Computational Biology and Chemistry 53 (2014) 84–96

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Computational Biology and Chemistry
journal homepage: www.elsevier.com/locate/compbiolchem

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, *
a
b

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

A R T I C L E I N F O

A B S T R A C T

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.

Keywords:
CpG-Islands
CGIs
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: yalmir@bio.demokritos.gr (Y. Almirantis).
http://dx.doi.org/10.1016/j.compbiolchem.2014.08.013
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

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

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

82 – 1. In Table 2. dealing with the study of masking of threshold-based CGIs.V. in some chromosomes for each organism.-5 2. In Supplementary Table all chromosomes are presented.50 – 1. computing the presented size distributions and simulating the evolutionary model are available upon request.88 1. In (b) the segmental duplications were 87 (50% of those in (a)) and the final sequence length 22 Mbp. we observe increase of the extent of linearity when orphan islands are considered instead of the full populations..V.70 M.V.51 1. – – – – 1.V.18 1.08 – – – altG-G&F altT&J M.33 1. see the Supplementary Table). In Table 2 mean values are given for the orphan CGI spacers’ size distribution in the same form with Table 1.V. In Table 1 the following information is included: (i) mean values of linearity extent E (M.16 – 1.-5 1.37 1.V. Here. 1000 markers (representing CGIs) are randomly inserted in a sequence 2 Mbp long. 3b and e). / 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. (2010) based on methylation data are studied and the power-law-like pattern is also found.19 1. 31 and human chr.-5 – – – – 1.52 1. After each such event a number of markers (CGIs) equal to 90% of the number of the duplicated ones are eliminated.59 M. 5(a–c).47 0. 5 are representative of a large number of numerical experiments conducted.-5).42 0.02 1. circles and diamonds are used respectively.79 1.15 M. which in two instances surpass the three orders of magnitude (in dog chr. Additionally.V.73 – 1.70 M.58 0. These eliminations represent cases of loss of function of ancestral CGIs with a subsequent progressive decomposition.V. (ii) mean values of linearity extent E for the five more extended power-law incidences (M. 3a and d). 3. examples of these distributions are presented. with lengths sampled from a uniform distribution not exceeding in size the 5% of the actual length of the simulated sequence.V.67 2. Fig.04 – M.82 2.26 – 1. Scripts in Perl and programs in FORTRAN used for parsing genomic data files.33 1. For genomic and for model-generated size distributions. Results 3. – – – – M. 1.66 – 1. throughout. 1. The G-G&F or T&J thresholds values have been used here.V.03 1. We observe that power-law-like distributions are again formed. 2.-5 1.32 1. in some instances of masked genomes.V. We name these Islands “non-TSS”.87 – – – M.89 M. 1.78 1.-5 – – – – .74 M. while in Supplementary Table all the studied cases are included. serving as an additional estimator of the intensity of the appearance of the power-law-like pattern per organism.66 1.4.93 – 1.61 0.56 M. along with the corresponding CGI subsets remaining after gene-masking (non-TSS CGIs.89 1. as well as the fraction of the TSS-unrelated CGIs (Fig.15 – 1.1.03 – Epigenetically determined CGIs (complete population) M. 173 segmental duplication events occurred.49 2. 1. see sub-Section 2. 1. 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.67 – – – T&J M. 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 > 2.70 1.G.V. 1 we present examples of the complementary cumulative inter-CGI distances’ size distributions. Simulations using the segmental duplication – CGI loss model Examples of simulations are given in Fig.29 1. Alternatively. see in the Section 4.39 1. 1.V.38 M. 3c and f). 1. for the same chromosomes as in Fig. This filtering is analogous to the case (i) of the previous paragraph.68 – 1.13 – M. In (c) the number of segmental duplications is as in (a) and the finally reached length 119 Mbp. When a masking procedure is applied in the epigenetically determined CGI collection (for details see Methods.6. although the extent of linearity is somewhat reduced. The full set of epigenetically determined CGI populations and their orphan subsets are presented in the Supplementary Table. while.34 1.02 1. chromosomal distributions for the islands determined by Illingworth et al.33 M.-5 1.01 1. the two classes of epigenetically determined CGIs defined above are considered as orphan. In the framework of the present study.44 1. In these Tables we have included along with the standard parameter sets. in double logarithmic scale. In Fig.V.-5 1.01 1. we have formed the subset of Illingworth and co-workers original CGIs.5) the picture remains qualitatively the same. 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.54 0.37 1.V.V. 1.V.79 1.V.24 – 1.-5 1.86 1.87 1. 87 for whole chromosomes from the 11 considered genomes.V.V. for the human and mouse genomes.V. the ones we called “alternative” in sub-Section 2. 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). We have also performed gene masking and subsequently we studied the spacers’ size distribution for orphan CGIs. summary information about non-gene-related epigenetically determined CGIs is also included.45 M. (ii) mean values of linearity Extent E for the five more extended power-law incidences (M.09 M. The length reached by the simulated chromosome was 195 Mbp (steps i and ii of the model. Standard and alternative threshold values are considered. 2.74 1.41 – – – M. More plots are included in “Supplementary Plots”. 3. Chromosomal distributions of CpG-Islands in various genomes In Fig. Tsiagkas et al.) for all studied chromosomes from each organism. as described in detail in the Methods. See also the Supplementary Plots. like the ones found in the orphan CGI populations derived on the basis of compositional criteria. In (a).-5). Initially.40 1. for one chromosome of each organism. 1.90 1.4. 256 additional events of non-duplicated CGIs eliminations are also allowed (step iii of the model). Simulations presented in Fig. 21.V.05 1.29 1.) for all studied chromosomes from each organism.-5 1. 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. the complete sets of epigenetically determined CGI are presented (Fig.-5 1.V.59 2. Power-law-like distributions of orphan CGIs are widespread. In Fig. 2010) not intersecting with TSSs and having a minimal distance of 100 bp from a TSS of the RefSeq annotation. sub-Section 2.V.

_1)TD$IG] Fig. 4. CpGo/e > 0.65) sets of thresholds have been used. Either the Gardiner–Garden and Frommer. Inter-CGI spacers’ complementary cumulative size distributions in whole chromosomes. Logarithms are to base 10. 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.2. GC > 50%. while characteristic plots are given in Fig. The linear segments are inferred by linear regression. 1. G + C > 55%. 3. Each sub-plot (a–f) corresponds to a chromosome of one of the examined genomes. Linearity in log–log scale (a power-law-like pattern) is observed. 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. CpGo/e > 0. / Computational Biology and Chemistry 53 (2014) 84–96 threshold sets different than the standard and the “alternative” G-G&F and T&J. [(Fig. for a specific choice of thresholds in the detection of CpG–Islands. ..88 G. Genomic curves are accompanied in each plot by 10 curves of surrogate data (continuous lines). Tsiagkas et al. G-G&F (Lmin = 200 bp. corresponding to randomly distributed markers. T&J (Lmin = 500 bp. 2008.6) or the Takai and Jones.

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

-5 1.V. Random eliminations of a number of CGIs which is lower or equal to the number of the duplicated ones. – – M.-5 1. Occasionally. 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.19 1. 1. In a completely different genomic framework.V. 2000). Lynch and Conery.69 1. 1.27 – M.29 1. Moreover. 1. This model includes events of the types: i Segmental duplications of extended regions of chromosomes. i. as all authors agree. eliminations of repeat copies of the studied TE family.-5 1. In other cases.V. 1.44 M.41 1.-5 2. De Grassi et al. see e.96 0. +100 bp).38 2.V.V.V.V. emancipation of genes from their associate CGI.11 – 1. Masked TSS (-500 bp. 1.19 1.V.V. – – M.55 1.V.V..53 1. Deletions of sequence stretches (which usually are under weak or no purifying selection).-5 1.V.82 1.12 M.84 1. the fate of most duplicated genes is that one copy is silenced. 1. +2 kbp) only for large genomes M. regarded as orphan.V. sequencing and analysis of the human genome has shown that segmental duplications and gene loss are widespread phenomena of genome remodeling during evolution. / Computational Biology and Chemistry 53 (2014) 84–96 genomic localizations.-5 – – M. 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.28 – 1.68 1.22 0. 1.48 1. given that the population of the genomic elements we study are (principally) functional and thus preserved by purifying selection.26 M. 2005.). orphan CGIs becoming redundant.97 – M.V. the two copies continue to survive in the genome sharing the multiple functions of the initial gene between them. for several choices of gene-unrelated (orphan) sets of CGIs.46 M. 1.02 1. 2008.32 – 2.09 1. retroviruses.93 1.V. Moreover.V. – – T&J M.69 1.V. Several cases of syntenic genes of different organisms have been shown to be under differential control of CGIs.41 M.96 – 1.19 1. and then disintegrates progressively by random mutations. 1.-5 1. which has been subsequently decomposed (for details see in the following sub-section). Kasahara (2007). with one gene being under the regulatory control of a CGI.V.02 1.02 1.37 M. 2000): In some cases one member of the gene pair adopts a new function while the other remains unchanged. there are reported three possibilities for the evolution of the duplicated genes (Adams and Wendel.-5 – – M.V.V. 2001).43 1. Even if there are not available quantitative data for the CGI corresponding populations. – – T&J M.28 1.01 – M.-5 1.e.24 2.21 1. These orphan CGIs will be gradually decomposed and lost.-5).-5 – – M.43 1.25 1. 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. The existence of another source of CGI loss can be supported by current findings of comparative genomics.90 G.19 1.g.97 – 1. e. +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.V.V. while its syntenic counterpart in another genome appears to have been emancipated from the action of its ancestral CGI.V.V.70 2.25 Masked genes (5 kbp. Sémon and Wolfe (2007). In the literature. We can consider that CGIs with yet unknown roles. (ii) mean values for the five more extended power-law incidences cases (M. when duplicated often become superfluous and stop being under purifying selection.35 1. ii iii iv v This step may include as limiting case whole genome duplications. which is consistent with findings suggesting massive functional gene loss in the last 10 Myr (IHGSC.98 2. – – M.23 G-G&F M. Tsiagkas et al.36 – Masked TSS (500 bp. in the study of non-conserved elements.V.31 M. Lynch and Conery (2000).24 2. microsatellite expansions etc). while it is also exposed to the possibility of excision due to recombination driven eliminations. event types iii and iv (in that context.93 1. The proposed evolutionary scenario reproduces power-law-like inter-CGI distances size distributions. Adams and Wendel (2005).V. Only events i and ii are indispensable for the appearance of the power-law-like pattern.81 1.V. segmental duplications occurring during genomic evolution and (in some cases) complete genome duplications.-5 1. this property is proven numerically to be robust to quantitative modifications of all the involved types of molecular events.78 M. However. cds (50) only for small genomes G-G&F Large genomes Homo sapiens Mus musculus Small genomes Apis melifera Drosophila melanogaster M. like CGIs.48 – 2.g.-5 1.24 1.V.V. 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. transposable elements (TE) or microsatellites.09 M. additional eliminations of non-duplicated CGIs.44 1.24 M.31 M.64 1. 1. (100 bp.-5 – – .-5 1.V.19 M.-5 – – Epigenetically determined CGIs (non-TSS CGIs only) Epigenetically determined CGIs (TSS-unrelated only) M.V.98 1.41 1.V. although not explicitly considered in the present implementation. Insertions of sequences increasing the total chromosomal length (these could be transposable elements.18 M.12 1.V.-5 – – M. losing the ability to be transcribed.56 2.80 0. – – M. we may expect that loss of CGIs due to one of the above mentioned reasons. with the accelerated rate imposed by the rapid turnover of the CpG dinucleotide (Nachman and Crowell.87 – T&J M.91 1.V. 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. +100 bp) for large genomes.

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

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

More specifically. A decrease in the number of allowed segmental duplications. as observed in real chromosomes. 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. 2012). For a recent in depth view of the requirements for having a power-law. 5a. 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).g. (2012). 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. Discussion 4. power-law-like curves (linear in log–log scale) are formed in the inter-CGI spacers' size distributions. We see that. Tsiagkas et al.. In the previous paragraph we consider the possibility that the genomic power-law-like size distributions of CGIs might be an indication of functionality. however.G. under no purifying selection. the case of the human genome) with many genes inactivated (e. 5c). decreases the extent of the linearity. corroborates the hypothesis that the evolutionary dynamics described by this model is at the origin of the observed genomic patterns. CGIs). as intuitively expected._5)TD$IG] 93 simulations and is in accordance with the variety of slope values met in the study of genomic CGI distributions. On the other hand. Simulations using the proposed evolutionary model. in line with the view that functionality is a necessary condition for CpG islands to form stable power-laws. as an absolute proof that this model is at the origin of the genomic pattern. 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. If we include additional elimination of CGI (events of type iii). the expansion–modification model proposed by Li (1991). This is the principal reason why we call the pattern we have found “power-law-like” throughout this article. Logarithms are to base 10. it is probable that the observed distributions are the result of the proposed mechanism in synergy with other aspects of genomic dynamics. 4. The power-law inter-repeat size distributions of distances between TEs could be seen as a counter-example (Klimopoulos et al. In the simulation of Fig. the linearity is considerably increased (see Fig. 5. along with the common dependence on the evolutionary parameters shared between model and genomic distributions. Thus. as found in several instances. For details see in Section 2 and Section 4. 5b. this is a feature common to all cases of naturally occurring “power-laws”) but mainly because they lack any universal exponent (slope). 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. 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. as extensively discussed therein. 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. Linearity in log–log scale similar to the one observed in the plots of inter-CGI spacers’ complementary cumulative size distributions is found. Moreover. / Computational Biology and Chemistry 53 (2014) 84–96 [(Fig. Analysis of the observed power-law-like chromosomal CGI distributions. the case of human olfactory receptors) and several genes having their regulatory pattern changed. protein coding segments. 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. TEs are long-lived genomic objects. For a related discussion see Klimopoulos et al. depicted in Fig. only events of the types i and ii are included (segmental duplications followed by CGI loss). especially in small genomes. in cases where an extended genic remodeling in the recent past of the organism is plausible (perhaps.1. see Stumpf and Porter (2012). Fig. This feature. recognizable in mammalian genomes up to . These results are compatible with extended powerlaw linearity found.

slowing down of the transposition dynamics. Matsuo et al. It is also worthy to note that the two chromosomes (I and XI) reported by Bradnam et al.e. (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 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. this being a corroboration of the proposed model. but also in a variety of other genomes..5 respectively). as the erosion of mouse CGIs probably makes the relaxed thresholds more suitable for filtering in most of the functional CGIs. and in fact other vertebrate genomes too. rerio.) of all examined genomes. 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. to some extent. type iii events of the proposed model occur according to the cited literature with a particularly higher rate in rodents. The situation changes. while sporadically high values of thresholds may perform better (see data in the “grid”). reported to disappear from a given position at least one order of magnitude faster than any other dinucleotide in the eukaryotic genome. the lengthier log–log linear extents (the only ones above 2) are found in the higher threshold value region. are losing CpG Islands over evolutionary time due to de novo methylation in the germ line followed by CpG loss through mutation.. not spatially connected to genes. 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. by using several different approaches (Sellis and Almirantis. On the other hand. (2008) that the dog genome hosts the highest percentage of gene-unrelated functional CGIs if compared to any studied genome is compatible. i. mouse and other mammalian genomes. Especially in mouse. 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. These are events not requiring evolutionary conservation of the involved genomic elements in order to generate power-law-like distributions. 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. 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. Considering mean values from all chromosomes as depicted in Tables 1 and 2. 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. on the basis of the argument presented above: i.67 vs. for both standard threshold choices. functional islands in general might be compositionally moved toward high CG % and CpGo/e values.e. CpG Islands retain their identity in the evolutionary time scale (i. from which they are principally derived. Contrary to TEs. 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. 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. 2001) thus allowing the interplay of event types iii and iv of the proposed model. This is in accordance with the findings of Li et al. according to our proposed model. In H.2. to all examined genomes. (1998) and Bradnam et al. highest mean value of log–log linearity (M. where a decrease of the linearity extent in log–log scale was observed (figure not included herein). i. by simple inspection of Table 1 we see that the mouse genome presents for G-G&F the highest mean extent.e. The existence of several organisms with higher power law linearities for lower thresholds and shorter minimum length (i. long-rangeness and fractality. Athanasopoulou et al.6 and 1. which makes its genomic turnover rate to be the highest of any other dinucleotide. often focussing on their non-gene-related subset (orphan islands).V. More specifically. that log–log linearity implies functionality for CGI populations.e. On the other hand. In other genomes the optimum (maximum linear extent) is positioned at lower value combinations. 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. according to Antequera and Bird (1993). 1993. The same optimum is reached if we examine the M. This . Gene-related vs. sapiens.85) and the only one which exhibits linearity for alternative threshold set (altG-G&F and altT&J). This has also been shown numerically through computer simulations allowing random transpositions.. / Computational Biology and Chemistry 53 (2014) 84–96 200My. they stay above given thresholds for CG% and for CpGo/e) only for relatively short times after ceasing to be under purifying selection. with our result (see Table 2) that dog genome.5 values. 2006). 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. The prevalence of the higher thresholds in the formation of the most extended linear segments in log–log scale suggests that in fish genomes. 0.V. in fact. The result of Han et al. (1999). As already mentioned.94 G. given the systematic connection of many CGIs with promoters of protein-coding genes. 4. This is due to the mutability of CpG after being methylated. 1993) we observe that the maximum linear length is systematically positioned at lower threshold combinations than the standard ones. Moreover. with no signs of skewed deviations to any direction in the parameter (threshold) space for all analyzed chromosomes. in our study we attempt to identify the distributional patterns of CGI populations of different functionalities and not only the gene-transcription related. CpG is. 2010). where CGIs are known to be eroded. see Nachman and Crowell (2000) and Antequera (2003). they are decreased in number while the “surviving” ones are shorter and with lower CG% and CpGo/e values (Antequera and Bird.45 respectively). we extended our analysis to the subset of CGIs characterized as orphan. we note that this increase is much higher for the GG&F than for the T&J threshold set (0. represents the global optimum of linearity extent.e. Human and mouse. 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. see also Sharp and Lloyd (1993). 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. for several of the other studied genomes as may be revealed by an inspection of the data presented in the supplementary file “grid”. when full gene and flanks masking is applied. i. 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).e. 2009. (Ostertag and Kazazian. Tsiagkas et al. 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. in view of the proposed model. 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. On the other hand.

An alternative explanation for compositionally predicted but methylated CGIs is that these sequences could be functional islands (thus. 3. CpG islands as gene markers in the vertebrate nucleus. Hackenberg.. University of Athens) for serving as academic advisors to G. Zipf’s law and the internet.org/ 10. K. Linearity in log– log scale was often found in the range between two and three orders of magnitude. C. A simple evolutionary model.. Khulan. P. S.. 2003. Phys. C.J. Conclusions In this work we investigated the distributional features of CpG–Islands in several genomes by means of a study of inter-CGI distances considering only entire chromosomes. Wolfe. P. 2007.. Bouhassira. Han. R. At the present time only CGIs involved in gene transcription represent a well defined island set. P. A. CpG islands in vertebrate genomes. A 90. E.A. C.. Lanave.W. Funct. 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