376:
When functionally related genes came in close proximity to each other, this proximity was conserved. They determined all possible recombination sites between genes of human and mouse. After that, they compared the clustering of the mouse and human genome and looked if recombination had occurred at the potentially recombination sites. It turned out that recombination between genes of the same cluster was very rare. So, as soon as a functional cluster is formed recombination is suppressed by the cell. On sex chromosomes, the amount of clusters is very low in both human and mouse. The authors reasoned this was due to the low rate of chromosomal rearrangements of sex chromosomes.
119:; although their operons are different from the prokaryotic operons. In eukaryotes each gene has a transcription regulation site of its own. Therefore, genes don't have to be in close proximity to be co-expressed. Therefore, it was long assumed that eukaryotic genes were randomly distributed across the genome due to the high rate of chromosome rearrangements. But because the complete sequence of genomes became available it became possible to absolutely locate a gene and measure its distance to other genes.
168:
either became a functional part of the pathway of their parent gene, or (because they are no longer favored by natural selection) gain deleterious mutations and turn into pseudogenes. Because these duplicates are false positives in the search for gene clusters they have to be excluded. Lercher excluded neighboring genes with high resemblance to each other, after that he searched with a sliding window for regions with 15 neighboring genes.
180:
characteristics that were the opposite of RIDGEs, therefore those clusters were called antiridges. LINE repeats are junk DNA which contains a cleavage site of endonuclease (TTTTA). Their scarcity in RIDGEs can be explained by the fact that natural selection favors the scarcity of LINE repeats in ORFs because their endonuclease sites can cause deleterious mutation to the genes. Why SINE repeats are abundant is not yet understood.
372:
ancestor. If all co-expressed genes in a cluster were evolved from a common ancestral gene it would have been expected that they're co-expressed because they all have comparable promoters. However, gene clustering is a very common tread in genomes and it isn't clear how this duplication model could explain all of the clustering. Furthermore, many genes that are present in clusters are not homologous.
142:-phase arrested cells). Because in yeast all genes have a promoter unit of their own it was not suspected that genes would cluster near to each other but they did. Clusters were present on all 16 yeast chromosomes. A year later Cho et al. also reported (although in more detail) that certain genes are located near to each other in yeast.
354:
of gene clusters first the workings chromatin and gene regulation needs to be illuminated. Furthermore, most papers that identified clusters of co-regulated genes focused on transcription levels whereas few focused on clusters regulated by the same transcription-factors. Johnides et al. discovered strange phenomena when they did.
350:
adjacent genes is also until this modification meets a boundary element. In that way genes is close proximity are expressed on the same time. So, genes are clustered in “expression hubs”. In comparison with this model
Gilbert et al. (2004) showed that RIDGEs are mostly present in open chromatin structures.
383:
It is possible that some regions in the genome are better suited for important genes. It is important for the cell that genes that are responsible for basal functions are protected from recombination. It has been observed in yeast and worms that essential genes tend to cluster in regions with a small
375:
How did evolutionary non-related genes come in close proximity in the first place? Either there is a force that brings functionally related genes near to each other, or the genes came near by change. Singer et al. proposed that genes came in close proximity by random recombination of genome segments.
349:
DNA with genes that aren't needed can be covered with histones. When a gene must be expressed special proteins can alter the chemical that are attached to the histones (histone modifications) that cause the histones to open the structure. When the chromatin of one gene is opened, the chromatin of the
345:
and other junk DNA. Because of tight packing the DNA is almost unreachable for the transcript machinery, covering deleterious DNA with proteins is the way in which the cell can protect itself. Chromatin which consists of functional genes is often an open structure were the DNA is accessible. However,
297:
Previous observations and the research of
Gierman et al. proved that the activity of a domain has great impact on the expression of the genes located in it. And the genes within a RIDGE are co-expressed. However the constructs used by Gierman et al. were regulated by al full-time active promoter. The
289:
They investigated if these differences in expressions were due to genes in the direct neighborhood of the constructs or by the domain as a whole. They found that constructs next to highly expressed genes were slightly more expressed than others. But when to enlarged the window size to the surrounding
269:
The genes that were controlled by aire clustered. 53 of the genes most activated by aire had an aire-activated neighbor within 200 Kb or less, and 32 of the genes most repressed by aire had an aire-repressed neighbor within 200 Kb; this is less than expected by change. They did the same screening for
159:
Caron et al. (2001) made a human transcriptome map of 12 different tissues (cancer cells) and concluded that genes are not randomly distributed across the chromosomes. Instead, genes tend to cluster in groups of sometimes 39 genes in close proximity. Clusters were not only gene dense. They identified
367:
suggests that individual genes were grouped together by vertical en horizontal transfer and were preserved as a single unit because that was beneficial for the genes, not per se for the organism. This model predicts that the gene clusters must have conserved between species. This is not the case for
265:
Contrary to previous discussed reports
Johnidis et al. (2005) have discovered that (at least some) genes within clusters are not co-regulated. Aire is a transcription factor which has an up- and down-regulation effect on various genes. It functions in negative selection of thymocytes, which responds
171:
It was clear that gene dense regions existed. There was a striking correlation between gene density and a high CG content. Some clusters indeed had high expression levels. But most of the highly expressed regions consisted of housekeeping genes; genes that are highly expressed in all tissues because
353:
However
Johnidis et al. (2005) have shown that genes in the same cluster can be very differently expressed. How eukaryotic gene regulation, and associated chromatin changes, precisely works is still very unclear and there is no consensus about it. In order to get a clear picture about the mechanism
261:
Many genes which are grouped into clusters show the same expression profiles in human invasive ductal breast carcinomas. Roughly 20% of the genes show a correlation with their neighbors. Clusters of co-expressed genes were divided by regions with less correlation between genes. These clusters could
387:
It is possible that genes came in close proximity by change. Other models have been proposed but none of them can explain all observed phenomena. It's clear that as soon as clusters are formed they are conserved by natural selection. However, a precise model of how genes came in close proximity is
183:
Versteeg et al. also concluded that, contrary to
Lerchers analysis, the transcription levels of many genes in RIDGEs (for example a cluster on chromosome 9) can vary strongly between different tissues. Lee et al. (2003) analyzed the trend of gene clustering between different species. They compared
277:
So it is not very clear if domains are co-regulated or not. A very effective way to test this would be by insert synthetic genes into RIDGEs, antiridges and/or random places in the genome and determine their expression. Those expression levels must be compared to each other. Gierman et al. (2007)
155:
Cho et al. were the first who determined that clustered genes have the same expression levels. They identified transcripts that show cell-cycle dependent periodicity. Of those genes 25% was located in close proximity to other genes which were transcript in the same cell cycle. Cohen et al. (2000)
391:
The bulk of the present clusters must have formed relatively recent because only seven clusters of functionally related genes are conserved between phyla. Some of these differences can be explained by the fact that gene expression is very differently regulated by different phyla. For example, in
371:
According to
Eichler and Sankoff the two mean processes in eukaryotic chromosome evolution are 1) rearrangements of chromosomal segments and 2) localized duplication of genes. Clustering could be explained by reasoning that all genes in a cluster are originated from tandem duplicates of a common
314:
Yamashita et al. (2004) showed that genes related to specific functions in organs tend to cluster. Six liver related domains contained genes for xenobiotic, lipid and alcohol metabolism. Five colon-related domains had genes for apoptosis, cell proliferation, ion transporter and mucin production.
273:
These transcription regulators didn't have the same effect on al genes in the same cluster. Genes that were activated and repressed or unaffected were sometimes present in the same cluster. In this case, it's impossible that aire-regulated genes were clustered because they were all co-regulated.
257:
This study also showed that within clusters the expression levels of on average 15 genes was much the same across the many experimental conditions which were used. These similarities were so striking that the authors reasoned that the genes in the clusters are not individually regulated by their
167:
Lercher et al. (2002) pointed to some weaknesses in Caron's approach. Clusters of genes in close proximity and high transcription levels can easily been generated by tandem duplicates. Genes can generate duplicates of themselves which are incorporated in their neighborhood. These duplicates can
179:
were treated as one gene, and genes without introns were rejected as pseudogenes. They determined that RIDGEs are very gene dense, have a high gene expression, short introns, high SINE repeat density and low LINE repeat density. Clusters containing genes with very low transcription levels had
318:
This shows that at least some clusters consist of functionally related genes. However, there are great exceptions. Spellman and Rubin have shown that there are clusters of co-expressed genes that are not functionally related. It seems like that clusters appear in very different forms.
293:
They also checked if the construct was expressed at similar levels as neighboring genes, and if that tight co-expression was present solely within RIDGEs. They found that the expressions were highly correlated within RIDGEs, and almost absent near the end and outside the RIDGEs.
331:(UAS) associated with that expression pattern. They suggested that UASs can activate genes that are not in immediate adjacency to them. This explanation could explain the co-expression of small clusters, but many clusters contain to many genes to be regulated by a single UAS.
298:
genes of the research of
Johnidis et al. were dependent of the present of the aire transcription factor. The strange expression of the aire regulated genes could partly have been caused by differences in expression and conformation of the aire transcription factor itself.
212:, and found a degree of clustering, as fraction of genes in loose clusters, of respectively (37%), (50%), (74%), (52%) and (68%). They concluded that pathways of which the genes are clusters across many species are rare. They found seven universally clustered pathways:
306:
It was known before the genomic era that clustered genes tend to be functionally related. Abderrahim et al. (1994) had shown that all the genes of the major histocompatibility complex were clustered on the 6p21 chromosome. Roy et al. (2002) showed that in the nematode
160:
27 clusters of genes with very high expression levels and called them RIDGEs. A common RIDGE counts 6 to 30 genes per centiray. However, there were great exceptions, 40 to 50% of the RIDGEs were not that gene dense; just like in yeast these RIDGEs were located in the
379:
Open chromatin regions are active regions. It is more likely that genes will be transferred to these regions. Genes from organelle and virus genome are inserted more often in these regions. In this way non-homologous genes can be pressed together in a small domain.
254:. Of all assayed genes 20% was clustered. Clusters consisted of 10 to 30 genes over a group size of about 100 kilobases. The members of the clusters were not functionally related and the location of clusters didn't correlate with know chromatin structures.
362:
The first models which tried to explain the clustering of genes were, of course, focused on operons because they were discovered before eukaryote gene clusters were. In 1999 Lawrence proposed a model for the origin operons. This
972:
Yamashita T, Honda M, Takatori H, Nishino R, Hoshino N, Kaneko S (November 2004). "Genome-wide transcriptome mapping analysis identifies organ-specific gene expression patterns along human chromosomes".
290:
49 genes (domain level) they saw that constructs located in domains with an overall high expression had a more than 2-fold higher expression then those located in domains with a low expression level.
247:
Lee et al. used very diverse groups of animals. Within these groups clustering is conserved, for example the clustering motifs of Homo sapiens and Mus musculus are more or less the same.
130:
data with the now available genome map. During a cell cycle different genes are active in a cell. Therefore, they used SAGE data from three moments of the cell cycle (log phase,
258:
personal promoter but that changes in the chromatin structure were involved. A similar co-regulation pattern was published in the same year by Roy et al. (2002) in C. elegans.
341:
that are attached to the DNA. Regions were chromatin is very tightly packed are called heterochromatin. Heterochromatin consists very often of remains of viral genomes,
282:
gene driven by the ubiquitously expressed human phosphoglycerate kinase (PGK) promoter. They integrated this construct in 90 different positions in the genome of human
107:, genes within operons share a common promoter unit. These genes are mostly functionally related. The genome of prokaryotes is relatively very simple and compact. In
286:. They found that the expression of the construct in Ridges was indeed higher than those inserted in antiridges (while all constructs have the same promoter).
615:"The human transcriptome map reveals extremes in gene density, intron length, GC content, and repeat pattern for domains of highly and weakly expressed genes"
1135:
Lefai E, Fernández-Moreno MA, Kaguni LS, Garesse R (June 2000). "The highly compact structure of the mitochondrial DNA polymerase genomic region of
311:
genes that are solely expressed in muscle tissue during the larval stage tend to cluster in small groups of 2–5 genes. They identified 13 clusters.
570:
Lercher MJ, Urrutia AO, Hurst LD (June 2002). "Clustering of housekeeping genes provides a unified model of gene order in the human genome".
175:
Versteeg et al. (2003) tried, with a better human genome map and better SAGE taqs, to determine the characteristics of RIDGEs more specific.
111:
the genome is huge and only a small amount of it are functionally genes, furthermore the genes are not arranged in operons. Except for
127:
126:, or budding yeast, in 1996. Half a year after that Velculescu et al. (1997) published a research in which they had integrated
172:
they code for basal mechanisms. Only a minority of the clusters contained genes that were restricted to specific tissues.
328:
337:
changes are a plausible explanation for the co-regulation seen in clusters. Chromatin consists of the DNA strand and
279:
233:
1263:
278:
were the first who proved co-regulation using this approach. As an insertion construct they used a fluorescing
123:
315:
These clusters were very small and expression levels were low. Brain and breast related genes didn't cluster.
208:
196:
526:
241:
817:
Roy PJ, Stuart JM, Lund J, Kim SK (August 2002). "Chromosomal clustering of muscle-expressed genes in
1061:"Chromatin architecture of the human genome: gene-rich domains are enriched in open chromatin fibers"
1017:
877:
448:
411:
202:
1207:
1164:
1041:
846:
595:
1182:
Pál C, Hurst LD (March 2003). "Evidence for co-evolution of gene order and recombination rate".
50:
1268:
1199:
1156:
1117:
1082:
1033:
990:
954:
905:
838:
799:
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693:
644:
587:
552:
507:
466:
176:
1238:
1191:
1148:
1109:
1072:
1025:
982:
944:
936:
895:
885:
830:
789:
779:
734:
724:
683:
675:
634:
626:
579:
542:
497:
456:
1227:"The role of DNA methylation in invertebrates: developmental regulation or genome defense?"
1243:
1226:
437:"The human transcriptome map: clustering of highly expressed genes in chromosomal domains"
87:
80:
46:
392:
vertebrates and plants DNA methylation is used, whereas it is absent in yeast and flies.
1021:
881:
713:"Clusters of co-expressed genes in mammalian genomes are conserved by natural selection"
452:
949:
924:
900:
865:
237:
225:
217:
1113:
794:
763:
688:
663:
639:
614:
547:
530:
502:
485:
1257:
1152:
244:
synthesis in non plant species). Not surprisingly these are basic cellular pathways.
139:
1211:
1168:
1059:
Gilbert N, Boyle S, Fiegler H, Woodfine K, Carter NP, Bickmore WA (September 2004).
1045:
850:
599:
406:
283:
221:
190:
116:
53:. The term was first used by Caron et al. in 2001. Characteristics of ridges are:
1100:
Lawrence JG (September 1997). "Selfish operons and speciation by gene transfer".
327:
Cohen et al. found that of a pair of co-expressed genes only one promoter has an
986:
864:
Johnnidis JB, Venanzi ES, Taxman DJ, Ting JP, Benoist CO, Mathis DJ (May 2005).
342:
100:
1077:
1060:
213:
108:
68:
866:"Chromosomal clustering of genes controlled by the aire transcription factor"
1029:
890:
729:
712:
461:
436:
401:
334:
1203:
1160:
1086:
1037:
994:
958:
909:
842:
803:
748:
697:
648:
613:
Versteeg R, van Schaik BD, van
Batenburg MF, et al. (September 2003).
591:
470:
1121:
784:
556:
511:
338:
161:
135:
112:
61:
834:
1008:
Kosak ST, Groudine M (October 2004). "Gene order and dynamic domains".
940:
630:
229:
131:
65:
739:
679:
104:
74:
42:
1195:
435:
Caron H, van Schaik B, van der Mee M, et al. (February 2001).
583:
531:"A genome-wide transcriptional analysis of the mitotic cell cycle"
923:
Gierman HJ, Indemans MH, Koster J, et al. (September 2007).
764:"Evidence for large domains of similarly expressed genes in the
925:"Domain-wide regulation of gene expression in the human genome"
346:
most of the genes are not needed to be expressed all the time.
664:"Genomic gene clustering analysis of pathways in eukaryotes"
484:
Velculescu VE, Zhang L, Zhou W, et al. (January 1997).
711:
Singer GA, Lloyd AT, Huminiecki LB, Wolfe KH (March 2005).
250:
Spellman and Rubin (2002) made a transcriptome map of
122:
The first eukaryote genome ever sequenced was that of
103:
was known for a long time. Their genes are grouped in
368:many operons and gene clusters seen in eukaryotes.
266:to the organisms own epitopes, by medullary cells.
156:also identified clusters of co-expressed genes.
1139:: functional and evolutionary implications".
486:"Characterization of the yeast transcriptome"
8:
16:Domain of a genome with high gene expression
1225:Regev A, Lamb MJ, Jablonka E (July 1998).
1242:
1076:
948:
899:
889:
793:
783:
738:
728:
687:
638:
546:
501:
460:
430:
428:
426:
422:
1244:10.1093/oxfordjournals.molbev.a025992
270:the transcriptional regulator CIITA.
7:
662:Lee JM, Sonnhammer EL (May 2003).
14:
230:hexachlorocyclohexane degradation
1153:10.1046/j.1365-2583.2000.00191.x
262:cover an entire chromosome arm.
762:Spellman PT, Rubin GM (2002).
41:xpression) are domains of the
1:
1114:10.1016/S0966-842X(97)01110-4
548:10.1016/S1097-2765(00)80114-8
503:10.1016/S0092-8674(00)81845-0
49:; the opposite of ridges are
870:Proc. Natl. Acad. Sci. U.S.A
329:Upstream Activating Sequence
146:Characteristics and function
987:10.1016/j.ygeno.2004.08.008
529:, et al. (July 1998).
218:aminoacyl-tRNA biosynthesis
1285:
1078:10.1016/j.cell.2004.08.011
234:cyanoamino acid metabolism
186:Saccharomyces cerevisiae
124:Saccharomyces cerevisiae
1137:Drosophila melanogaster
1030:10.1126/science.1103864
891:10.1073/pnas.0502670102
462:10.1126/science.1056794
209:Drosophila melanogaster
99:Clustering of genes in
819:Caenorhabditis elegans
197:Caenorhabditis elegans
785:10.1186/1475-4924-1-5
730:10.1093/molbev/msi062
525:Cho RJ, Campbell MJ,
412:Transcription factor
365:selfish operon model
203:Arabidopsis thaliana
1022:2004Sci...306..644K
882:2005PNAS..102.7233J
835:10.1038/nature01012
453:2001Sci...291.1289C
302:Functional relation
941:10.1101/gr.6276007
631:10.1101/gr.1649303
384:replication rate.
680:10.1101/gr.737703
447:(5507): 1289–92.
177:Overlapping genes
73:Genes have short
1276:
1249:
1248:
1246:
1222:
1216:
1215:
1179:
1173:
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1141:Insect Mol. Biol
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1102:Trends Microbiol
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742:
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625:(9): 1998–2004.
610:
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567:
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560:
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522:
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505:
481:
475:
474:
464:
432:
388:still lacking.
1284:
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1279:
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1264:Gene expression
1254:
1253:
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1224:
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1219:
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1176:
1134:
1133:
1129:
1099:
1098:
1094:
1058:
1057:
1053:
1016:(5696): 644–7.
1007:
1006:
1002:
971:
970:
966:
922:
921:
917:
863:
862:
858:
829:(6901): 975–9.
816:
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811:
761:
760:
756:
717:Mol. Biol. Evol
710:
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705:
661:
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612:
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47:gene expression
17:
12:
11:
5:
1282:
1280:
1272:
1271:
1266:
1256:
1255:
1251:
1250:
1237:(7): 880–891.
1217:
1196:10.1038/ng1111
1174:
1127:
1092:
1051:
1000:
964:
935:(9): 1286–95.
915:
876:(20): 7233–8.
856:
809:
754:
703:
654:
605:
562:
517:
476:
421:
419:
416:
415:
414:
409:
404:
397:
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359:
356:
324:
321:
303:
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238:photosynthesis
226:DNA polymerase
152:
149:
147:
144:
134:-arrested and
96:
93:
92:
91:
84:
77:
71:
58:
15:
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3:
2:
1281:
1270:
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1259:
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1231:Mol Biol Evol
1228:
1221:
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1201:
1197:
1193:
1189:
1185:
1178:
1175:
1170:
1166:
1162:
1158:
1154:
1150:
1147:(3): 315–22.
1146:
1142:
1138:
1131:
1128:
1123:
1119:
1115:
1111:
1107:
1103:
1096:
1093:
1088:
1084:
1079:
1074:
1071:(5): 555–66.
1070:
1066:
1062:
1055:
1052:
1047:
1043:
1039:
1035:
1031:
1027:
1023:
1019:
1015:
1011:
1004:
1001:
996:
992:
988:
984:
981:(5): 867–75.
980:
976:
968:
965:
960:
956:
951:
946:
942:
938:
934:
930:
926:
919:
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777:
773:
769:
767:
758:
755:
750:
746:
741:
736:
731:
726:
723:(3): 767–75.
722:
718:
714:
707:
704:
699:
695:
690:
685:
681:
677:
674:(5): 875–82.
673:
669:
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650:
646:
641:
636:
632:
628:
624:
620:
616:
609:
606:
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584:10.1038/ng887
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558:
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496:(2): 243–51.
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463:
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151:Co-expression
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94:
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60:Contain many
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36:
33:
29:
25:
21:
1234:
1230:
1220:
1190:(3): 392–5.
1187:
1183:
1177:
1144:
1140:
1136:
1130:
1108:(9): 355–9.
1105:
1101:
1095:
1068:
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1054:
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1003:
978:
974:
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932:
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775:
771:
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716:
706:
671:
667:
657:
622:
618:
608:
578:(2): 180–3.
575:
571:
565:
541:(1): 65–73.
538:
534:
520:
493:
489:
479:
444:
440:
407:DNA sequence
390:
386:
382:
378:
374:
370:
364:
361:
352:
348:
333:
326:
317:
313:
308:
305:
296:
292:
288:
284:HEK293 cells
276:
272:
268:
264:
260:
256:
251:
249:
246:
222:ATP synthase
207:
201:
195:
191:Homo sapiens
189:
185:
182:
174:
170:
166:
158:
154:
121:
117:trypanosomes
98:
45:with a high
38:
34:
31:
27:
23:
19:
18:
527:Winzeler EA
343:transposons
101:prokaryotes
88:LINE repeat
81:SINE repeat
69:nucleobases
1258:Categories
1184:Nat. Genet
929:Genome Res
766:Drosophila
740:2262/29227
668:Genome Res
619:Genome Res
572:Nat. Genet
323:Regulation
309:C. elegans
252:Drosophila
214:glycolysis
109:eukaryotes
57:Gene dense
51:antiridges
26:egions of
535:Mol. Cell
402:Chromatin
335:Chromatin
164:regions.
113:nematodes
95:Discovery
1269:Genomics
1212:21567576
1204:12577060
1169:39243989
1161:10886416
1087:15339661
1038:15499009
995:15475266
975:Genomics
959:17693573
910:15883360
843:12214599
804:12144710
778:(1): 5.
749:15574806
698:12695325
649:12915492
592:11992122
471:11181992
396:See also
339:histones
162:telomere
1122:9294891
1046:7293449
1018:Bibcode
1010:Science
950:1950897
901:1129145
878:Bibcode
851:4379384
772:J. Biol
768:genome"
600:5797987
557:9702192
512:9008165
449:Bibcode
441:Science
358:Origins
132:S phase
105:operons
90:density
83:density
75:introns
30:ncrease
1210:
1202:
1167:
1159:
1120:
1085:
1044:
1036:
993:
957:
947:
908:
898:
849:
841:
823:Nature
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795:117248
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647:
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637:
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590:
555:
510:
469:
236:, and
43:genome
20:Ridges
1208:S2CID
1165:S2CID
1042:S2CID
847:S2CID
596:S2CID
418:Notes
79:High
1200:PMID
1157:PMID
1118:PMID
1083:PMID
1065:Cell
1034:PMID
991:PMID
955:PMID
906:PMID
839:PMID
800:PMID
745:PMID
694:PMID
645:PMID
588:PMID
553:PMID
508:PMID
490:Cell
467:PMID
206:and
128:SAGE
115:and
86:Low
64:and
37:ene
1239:doi
1192:doi
1149:doi
1110:doi
1073:doi
1069:118
1026:doi
1014:306
983:doi
945:PMC
937:doi
896:PMC
886:doi
874:102
831:doi
827:418
821:".
790:PMC
780:doi
735:hdl
725:doi
684:PMC
676:doi
635:PMC
627:doi
580:doi
543:doi
498:doi
457:doi
445:291
280:GFP
242:ATP
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