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

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

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

70 M.56 M.V.29 1. see the Supplementary Table).V.32 1.-5 2.50 – 1.15 – 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.79 1. (ii) mean values of linearity extent E for the five more extended power-law incidences (M.) for all studied chromosomes from each organism..82 2. in double logarithmic scale.-5 1. When a masking procedure is applied in the epigenetically determined CGI collection (for details see Methods.-5 1.02 1.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.70 1.74 M. 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. Additionally.34 1. The full set of epigenetically determined CGI populations and their orphan subsets are presented in the Supplementary Table.V.88 1.40 1. for the human and mouse genomes. for one chromosome of each organism. These eliminations represent cases of loss of function of ancestral CGIs with a subsequent progressive decomposition. 31 and human chr. Chromosomal distributions of CpG-Islands in various genomes In Fig.67 – – – T&J M. as described in detail in the Methods. In Table 1 the following information is included: (i) mean values of linearity extent E (M.67 2.08 – – – altG-G&F altT&J M.87 – – – M.G. In Fig.82 – 1.-5).44 1.01 1.04 – M. (ii) mean values of linearity Extent E for the five more extended power-law incidences (M. 173 segmental duplication events occurred.01 1.V.V. which in two instances surpass the three orders of magnitude (in dog chr.24 – 1. 256 additional events of non-duplicated CGIs eliminations are also allowed (step iii of the model).54 0.V.4. see sub-Section 2. 2010) not intersecting with TSSs and having a minimal distance of 100 bp from a TSS of the RefSeq annotation.47 0.09 M.66 – 1.16 – 1.-5 1. This filtering is analogous to the case (i) of the previous paragraph. 3a and d). computing the presented size distributions and simulating the evolutionary model are available upon request.V. 3b and e). More plots are included in “Supplementary Plots”.-5 – – – – 1. 2.-5). 5 are representative of a large number of numerical experiments conducted.45 M.74 1. In Table 2 mean values are given for the orphan CGI spacers’ size distribution in the same form with Table 1.93 – 1. 3. 1. We have also performed gene masking and subsequently we studied the spacers’ size distribution for orphan CGIs.V.87 1. Fig.89 1.V. The G-G&F or T&J thresholds values have been used here.42 0. dealing with the study of masking of threshold-based CGIs. summary information about non-gene-related epigenetically determined CGIs is also included. For genomic and for model-generated size distributions.37 1. while in Supplementary Table all the studied cases are included.38 M.V.37 1. 5(a–c).-5 1. although the extent of linearity is somewhat reduced.02 1.26 – 1. The length reached by the simulated chromosome was 195 Mbp (steps i and ii of the model. Simulations presented in Fig. with lengths sampled from a uniform distribution not exceeding in size the 5% of the actual length of the simulated sequence. In Table 2. along with the corresponding CGI subsets remaining after gene-masking (non-TSS CGIs. 3c and f).4. In the framework of the present study.V.49 2. 3. 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. – – – – 1. 2.-5 1. Here.79 1. 1. 1. throughout.V. Tsiagkas et al. circles and diamonds are used respectively. 1. Simulations using the segmental duplication – CGI loss model Examples of simulations are given in Fig.V. we have formed the subset of Illingworth and co-workers original CGIs. 21.V. in some instances of masked genomes.86 1. the two classes of epigenetically determined CGIs defined above are considered as orphan.19 1.V. In (c) the number of segmental duplications is as in (a) and the finally reached length 119 Mbp. 1 we present examples of the complementary cumulative inter-CGI distances’ size distributions. 1. examples of these distributions are presented.5) the picture remains qualitatively the same. In (b) the segmental duplications were 87 (50% of those in (a)) and the final sequence length 22 Mbp.V. We observe that power-law-like distributions are again formed.52 1. Standard and alternative threshold values are considered. for the same chromosomes as in Fig. sub-Section 2. we observe increase of the extent of linearity when orphan islands are considered instead of the full populations. See also the Supplementary Plots. the complete sets of epigenetically determined CGI are presented (Fig.78 1.89 M.58 0.39 1.V. / 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.29 1. In Fig.61 0.V. like the ones found in the orphan CGI populations derived on the basis of compositional criteria. in some chromosomes for each organism. 1000 markers (representing CGIs) are randomly inserted in a sequence 2 Mbp long.33 1.6.15 M.-5 1.18 1. (2010) based on methylation data are studied and the power-law-like pattern is also found.13 – M. serving as an additional estimator of the intensity of the appearance of the power-law-like pattern per organism.70 M.V.V. chromosomal distributions for the islands determined by Illingworth et al. In (a).03 – Epigenetically determined CGIs (complete population) M.59 2.V. see in the Section 4. – – – – M.73 – 1. 1. 1. the ones we called “alternative” in sub-Section 2. while. After each such event a number of markers (CGIs) equal to 90% of the number of the duplicated ones are eliminated. Power-law-like distributions of orphan CGIs are widespread. In Supplementary Table all chromosomes are presented.) for all studied chromosomes from each organism. We name these Islands “non-TSS”. In these Tables we have included along with the standard parameter sets.V.51 1. 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).33 1. Scripts in Perl and programs in FORTRAN used for parsing genomic data files. 87 for whole chromosomes from the 11 considered genomes. Initially. 1.-5 1. Alternatively. as well as the fraction of the TSS-unrelated CGIs (Fig.90 1.66 1.-5 – – – – . Results 3.33 M. 1.05 1.1.59 M.68 – 1.41 – – – M.03 1.V.

Linearity in log–log scale (a power-law-like pattern) is observed. G + C > 55%. CpGo/e > 0.6) or the Takai and Jones. 1. T&J (Lmin = 500 bp. for a specific choice of thresholds in the detection of CpG–Islands.88 G. / Computational Biology and Chemistry 53 (2014) 84–96 threshold sets different than the standard and the “alternative” G-G&F and T&J. 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. GC > 50%. CpGo/e > 0._1)TD$IG] Fig. . while characteristic plots are given in Fig. 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.. corresponding to randomly distributed markers. Inter-CGI spacers’ complementary cumulative size distributions in whole chromosomes. The linear segments are inferred by linear regression. Either the Gardiner–Garden and Frommer.65) sets of thresholds have been used. Genomic curves are accompanied in each plot by 10 curves of surrogate data (continuous lines).2. G-G&F (Lmin = 200 bp. Logarithms are to base 10. Each sub-plot (a–f) corresponds to a chromosome of one of the examined genomes. 4. Tsiagkas et al. 3. [(Fig. 2008.

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

-5 – – M. transposable elements (TE) or microsatellites. Insertions of sequences increasing the total chromosomal length (these could be transposable elements.e. Moreover.64 1.-5 1.V. Lynch and Conery.V.V. 1. the two copies continue to survive in the genome sharing the multiple functions of the initial gene between them. eliminations of repeat copies of the studied TE family.V. 1. e.-5 2.V.21 1.90 G. 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. given that the population of the genomic elements we study are (principally) functional and thus preserved by purifying selection. orphan CGIs becoming redundant. we may expect that loss of CGIs due to one of the above mentioned reasons. Tsiagkas et al. as all authors agree.26 M.43 1. These orphan CGIs will be gradually decomposed and lost.23 G-G&F M.27 – M.11 – 1. event types iii and iv (in that context.24 1.31 M.43 1.35 1.53 1. Masked TSS (-500 bp.69 1. Adams and Wendel (2005). – – M. Lynch and Conery (2000). +2 kbp) only for large genomes M.09 1. – – M. +100 bp) for large genomes. cds (50) only for small genomes G-G&F Large genomes Homo sapiens Mus musculus Small genomes Apis melifera Drosophila melanogaster M.91 1. for several choices of gene-unrelated (orphan) sets of CGIs. with one gene being under the regulatory control of a CGI. – – T&J M. with the accelerated rate imposed by the rapid turnover of the CpG dinucleotide (Nachman and Crowell. 1.V. 1. Occasionally.02 1. additional eliminations of non-duplicated CGIs. when duplicated often become superfluous and stop being under purifying selection.78 M.37 M..28 – 1.-5 – – M. – – M. see e.41 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. Deletions of sequence stretches (which usually are under weak or no purifying selection). However. losing the ability to be transcribed.98 2. Random eliminations of a number of CGIs which is lower or equal to the number of the duplicated ones.12 M.12 1.02 1. in the study of non-conserved elements. 1.55 1.02 1.38 2.69 1. (100 bp. although not explicitly considered in the present implementation. 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.96 – 1.22 0.24 2.96 0.V.18 M.46 M.V.25 1.-5 1.V.V. the fate of most duplicated genes is that one copy is silenced. retroviruses.19 1.19 1.19 M.V.V.87 – T&J M. De Grassi et al.V.-5 1. Kasahara (2007).V.82 1.09 M. 1. – – T&J M.93 1. 2000). In the literature. In a completely different genomic framework. there are reported three possibilities for the evolution of the duplicated genes (Adams and Wendel.48 1. +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. emancipation of genes from their associate CGI. / Computational Biology and Chemistry 53 (2014) 84–96 genomic localizations.80 0.48 – 2.V.-5 1.97 – M. which is consistent with findings suggesting massive functional gene loss in the last 10 Myr (IHGSC.31 M.-5). 1.V.68 1.36 – Masked TSS (500 bp. 2005.V. This model includes events of the types: i Segmental duplications of extended regions of chromosomes.84 1. (ii) mean values for the five more extended power-law incidences cases (M.V.70 2.01 – M. 2001).V.g. We can consider that CGIs with yet unknown roles. and then disintegrates progressively by random mutations.44 M.41 M.93 1. The proposed evolutionary scenario reproduces power-law-like inter-CGI distances size distributions.V. this property is proven numerically to be robust to quantitative modifications of all the involved types of molecular events. 2008. Only events i and ii are indispensable for the appearance of the power-law-like pattern. 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.41 1.V. 1.25 Masked genes (5 kbp.V.98 1.V.81 1.29 1. In other cases. – – M.56 2.g.19 1. sequencing and analysis of the human genome has shown that segmental duplications and gene loss are widespread phenomena of genome remodeling during evolution. which has been subsequently decomposed (for details see in the following sub-section).V. Several cases of syntenic genes of different organisms have been shown to be under differential control of CGIs.-5 1. 2000): In some cases one member of the gene pair adopts a new function while the other remains unchanged.19 1.-5 – – M.V. like CGIs. 1.V.V.-5 – – . while it is also exposed to the possibility of excision due to recombination driven eliminations. +100 bp).).V.28 1. while its syntenic counterpart in another genome appears to have been emancipated from the action of its ancestral CGI.V.V.32 – 2. segmental duplications occurring during genomic evolution and (in some cases) complete genome duplications.V. microsatellite expansions etc).V. 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. regarded as orphan. 1.24 2.24 M.97 – 1. Sémon and Wolfe (2007). Even if there are not available quantitative data for the CGI corresponding populations. ii iii iv v This step may include as limiting case whole genome duplications. Moreover.-5 1.-5 – – Epigenetically determined CGIs (non-TSS CGIs only) Epigenetically determined CGIs (TSS-unrelated only) M.-5 1. i.-5 1. The existence of another source of CGI loss can be supported by current findings of comparative genomics.44 1.-5 – – M.-5 1.

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

Logarithms are to base 10.92 G. Both are based on an analytically solvable model introduced by Takayasu et al. Tsiagkas et al. conceived to describe the genomic dynamics of CGIs. 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. Here non-standard threshold sets are used. 4. . is not analytically solvable and thus no universal exponents (slopes for the linear segment in log–log scale) may be obtained. This is verified by all our computer [(Fig. for more details see the sub-Section 2. Plots of inter-CGI spacers’ complementary cumulative size distributions in whole chromosomes. 1. (1991) for the appearance of power-law size distributions in aggregative growth of particles in physicochemical systems. / Computational Biology and Chemistry 53 (2014) 84–96 because for many organisms important parts of the genome are generated by repeat proliferation. Notice that the model presented herein._4)TD$IG] Fig.4 and the supplementary file “grid”. in order to account for the appearance of a power-law-like pattern in the chromosomal distribution of genes (Sellis and Almirantis. 2009). Surrogate data curves and linear regression are similar to Fig. The model presented herein is formally similar to another model introduced previously.

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

5 respectively). The prevalence of the higher thresholds in the formation of the most extended linear segments in log–log scale suggests that in fish genomes. and in fact other vertebrate genomes too.e. Tsiagkas et al. It is also worthy to note that the two chromosomes (I and XI) reported by Bradnam et al.. 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). CpG is. sapiens. i. On the other hand.67 vs. Contrary to TEs. (1999). On the other hand. 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. slowing down of the transposition dynamics. 1993) we observe that the maximum linear length is systematically positioned at lower threshold combinations than the standard ones. functional islands in general might be compositionally moved toward high CG % and CpGo/e values. This . Considering mean values from all chromosomes as depicted in Tables 1 and 2. (1998) and Bradnam et al. which makes its genomic turnover rate to be the highest of any other dinucleotide. rerio.e. mouse and other mammalian genomes. highest mean value of log–log linearity (M. 2001) thus allowing the interplay of event types iii and iv of the proposed model. we extended our analysis to the subset of CGIs characterized as orphan. 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. that log–log linearity implies functionality for CGI populations. As already mentioned. The situation changes. according to our proposed model. while sporadically high values of thresholds may perform better (see data in the “grid”). from which they are principally derived.. More specifically. Human and 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. but also in a variety of other genomes. Moreover. this being a corroboration of the proposed model. 0. / Computational Biology and Chemistry 53 (2014) 84–96 200My. In H. we note that this increase is much higher for the GG&F than for the T&J threshold set (0.5 values. The result of Han et al.45 respectively). where CGIs are known to be eroded. Especially in mouse. 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. type iii events of the proposed model occur according to the cited literature with a particularly higher rate in rodents. by using several different approaches (Sellis and Almirantis. These are events not requiring evolutionary conservation of the involved genomic elements in order to generate power-law-like distributions.6 and 1. 2010). see Nachman and Crowell (2000) and Antequera (2003). Matsuo et al. 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. they are decreased in number while the “surviving” ones are shorter and with lower CG% and CpGo/e values (Antequera and Bird. on the basis of the argument presented above: i. for several of the other studied genomes as may be revealed by an inspection of the data presented in the supplementary file “grid”.2. (2008) that the dog genome hosts the highest percentage of gene-unrelated functional CGIs if compared to any studied genome is compatible. 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. 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. reported to disappear from a given position at least one order of magnitude faster than any other dinucleotide in the eukaryotic genome. 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. This is in accordance with the findings of Li et al. where a decrease of the linearity extent in log–log scale was observed (figure not included herein). Athanasopoulou et al. to some extent. the lengthier log–log linear extents (the only ones above 2) are found in the higher threshold value region. 4.. 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. 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. see also Sharp and Lloyd (1993). to all examined genomes. 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. long-rangeness and fractality. given the systematic connection of many CGIs with promoters of protein-coding genes. in our study we attempt to identify the distributional patterns of CGI populations of different functionalities and not only the gene-transcription related. often focussing on their non-gene-related subset (orphan islands).e. 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. 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. are losing CpG Islands over evolutionary time due to de novo methylation in the germ line followed by CpG loss through mutation. 1993. This is due to the mutability of CpG after being methylated. not spatially connected to genes. by simple inspection of Table 1 we see that the mouse genome presents for G-G&F the highest mean extent. according to Antequera and Bird (1993). as the erosion of mouse CGIs probably makes the relaxed thresholds more suitable for filtering in most of the functional CGIs. This has also been shown numerically through computer simulations allowing random transpositions. 2009. 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. with our result (see Table 2) that dog genome.94 G. represents the global optimum of linearity extent. (Ostertag and Kazazian. In other genomes the optimum (maximum linear extent) is positioned at lower value combinations. when full gene and flanks masking is applied. in fact.e.e. CpG Islands retain their identity in the evolutionary time scale (i. The same optimum is reached if we examine the M. (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. 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). they stay above given thresholds for CG% and for CpGo/e) only for relatively short times after ceasing to be under purifying selection.) of all examined genomes. for both standard threshold choices.e. 2006). Gene-related vs. 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.V. i. The existence of several organisms with higher power law linearities for lower thresholds and shorter minimum length (i.V. On the other hand.

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