420:
432:) was limited until the late 1990s, when technological advances made practical the handling of the vast quantities of complex data involved in the process. Historically, full-genome shotgun sequencing was believed to be limited by both the sheer size of large genomes and by the complexity added by the high percentage of repetitive DNA (greater than 50% for the human genome) present in large genomes. It was not widely accepted that a full-genome shotgun sequence of a large genome would provide reliable data. For these reasons, other strategies that lowered the computational load of sequence assembly had to be utilized before shotgun sequencing was performed. In hierarchical sequencing, also known as top-down sequencing, a low-resolution
212:. As sequencing projects began to take on longer and more complicated DNA sequences, multiple groups began to realize that useful information could be obtained by sequencing both ends of a fragment of DNA. Although sequencing both ends of the same fragment and keeping track of the paired data was more cumbersome than sequencing a single end of two distinct fragments, the knowledge that the two sequences were oriented in opposite directions and were about the length of a fragment apart from each other was valuable in reconstructing the sequence of the original target fragment.
486:. Two clones that have several fragment sizes in common are inferred to overlap because they contain multiple similarly spaced restriction sites in common. This method of genomic mapping is called restriction or BAC fingerprinting because it identifies a set of restriction sites contained in each clone. Once the overlap between the clones has been found and their order relative to the genome known, a scaffold of a minimal subset of these contigs that covers the entire genome is shotgun-sequenced.
460:
1641:
392:. For example, a hypothetical genome with 2,000 base pairs reconstructed from 8 reads with an average length of 500 nucleotides will have 2x redundancy. This parameter also enables one to estimate other quantities, such as the percentage of the genome covered by reads (sometimes also called coverage). A high coverage in shotgun sequencing is desired because it can overcome errors in
471:
another and then selecting the fewest clones required to form a contiguous scaffold that covers the entire area of interest. The order of the clones is deduced by determining the way in which they overlap. Overlapping clones can be identified in several ways. A small radioactively or chemically labeled probe containing a
475:(STS) can be hybridized onto a microarray upon which the clones are printed. In this way, all the clones that contain a particular sequence in the genome are identified. The end of one of these clones can then be sequenced to yield a new probe and the process repeated in a method called chromosome walking.
470:
Although the full sequences of the BAC contigs is not known, their orientations relative to one another are known. There are several methods for deducing this order and selecting the BACs that make up a tiling path. The general strategy involves identifying the positions of the clones relative to one
423:
In whole genome shotgun sequencing (top), the entire genome is sheared randomly into small fragments (appropriately sized for sequencing) and then reassembled. In hierarchical shotgun sequencing (bottom), the genome is first broken into larger segments. After the order of these segments is deduced,
159:
In this extremely simplified example, none of the reads cover the full length of the original sequence, but the four reads can be assembled into the original sequence using the overlap of their ends to align and order them. In reality, this process uses enormous amounts of information that are rife
489:
Because it involves first creating a low-resolution map of the genome, hierarchical shotgun sequencing is slower than whole-genome shotgun sequencing, but relies less heavily on computer algorithms than whole-genome shotgun sequencing. The process of extensive BAC library creation and tiling path
302:
by following connections between mate pairs. The distance between contigs can be inferred from the mate pair positions if the average fragment length of the library is known and has a narrow window of deviation. Depending on the size of the gap between contigs, different techniques can be used to
222:
locus, although the use of paired ends was limited to closing gaps after the application of a traditional shotgun sequencing approach. The first theoretical description of a pure pairwise end sequencing strategy, assuming fragments of constant length, was in 1991. At the time, there was community
323:
at once using large arrays of sequencers, which makes the whole process much more efficient than more traditional approaches. Detractors argue that although the technique quickly sequences large regions of DNA, its ability to correctly link these regions is suspect, particularly for eukaryotic
510:
Short-read or "next-gen" sequencing produces shorter reads (anywhere from 25–500bp) but many hundreds of thousands or millions of reads in a relatively short time (on the order of a day). This results in high coverage, but the assembly process is much more computationally intensive. These
490:
selection, however, make hierarchical shotgun sequencing slow and labor-intensive. Now that the technology is available and the reliability of the data demonstrated, the speed and cost efficiency of whole-genome shotgun sequencing has made it the primary method for genome sequencing.
537:
are: not being limited to bacteria; strain-level classification where amplicon sequencing only gets the genus; and the possibility to extract whole genes and specify their function as part of the metagenome. The sensitivity of metagenomic sequencing makes it an attractive choice for
498:
The classical shotgun sequencing was based on the Sanger sequencing method: this was the most advanced technique for sequencing genomes from about 1995–2005. The shotgun strategy is still applied today, however using other sequencing technologies, such as
436:
of the genome is made prior to actual sequencing. From this map, a minimal number of fragments that cover the entire chromosome are selected for sequencing. In this way, the minimum amount of high-throughput sequencing and assembly is required.
69:. Multiple overlapping reads for the target DNA are obtained by performing several rounds of this fragmentation and sequencing. Computer programs then use the overlapping ends of different reads to assemble them into a continuous sequence.
878:
Edwards, Al; Voss, Hartmut; Rice, Peter; Civitello, Andrew; Stegemann, Josef; Schwager, Christian; Zimmermann, Juergen; Erfle, Holger; Caskey, C.Thomas; Ansorge, Wilhelm (April 1990). "Automated DNA sequencing of the human HPRT locus".
227:
et al. introduced the innovation of using fragments of varying sizes, and demonstrated that a pure pairwise end-sequencing strategy would be possible on large targets. The strategy was subsequently adopted by
444:(PAC). Because multiple genome copies have been sheared at random, the fragments contained in these clones have different ends, and with enough coverage (see section above) finding the smallest possible
529:
software. With millions of reads from next generation sequencing of an environmental sample, it is possible to get a complete overview of any complex microbiome with thousands of species, like the
175:; that is, each base in the final sequence was present on average in 12 different reads. Even so, current methods have failed to isolate or assemble reliable sequence for approximately 1% of the (
1645:
519:
Having reads of 400-500 base pairs length is sufficient to determine the species or strain of the organism where the DNA comes from, provided its genome is already known, by using for example a
411:. Sequence coverage is the average number of times a base is read (as described above). Physical coverage is the average number of times a base is read or spanned by mate paired reads.
467:
Once a tiling path has been found, the BACs that form this path are sheared at random into smaller fragments and can be sequenced using the shotgun method on a smaller scale.
167:
Many overlapping reads for each segment of the original DNA are necessary to overcome these difficulties and accurately assemble the sequence. For example, to complete the
390:
192:
Whole genome shotgun sequencing for small (4000- to 7000-base-pair) genomes was first suggested in 1979. The first genome sequenced by shotgun sequencing was that of
282:. Since the chain termination method usually can only produce reads between 500 and 1000 bases long, in all but the smallest clones, mate pairs will rarely overlap.
1536:
Thoendel, Matthew; Jeraldo, Patricio; Greenwood-Quaintance, Kerryl E.; Yao, Janet; Chia, Nicholas; Hanssen, Arlen D.; Abdel, Matthew P.; Patel, Robin (June 2017).
1261:
Bozdag, Serdar; Close, Timothy J.; Lonardi, Stefano (March 2013). "A Graph-Theoretical
Approach to the Selection of the Minimum Tiling Path from a Physical Map".
307:(PCR) to amplify the region is required, followed by sequencing. If the gap is large (>20kb) then the large fragment is cloned in special vectors such as
428:
Although shotgun sequencing can in theory be applied to a genome of any size, its direct application to the sequencing of large genomes (for instance, the
914:
Roach, Jared C.; Boysen, Cecilie; Wang, Kai; Hood, Leroy (March 1995). "Pairwise end sequencing: a unified approach to genomic mapping and sequencing".
511:
technologies are vastly superior to Sanger sequencing due to the high volume of data and the relatively short time it takes to sequence a whole genome.
65:
In shotgun sequencing, DNA is broken up randomly into numerous small segments, which are sequenced using the chain termination method to obtain
256:
To apply the strategy, a high-molecular-weight DNA strand is sheared into random fragments, size-selected (usually 2, 10, 50, and 150 kb), and
219:
1656:
58:. Due to this size limit, longer sequences are subdivided into smaller fragments that can be sequenced separately, and these sequences are
1001:
1650:
1538:"Impact of Contaminating DNA in Whole-Genome Amplification Kits Used for Metagenomic Shotgun Sequencing for Infection Diagnosis"
727:
Gardner, Richard C.; Howarth, Alan J.; Hahn, Peter; Brown-Luedi, Marianne; Shepherd, Robert J.; Messing, Joachim (1981-06-25).
223:
consensus that the optimal fragment length for pairwise end sequencing would be three times the sequence read length. In 1995
1326:
1229:
1191:
1131:
Meyerson, M.; Gabriel, S.; Getz, G. (2010). "Advances in understanding cancer genomes through second-generation sequencing".
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160:
with ambiguities and sequencing errors. Assembly of complex genomes is additionally complicated by the great abundance of
419:
328:
programs become more sophisticated and computing power becomes cheaper, it may be possible to overcome this limitation.
229:
205:
441:
440:
The amplified genome is first sheared into larger pieces (50-200kb) and cloned into a bacterial host using BACs or
729:"The complete nucleotide sequence of an infectious clone of cauliflower mosaic virus by M13mp7 shotgun sequencing"
949:
Fleischmann, RD; et al. (1995). "Whole-genome random sequencing and assembly of
Haemophilus influenzae Rd".
551:
539:
308:
1682:
1614:"Shotgun sequencing finds nanoorganisms - Probe of acid mine drainage turns up unsuspected virus-sized Archaea"
218:. The first published description of the use of paired ends was in 1990 as part of the sequencing of the human
526:
1436:
Roumpeka, Despoina D.; Wallace, R. John; Escalettes, Frank; Fotheringham, Ian; Watson, Mick (6 March 2017).
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500:
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193:
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361:
244:
161:
73:
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1024:
542:. It however emphasizes the problem of contamination of the sample or the sequencing pipeline.
234:
1504:
851:
Edwards, Al; Caskey, C. Thomas (August 1991). "Closure strategies for random DNA sequencing".
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556:
397:
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in the reconstructed sequence. It can be calculated from the length of the original genome (
1050:
433:
265:
47:
1016:
958:
797:
691:
504:
479:
472:
168:
72:
Shotgun sequencing was one of the precursor technologies that was responsible for enabling
294:
software. First, overlapping reads are collected into longer composite sequences known as
164:, meaning similar short reads could come from completely different parts of the sequence.
8:
534:
337:
1020:
962:
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A BAC contig that covers the entire genomic area of interest makes up the tiling path.
1613:
1567:
1518:
1469:
1438:"A Review of Bioinformatics Tools for Bio-Prospecting from Metagenomic Sequence Data"
1422:
1410:
1383:
Metzker, Michael L. (January 2010). "Sequencing technologies — the next generation".
1365:
1322:
1286:
1278:
1225:
1212:
Venter, J Craig (9 September 2005). "Shotgunning the Human Genome: A Personal View".
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1148:
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1042:
974:
931:
927:
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833:
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that covers the entire genome is theoretically possible. This scaffold is called the
325:
291:
59:
986:
1557:
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1402:
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1314:
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520:
342:
Coverage (read depth or depth) is the average number of reads representing a given
257:
1038:
1360:
1343:
239:
1597:
677:
278:
51:
1091:
1666:
1454:
1282:
1099:
819:
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36:
1318:
1221:
1183:
970:
810:
744:
646:
319:
Proponents of this approach argue that it is possible to sequence the whole
303:
find the sequence in the gaps. If the gap is small (5-20kb) then the use of
54:("Sanger sequencing") can only be used for short DNA strands of 100 to 1000
1571:
1522:
1473:
1414:
1369:
1290:
1152:
1117:
1046:
837:
713:
597:
449:
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they are further sheared into fragments appropriately sized for sequencing.
393:
978:
935:
900:
770:
664:
1553:
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615:
224:
176:
35:
strands. It is named by analogy with the rapidly expanding, quasi-random
1489:"Clinical Metagenomic Next-Generation Sequencing for Pathogen Detection"
704:
679:
1342:
Voelkerding, Karl V; Dames, Shale A; Durtschi, Jacob D (1 April 2009).
343:
261:
28:
1535:
1435:
530:
55:
1406:
1144:
678:
International Human Genome
Sequencing Consortium (21 October 2004).
20:
1263:
IEEE/ACM Transactions on
Computational Biology and Bioinformatics
631:"Shotgun DNA sequencing using cloned DNase I-generated fragments"
84:
For example, consider the following two rounds of shotgun reads:
40:
1344:"Next-Generation Sequencing: From Basic Research to Diagnostics"
320:
248:(fruit fly) genome in 2000, and subsequently the human genome.
459:
726:
1487:
Gu, Wei; Miller, Steve; Chiu, Charles Y. (24 January 2019).
290:
The original sequence is reconstructed from the reads using
171:, most of the human genome was sequenced at 12X or greater
582:"A strategy of DNA sequencing employing computer programs"
268:
yielding two short sequences. Each sequence is called an
264:. The clones are then sequenced from both ends using the
32:
1341:
1076:"Bioinformatics challenges of new sequencing technology"
877:
680:"Finishing the euchromatic sequence of the human genome"
1174:
Dunham, Ian (9 September 2005). "Genome
Sequencing".
364:
276:
and two reads from the same clone are referred to as
1309:Dear, Paul H (9 September 2005). "Genome Mapping".
1130:
913:
1260:
414:
384:
182:
1493:Annual Review of Pathology: Mechanisms of Disease
1167:
514:
1664:
1002:"The genome sequence of Drosophila melanogaster"
493:
400:addresses the relationships of such quantities.
790:Proceedings of the National Academy of Sciences
232:(TIGR) to sequence the genome of the bacterium
1074:Pop, Mihai; Salzberg, Steven L. (March 2008).
1657:National Center for Biotechnology Information
1304:
1302:
1300:
850:
16:Method used for sequencing random DNA strands
1486:
1124:
311:(BAC) followed by sequencing of the vector.
1243:
1241:
1073:
948:
1297:
1561:
1512:
1505:10.1146/annurev-pathmechdis-012418-012751
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458:
418:
403:Sometimes a distinction is made between
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1382:
783:
1665:
1211:
1200:
1173:
671:
579:
298:. Contigs can be linked together into
999:
568:
1308:
324:genomes with repeating regions. As
204:Broader application benefited from
13:
1581:
230:The Institute for Genomic Research
14:
1704:
1634:
1590:"Shotgun sequencing comes of age"
442:P1-derived artificial chromosomes
1644: This article incorporates
1639:
1542:Journal of Clinical Microbiology
314:
309:bacterial artificial chromosomes
210:double-barrel shotgun sequencing
1529:
1480:
1429:
1376:
1335:
1254:
1067:
1000:Adams, MD; et al. (2000).
993:
552:Clinical metagenomic sequencing
415:Hierarchical shotgun sequencing
354:), and the average read length(
183:Whole genome shotgun sequencing
942:
907:
871:
844:
777:
720:
622:
515:Metagenomic shotgun sequencing
62:to give the overall sequence.
1:
1311:Encyclopedia of Life Sciences
1214:Encyclopedia of Life Sciences
1176:Encyclopedia of Life Sciences
1039:10.1126/science.287.5461.2185
865:10.1016/S1046-2023(05)80162-8
784:Doctrow, Brian (2016-07-19).
562:
494:Newer sequencing technologies
396:and assembly. The subject of
1361:10.1373/clinchem.2008.112789
928:10.1016/0888-7543(95)80219-C
893:10.1016/0888-7543(90)90493-E
786:"Profile of Joachim Messing"
179:) human genome, as of 2004.
7:
1247:Gibson, G. and Muse, S. V.
545:
533:. Advantages over 16S rRNA
385:{\displaystyle N\times L/G}
331:
285:
251:
10:
1709:
1249:A Primer of Genome Science
629:Anderson, Stephen (1981).
335:
187:
151:AGCATGCTGCAGTCATGCTTAGGCTA
139:------CTGCAGTCATGCTTAGGCTA
133:AGCATG--------------------
121:-------------------TAGGCTA
115:AGCATGCTGCAGTCATGCT-------
103:AGCATGCTGCAGTCATGCTTAGGCTA
79:
1092:10.1016/j.tig.2007.12.006
305:polymerase chain reaction
1455:10.3389/fgene.2017.00023
266:chain termination method
208:, known colloquially as
194:cauliflower mosaic virus
128:Second shotgun sequence
48:chain-termination method
1385:Nature Reviews Genetics
1319:10.1038/npg.els.0005353
1222:10.1038/npg.els.0005850
1184:10.1038/npg.els.0005378
1133:Nature Reviews Genetics
971:10.1126/science.7542800
811:10.1073/pnas.1608857113
350:), the number of reads(
245:Drosophila melanogaster
206:pairwise end sequencing
110:First shotgun sequence
74:whole genome sequencing
1646:public domain material
733:Nucleic Acids Research
635:Nucleic Acids Research
586:Nucleic Acids Research
464:
425:
386:
235:Haemophilus influenzae
1683:1981 in biotechnology
1442:Frontiers in Genetics
745:10.1093/nar/9.12.2871
647:10.1093/nar/9.13.3015
557:DNA sequencing theory
501:short-read sequencing
462:
422:
398:DNA sequencing theory
387:
238:in 1995, and then by
200:Paired-end sequencing
196:, published in 1981.
27:is a method used for
1554:10.1128/JCM.02402-16
1275:10.1109/tcbb.2013.26
598:10.1093/nar/6.7.2601
527:taxonomic classifier
505:long-read sequencing
484:restriction-digested
473:sequence-tagged site
362:
260:into an appropriate
169:Human Genome Project
162:repetitive sequences
1021:2000Sci...287.2185.
963:1995Sci...269..496F
802:2016PNAS..113.7935D
705:10.1038/nature03001
696:2004Natur.431..931H
580:Staden, R. (1979).
535:amplicon sequencing
478:Alternatively, the
454:minimum tiling path
338:Coverage (genetics)
1620:. 22 December 2006
1348:Clinical Chemistry
1080:Trends in Genetics
465:
426:
382:
25:shotgun sequencing
1673:Molecular biology
1328:978-0-470-01617-6
1231:978-0-470-01617-6
1193:978-0-470-01617-6
1015:(5461): 2185–95.
957:(5223): 496–512.
796:(29): 7935–7937.
739:(12): 2871–2888.
690:(7011): 931–945.
641:(13): 3015–3027.
409:physical coverage
405:sequence coverage
326:sequence assembly
292:sequence assembly
274:read 1 and read 2
157:
156:
1700:
1660:
1643:
1642:
1629:
1627:
1625:
1609:
1607:
1605:
1596:. Archived from
1576:
1575:
1565:
1548:(6): 1789–1801.
1533:
1527:
1526:
1516:
1484:
1478:
1477:
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1165:
1164:
1128:
1122:
1121:
1111:
1071:
1065:
1064:
1062:
1061:
1055:
1049:. Archived from
1032:
1006:
997:
991:
990:
946:
940:
939:
911:
905:
904:
875:
869:
868:
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841:
831:
813:
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764:
724:
718:
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707:
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626:
620:
619:
609:
592:(7): 2601–2610.
577:
391:
389:
388:
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378:
242:to sequence the
153:
141:
135:
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117:
105:
87:
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1600:on May 14, 2011
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1584:
1582:Further reading
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1534:
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1407:10.1038/nrg2626
1398:10.1.1.719.3885
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1145:10.1038/nrg2841
1139:(10): 685–696.
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1030:10.1.1.549.8639
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240:Celera Genomics
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146:Reconstruction
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1251:. 3rd ed. P.84
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1688:Metagenomics
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1624:December 23,
1622:. Retrieved
1618:SpaceRef.com
1617:
1604:December 31,
1602:. Retrieved
1598:the original
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1391:(1): 31–46.
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480:BAC library
450:BAC contigs
177:euchromatic
1667:Categories
1060:2017-10-25
563:References
524:-mer based
344:nucleotide
279:mate pairs
56:base pairs
29:sequencing
1423:205484500
1393:CiteSeerX
1283:1545-5963
1100:0168-9525
1025:CiteSeerX
820:0027-8424
753:0305-1048
531:gut flora
369:×
300:scaffolds
98:Original
93:Sequence
60:assembled
1572:28356418
1523:30355154
1474:28321234
1415:19997069
1370:19246620
1291:23929859
1153:20847746
1118:18262676
1047:10731132
987:10423613
916:Genomics
881:Genomics
838:27382176
714:15496913
546:See also
446:scaffold
332:Coverage
286:Assembly
270:end-read
252:Approach
173:coverage
21:genetics
1563:5442535
1514:6345613
1465:5337752
1161:2544266
1109:2680276
1017:Bibcode
1009:Science
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959:Bibcode
951:Science
936:7601461
901:2341149
853:Methods
829:4961156
798:Bibcode
771:6269062
692:Bibcode
665:6269069
482:can be
296:contigs
216:History
188:History
90:Strand
80:Example
41:shotgun
31:random
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321:genome
262:vector
258:cloned
1648:from
1419:S2CID
1157:S2CID
1054:(PDF)
1005:(PDF)
983:S2CID
358:) as
225:Roach
220:HGPRT
67:reads
39:of a
1626:2006
1606:2002
1568:PMID
1519:PMID
1470:PMID
1411:PMID
1366:PMID
1323:ISBN
1287:PMID
1279:ISSN
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834:PMID
816:ISSN
767:PMID
749:ISSN
710:PMID
661:PMID
612:PMID
503:and
407:and
46:The
1558:PMC
1550:doi
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1450:doi
1403:doi
1356:doi
1315:doi
1271:doi
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1180:doi
1141:doi
1104:PMC
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1035:doi
1013:287
967:doi
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824:PMC
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448:of
272:or
50:of
33:DNA
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348:G
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