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Exome sequencing

ex ome sequencing, ex ome sequencing project
Exome sequencing, also known as whole exome sequencing WES, is a genomic technique for sequencing all of the protein-coding genes in a genome known as the exome It consists of two steps: the first step is to select only the subset of DNA that encodes proteins These regions are known as exons – humans have about 180,000 exons, constituting about 1% of the human genome, or approximately 30 million base pairs The second step is to sequence the exonic DNA using any high-throughput DNA sequencing technology[1]

The goal of this approach is to identify genetic variants that alter protein sequences, and to do this at a much lower cost than whole-genome sequencing Since these variants can be responsible for both Mendelian and common polygenic diseases, such as Alzheimer's disease, whole exome sequencing has been applied both in academic research and as a clinical diagnostic

Exome sequencing workflow: part 2

Contents

  • 1 Motivation and comparison to other approaches
  • 2 Technical methodology
    • 21 Step 1: Target-enrichment strategies
      • 211 Array-based capture
      • 212 In-solution capture
    • 22 Step 2: Sequencing
  • 3 Comparison with other technologies
    • 31 Microarray-based genotyping
    • 32 Whole-genome sequencing
  • 4 Data analysis
  • 5 Ethical implications
  • 6 Applications of exome sequencing
    • 61 Rare variant mapping in complex disorders
    • 62 Discovery of Mendelian disorders
      • 621 Case studies
    • 63 Clinical diagnostics
    • 64 Direct-to-consumer exome sequencing
  • 7 See also
  • 8 References
  • 9 External links

Motivation and comparison to other approaches

Exome sequencing is especially effective in the study of rare Mendelian diseases, because it is an efficient way to identify the genetic variants in all of an individual's genes These diseases are most often caused by very rare genetic variants that are only present in a tiny number of individuals;[2] by contrast, techniques such as SNP arrays can only detect shared genetic variants that are common to many individuals in the wider population[3] Furthermore, because severe disease-causing variants are much more likely but by no means exclusively to be in the protein coding sequence[citation needed], focusing on this 1% costs far less than whole genome sequencing but still detects a high yield of relevant variants

In the past, clinical genetic tests were chosen based on the clinical presentation of the patient ie focused on one gene or a small number known to be associated with a particular syndrome, or surveyed only certain types of variation eg comparative genomic hybridization but provided definitive genetic diagnoses in fewer than half of all patients[4] Exome sequencing is now increasingly used to complement these other tests: both to find mutations in genes already known to cause disease as well as to identify novel genes by comparing exomes from patients with similar features[citation needed]

Technical methodology

Step 1: Target-enrichment strategies

Target-enrichment methods allow one to selectively capture genomic regions of interest from a DNA sample prior to sequencing Several target-enrichment strategies have been developed since the original description of the direct genomic selection DGS method in 2005[5]

Though many techniques have been described for targeted capture, only a few of these have been extended to capture entire exomes[6] The first target enrichment strategy to be applied to whole exome sequencing was the array-based hybrid capture method in 2007, but in-solution capture has gained popularity in recent years Twist Bioscience recently introduced Human Core Exome Enrichment Kit that enables researchers to perform more efficient capture of exomes than any other available method resulting in more complete enrichment of target sequences and lower sequencing depth requirements[7][8]

Array-based capture

In-solution capture

Microarrays contain single-stranded oligonucleotides with sequences from the human genome to tile the region of interest fixed to the surface Genomic DNA is sheared to form double-stranded fragments The fragments undergo end-repair to produce blunt ends and adaptors with universal priming sequences are added These fragments are hybridized to oligos on the microarray Unhybridized fragments are washed away and the desired fragments are eluted The fragments are then amplified using PCR[9][10]

Roche NimbleGen was first to take the original DGS technology[5] and adapt it for next-generation sequencing They developed the Sequence Capture Human Exome 21M Array to capture ~180,000 coding exons[11] This method is both time-saving and cost-effective compared to PCR based methods The Agilent Capture Array and the comparative genomic hybridization array are other methods that can be used for hybrid capture of target sequences Limitations in this technique include the need for expensive hardware as well as a relatively large amount of DNA[12]

In-solution capture

To capture genomic regions of interest using in-solution capture, a pool of custom oligonucleotides probes is synthesized and hybridized in solution to a fragmented genomic DNA sample The probes labeled with beads selectively hybridize to the genomic regions of interest after which the beads now including the DNA fragments of interest can be pulled down and washed to clear excess material The beads are then removed and the genomic fragments can be sequenced allowing for selective DNA sequencing of genomic regions eg, exons of interest

This method was developed to improve on the hybridization capture target-enrichment method In solution capture as opposed to hybrid capture, there is an excess of probes to target regions of interest over the amount of template required[12] The optimal target size is about 35 megabases and yields excellent sequence coverage of the target regions The preferred method is dependent on several factors including: number of base pairs in the region of interest, demands for reads on target, equipment in house, etc[13]

Step 2: Sequencing

Main article: DNA Sequencing § High-throughput methods

There are many Next Generation Sequencing sequencing platforms available, postdating classical Sanger sequencing methodologies Other platforms include Roche 454 sequencer and Life Technologies SOLiD systems, the Life Technologies Ion Torrent and Illumina's Illumina Genome Analyzer II defunct and subsequent Illumina MiSeq, HiSeq, and NovaSeq series instruments, all of which can be used for massively parallel exome sequencing These 'short read' NGS systems are particularly well suited to analyse many relatively short stretches of DNA sequence, as found in human exons

Comparison with other technologies

There are multiple technologies available that identify genetic variants Each technology has advantages and disadvantages in terms of technical and financial factors Two such technologies are microarrays and whole-genome sequencing

Microarray-based genotyping

Microarrays use hybridization probes to test the prevalence of known DNA sequences, thus they cannot be used to identify unexpected genetic changes[12] In contrast, the high-throughput sequencing technologies used in exome sequencing directly provide the nucleotide sequences of DNA at the thousands of exonic loci tested[14] Hence, WES addresses some of the present limitations of hybridization genotyping arrays

Although exome sequencing is more expensive than hybridization-based technologies on a per-sample basis, its cost has been decreasing due to the falling cost and increased throughput of whole genome sequencing[citation needed]

Whole-genome sequencing

Exome sequencing is only able to identify those variants found in the coding region of genes which affect protein function It is not able to identify the structural and non-coding variants associated with the disease, which can be found using other methods such as whole genome sequencing[1] There remains 99% of the human genome that is not covered using exome sequencing Presently, whole genome sequencing is rarely practical in the clinical context due to the high costs and time associated with sequencing full genomes Exome sequencing allows sequencing of portions of the genome over at least 20 times as many samples compared to whole genome sequencing, at the same cost[1] For translation of identified rare variants into the clinic, sample size and the ability to interpret the results to provide a clinical diagnosis indicates that with the current knowledge in genetics, exome sequencing may be the most valuable[11]

Data analysis

The statistical analysis of the large quantity of data generated from sequencing approaches is a challenge Even by only sequencing the exomes of individuals, a large quantity of data and sequence information is generated which requires a significant amount of data analysis Challenges associated with the analysis of this data include changes in programs used to align and assemble sequence reads[12] Various sequence technologies also have different error rates and generate various read-lengths which can pose challenges in comparing results from different sequencing platforms

False positive and false negative findings are associated with genomic resequencing approaches and is a critical issue A few strategies have been developed to improve the quality of exome data such as:

  • Comparing the genetic variants identified between sequencing and array-based genotyping[1]
  • Comparing the coding SNPs to a whole genome sequenced individual with the disorder[1]
  • Comparing the coding SNPs with Sanger sequencing of HapMap individuals[1]

Rare recessive disorders would not have single nucleotide polymorphisms SNPs in public databases such as dbSNP More common recessive phenotypes may have disease-causing variants reported in dbSNP For example, the most common cystic fibrosis variant has an allele frequency of about 3% in most populations Screening out such variants might erroneously exclude such genes from consideration Genes for recessive disorders are usually easier to identify than dominant disorders because the genes are less likely to have more than one rare nonsynonymous variant[1] The system that screens common genetic variants relies on dbSNP which may not have accurate information about the variation of alleles Using lists of common variation from a study exome or genome-wide sequenced individual would be more reliable A challenge in this approach is that as the number of exomes sequenced increases, dbSNP will also increase in the number of uncommon variants It will be necessary to develop thresholds to define the common variants that are unlikely to be associated with a disease phenotype[14]

Genetic heterogeneity and population ethnicity are also major limitations as they may increase the number of false positive and false negative findings which will make the identification of candidate genes more difficult Of course, it is possible to reduce the stringency of the thresholds in the presence of heterogeneity and ethnicity, however this will reduce the power to detect variants as well Using a genotype-first approach to identify candidate genes might also offer a solution to overcome these limitations

Ethical implications

New technologies in genomics have changed the way researchers approach both basic and translational research With approaches such as exome sequencing, it is possible to significantly enhance the data generated from individual genomes which has put forth a series of questions on how to deal with the vast amount of information Should the individuals in these studies be allowed to have access to their sequencing information Should this information be shared with insurance companies This data can lead to unexpected findings and complicate clinical utility and patient benefit This area of genomics still remains a challenge and researchers are looking into how to address these questions[14]

Applications of exome sequencing

By using exome sequencing, fixed-cost studies can sequence samples to much higher depth than could be achieved with whole genome sequencing This additional depth makes exome sequencing well suited to several applications that need reliable variant calls

Rare variant mapping in complex disorders

Current association studies have focused on common variation across the genome, as these are the easiest to identify with our current assays However, disease-causing variants of large effect have been found to lie within exomes in candidate gene studies, and because of negative selection, are found in much lower allele frequencies and may remain untyped in current standard genotyping assays Whole genome sequencing is a potential method to assay novel variant across the genome However, in complex disorders such as autism, a large number of genes are thought to be associated with disease risk[15] This heterogeneity of underlying risk means that very large sample sizes are required for gene discovery, and thus whole genome sequencing is not particularly cost-effective This sample size issue is alleviated by the development of novel advanced analytic methods, which effectively map disease genes despite the genetic mutations are rare at variant level[15] In addition, variants in coding regions have been much more extensively studied and their functional implications are much easier to derive, making the practical applications of variants within the targeted exome region more immediately accessible

Exome sequencing in rare variant gene discovery remains a very active and ongoing area of research: to date, few associated genes have been uncovered thus far, but there is growing evidence that a significant burden of risk is observed across sets of genes

Discovery of Mendelian disorders

In Mendelian disorders of large effect, findings thus far suggest one or a very small number of variants within coding genes underlie the entire condition Because of the severity of these disorders, the few causal variants are presumed to be extremely rare or novel in the population, and would be missed by any standard genotyping assay Exome sequencing provides high coverage variant calls across coding regions, which are needed to separate true variants from noise A successful model of Mendelian gene discovery involves the discovery of de novo variants using trio sequencing, where parents and proband are genotyped

Case studies

A study published in September 2009 discussed a proof of concept experiment to determine if it was possible to identify causal genetic variants using exome sequencing They sequenced four individuals with Freeman-Sheldon syndrome FSS OMIM 193700, a rare autosomal dominant disorder known to be caused by a mutation in the gene MYH3[1] Eight HapMap individuals were also sequenced to remove common variants in order to identify the causal gene for FSS After exclusion of common variants, the authors were able to identify MYH3, which confirms that exome sequencing can be used to identify causal variants of rare disorders[1] This was the first reported study that used exome sequencing as an approach to identify an unknown causal gene for a rare mendelian disorder

Subsequently, another group reported successful clinical diagnosis of a suspected Bartter syndrome patient of Turkish origin[11] Bartter syndrome is a renal salt-wasting disease Exome sequencing revealed an unexpected well-conserved recessive mutation in a gene called SLC26A3 which is associated with congenital chloride diarrhea CLD This molecular diagnosis of CLD was confirmed by the referring clinician This example provided proof of concept of the use of whole-exome sequencing as a clinical tool in evaluation of patients with undiagnosed genetic illnesses This report is regarded as the first application of next generation sequencing technology for molecular diagnosis of a patient

A second report was conducted on exome sequencing of individuals with a mendelian disorder known as Miller syndrome MIM#263750, a rare disorder of autosomal recessive inheritance Two siblings and two unrelated individuals with Miller syndrome were studied They looked at variants that have the potential to be pathogenic such as non-synonymous mutations, splice acceptor and donor sites and short coding insertions or deletions[2] Since Miller syndrome is a rare disorder, it is expected that the causal variant has not been previously identified Previous exome sequencing studies of common single nucleotide polymorphisms SNPs in public SNP databases were used to further exclude candidate genes After exclusion of these genes, the authors found mutations in DHODH that were shared among individuals with Miller syndrome Each individual with Miller syndrome was a compound heterozygote for the DHODH mutations which were inherited as each parent of an affected individual was found to be a carrier[2]

This was the first time exome sequencing was shown to identify a novel gene responsible for a rare mendelian disease This exciting finding demonstrates that exome sequencing has the potential to locate causative genes in complex diseases, which previously has not been possible due to limitations in traditional methods Targeted capture and massively parallel sequencing represents a cost-effective, reproducible and robust strategy with high sensitivity and specificity to detect variants causing protein-coding changes in individual human genomes

Clinical diagnostics

Exome sequencing can be used to diagnose the genetic cause of disease in a patient Identification of the underlying disease gene mutations can have major implications for diagnostic and therapeutic approaches, can guide prediction of disease natural history, and makes it possible to test at-risk family members[1][2][11][16][17][18] There are many factors that make exome sequencing superior to single gene analysis including the ability to identify mutations in genes that were not tested due to an atypical clinical presentation[18] or the ability to identify clinical cases where mutations from different genes contribute to the different phenotypes in the same patient[2]

Having diagnosed a genetic cause of a disease, this information may guide the selection of appropriate treatment The first time this strategy was performed successfully in the clinic was in the treatment of an infant with inflammatory bowel disease[17][8] A number of conventional diagnostics had previously been used, but the results could not explain the infant's symptoms Analysis of exome sequencing data identified a mutation in the XIAP gene Knowledge of this gene's function guided the infant's treatment, leading to a bone marrow transplantation which cured the child of disease[17]

The first laboratory to offer a WES diagnostic service for clinicians, including medical interpretation, was Ambry Genetics with the "Clinical Diagnostic Exome"[19][better source needed]

Researchers have used exome sequencing to identify the underlying mutation for a patient with Bartter Syndrome and congenital chloride diarrhea[11] Bilgular's group also used exome sequencing and identified the underlying mutation for a patient with severe brain malformations, stating "highlight the use of whole exome sequencing to identify disease loci in settings in which traditional methods have proved challenging Our results demonstrate that this technology will be particularly valuable for gene discovery in those conditions in which mapping has been confounded by locus heterogeneity and uncertainty about the boundaries of diagnostic classification, pointing to a bright future for its broad application to medicine"[16]

Researchers at University of Cape Town, South Africa used exome sequencing to discover the genetic mutation of CDH2 as the underlying cause of a genetic disorder known as arrhythmogenic right ventricle cardiomyopathy ARVC‚ which increases the risk of heart disease and cardiac arrest

Direct-to-consumer exome sequencing

Further information: Personal genomics

Multiple companies have offered exome sequencing to consumers

Knome was the first company to offer exome sequencing services to consumers[when], at a cost of several thousand dollars[20] Later, 23andMe ran a pilot WES program that was announced in September 2011 and was discontinued in 2012 Consumers could obtain exome data at a cost of $999 The company provided raw data, and did not offer analysis[20][21][22]

In November 2012, DNADTC, a division of Gene by Gene started offering exomes at 80X coverage and introductory price of $695[23] This price per DNADTC web site is currently $895 In October 2013, BGI announced a promotion for personal whole exome sequencing at 50X coverage for $499[24] In June 2016 Genos was able to achieve an even lower price of $399 with a CLIA-certified 75X consumer exome sequenced from saliva[25][26][27] Helix launched their first offering of "exome plus" sequencing in November 2016 partnering with National Geographic which will empower consumers to learn about their genetic information through their application based platform[28][29]

See also

  • DNA profiling
  • Genetic counseling
  • Personalized medicine
  • Transcriptomics
  • Whole genome sequencing

References

  1. ^ a b c d e f g h i j Ng SB, Turner EH, Robertson PD, Flygare SD, Bigham AW, Lee C, Shaffer T, Wong M, Bhattacharjee A, Eichler EE, Bamshad M, Nickerson DA, Shendure J 10 September 2009 "Targeted capture and massively parallel sequencing of 12 human exomes" Nature 461 7261: 272–276 Bibcode:2009Natur461272N doi:101038/nature08250 PMC 2844771  PMID 19684571 
  2. ^ a b c d e Sarah B Ng; Kati J Buckingham; Choli Lee; Abigail W Bigham; Holly K Tabor; Karin M Dent; Chad D Huff; Paul T Shannon; Ethylin Wang Jabs; Deborah A Nickerson; Jay Shendure; Michael J Bamshad 2010 "Exome sequencing identifies the cause of a mendelian disorder" Nature Genetics 42 1: 30–35 doi:101038/ng499 PMC 2847889  PMID 19915526 
  3. ^ Wang, D G; Fan, J B; Siao, C J; Berno, A; Young, P; Sapolsky, R; Ghandour, G; Perkins, N; Winchester, E 1998-05-15 "Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome" Science 280 5366: 1077–1082 Bibcode:1998Sci2801077W doi:101126/science28053661077 ISSN 0036-8075 PMID 9582121 
  4. ^ Rauch, A; Hoyer, J; Guth, S; Zweier, C; Kraus, C; Becker, C; Zenker, M; Hüffmeier, U; Thiel, C; Rüschendorf, F; Nürnberg, P; Reis, A; Trautmann, U Oct 1, 2006 "Diagnostic yield of various genetic approaches in patients with unexplained developmental delay or mental retardation" American Journal of Medical Genetics Part A 140 19: 2063–74 doi:101002/ajmga31416 PMID 16917849 
  5. ^ a b Stavros Basiardes; Rose Veile; Cindy Helms; Elaine R Mardis; Anne M Bowcock; Michael Lovett 2005 "Direct Genomic Selection" Nature Methods 1 2: 63–69 doi:101038/nchembio0705-63 
  6. ^ Teer, J K; Mullikin, J C 12 August 2010 "Exome sequencing: the sweet spot before whole genomes" Human Molecular Genetics 19 R2: R145–R151 doi:101093/hmg/ddq333 PMC 2953745  PMID 20705737 
  7. ^ Template:Cite ,journal
  8. ^ a b Warr, A; Robert, C; Hume, D; Archibald, A; Deeb, N; Watson, M 2 July 2015 "Exome Sequencing: Current and Future Perspectives" G3 5 8: 1543–1550 doi:101534/g3115018564 PMC 4528311  PMID 26139844 
  9. ^ Emily H Turner; Sarah B Ng; Deborah A Nickerson; Jay Shendure 2009 "Methods for Genomic Partitioning" Annu Rev Genom Hum Genet 10 1: 30–35 doi:101146/annurev-genom-082908-150112 PMID 19630561 
  10. ^ Mertes F, Elsharawy A, Sauer S, van Helvoort JM, van der Zaag PJ, Franke A, Nilsson M, Lehrach H, Brookes AJ 2011 "Targeted enrichment of genomic DNA regions for next-generation sequencing" Brief Funct Genomics 10 6: 374–386 doi:101093/bfgp/elr033 PMC 3245553  PMID 22121152 
  11. ^ a b c d e Choi M, Scholl UI, Ji W, Liu T, Tikhonova IR, Zumbo P, Nayir A, Bakkaloğlu A, Ozen S, Sanjad S, Nelson-Williams C, Farhi A, Mane S, Lifton RP 10 November 2009 "Genetic diagnosis by whole exome capture and massively parallel DNA sequencing" Proc Natl Acad Sci U S A 106 45: 19096–19101 Bibcode:2009PNAS10619096C doi:101073/pnas0910672106 PMC 2768590  PMID 19861545 
  12. ^ a b c d Kahvejian A, Quackenbush J, Thompson JF 2008 "What would you do if you could sequence everything" Nature Biotechnology 26 10: 1125–1133 doi:101038/nbt1494 PMC 4153598  PMID 18846086 
  13. ^ Lira Mamanova; Coffey, Alison J; Scott, Carol E; Kozarewa, Iwanka; Turner, Emily H; Kumar, Akash; Howard, Eleanor; Shendure, Jay; Turner, Daniel J; et al February 2010 "Target-enrichment strategies for nextgeneration sequencing" Nature Methods 7 2: 111–118 doi:101038/nmeth1419 PMID 20111037 
  14. ^ a b c Biesecker LG Jan 2010 "Exome sequencing makes medical genomics a reality" Nat Genet 42 1: 13–14 doi:101038/ng0110-13 PMID 20037612 
  15. ^ a b Weijun Luo; Chaolin Zhang; Yong-hui Jiang; Cory R Brouwer 2018 "Systematic reconstruction of autism biology from massive genetic mutation profiles" Science Advances 4 4: e1701799 doi:101126/sciadv1701799 
  16. ^ a b Bilgüvar K, Oztürk AK, Louvi A, Kwan KY, Choi M, Tatli B, Yalnizoğlu D, Tüysüz B, Cağlayan AO, Gökben S, Kaymakçalan H, Barak T, Bakircioğlu M, Yasuno K, Ho W, Sanders S, Zhu Y, Yilmaz S, Dinçer A, Johnson MH, Bronen RA, Koçer N, Per H, Mane S, Pamir MN, Yalçinkaya C, Kumandaş S, Topçu M, Ozmen M, Sestan N, Lifton RP, State MW, Günel M 9 September 2010 "Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations" Nature 467 7312: 207–210 Bibcode:2010Natur467207B doi:101038/nature09327 PMC 3129007  PMID 20729831 CS1 maint: Uses authors parameter link
  17. ^ a b c Worthey EA, Mayer AN, Syverson GD, Helbling D, Bonacci BB, Decker B, Serpe JM, Dasu T, Tschannen MR, Veith RL, Basehore MJ, Broeckel U, Tomita-Mitchell A, Arca MJ, Casper JT, Margolis DA, Bick DP, Hessner MJ, Routes JM, Verbsky JW, Jacob HJ, Dimmock DP Mar 2011 "Making a definitive diagnosis: successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease" Genet Med 13 3: 255–262 doi:101097/GIM0b013e3182088158 PMID 21173700 
  18. ^ a b Raffan E, Hurst LA, Turki SA, Carpenter G, Scott C, Daly A, Coffey A, Bhaskar S, Howard E, Khan N, Kingston H, Palotie A, Savage DB, O'Driscoll M, Smith C, O'Rahilly S, Barroso I, Semple RK 2011 "Early Diagnosis of Werner's Syndrome Using Exome-Wide Sequencing in a Single, Atypical Patient" Front Endocrinol Lausanne 2 8: 8 doi:103389/fendo201100008 PMC 3356119  PMID 22654791 
  19. ^ 'Ambry Genetics First to Offer Exome Sequencing Service for Clinical Diagnostics'
  20. ^ a b Herper, Matthew 27 September 2011 "The Future Is Now: 23andMe Now Offers All Your Genes For $999" Forbes Retrieved 11 December 2011 
  21. ^ "23andMe Launches Pilot Program for Direct-to-Consumer Exome Sequencing" GenomeWeb GenomeWeb LLC 28 September 2011 Retrieved 11 December 2011 
  22. ^ "Personal Genome Sequencing in Ostensibly Healthy Individuals and the PeopleSeq Consortium" PDF Genomes2People 14 June 2016 
  23. ^ Vorhaus, Dan 29 November 2012 "DNA DTC: The Return of Direct to Consumer Whole Genome Sequencing" Genomics Law Report Retrieved 30 May 2013 
  24. ^ "Ultimate Exome Promotion" BGI Americas 18 October 2013 
  25. ^ "Owning Your Data: The Genos Model" Bio-IT World 6 July 2016 
  26. ^ "Consumer Genomics Startup Genos Research Plans to Let Customers Explore, Share Their Data" GenomeWeb LLC 13 June 2016 
  27. ^ "Genos - Own your DNA, Learn about Yourself, Drive Research" wwwgenosresearchcom Retrieved 2016-10-18 
  28. ^ "Press Release" wwwilluminacom Retrieved 2016-12-10 
  29. ^ "Helix Announces New Partnerships with National Geographic and Mount Sinai | Business Wire" wwwbusinesswirecom Retrieved 2016-12-10 

External links

  • WaferGen SmartChip TE Target Enrichment System
  • Centrillion Exome Sequencing Service
  • Roche NimbleGen Sequence Arrays
  • News on Exome Sequencing
  • CMSpdf Agilent Target Enrichment System
  • Guide for Patients and Families
  • wwwexome-seqcom
  • NSG Exome and Target Region Sequencing

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