characteristic plots are given in Fig.88 G. corresponding to randomly distributed markers. Either the Gardiner–Garden and Frommer. The linear segments are inferred by linear regression. Tsiagkas et al. / Computational Biology and Chemistry 53 (2014) 84–96 threshold sets different than the standard and the “alternative” G-G&F and T&J. for a specific choice of thresholds in the detection of CpG–Islands. G + C > 55%. G-G&F (Lmin = 200 bp. CpGo/e > 0. Genomic curves are accompanied in each plot by 10 curves of surrogate data (continuous lines)._1)TD$IG] Fig. Linearity in log–log scale (a power-law-like pattern) is observed. CpGo/e > 0. 1.65) sets of thresholds have been used. T&J (Lmin = 500 bp.2.

2002. Same cases of chromosomal distributions as in Fig. but here excluding gene-related CGIs. Again. 2. Surrogate data curves and linear regression are similar to Fig. Logarithms are to base 10.e._2)TD$IG] Fig. 2008. / Computational Biology and Chemistry 53 (2014) 84–96 Kehrer-Sawatzki and Cooper. Gibson and Spring (2000). . Several alternative ways of retaining only orphan CGIs have been used.. duplication of the whole genome and subsequent reduction to diploidy). power-law-like linearity is observed. Tsiagkas et al. 1. sub-plot (a–f).e. 2002). Shapira and Finnerty... It is estimated that 50% of all genes in a genome are expected to duplicate giving an “offspring” at least once on time scales of 35–350 million years. see e. not taking into account events of polyploidization (Lynch and Conery. McLysaght et al. 89 Adams and Wendel (2005). Sémon and Wolfe (2007) and references therein. but also of other functional [(Fig. 1986). Kirsch et al. 1. It has been shown that at least 10% of the non-repetitive human genome consists of identifiable (i. most extant taxa have experienced paleopolyploidy during their evolution (i. often more extended than in the corresponding complete population. Additionally. 2008.g. 2000).G. Segmental duplication and polyploidisation generate copies of some or all the genes of an organism. relatively recent) segmental duplications (Bailey et al.

while it is also exposed to the possibility of excision due to recombination driven eliminations. ii iii iv v This step may include as limiting case whole genome duplications.V. Insertions of sequences increasing the total chromosomal length (these could be transposable elements. with the accelerated rate imposed by the rapid turnover of the CpG dinucleotide (Nachman and Crowell.V. The proposed evolutionary scenario reproduces power-law-like inter-CGI distances size distributions.91 1.80 0.V. Lynch and Conery (2000). transposable elements (TE) or microsatellites. 2000): In some cases one member of the gene pair adopts a new function while the other remains unchanged.V.98 1.96 0.97 – M. – – T&J M. the fate of most duplicated genes is that one copy is silenced. Moreover.-5 1. Sémon and Wolfe (2007).41 M. +100 bp) for small genomes G-G&F Large genomes Bos taurus Canis familiaris Danio rerio Gallus gallus Homo sapiens Monodelphis domestica Mus musculus Small genomes Apis melifera Drosophila melanogaster M.44 M.82 1.V.01 – M. 1.V.-5 – – Epigenetically determined CGIs (non-TSS CGIs only) Epigenetically determined CGIs (TSS-unrelated only) M. Only events i and ii are indispensable for the appearance of the power-law-like pattern.46 M.-5 – – M. Kasahara (2007).02 1.V.-5 1. segmental duplications occurring during genomic evolution and (in some cases) complete genome duplications. with one gene being under the regulatory control of a CGI. event types iii and iv (in that context. This model includes events of the types: i Segmental duplications of extended regions of chromosomes.V.23 G-G&F M. orphan CGIs becoming redundant.64 1. Deletions of sequence stretches (which usually are under weak or no purifying selection).35 1.97 – 1. 2005. – – M.V.V.18 M. emancipation of genes from their associate CGI. 2001).V.43 1.V.69 1. 1. The above fate of duplicated genes is normal to have its parallel to the fate of CGIs accompanying genes and being involved in their regulatory mechanism. there are reported three possibilities for the evolution of the duplicated genes (Adams and Wendel. +100 bp). 1. +2 kbp) only for large genomes M. i.19 1.41 1. An example of relatively recent gene loss is that 60% of the olfactory receptors in the human genome (1000 genes and pseudogenes in total) have disrupted ORFs and appear to be pseudogenes.-5 1.V.e. 1.70 2.25 1. in the study of non-conserved elements. 1. 1.11 – 1..36 – Masked TSS (500 bp.V. In the literature.-5 1.V.31 M. (100 bp. – – M. 1. the two copies continue to survive in the genome sharing the multiple functions of the initial gene between them.27 – M. Random eliminations of a number of CGIs which is lower or equal to the number of the duplicated ones.21 1. – – M.V.24 2. and insertions of TE families more recent than the studied one) are required instead of i Table 2 Values of linearity extent E as: (i) Mean values (M.V. (ii) mean values for the five more extended power-law incidences cases (M.25 Masked genes (5 kbp. microsatellite expansions etc).-5 1. – – M.-5).19 1. However. Even if there are not available quantitative data for the CGI corresponding populations.55 1. while its syntenic counterpart in another genome appears to have been emancipated from the action of its ancestral CGI. like CGIs. cds (50) only for small genomes G-G&F Large genomes Homo sapiens Mus musculus Small genomes Apis melifera Drosophila melanogaster M. see e.09 M.-5 1. which has been subsequently decomposed (for details see in the following sub-section).32 – 2. In other cases. In a completely different genomic framework.69 1.-5 – – M.V.24 M.93 1.48 1.90 G.56 2.-5 1.98 2.V.26 M. which is consistent with findings suggesting massive functional gene loss in the last 10 Myr (IHGSC.V. 2008. for several choices of gene-unrelated (orphan) sets of CGIs. Tsiagkas et al.93 1.43 1.68 1.19 1. 1.24 1.37 M. The implementation of a “genomic duplication–CGI loss” model is based on the following genomic phenomena: occasional gene (and associate CGI) silencing and subsequent degradation.V.02 1.V.28 1. We can consider that CGIs with yet unknown roles. regarded as orphan.-5 – – .g. given that the population of the genomic elements we study are (principally) functional and thus preserved by purifying selection. as all authors agree.28 – 1.41 1.-5 – – M.31 M. 1.-5 1.g. 2000).V. this property is proven numerically to be robust to quantitative modifications of all the involved types of molecular events. De Grassi et al.48 – 2. sequencing and analysis of the human genome has shown that segmental duplications and gene loss are widespread phenomena of genome remodeling during evolution.38 2.12 1.02 1. These orphan CGIs will be gradually decomposed and lost. eliminations of repeat copies of the studied TE family. Masked TSS (-500 bp. often connected to the loss of (protein-coding or not) genes due to changes of the needs of a given species is also a widespread phenomenon in genomic evolution. Adams and Wendel (2005).-5 – – M.12 M.V. retroviruses.).V.V. Occasionally. – – T&J M. and then disintegrates progressively by random mutations.09 1. / Computational Biology and Chemistry 53 (2014) 84–96 genomic localizations. +100 bp) for large genomes.V.19 1.V.19 M. The existence of another source of CGI loss can be supported by current findings of comparative genomics. although not explicitly considered in the present implementation. when duplicated often become superfluous and stop being under purifying selection.96 – 1.-5 1.22 0. e. Lynch and Conery. 1.53 1. Several cases of syntenic genes of different organisms have been shown to be under differential control of CGIs. Moreover.84 1.24 2.29 1. additional eliminations of non-duplicated CGIs.-5 2.81 1.V.44 1.V.V.V. losing the ability to be transcribed.78 M.V. we may expect that loss of CGIs due to one of the above mentioned reasons.V.87 – T&J M.

3. ._3)TD$IG] Fig. 1. 2012). Logarithms are to base 10. [(Fig. iv and v are numerically shown to be dispensable for the emergence of power-laws in the computer simulations studied herein. are important. Inter-CGI spacers’ complementary cumulative size distributions in whole chromosomes for epigenetically determined CGIs from the human and mouse genome.g. as several authors bring evidence about loss of CGIs over evolutionary time due to de novo 91 methylation (see e. 2007. as the above authors remark (see also discussion in the next sub-section). / Computational Biology and Chemistry 53 (2014) 84–96 and ii (see Sellis et al. The inclusion of events type iv tests the robustness of the model. Surrogate data curves and linear regression are similar to Fig. The involvement of this type of events in the formation of the observed linearities is indicated by the relatively higher linearities observed in mouse where higher island elimination rates are observed.. 1993). Antequera and Bird. Events of type iii. Several cases of non-TSS or TSS-unrelated (orphan) islands are considered. Klimopoulos et al.G. although not essential for the emergence of power-lawtype linearity. Events iii.. Tsiagkas et al.

in order to account for the appearance of a power-law-like pattern in the chromosomal distribution of genes (Sellis and Almirantis. Both are based on an analytically solvable model introduced by Takayasu et al. conceived to describe the genomic dynamics of CGIs. 1. Events of type v represent either deletion of sequence regions usually due to unequal recombination or gradual shrinkage by a balance of indel (insertion/deletion) events favoring decrease of the sequence length.92 G. for more details see the sub-Section 2. The model presented herein is formally similar to another model introduced previously.4 and the supplementary file “grid”. is not analytically solvable and thus no universal exponents (slopes for the linear segment in log–log scale) may be obtained. Surrogate data curves and linear regression are similar to Fig. Notice that the model presented herein. Plots of inter-CGI spacers’ complementary cumulative size distributions in whole chromosomes. Tsiagkas et al. / Computational Biology and Chemistry 53 (2014) 84–96 because for many organisms important parts of the genome are generated by repeat proliferation. 4. 2009)._4)TD$IG] Fig. (1991) for the appearance of power-law size distributions in aggregative growth of particles in physicochemical systems. Here non-standard threshold sets are used. Logarithms are to base 10. . This is verified by all our computer [(Fig.

For a recent in depth view of the requirements for having a power-law. corroborates the hypothesis that the evolutionary dynamics described by this model is at the origin of the observed genomic patterns. Logarithms are to base 10. decreases the extent of the linearity. see Stumpf and Porter (2012). CGIs). along with the common dependence on the evolutionary parameters shared between model and genomic distributions. More specifically. power-law-like curves (linear in log–log scale) are formed in the inter-CGI spacers' size distributions. Moreover. The power-law inter-repeat size distributions of distances between TEs could be seen as a counter-example (Klimopoulos et al.G. in line with the view that functionality is a necessary condition for CpG islands to form stable power-laws. 2012). If we include additional elimination of CGI (events of type iii). (2012). this is a feature common to all cases of naturally occurring “power-laws”) but mainly because they lack any universal exponent (slope).1. especially in small genomes. as found in several instances. Analysis of the observed power-law-like chromosomal CGI distributions. only events of the types i and ii are included (segmental duplications followed by CGI loss). This is the principal reason why we call the pattern we have found “power-law-like” throughout this article. In the previous paragraph we consider the possibility that the genomic power-law-like size distributions of CGIs might be an indication of functionality. it is probable that the observed distributions are the result of the proposed mechanism in synergy with other aspects of genomic dynamics. however. Discussion 4. under no purifying selection. / Computational Biology and Chemistry 53 (2014) 84–96 [(Fig. as observed in real chromosomes. In the simulation of Fig. depicted in Fig._5)TD$IG] 93 simulations and is in accordance with the variety of slope values met in the study of genomic CGI distributions. the case of the human genome) with many genes inactivated (e. On the other hand. the expansion–modification model proposed by Li (1991). We see that. Simulations using the proposed evolutionary model. as an absolute proof that this model is at the origin of the genomic pattern. Linearity in log–log scale similar to the one observed in the plots of inter-CGI spacers’ complementary cumulative size distributions is found. our data deviate from the typical power-law not only because they always have the linearity in log–log scale truncated at a lower and an upper cut-off (in fact. protein coding segments. recognizable in mammalian genomes up to .. The similarity of the power-law-like pattern emerging in simulations of this model with the genomic distributions of inter-CGI distances cannot be considered. the case of human olfactory receptors) and several genes having their regulatory pattern changed. TEs are long-lived genomic objects. 5a. For details see in Section 2 and Section 4. as intuitively expected. this deviation from universality is a characteristic feature shared between the genomic inter-CGI distributional patterns we describe herein and the simulations of the proposed evolutionary model. For a related discussion see Klimopoulos et al. as extensively discussed therein. the linearity is considerably increased (see Fig. In our case we clearly show that the log–log linearities we observe in our genomic data (often being quite extended) lack a universal exponent (slope). These results are compatible with extended powerlaw linearity found. A decrease in the number of allowed segmental duplications. in cases where an extended genic remodeling in the recent past of the organism is plausible (perhaps. 5c).g. 5b. Thus. This feature. 5. 4. These authors state that these requirements include a statistically sound power-law (extended linearity in log–log scale with indications of convergence to a universal exponent) and a concrete underlying theory to support it. We may infer that gene inactivation and reassignment of the roles of genes (which may have caused their emancipation from an associate CGI) led several CGIs to cease being under purifying selection and thus they progressively decomposed. Tsiagkas et al. Fig. However. shown to generate long-range correlations in nucleotide sequences might have significantly contributed to power-law-like distributional patterns of several genomic components (repeats. Taxonomy-related evidence The property of the formulated simple model to produce power-law-like distributions is an indication that it could be extended to include more detailed modeling of conservation through evolutionary time.

where CGIs are known to be eroded. Athanasopoulou et al. Human and mouse. The situation changes. Matsuo et al. which makes its genomic turnover rate to be the highest of any other dinucleotide. sapiens. Considering mean values from all chromosomes as depicted in Tables 1 and 2.6 and 1. we extended our analysis to the subset of CGIs characterized as orphan.e. type iii events of the proposed model occur according to the cited literature with a particularly higher rate in rodents. On the other hand. orphan CGIs The distributions of coding segments and of genes in a variety of genomes are shown to follow a power-law-like spatial distribution. On the other hand.V. when full gene and flanks masking is applied. i. (1999). also has as effect the protection of the power-law-like pattern from random interruptions of the inter-CGI spacers thus maximizing linearity in log–log scale. about chromosome III being atypical in many regards: It presents large-scale compositional (C + G content) inhomogeneity and high extent of compositional mosaicism of genes found only in this chromosome. 2006). 1993. In H. they are decreased in number while the “surviving” ones are shorter and with lower CG% and CpGo/e values (Antequera and Bird. often focussing on their non-gene-related subset (orphan islands).67 vs. This is due to the mutability of CpG after being methylated. according to our proposed model. given the systematic connection of many CGIs with promoters of protein-coding genes. according to Antequera and Bird (1993). This has also been shown numerically through computer simulations allowing random transpositions. for both standard threshold choices. highest mean value of log–log linearity (M. Gene-related vs. As already mentioned. this being a corroboration of the proposed model. (1998) and Bradnam et al. The same optimum is reached if we examine the M. These are events not requiring evolutionary conservation of the involved genomic elements in order to generate power-law-like distributions. Another point compatible with the model is that this optimum is reached for the relaxed (G-G&F) and not for the stringent (T&J) threshold set. with no signs of skewed deviations to any direction in the parameter (threshold) space for all analyzed chromosomes.85) and the only one which exhibits linearity for alternative threshold set (altG-G&F and altT&J). Especially in mouse. Tsiagkas et al. to some extent.e. i. not spatially connected to genes. that log–log linearity implies functionality for CGI populations. as the erosion of mouse CGIs probably makes the relaxed thresholds more suitable for filtering in most of the functional CGIs.5 respectively).V. The result of Han et al. This . It is also worthy to note that the two chromosomes (I and XI) reported by Bradnam et al. in fact. Another point where findings presented herein comply with findings of other research groups following a different approach is our observation that chromosome III of Saccharomyces cerevisiae is the one presenting the globally maximal extent of linear segment (E = 1. (Ostertag and Kazazian. reported to disappear from a given position at least one order of magnitude faster than any other dinucleotide in the eukaryotic genome. These authors consider as the more likely reason for the particularities of chromosome III that it contains the mating type loci thus being under a selective pressure protecting it from disruptions and keeping it intact in evolutionary time.e. CpG is.5 values. and in fact other vertebrate genomes too. / Computational Biology and Chemistry 53 (2014) 84–96 200My. 0. long-rangeness and fractality. i. in our study we attempt to identify the distributional patterns of CGI populations of different functionalities and not only the gene-transcription related. This is in accordance with the findings of Li et al. The prevalence of the higher thresholds in the formation of the most extended linear segments in log–log scale suggests that in fish genomes. while sporadically high values of thresholds may perform better (see data in the “grid”). are losing CpG Islands over evolutionary time due to de novo methylation in the germ line followed by CpG loss through mutation. we note that this increase is much higher for the GG&F than for the T&J threshold set (0.e.. the maximum of the linearity in log–log scale is indeed observed for the standard threshold sets or for values being in their close vicinity. 2010). The existence of several organisms with higher power law linearities for lower thresholds and shorter minimum length (i. see also Sharp and Lloyd (1993). The observation that power-law-like linearity persists (and is sporadically more extended) in orphan CGI distributions is indicative of distinct functionalities for this type of genomic localizations.) of all examined genomes.2.e. functional islands in general might be compositionally moved toward high CG % and CpGo/e values. 1993) we observe that the maximum linear length is systematically positioned at lower threshold combinations than the standard ones. but also in a variety of other genomes.. More specifically.. (2008) that the dog genome hosts the highest percentage of gene-unrelated functional CGIs if compared to any studied genome is compatible. CpG Islands retain their identity in the evolutionary time scale (i. In order to exclude the possibility that the power-law-like spatial distribution of CGIs is a mere consequence of a power-law distribution of genes.45 respectively). Contrary to TEs. on the basis of the argument presented above: i. represents the global optimum of linearity extent. the lengthier log–log linear extents (the only ones above 2) are found in the higher threshold value region. slowing down of the transposition dynamics. mouse and other mammalian genomes. (1999) to be next to III in their degree of variation of silent-site C + G content are the ones with the next higher extents of linearity (1. the observation of Han and Zhao (2008) that in fish genomes stringent thresholds (T&J) gave the best results on functional CGIs determination is compatible with our finding that in D. from which they are principally derived. rerio. On the other hand. they stay above given thresholds for CG% and for CpGo/e) only for relatively short times after ceasing to be under purifying selection. Moreover. to all examined genomes. 4.e. by using several different approaches (Sellis and Almirantis. 2001) thus allowing the interplay of event types iii and iv of the proposed model. Note that this result does not contradict the earlier finding of Han and Zhao (2009) that the T&J threshold set is particularly suitable for identifying promoterassociated CGIs in human and probably other genomes as well. where a decrease of the linearity extent in log–log scale was observed (figure not included herein).94 G. see Nachman and Crowell (2000) and Antequera (2003). From log–log linearities found herein one might infer that an important proportion of the CGIs detected in all examined genomes using these thresholds are functional. for several of the other studied genomes as may be revealed by an inspection of the data presented in the supplementary file “grid”. An immediate observation stemming from our study is that the standard threshold sets (G-G&F and T&J) may produce power-lawlike distributions not only in human. by simple inspection of Table 1 we see that the mouse genome presents for G-G&F the highest mean extent. when Lmin = 200 performs better than Lmin = 500) is compatible with the finding that “many known functional CGIs are shorter than commonly assumed – the extreme example being Xenopus CGIs” (Hackenberg et al. In other genomes the optimum (maximum linear extent) is positioned at lower value combinations. in view of the proposed model. the separated study of orphan CGIs allows for the investigation of different modes of chromosomal distribution and thus of different functionalities of this class of genomic element compared to entire CGI populations. 2009. Along the same lines is the observation that this genome is characterized by the maximum of increase of linearity when full gene and flanks masking is applied either for G-G&F or for T&J thresholds (if masked and unmasked genomes are compared). with our result (see Table 2) that dog genome.

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