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Journal Article•DOI•

Sequencing technologies-the next generation

Michael L. Metzker1•
Baylor College of Medicine1
01 Jan 2010-Nature Reviews Genetics (Nature Publishing Group)-Vol. 11, Iss: 1, pp 31-46
TL;DR: A technical review of template preparation, sequencing and imaging, genome alignment and assembly approaches, and recent advances in current and near-term commercially available NGS instruments is presented.
Abstract: Demand has never been greater for revolutionary technologies that deliver fast, inexpensive and accurate genome information. This challenge has catalysed the development of next-generation sequencing (NGS) technologies. The inexpensive production of large volumes of sequence data is the primary advantage over conventional methods. Here, I present a technical review of template preparation, sequencing and imaging, genome alignment and assembly approaches, and recent advances in current and near-term commercially available NGS instruments. I also outline the broad range of applications for NGS technologies, in addition to providing guidelines for platform selection to address biological questions of interest.

Summary (1 min read)

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Summary

  • DNA sequencing is one of the most important platforms for study in biological systems today.
  • The high-throughput-next generation sequencing technologies delivers fast, inexpensive, and accurate genome information.
  • Next generation sequencing can produce over 100 times more data than methods based on Sanger Sequencing.
  • The next generation sequencing technologies offered from Illumina / Solexa, ABI/SOLiD, 454/Roche, and Helicos has provided unprecedented opportunity for high-throughput functional genomic research.
  • Next generation sequence technologies offer novel and rapid ways for genome-wide characterization and profiling of mRNA's, transcription factor regions, and DNA patterns.

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ABSTRACT
Conclusion and Future Work
Next Generation Sequencing
CONTACT INFO
Data Analysis Comparisons
Downstream Analysis
REFERENCES
DNA sequencing is one of the most important platforms for
study in biological systems today. The high-throughput-next
generation sequencing technologies delivers fast,
inexpensive, and accurate genome information. Next
generation sequencing can produce over 100 times more data
than methods based on Sanger Sequencing. The next
generation sequencing technologies offered from Illumina /
Solexa, ABI/SOLiD, 454/Roche, and Helicos has provided
unprecedented opportunity for high–throughput functional
genomic research. Next generation sequence technologies
offer novel and rapid ways for genome-wide characterization
and profiling of mRNA’s, transcription factor regions, and DNA
patterns.
Fig. 7) This is a plot of the frequency of each percentage covered for all nodes.
BLAST is in blue, MUMmer is in green.
Sequencing Technologies – the Next Generation,
Micahel L. Metzkerh
Next Generation Sequencing Pipeline Development and Data Analysis
Fig. 9) This is a plot of the coverage of each Node. BLAST points are blue,
MUMmer points are red.
Fig. 6) This is a plot of the frequency of each percentage covered for all contigs.
BLAST is in blue, MUMmer is in green.
•  454/Roche – 454 Life Sciences is a Biotechnology company
that is a part of Roche and based in Branford, Connecticut.
The center develops ultra-fast high-throughput DNA
sequencing methods and tools.
•  Illumina/Solexa– Illumina is a company that develops and
manufactures integrated systems for the analysis of gene
variation. Solexa was founded to develop genome
sequencing technology.
•  ABI/SOLiD - (Sequencing by Oligonucleotide Ligation and
Detection) is a next-generation DNA sequencing technology
developed by Life Technologies and has been commercially
available since 2006. This next generation technology
generates hundreds of millions to billions of small sequence
reads at one time.
•  Helicos - Helicos's technology images the extension of
individual DNA molecules using a defined primer and
individual fluorescently labeled nucleotides, which contain a
"virtual terminator" preventing incorporation of multiple
nucleotides per cycle.
Julian Pierre
1
, Jordan Taylor
2
, Amit Upadhyay
3
, Bhanu Rekepalli
3
Fig. 8) This is a plot of the coverage of each Contig. BLAST points are blue,
MUMmer points are red.
Using the coverage of
each individual contig
ID, the results for both
BLAST and MUMmer
were plotted. While
BLAST hit more contigs,
there are more contigs
with a higher coverage
that were hit by
MUMmer.
Using the data gathered
from both BLAST and
MUMmer, the frequency
of the amount covered
for each contig was
plotted. From Fig 6), it
can be inferred that
MUMmer hit more
accurately for contigs.
Fig 4) from main.g2.bx.psu.edu
Once the results were found using both the BLAST and
MUMmer search tools, we created a program to see which
sequencing tool had the most hits per contig. The total
number of contigs in the database file is 160,749 and the
total number of nodes in the query file is 552,305. BLAST
returned a total of 123,070 hits and MUMmer returned a
total of 121,829 hits. From the results, MUMmer hit more
accurately than BLAST while BLAST hit more contigs than
MUMmer.
In Next-Generation Sequencing, data analysis is one of the
most expensive processes. While the cost of genome
sequencing goes down, the cost of analyzing data is still
expensive. In the future, the “$1,000 genome will come with
a $20,000 analysis price tag.”
The same process was
done with the Nodes.
From Fig 7), it can be
inferred that BLAST hit
more accurately with
nodes. However, there
are more BLAST results
with lower coverage.
The future of next generation sequencing can be broken
down into a variety of categories such as personalized
medicine, bio fuels, climate change, and other life science
fields.
•  Personalized Medicine is a medical model that proposes
the customization of medical decision to tailor an
individual
•  Bio Fuels present a source of alternative energy.
Microalgal biofuels use algae to synthesize the fuel. In
order to optimize the process, an understanding of the
gene-function relationship of algae would prove helpful.
•  Climate change is the active study of past and future
theoretical models which uses the past climate data to
make future projections.
In conclusion, we hope to contribute the knowledge we
have gained to contribute to fields such as these.
The same process was
done with the Nodes.
While BLAST hit more
Nodes, there are more
Nodes that hit with a
lower coverage using
BLAST.
1 Texas Southern University, 2 Austin Peay State University, 3 University of Tennessee
Next Gen Sequencing uses a wide array of tools to obtain results based
on the genome sequence. The most widely used Tools are BLAST,
HMMER, and MUMmer.
•  BLAST (Basic Local Alignment Search Tool) is a multi-sequence
alignment tool developed by NIH (National Institute of Health). It is
used find similar regions in different sequences and then compare
their similarities.
•  MUMmer (Maximum Unique Matches) is a rapid alignment system
used for rapidly aligning entire genomes. It can also align incomplete
genomes and can easily handle 1000’s of contigs from a shotgun
sequencing project.
•  HMMER (Hidden Markov Modeler) is used for searching sequence
databases for homologs of protein sequences, and for making protein
sequence alignments. It implements methods using probabilistic
models called profile hidden Markov models (HMMs)
Genome Assembly
Sequence Analysis refers to
the process of subjecting a
DNA, RNA or peptide
sequence to a wide range of
analytical methods to:
•  Compare sequences to find
similarities and infer if they
are Homologous
•  To identify the features of
the sequence such as gene
structure, distribution,
introns and exons, and
regulation of gene
expression
•  Identify Sequence
differences and variations
such as mutations
Fig. 1) This is figure shows three different Next Generation Sequencing methods. [2]
Fig. 2) Taken from A Hitchhiker’s Guide to Next-Generation Sequencing, by Gabe Rudy
Fig. 3) Taken from bio.davidson.edu/courses. Shows alignment results for yeast.
Fig 5) from jcvi.org shows the mapping of chr6 of a Human Genome
Julian Pierre – julz_pierre@yahoo.com
Jordan Taylor – jtaylor74@my.apsu.edu
Amit Upadhyay – aupadhy1@utk.edu
Bhanu Rekepalli – brekapal@utk.edu
•  http://www.roche.com/research_and_development/r_d_overview/
r_d_sites.htm?id=18
•  http://www.pnas.org/content/99/6/3712/F1.expansion.html
•  http://www.yerkes.emory.edu/nhp_genomics_core/Services/
Sequencing.html
•  http://www.illumina.com/technology/solexa_technology.ilmn
•  http://blast.ncbi.nlm.nih.gov/Blast.cgi
•  https://main.g2.bx.psu.edu/u/dan/p/fastq
•  http://ori.dhhs.gov/education/products/n_illinois_u/datamanagement/
datopic.htmll
•  http://www.jcvi.org/medicago/include/images/chr6.BamHI.maps.jpg
•  Gabe Rudy, (2010) A Hitchhiker’s Guide to Next-Generation
Sequencing, :1-9, Golden Helix
•  [1] John D. McPherson, (2009) Next-Generation Gap, 6:1-4, Nature
Methods Supplement
•  [2]Michael L. Metzker, (2010) Sequencing Technologies, - the next
generation, 11:1-5, Nature Reviews
•  Md. Fakruddin,Khanjada Shahnewaj Bin mannan, (2012) Next
Generation sequencing technologies – Principles and prospects,
6:1-9, Research and Reviews in Biosciences
•  Misra N., Panda P. K., Parida B. K., Mishra B. K., (2012)
Phylogenomic Study of Lipid Genes Involved in Mocroalgal Biofuel
Production – Candidate Gene Mining and Metabolic Pathway
Analyses, Evolutionary Bioinformatics 8:545-564, doi: 10.4137/
EBO.S10159
Galaxy is an open, web-based
platform for data intensive
biomedical research. It can be
used on its own free public
server where you can perform,
reproduce, and share complete
analyses.
An example of how Galaxy
reflects its data is shown in Fig 5.
Two FASTA files related to the same nucleotide sequence
were input into both BLAST and MUMmer and the results
were parsed into tables. Then, the coverage of all hit contigs
and nodes from both programs was found.
Citations
More filters
Journal Article•DOI•
Single-Molecule Real-Time Sequencing Combined with Optical Mapping Yields Completely Finished Fungal Genome

[...]

Luigi Faino1, Michael F. Seidl1, Erwin Datema, Grardy C. M. van den Berg1, Antoine Janssen, Alexander H. J. Wittenberg, Bart P. H. J. Thomma1 •
Wageningen University and Research Centre1
01 Sep 2015-Mbio
TL;DR: Assessment of state-of-the-art sequencing and assembly strategies in order to produce a contiguous and complete eukaryotic genome assembly on the filamentous fungus Verticillium dahliae shows that a combination of PacBio-generated long reads and optical mapping yields a gapless telomere-to-telomere genome assembly, allowing in-depth genome analyses to facilitate functional studies into an organism's biology.
Abstract: Next-generation sequencing (NGS) technologies have increased the scalability, speed, and resolution of genomic sequencing and, thus, have revolutionized genomic studies. However, eukaryotic genome sequencing initiatives typically yield considerably fragmented genome assemblies. Here, we assessed various state-of-the-art sequencing and assembly strategies in order to produce a contiguous and complete eukaryotic genome assembly, focusing on the filamentous fungus Verticillium dahliae. Compared with Illumina-based assemblies of the V. dahliae genome, hybrid assemblies that also include PacBio-generated long reads establish superior contiguity. Intriguingly, provided that sufficient sequence depth is reached, assemblies solely based on PacBio reads outperform hybrid assemblies and even result in fully assembled chromosomes. Furthermore, the addition of optical map data allowed us to produce a gapless and complete V. dahliae genome assembly of the expected eight chromosomes from telomere to telomere. Consequently, we can now study genomic regions that were previously not assembled or poorly assembled, including regions that are populated by repetitive sequences, such as transposons, allowing us to fully appreciate an organism9s biological complexity. Our data show that a combination of PacBio-generated long reads and optical mapping can be used to generate complete and gapless assemblies of fungal genomes. IMPORTANCE Studying whole-genome sequences has become an important aspect of biological research. The advent of next-generation sequencing (NGS) technologies has nowadays brought genomic science within reach of most research laboratories, including those that study nonmodel organisms. However, most genome sequencing initiatives typically yield (highly) fragmented genome assemblies. Nevertheless, considerable relevant information related to genome structure and evolution is likely hidden in those nonassembled regions. Here, we investigated a diverse set of strategies to obtain gapless genome assemblies, using the genome of a typical ascomycete fungus as the template. Eventually, we were able to show that a combination of PacBio-generated long reads and optical mapping yields a gapless telomere-to-telomere genome assembly, allowing in-depth genome analyses to facilitate functional studies into an organism9s biology.

160 citations

Cites background from "Sequencing technologies-the next ge..."

  • ...While Sanger and Illumina sequencing produce high-quality reads (2), PacBio sequencing generates long reads of relatively low-quality (~1 to 2 errors per 100 bp) that can only be used for genome assemblies after error correction....

    [...]

  • ...NGS technologies can be divided in those that generate large amounts of short DNA sequence reads ( 500 bp) that are typically characterized by their high quality (1 sequence error per 1 kb) and technologies that produce long reads ( 1 kb), although often with relatively low quality (1 to 2 sequence errors per 100 bases) (2)....

    [...]

Journal Article•DOI•
Identification of viruses and viroids by next-generation sequencing and homology-dependent and homology-independent algorithms.

[...]

Qingfa Wu1, Shou-Wei Ding, Yongjiang Zhang, Shuifang Zhu•
University of Science and Technology of China1
04 Aug 2015-Annual Review of Phytopathology
TL;DR: A comparison of enrichment strategies reveals that full indexing of RNA and DNA viruses as well as viroids in a plant sample at single-nucleotide resolution is made possible by one NGS run of total small RNAs, followed by data mining with homology-dependent andhomology-independent computational algorithms.
Abstract: A fast, accurate, and full indexing of viruses and viroids in a sample for the inspection and quarantine services and disease management is desirable but was unrealistic until recently. This article reviews the rapid and exciting recent progress in the use of next-generation sequencing (NGS) technologies for the identification of viruses and viroids in plants. A total of four viroids/viroid-like RNAs and 49 new plant RNA and DNA viruses from 18 known or unassigned virus families have been identified from plants since 2009. A comparison of enrichment strategies reveals that full indexing of RNA and DNA viruses as well as viroids in a plant sample at single-nucleotide resolution is made possible by one NGS run of total small RNAs, followed by data mining with homology-dependent and homology-independent computational algorithms. Major challenges in the application of NGS technologies to pathogen discovery are discussed.

160 citations

Recent Advances of Genome Mapping and Marker-Assisted Selection in Aquaculture

[...]

Gen Hua Yue1•
National University of Singapore1
19 Mar 2013
TL;DR: The recent advances of linkage and QTL mapping, as well as MAS in aquaculture species, are summarized and the potentials of genome-wide association studies (GWAS) and GS in aquACulture species are discussed.
Abstract: Aquaculture is the fastest growing sector in agriculture. Substantial genetic gains have been achieved in a few cultured species using conventional selective breeding approaches. However, the majority of fish and shellfish species remain in their wild state. Due to the recognition of the enormous potential of marker-assisted selection (MAS) to speed up genetic gain through early selection, aquaculture scientists have constructed linkage maps in over 40 species and mapped quantitative trait loci (QTL) for important traits in over 20 species since the 1990s. Although MAS and genomic selection (GS) have not been widely used in aquaculture, their application in breeding programmes is expected to be a fertile area of research. In this paper, I summarized the recent advances of linkage and QTL mapping, as well as MAS in aquaculture species. I also discussed the potentials of genome-wide association studies (GWAS) and GS in aquaculture species.

160 citations

Cites methods from "Sequencing technologies-the next ge..."

  • ...Currently, due to the advent of the next-generation sequencing technologies (Metzker 2009), resequencing of a genome of three giga bases (Gb) costs <1000 USD using the Illumina’s Hiseq 2000....

    [...]

Journal Article•DOI•
Comparison of somatic mutation calling methods in amplicon and whole exome sequence data

[...]

Huilei Xu, John DiCarlo, Ravi Vijaya Satya, Quan Peng, Yexun Wang 
28 Mar 2014-BMC Genomics
TL;DR: It is demonstrated that the five commonly used somatic SNV calling methods are applicable to both targeted amplicon and exome sequencing data, however, the sensitivities of these methods vary based on the allelic fraction of the mutation in the tumor sample.
Abstract: High-throughput sequencing is rapidly becoming common practice in clinical diagnosis and cancer research. Many algorithms have been developed for somatic single nucleotide variant (SNV) detection in matched tumor-normal DNA sequencing. Although numerous studies have compared the performance of various algorithms on exome data, there has not yet been a systematic evaluation using PCR-enriched amplicon data with a range of variant allele fractions. The recently developed gold standard variant set for the reference individual NA12878 by the NIST-led “Genome in a Bottle” Consortium (NIST-GIAB) provides a good resource to evaluate admixtures with various SNV fractions. Using the NIST-GIAB gold standard, we compared the performance of five popular somatic SNV calling algorithms (GATK UnifiedGenotyper followed by simple subtraction, MuTect, Strelka, SomaticSniper and VarScan2) for matched tumor-normal amplicon and exome sequencing data. We demonstrated that the five commonly used somatic SNV calling methods are applicable to both targeted amplicon and exome sequencing data. However, the sensitivities of these methods vary based on the allelic fraction of the mutation in the tumor sample. Our analysis can assist researchers in choosing a somatic SNV calling method suitable for their specific needs.

160 citations

Cites methods from "Sequencing technologies-the next ge..."

  • ...Over the last few years, next-generation sequencing (NGS) has become a popular strategy for genotyping, enabling more precise mutation detection compared to traditional methods due to its high resolution and high throughput [3]....

    [...]

Journal Article•DOI•
De novo DNA synthesis using polymerase-nucleotide conjugates

[...]

Sebastian Palluk1, Sebastian Palluk2, Sebastian Palluk3, Daniel H. Arlow, Tristan de Rond1, Tristan de Rond3, Tristan de Rond4, Sebastian Barthel1, Sebastian Barthel2, Sebastian Barthel3, Justine S Kang1, Justine S Kang3, Justine S Kang4, Rathin Bector1, Rathin Bector3, Rathin Bector4, Hratch M. Baghdassarian1, Hratch M. Baghdassarian3, Hratch M. Baghdassarian4, Alisa N Truong1, Alisa N Truong3, Peter W. Kim3, Peter W. Kim5, Anup K. Singh5, Anup K. Singh3, Nathan J. Hillson1, Nathan J. Hillson3, Nathan J. Hillson6, Jay D. Keasling •
Lawrence Berkeley National Laboratory1, Technische Universität Darmstadt2, Joint BioEnergy Institute3, University of California, Berkeley4, Sandia National Laboratories5, Joint Genome Institute6
18 Jun 2018-Nature Biotechnology
TL;DR: It is demonstrated that TdT–dNTP conjugates can quantitatively extend a primer by a single nucleotide in 10–20 s, and that the scheme can be iterated to write a defined sequence.
Abstract: Oligonucleotides are almost exclusively synthesized using the nucleoside phosphoramidite method, even though it is limited to the direct synthesis of ∼200 mers and produces hazardous waste. Here, we describe an oligonucleotide synthesis strategy that uses the template-independent polymerase terminal deoxynucleotidyl transferase (TdT). Each TdT molecule is conjugated to a single deoxyribonucleoside triphosphate (dNTP) molecule that it can incorporate into a primer. After incorporation of the tethered dNTP, the 3' end of the primer remains covalently bound to TdT and is inaccessible to other TdT-dNTP molecules. Cleaving the linkage between TdT and the incorporated nucleotide releases the primer and allows subsequent extension. We demonstrate that TdT-dNTP conjugates can quantitatively extend a primer by a single nucleotide in 10-20 s, and that the scheme can be iterated to write a defined sequence. This approach may form the basis of an enzymatic oligonucleotide synthesizer.

160 citations

Cites methods from "Sequencing technologies-the next ge..."

  • ...Synthetic DNA is used to introduce indices and perform target capturing for Next Generation Sequencing methods [2,7,67,68,88], or to provide fixing templates for a cell, once synthetic RNA has guided CRISPR-CAS9 to the right location [5,82]....

    [...]

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Journal Article•DOI•
RNA-Seq: a revolutionary tool for transcriptomics

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Zhong Wang1, Mark Gerstein1, Michael Snyder1•
Yale University1
01 Jan 2009-Nature Reviews Genetics
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Daniel R. Zerbino1, Ewan Birney1•
European Bioinformatics Institute1
01 May 2008-Genome Research
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Journal Article•DOI•
Genome sequencing in microfabricated high-density picolitre reactors

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Marcel Margulies, Michael Egholm, William E. Altman, Said Attiya, Joel S. Bader, Lisa A. Bemben, Jan Berka, Michael S. Braverman, Yi-Ju Chen, Zhoutao Chen, Scott Dewell, Lei Du, J. M. Fierro, Xavier V. Gomes, Brian C. Godwin, Wen He, Scott Edward Helgesen, Chun Heen Ho, Gerard P. Irzyk, Szilveszter C. Jando, Maria L. I. Alenquer, Thomas P. Jarvie, Kshama B. Jirage, Jong-Bum Kim, James R. Knight, Janna R. Lanza, John H. Leamon, Steven Lefkowitz, Ming Lei, Jing Li, Kenton Lohman, Hong Lu, Vinod Makhijani, Keith Mcdade, Michael P. McKenna, Eugene W. Myers1, Elizabeth Nickerson, John Nobile, Ramona Plant, Bernard P. Puc, Michael T. Ronan, George T. Roth, Gary J. Sarkis, Jan Fredrik Simons, John Simpson, Maithreyan Srinivasan, Karrie R. Tartaro, Alexander Tomasz2, Kari A. Vogt, Greg A. Volkmer, Shally H. Wang, Yong Wang, Michael P. Weiner3, Pengguang Yu, Richard F. Begley, Jonathan M. Rothberg •
University of California, Berkeley1, Rockefeller University2, Rothberg Institute For Childhood Diseases3
15 Sep 2005-Nature
TL;DR: A scalable, highly parallel sequencing system with raw throughput significantly greater than that of state-of-the-art capillary electrophoresis instruments with 96% coverage at 99.96% accuracy in one run of the machine is described.
Abstract: The proliferation of large-scale DNA-sequencing projects in recent years has driven a search for alternative methods to reduce time and cost. Here we describe a scalable, highly parallel sequencing system with raw throughput significantly greater than that of state-of-the-art capillary electrophoresis instruments. The apparatus uses a novel fibre-optic slide of individual wells and is able to sequence 25 million bases, at 99% or better accuracy, in one four-hour run. To achieve an approximately 100-fold increase in throughput over current Sanger sequencing technology, we have developed an emulsion method for DNA amplification and an instrument for sequencing by synthesis using a pyrosequencing protocol optimized for solid support and picolitre-scale volumes. Here we show the utility, throughput, accuracy and robustness of this system by shotgun sequencing and de novo assembly of the Mycoplasma genitalium genome with 96% coverage at 99.96% accuracy in one run of the machine.

8,434 citations

Journal Article•DOI•
Origins and Mechanisms of miRNAs and siRNAs

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Richard W. Carthew1, Erik J. Sontheimer1•
Northwestern University1
20 Feb 2009-Cell
TL;DR: This work has revealed unexpected diversity in their biogenesis pathways and the regulatory mechanisms that they access, which has direct implications for fundamental biology as well as disease etiology and treatment.

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Journal Article•DOI•
Evolution and functions of long noncoding RNAs

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Chris P. Ponting1, Peter L. Oliver1, Wolf Reik2•
University of Oxford1, University of Cambridge2
20 Feb 2009-Cell
TL;DR: The evolution of long noncoding RNAs and their roles in transcriptional regulation, epigenetic gene regulation, and disease are reviewed.

4,277 citations

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