Human Molecular Genetics, 2002, Vol. 11, No. 1 13-21
© 2002 Oxford University Press
Chromosome-wide assessment of replication timing for human chromosomes 11q and 21q: disease-related genes in timing-switch regions
1Division of Evolutionary Genetics, Department of Population Genetics and 2Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Yata 1111, Mishima, Shizuoka-ken 411-8540, Japan and 3Human Genome Research Group, RIKEN Genomic Sciences Center, RIKEN, Suehiro-cho 1-7-22, Turumi-ku, Yokohama, Kanagawa-ken 230-0045, Japan
Received August 15, 2001; Revised and Accepted November 2, 2001.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The completion of the human genome sequence will greatly accelerate development of a new branch of bioscience and provide fundamental knowledge to biomedical research. We used the sequence information to measure replication timing of the entire lengths of human chromosomes 11q and 21q. Megabase-sized zones that replicate early or late in S phase (thus early/late transition) were defined at the sequence level. Early zones were more GC-rich and gene-rich than were late zones, and early/late transitions occurred primarily at positions identical to or near GC% transitions. We also found the single nucleotide polymorphism (SNP) frequency was high in the late-replicating and replication-transition regions. In the early/late transition regions, concentrated occurrence of cancer-related genes that include CCND1 encoding cyclin D1 (BCL1), FGF4 (KFGF), TIAM1 and FLI1, was observed. The transition regions contained other disease-related genes including APP associated with familial Alzheimer’s disease (AD1), SOD1 associated with familial amyotrophic lateral sclerosis (ALS1) and PTS associated with phenylketonuria. These findings are discussed with respect to the prediction that increased DNA damage occurs in replication-transition regions. We propose that genome-wide assessment of replication timing serves as an efficient strategy for identifying disease-related genes.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Mammalian DNA replication proceeds in a precisely regulated manner whereby megabase-sized clusters of replicons are activated at distinct times in S phase (1,2). The replicons are heterogeneous in size, but most are 50–450 kb in length. Several to 10 (or more) contiguous replicons with origins that fire synchronously at a specific time comprise a megabase-sized domain that can be visualized cytogenetically as a band by the replication-banding method (3–5). The replication-banding pattern is known to be fairly equivalent to G- or R-banding patterns. In general, G bands, which are composed primarily of AT-rich sequences, correspond to late-replicating zones; T bands (a subgroup of R bands), composed of GC-rich sequences, correspond to zones that replicate very early (3–11). Ordinary R bands replicate early and are composed of both GC- and AT-rich sequences (9–11). In the present study, we measured replication timing for the entire lengths of human chromosomes 11q and 21q, large portions of which our group (RIKEN) sequenced as a member of the International Human Genome Sequencing Consortium (12,13). We then examined the correlations between replication timing and genome characteristics that have biomedical significance and have been compiled on a genome-wide scale. Ten of the 15 known oncogenes/tumor suppressor genes on 11q and 21q were found to be located in or in the close vicinity of replication-timing transition regions. Furthermore, additional 21 genes related to well characterized diseases were found in the transition regions. This indicates that replication-timing transition regions are disease-gene-rich and therefore, are of medical significance.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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General correlation between replication timing and GC% level
We measured replication timing of chromosomes 21q and 11q at the sequence level (14,15) by examining 171 and 278 sequence-tagged sites (STSs), respectively. The average distance between the adjacent STSs was designed to be
200 kb for 21q and thus represents the length of a mid-sized replicon (1–5). The average STS spacing for chromosome 11q, which is larger, was 300 kb. It should be noted that as the study progressed, STS markers were designed more closely (e.g. one STS per 100 kb) in and near early/late transition regions to define these regions more accurately. The level of newly replicated DNA from cell-cycle fractionated THP-1 cells (a monocytic leukemia cell line) was quantified for each STS locus by a PCR-based method (14,15) (Fig. 1). To verify the protocol used, two X-chromosome genes F9 and PGK1, for which the replication timing was reported previously (14), were analysed in advance using two different PCR primer sets each (Fig. 1B and C). The replication period (S1–S4) for each locus was assigned on the basis of the cell-cycle fraction showing the highest level of replicated DNA. Replication timings of the two genes thus obtained were consistent with those reported previously (14).
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Examples of electrophoretic patterns for 11q and 21q loci were presented in Figure 1D. In Figures 2 and 3, early (S1–S2)- and late (S3–S4)-replicated loci are denoted by red and blue ovals, respectively, and the intermediate stage (S2.5) is denoted by green ovals. Several to 10 contiguous loci that covered a few to several megabase areas replicated at identical or similar times during S phase. This provided molecular confirmation of the cytogenetic observation that early or late replicons cluster into a megabase-sized domain in which multiple origins fire fairly synchronously at a specific time during S phase (1–5).
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General correlation between replication timing and GC% level was observed for both 21q and 11q (Figs 2 and 3; atypical cases such as those observed near the centromeres or telomeres are described in the legends). Early zones were more GC-rich than were late zones. This was especially evident between the adjacent early and late zones, and replication transition occurred at positions identical to or near GC% transitions. The concordant transition of replication timing and GC% level is consistent with the molecular characteristics that were predicted for chromosome band boundaries (16,17). The histograms in Figure 4A, in which the GC% of BAC sequences containing individual STSs were examined for each timing category, reveal a general correlation between replication timing and GC% level. Late-replicating sequences corresponding to the S3 or S4 fraction had major peaks in the AT-rich range (<40% GC). In contrast, the major peaks for the earliest S1 sequences were more GC-rich (47.5–52.5% GC). The GC% of S2 sequences was distributed over a wider range.
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A megabase-sized zone composed primarily of STSs belonging to one timing category is denoted in italic letters that specify the timing. The S1 and S2 zones are indicated with red and pink horizontal lines, respectively, in Figures 2 and 3. An ideogram of the 11q banding pattern reported by Saccone et al. (10) and Bernardi et al. (11), in which the isochore distribution was included, is redrawn in Figure 3B. Bands composed primarily of GC-rich H3 isochores and thus corresponding to T bands are indicated in red; ordinary R bands are indicated in white. The ideogram of the isochore distribution and the known mapping data compiled for STSs and genes by NCBI UniSTS (http://www.ncbi.nlm.nih.gov/sts/) and OMIM (http://www.ncbi.nlm.nih.gov/Omim/) indicate that the S1 zones correspond primarily to T bands and that the S2 zones correspond primarily to ordinary R bands. That the GC% of S2 sequences was distributed over a wide range (Fig. 4A) is consistent with the known complex characteristics of ordinary R bands; although R bands replicate early, they are composed of both GC- and AT-rich sequences (9,11). This indicates that differential replication timing is not merely a reflection of segmental GC% distribution. The S4 and S3 zones, which are shown by dark- and light-blue horizontal lines in Figure 3A, respectively, were found to correspond primarily to G bands composed of AT-rich L isochores and those of composed both L and H isochores (10,11), respectively (Fig. 3B). General correlations between replication timing zones and chromosomal bands were also observed for 21q, which has a much simpler banding pattern (10,11) (data not shown). Strehl et al. (18) have reported correlation of replication timing zones with chromosomal bands and identified a band transition in the 5 Mb region on human chromosome 13q.
Gene and single nucleotide polymorphism (SNP) densities in individual timing categories
The positions of genes with known functions on 21q (12) are indicated in Figure 2. Genes, but not pseudogenes, were found to be densely clustered in early replication zones. The histograms in Figure 4B show that the gene densities in the S1 and S2 zones on both 21q and 11q are higher than those in the S3 and S4 zones and the early/late transition zones. The gene density on 11q was lower than that on 21q and this may be due to the fact that the genomic sequence of 11q is incomplete (13). We then examined correlation of replication timing with other genome characteristics that have biomedical significance. Distributions of SNPs compiled by the SNP Consortium (http://snp.cshl.org/) are shown in Figures 2 and 3. In general, SNP density in late-replicating zones appeared to be higher than that in early zones, and interestingly, major peaks of SNP frequency were often located in or near replication-transition regions especially belonging to late-replicating zones. Statistical analysis of SNP density on 21q showed that the SNP density in the S3 and S4 zones was higher than that in the S1 and S2 zones and the density in the S3/S4 transition was slightly higher than that in the S3 and S4 zones (Fig. 4C). Histogram analysis in Figure 4D shows also that SNP-rich regions are more abundant in the late and S3/S4 zones than in the early zones. Analysis on the incomplete 11q sequence available gave analogous results. However, from the viewpoint of statistical analysis, results were too preliminary to be published because of a vast amount of undetermined bases and abnormally long stretches of SNP-deficient sequence. Statistical analyses presented in Figure 4C and D support the results found in the SNP distribution on 21q presented in Figure 2. The present findings are consistent with the prediction that the mutation rate in late-replicating zones may be higher than that in early zones (19,20) and that levels of DNA damage may be elevated in paused regions for replication-fork movement (21–23) (the mechanism is discussed later).
Characteristic locations of oncogenes and tumor suppressor genes
We then investigated correlation of replication timing and localization of disease-related genes. Cancer-related genes were examined initially because 226 genes have been compiled in the Tumor Suppressor/Oncogenes file in the Curated Gene Lists of the Cancer Genome Anatomy Project (http://cgap.nci.nih.gov/Genes/CuratedGeneLists) and therefore, synthetic information for the oncogenes/tumor suppressor genes is available. Fifteen genes that have been mapped precisely on 21q and 11q were found in the list (Table 1). To show their genomic positions, all genes are listed above replication-timing graphs on Figures 2 and 3. It should be noted that these genes were located primarily in or near replication-transition regions. Eight of the 15 genes were located in early/late transitions (indicated in bold in Table 1), and these included CCND1, which encodes cyclin D1, FGF4, ETS1 and FLI1. Oncogene ETS2 at an edge of the early/late transition and AML1 (RUNX1) in the S1/S2 transition are also indicated in bold. Collectively, 10 of the 15 genes were located in or in the close vicinity of the replication-transition regions. It is worth noting that three of the remaining five genes appeared to be located near the small-sized local transition of replication timing that could not be evaluated conclusively at the present level of resolution (Figs 2 and 3).
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Recurrent chromosome aberrations found in cancer were also compiled by the Cancer Genome Anatomy Project (http://cgap.nci.nih.gov/Chromosomes/RecurrentAberrationsTranslocations). Translocation cases were observed for four oncogenes/tumor suppressor genes on 21q and 11q and high frequencies (>100 cases) were observed for the three genes located in replication-transition regions (Table 1; indicated in yellow on Figs 2 and 3).
Genes in replication-transition regions
To further clarify the characteristics of the genes present in replication-transition regions, we searched for genes with known functions that were localized in early/late transition regions with the Human Genome Server ‘Ensembl’ (http://www.ensembl.org/) and ‘HGREP’ (http://hgrep.ims.u-tokyo.ac.jp/). In addition to the eight oncogenes/tumor suppressor genes indicated in bold in Table 1, 44 genes were found in the early/late transition regions (Table 2). Twenty-one genes associated with well characterized diseases in OMIM are indicated in bold. To show their genomic positions, 11 examples are listed below the replication-timing graphs on Figures 2 and 3. These include APP, which is related to familial Alzheimer’s disease (AD1); GRIK1, which encodes the neuronal glutamate receptor subunit GluR-5 that is related to juvenile absence epilepsy; SOD1, which is related to familial amyotrophic lateral sclerosis (ALS1); PTS, which is related to phenylketonuria III, IV; and three genes involved in lymphoma- or leukemia-associated gene fusion (NUMA1, API2, ARHGEF12).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Twenty-nine of the 52 genes located in early/late transition regions were found to be associated with well characterized diseases: eight oncogenes/tumor suppressor genes indicated in bold in Table 1 and 21 genes indicated in bold in Table 2. Hypothetical genes predicted by computer analyses are not listed in Table 2. Disease-related genes might be found among these hypothetical genes. We also did not include genes located in the S1/S2 or S3/S4 transitions (e.g. MLL or USP25, respectively) or close to the early/late transition (e.g. ATM). At the present level of PCR-marker density, it is unclear whether these genes are localized within the transition region. Further high density mapping of replication timing may be necessary because oncogenes/tumor suppressor genes are often located in or near S1/S2 transition regions (Figs 2 and 3).
It is unclear whether the present findings can be generalized to other chromosomes because this is the first chromosome-wide study of replication timing at the sequence level. However, several replication-timing transitions have been localized at the sequence level by megabase-sized measurements of replication timing. One transition was found in the junction region of MHC classes II and III where NOTCH4 is located (16,17,24). Other transitions were found in the 3' end of XIST (15) and near FMR1 (25) on chromosome X. An early/late transition was found in the mouse Igh locus (26). The respective genes have been associated with diseases in OMIM. It has been suggested that the probability of DNA damage, including DNA rearrangements, is higher for replication-transition regions than for other genome regions (21–23). Multiple origins belonging to a single early-replicating zone are known to fire fairly synchronously at a specific time in early S phase, and the individual DNA forks meet and merge with oncoming adjacent forks in this early zone typically within 1 h (2,27,28). However, only the fork that starts at the edge of the early zone is predicted to continue replicating for a period of a few additional hours or pause at specific sites in the replication-transition region until it meets the edge fork initiated in the adjacent later-replicating zone (2,17,26). A pause during replication is known to increase DNA breaks and rearrangements (21–23). These characteristics may be associated with the present finding that disease-related genes tend to be located in or in the close vicinity of the transition regions.
It has been shown that early-replicating zones are composed primarily of loose chromatin structures and that late zones comprise compact chromatin in metaphase or interphase nuclei (1,4,5,7). Therefore, transition of chromatin compaction likely occurs within replication-transition regions. In terminally differentiated cells, such as neurons, the level of chromatin compaction that is established during the final round of DNA replication may be maintained. In the early/late transition regions, four neural disease genes (APP, GRIK1, SOD1 and DSCAM) were found (Table 2). Interestingly, the 5' ends of all four of these genes were found to replicate later than did the 3' ends. For example, the 5' end of APP replicated in S3, but the 3' end, which is located 290 kb downstream, replicated in S2. This may reflect tissue-specific expression of these genes and suggests that the chromatin is more compact at the 5' end. The transition of chromatin compaction within a gene might lead to reduced stability and increased susceptibility of the chromatin to various reagents in the gene locus including regulatory regions for gene expression.
Cytogenetic data have shown that the replication-banding pattern and the R- and G-banding patterns are tissue invariant (3–5). This, and the global correlation of replication timing with GC% level, suggest that the megabase-sized early- or late-replicating domains should be common among cell types. Despite the tissue-related invariance of the megabase-sized banding patterns, replicon-sized segments that harbor tissue-specifically expressed genes are known to replicate early in the respective tissues even if the segment is located within a late-replicating G-band zone (4,5,29). Therefore, if the edge replicon in a G-band zone contains a tissue-specific gene, the edge segment may replicate early in that tissue. In such a case, the exact area of the replication-transition is cell-type dependent (25,26). If such a situation exists, it does not limit the usefulness of the present chromosome-wide approach, because the hypothesized dependence represents an important functional characteristic of the genomic region. Information acquired through genome-wide studies of replication timing will contribute substantially to our understanding of genome structure and function and of the molecular mechanisms in the pathogenesis of diseases. It may also serve as an efficient strategy for identifying disease-related genes.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Cell-cycle fractionation and isolation of newly replicated DNA
Human acute monocytic leukemia cell line (THP-1; 2n = 46, XY; obtained from Health Science Research Resources Bank, Tokyo, Japan) was chosen because of the integrity of the karyotype (30); the integrities of chromosomes 11 and 21 were confirmed prior to this study (31). THP-1 cells were labeled for 60 min with 75 µM 5'-bromo-2'-deoxyuridine (BrdU; Boehringer Mannheim, Germany). The BrdU labeling, cell-cycle fractionation, and isolation of newly replicated DNA were performed according to the methods described by Hansen et al. (14) but with minor modifications (15). The BrdU-labeled cells were washed with cold phosphate-buffered saline, fixed in 70% ethanol for 60 min, pelleted and resuspended in 70% ethanol at 4°C; they were then resuspended in staining buffer (14) followed by a 30 min incubation at room temperature. The cells were fractionated into six parts on the basis of the cell-cycle phase, G1, S1–S4 and G2/M, using an EPICS Elite cell sorter (Beckman Coulter, Fullerton, CA). Equal numbers of cells (4 x 104) were collected in microfuge tubes containing lysis buffer (14) followed by a 2 h incubation at 50°C. To provide controls for recovery of BrdU-labeled DNA, a mixture of [14C]thymidine-labeled (5 x 104 d.p.m.) Chinese hamster ovary cell (CHO) DNA and BrdU- and [3H]deoxycytidine-labeled (5 x 104 d.p.m.) CHO DNA was added to each fraction. The DNA samples were purified by phenol/chloroform extraction and ethanol precipitation and dissolved in 460 µl of TE containing sheared salmon testis DNA (0.5 mg/ml); they were then sonicated to obtain fragments with an average size of
1 kb. These fragments were heat-denatured for 3 min at 95°C and cooled on ice. After addition of 56 µl of 10x immunoprecipitation buffer (14) and 80 µl of anti-BrdU mouse monoclonal antibody (25 µg/ml), the samples were incubated at room temperature for 20 min under constant rotation. Antibody-bound BrdU DNA was precipitated by addition of 15 µl of 2.5 mg/ml anti-mouse IgG, and the mixture was incubated for 20 min at room temperature. After centrifugation, the pellet was washed with 1x immunoprecipitation buffer, resuspended in 200 µl of digestion buffer (14), and incubated overnight at 37°C. An additional 100 µl of digestion buffer was added, followed by overnight incubation at 37°C. The sample was subjected to phenol/chloroform extraction and, after addition of 20 µg yeast tRNA, DNA was precipitated with ethanol and dissolved in TE. The recovery and purity level of the BrdU DNA was checked by monitoring the radioactivity of the [3H] and [14C] counts of the CHO DNA (15,17). BrdU-labeled DNAs isolated from five independent FACS sorts were used and each DNA sample was tested in advance for two X-chromosome genes F9 and PGK1, for which replication timing was reported previously (14). Bar diagrams in Figure 1C summarize the quantification data of the two genes testing the five independent DNA samples.
PCR-based quantification of replicated DNA
Replication timing of a particular locus was determined by quantifying the number of copies of that locus in the newly replicated DNA of each fraction with quantitative PCR (14,15). Locus-specific primers were selected based on the criterion that a single PCR product of the predicted size was amplified from THP-1 genomic DNA but not from CHO DNA. Primer pairs for two different loci were added to a single tube containing a constant amount of BrdU-labeled DNA from each cell-cycle fraction, which had been calibrated on the basis of the [3H] count as described previously (15,17). In addition to locus-specific primers, each reaction contained a constant amount of plasmid pKF3 DNA and pKF3-specific primers for assessment of the PCR efficiency (15). The reaction buffer contained 0.5 U AmpliTaq Gold (Perkin-Elmer, Branchburg, NJ) in 100 µl of the manufacturer’s reaction buffer. The PCR conditions were as follows: 95°C for 9 min to activate AmpliTaq Gold; 32 cycles of 94°C for 30 s, 55°C for 1 min, 72°C for 1 min and a final extension at 72°C for 10 min. Gel electrophoresis, and FluorImager quantification were performed as described previously (15). Replication timing of each locus was assigned after quantification of at least three independent PCR products from reactions in which annealing temperature, ratio of BrdU-labeled DNAs to pKF3 DNA, and pairs of locus-specific primers were altered. Unusual cases where a certain combination of primer sets brought on PCR products with unexpected sizes, additional bands or bands of evidently unequal intensity, were omitted from the analysis. For each locus, at least two independent DNAs isolated from independent FACS sorts were used. Sequences and positions of the locus-specific primers used in this study and the timing of each locus will be published on the web pages (http://spinner.lab.nig.ac.jp/lab_evol/home-e.html; http://hgp.gsc.riken.go.jp/).
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ACKNOWLEDGEMENTS |
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This work was supported by a Grant-in-Aid for Scientific Research on Priority Areas (Human Genome Project) and by a Grant-in-Aid for Scientific Research from Ministry of Education, Science, and Culture of Japan. We thank Dr Mizuki Ohno (National Institute of Genetics; Kyusyu University) for karyotype analysis of THP-1 cells.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +81 559 81 6788; Fax: +81 559 81 6794; Email: tikemura@lab.nig.ac.jp
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REFERENCES |
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1 Craig,J.M. and Bickmore,W.A. (1993) Chromosome bands—flavours to savour. Bioessays, 15, 349–354.[Web of Science][Medline]
2 Berezney,R., Dubey,D.D. and Huberman,J.A. (2000) Heterogeneity of eukaryotic replicons, replicon clusters, and replication foci. Chromosoma, 108, 471–484.[Web of Science][Medline]
3 Drouin,R., Holmquist,G.P. and Richer,C.L. (1994) High-resolution replication bands compared with morphologic G- and R-bands. Adv. Hum. Genet., 22, 47–115.[Web of Science][Medline]
4 Holmquist,G., Gray,M., Porter,T. and Jordan,J. (1982) Characterization of Giemsa dark- and light-band DNA. Cell, 31, 121–129.[Web of Science][Medline]
5 Holmquist,G.P. (1989) Evolution of chromosome bands: molecular ecology of noncoding DNA. J. Mol. Evol., 28, 469–486.[Web of Science][Medline]
6 Ikemura,T. and Aota,S. (1988) Global variation in G+C content along vertebrate genome DNA: possible correlation with chromosome band structures. J. Mol. Biol., 203, 1–13.[Web of Science][Medline]
7 Bernardi,G. (1989) The isochore organization of the human genome. Annu. Rev. Genet., 23, 637–661.[Web of Science][Medline]
8 Ikemura,T., Wada,K. and Aota,S. (1990) Giant G+C% mosaic structures of the human genome found by arrangement of GeneBank human DNA sequences according to genetic positions. Genomics, 8, 207–216.[Web of Science][Medline]
9 Ikemura,T. and Wada,K. (1991) Evident diversity of codon usage patterns of human genes with respect to chromosome banding patterns and chromosome numbers; relation between nucleotide sequence data and cytogenetic data. Nucleic Acids Res., 19, 4333–4339.
10 Saccone,S., Federico,C., Solovei,I., Croquette,M.F., Valle,G.D. and Bernardi,G. (1999) Identification of the gene-richest bands in human prometaphase chromosomes. Chromosome Res., 7, 379–386.[Web of Science][Medline]
11 Bernardi,G. (2000) Isochores and the evolutionary genomics of vertebrates: organization of the human genome. Gene, 241, 3–17.[Web of Science][Medline]
12 Hattori,M., Fujiyama,A., Taylor,T.D., Watanabe,H., Yada,T., Park,H.S., Toyoda,A., Ishii,K., Totoki,Y., Choi,D.K. et al. (2000) The DNA sequence of human chromosome 21. Nature, 405, 311–319.[Medline]
13 International Human Genome Sequencing Consortium (2001) Initial sequencing and analysis of the human genome. Nature, 409, 860–921.[Medline]
14 Hansen,R.S., Canfield,T.K., Lamb,M.M., Gartler,S.M. and Laird,C.D. (1993) Association of fragile X syndrome with delayed replication of the FMR1 gene. Cell, 73, 1403–1409.[Web of Science][Medline]
15 Watanabe,Y., Tenzen,T., Nagasaka,Y., Inoko,H. and Ikemura,T. (2000) Replication timing of the human X-inactivation center (XIC) region: correlation with chromosome bands. Gene, 252, 163–172.[Web of Science][Medline]
16 Fukagawa,T. , Sugaya,K., Matumoto,K., Okumura,K., Ando,A., Inoko,H. and Ikemura,T. (1995) A boundary of long-range G+C% mosaic domains in the human MHC locus: pseudoautosomal boundary-like sequence exists near the boundary. Genomics, 25, 184–191.[Web of Science][Medline]
17 Tenzen,T., Yamagata,T., Fukagawa,T., Sugaya,K., Ando,A., Inoko,H., Gojobori,T., Fujiyama,A., Okumura,K. and Ikemura,T. (1997) Precise switching of DNA replication timing in the GC content transition area in the human major histocompatibility complex. Mol. Cell. Biol., 17, 4043–4050.[Abstract]
18 Strehl,S., LaSalle,J.M. and Lalande,M. (1997) High-resolution analysis of DNA replication domain organization across an R/G-band boundary. Mol. Cell. Biol., 17, 6157–6166.[Abstract]
19 Filipski,J. (1990) Evolution of DNA sequence contributions of mutational bias and selection to the origin of chromosomal compartments. In Obe,G. (ed.), Advances in Mutagenesis Research 2. Springer-Verlag, Berlin Heidelberg, Germany, pp. 1–54.
20 Deschanne,P. and Filipski,J. (1995) Correlation of GC content with replication timing and repair mechanisms in weakly expressed E.coli genes. Nucleic Acids Res., 23, 1350–1353.
21 Bierne,H. and Michel,B. (1994) When replication forks stop. Mol. Microbiol., 13, 17–23.[Web of Science][Medline]
22 Verbovaia,L.V. and Razin,S.V. (1997) Mapping of replication origins and termination sites in the Duchenne muscular dystrophy gene. Genomics, 45, 24–30.[Web of Science][Medline]
23 Rothstein,R., Michel,B. and Gangloff,S. (2000) Replication fork pausing and recombination or ‘gimme a break’. Genes Dev., 14, 1–14.
24 Sugaya,K., Fukagawa,T., Matsumoto,K., Mita,K., Takahashi,E., Ando,A., Inoko,H. and Ikemura,T. (1994) Three genes in the human MHC class III region near the junction with the class II: gene for receptor of advanced glycosylation end products, PBX2 homeobox gene and a Notch-homolog, human counterpart of mouse mammary tumor gene int-3. Genomics, 23, 408–419.[Web of Science][Medline]
25 Hansen,R.S., Canfield,T.K., Fjeld,A.D., Mumm,S., Laird,C.D. and Gartler,S.M. (1997) A variable domain of delayed replication in FRAXA fragile X chromosomes: X inactivation-like spread of late replication. Proc. Natl Acad. Sci. USA, 94, 4587–4592.
26 Ermakova,O.V., Nguyen,L.H., Little,R.D., Chevillard,C., Riblet,R., Ashouian,N., Birshtein,B.K. and Schildkraut,C.L. (1999) Evidence that a single replication fork proceeds from early to late replicating domains in the Igh locus in a non-B cell line. Mol. Cell, 3, 321–330.[Web of Science][Medline]
27 Jackson,D.A. and Pombo,A. (1998) Replicon clusters are stable units of chromosome structure: evidence that nuclear organization contributes to the efficient activation and propagation of S phase in human cells. J. Cell Biol., 140, 1285–1295.
28 Ma,H., Samarabandu,J., Devdhar,R.S., Acharya,R., Cheng,P., Meng,C. and Berezney,R. (1998) Spatial and temporal dynamics of DNA replication sites in mammalian cells. J. Cell Biol., 143, 1415–1425.
29 Goldman,M.A., Holmquist,G.P., Gray,M.C., Caston,L.A. and Nag,A. (1984) Replication timing of genes and middle repetitive sequences. Science, 224, 686–692.
30 Tsuchiya,S., Yamabe,M., Yamaguchi,Y., Kobayashi,Y., Konno,T and Tada,K. (1980) Establishment and characterization of a human acute monocytic leukemia cell line (THP-1). Int. J. Cancer, 26, 171–176.[Web of Science][Medline]
31 Ohno,M., Tenzen,T., Watanabe,Y., Yamagata,T., Kanaya,S. and Ikemura,T. (2000) Non-B DNA structures spatially and sequence-specifically associated with individual centromeres in the human interphase nucleus. In Olmo,E. and Redi,C.A. (eds), Chromosomes Today. Birkhauser Verlag, Basel, Boston, Berlin, Vol. 13, pp. 57–69.
32 Venter,J.C., Adams,M.D., Myers,E.W., Li,P.W., Mural,R.J., Sutton,G.G., Smith,H.O., Yandell,M., Evans,C.A., Holt,R.A. et al. (2001) The sequence of the human genome. Science, 291, 1304–1351.
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N. Karnani, C. Taylor, A. Malhotra, and A. Dutta Pan-S replication patterns and chromosomal domains defined by genome-tiling arrays of ENCODE genomic areas Genome Res., June 1, 2007; 17(6): 865 - 876. [Abstract] [Full Text] [PDF]
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G. Bernardi The neoselectionist theory of genome evolution PNAS, May 15, 2007; 104(20): 8385 - 8390. [Abstract] [Full Text] [PDF]
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 C. Schmegner, J. Hoegel, W. Vogel, and G. Assum The Rate, Not the Spectrum, of Base Pair Substitutions Changes at a GC-Content Transition in the Human NF1 Gene Region: Implications for the Evolution of the Mammalian Genome Structure Genetics, January 1, 2007; 175(1): 421 - 428. [Abstract] [Full Text] [PDF]
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W.-Y. Ko, S. Piao, and H. Akashi Strong Regional Heterogeneity in Base Composition Evolution on the Drosophila X Chromosome Genetics, September 1, 2006; 174(1): 349 - 362. [Abstract] [Full Text] [PDF]
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M. Ohno, T. Miura, M. Furuichi, Y. Tominaga, D. Tsuchimoto, K. Sakumi, and Y. Nakabeppu A genome-wide distribution of 8-oxoguanine correlates with the preferred regions for recombination and single nucleotide polymorphism in the human genome. Genome Res., May 1, 2006; 16(5): 567 - 575. [Abstract] [Full Text] [PDF]
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 M. Semon, D. Mouchiroud, and L. Duret Relationship between gene expression and GC-content in mammals: statistical significance and biological relevance Hum. Mol. Genet., February 1, 2005; 14(3): 421 - 427. [Abstract] [Full Text] [PDF]
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I. Hiratani, A. Leskovar, and D. M. Gilbert Differentiation-induced replication-timing changes are restricted to AT-rich/long interspersed nuclear element (LINE)-rich isochores PNAS, November 30, 2004; 101(48): 16861 - 16866. [Abstract] [Full Text] [PDF]
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 N. Shimizu and K. Shingaki Macroscopic folding and replication of the homogeneously staining region in late S phase leads to the appearance of replication bands in mitotic chromosomes J. Cell Sci., October 15, 2004; 117(22): 5303 - 5312. [Abstract] [Full Text] [PDF]
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 J. Meunier and L. Duret Recombination Drives the Evolution of GC-Content in the Human Genome Mol. Biol. Evol., June 1, 2004; 21(6): 984 - 990. [Abstract] [Full Text] [PDF]
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K. Woodfine, H. Fiegler, D. M. Beare, J. E. Collins, O. T. McCann, B. D. Young, S. Debernardi, R. Mott, I. Dunham, and N. P. Carter Replication timing of the human genome Hum. Mol. Genet., January 15, 2004; 13(2): 191 - 202. [Abstract] [Full Text] [PDF]
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M. Iwase, Y. Satta, Y. Hirai, H. Hirai, H. Imai, and N. Takahata From the Cover: The amelogenin loci span an ancient pseudoautosomal boundary in diverse mammalian species PNAS, April 29, 2003; 100(9): 5258 - 5263. [Abstract] [Full Text] [PDF]
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T. Abe, S. Kanaya, M. Kinouchi, Y. Ichiba, T. Kozuki, and T. Ikemura Informatics for Unveiling Hidden Genome Signatures Genome Res., April 1, 2003; 13(4): 693 - 702. [Abstract] [Full Text] [PDF]
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