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The exome composed of all of the exons within the genome, the sequences which, when transcribed, remain within the mature RNA after introns are removed by RNA splicing. This includes untranslated regions of mRNA, and coding sequence (or CDS). Exome sequencing has proven to be an efficient method to determine the genetic basis of more than two dozen Mendelian or single gene disorders.[1]

Statistics

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The human exome consists of roughly 233,785 exons, about 80% of which are less than 200 base pairs in length, constituting a total of about 1.1% of the total genome, or about 30 megabases of DNA.[2][3][4] Though composing a very small fraction of the genome, mutations in the exome are thought to harbor 85% of mutations that have a large effect on disease.[5]

Distinction between genome, exome, and transcriptome. The exome consists of all of the exons within the genome. In contrast, the trascriptome varies between cell types (e.g. neurons vs cardiac cells), only involving a portion of the exons that are actually transcribed into mRNA.

Definition

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It is important to note that the exome is distinct from the transcriptome, which is all of the transcribed RNA within a cell type. While the exome is constant from cell-type to cell-type, the transcriptome changes based on the structure and function of the cells. As a result, the entirety of the exome is not translated into protein in every cell. Different cell types only transcribe portions of the exome, and only the coding regions of the exons are eventually translated into proteins.

Next-Generation Sequencing of the Exome

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Next-generation sequencing (next-gen sequencing) allows for the rapid sequencing of large amounts of DNA, significantly advancing the study of genetics, and replacing older methods such as Sanger sequencing. This technology is starting to become more common in healthcare and research not only because it is reliable method of determining genetic variations, but also because it is cost effective and allows researchers to sequence entire genomes in anywhere between days to weeks. This compares to former methods which may have taken months. Next-gen sequencing includes both whole-exome sequencing and whole-genome sequencing.[6]

Whole-Exome Sequencing

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Sequencing an individual's exome instead of his or her entire genome has been proposed to be a more cost-effective and efficient way to diagnose rare genetic disorders.[7] It has also been found to more effective than other methods such as karyotyping and microarrays.[8] This distinction is largely due to the fact that phenotypes of genetic disorders are a result of mutated exons. In addition, since the exome only comprises 1.5% of the total genome, this process is more cost efficient and fast as it involves sequencing around 40 million bases rather than the 3 billion bases pairs that make up the genome.[9]

Whole-Genome Sequencing

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On the other hand, whole genome sequencing has been found to capture a more comprehensive view of variants in the DNA compared to whole-exome sequencing. Especially for single nucleotide variants, whole genome sequencing is more powerful and more sensitive than whole-exome sequencing in detecting potentially disease-causing mutations within the exome.[10] One must also keep in mind that non-coding regions can be involved in the regulation of the exons that make up the exome, and so whole-exome sequencing may not be complete in showing all the sequences at play in forming the exome.

Ethical Considerations

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With either form of sequencing, whole-exome sequencing or whole genome sequencing, some have argued that such practices should be done under the consideration of medical ethics. While physicians strive to preserve patient autonomy, sequencing deliberately asks laboratories to look at genetic variants that may be completely unrelated to the patient's condition at hand and have to potential of revealing findings that were not intentionally sought. In addition, such testing have been suggested to have imply forms of discrimination against particular groups for having certain genes, creating the potential for stigmas or negative attitudes towards that group as a result. [11]

Diseases and Diagnoses

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Rare mutations that affect the function of essential proteins constitute the majority of Mendelian diseases. In addition, the overwhelming majority of disease-causing mutations in Mendelian loci can be found within the coding region.[5] With the goal of finding methods to best detect harmful mutations and successfully diagnose patients, researchers are looking to the exome for clues to aid in this process.

Whole-exome sequencing has been a recent technologies that has led to the discovery of various genetic disorders and increased the rate of diagnoses of patients with rare genetic disorders. Overall, researchers believe that whole-exome sequencing has allowed healthcare providers to diagnose 30-50% of patients who were thought to have rare Mendelian disorders.[12] It has been suggested that whole-exome sequencing in clinical settings has many unexplored advantages. Not only can the exome increase our understanding of genetic patterns, but under clinical settings, it has the potential to the change in management of patients with rare and previously unknown disorders, allowing physicians to develop more targeted and personalized interventions.[13]

For example, Bartter Syndrome, also known as salt-wasting nephropathy, is a hereditary disease of the kidney characterized by hypotension (low blood pressure), hypokalemia (low potassium), and alkalosis (high blood pH) leading to muscle fatigue and varying levels of fatality.[14] It is an example of a rare disease, affecting fewer than one per million people, whose patients have been positively impacted by whole-exome sequencing. Thanks to this method, patients who formerly did not exhibit the classical mutations associated with Bartter Syndrome were formally diagnosed with it after the discovery that the disease has mutations outside of the loci of interest.[5] They were thus able to gain more targeted and productive treatment for the disease.

Much of the focus of exome sequencing in the context of disease diagnosis has been on protein coding "loss of function" alleles. Research has shown, however, that future advances that allow the study of non-coding regions, within and without the exome, may lead to additional abilities in the diagnoses of rare Mendelian disorders.[15]

See also

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References

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  1. ^ Bamshad MJ, Ng SB, Bigham AW, Tabor HK, Emond MJ, Nickerson DA, Shendure J (27 September 2011). "Exome sequencing as a tool for Mendelian disease gene discovery". Nat Rev Genet. 12 (11): 745–755. doi:10.1038/nrg3031. PMID 21946919.
  2. ^ Sakharkar, Meena Kishore; Chow, Vincent T. K.; Kangueane, Pandjassarame (2004). "Distributions of exons and introns in the human genome". In Silico Biology. 4 (4): 387–393. ISSN 1386-6338. PMID 15217358.
  3. ^ Venter, J. Craig; Adams, Mark D.; Myers, Eugene W.; Li, Peter W.; Mural, Richard J.; Sutton, Granger G.; Smith, Hamilton O.; Yandell, Mark; Evans, Cheryl A.; Holt, Robert A.; Gocayne, Jeannine D. (2001-02-16). "The Sequence of the Human Genome". Science. 291 (5507): 1304–1351. doi:10.1126/science.1058040. ISSN 0036-8075.
  4. ^ 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. doi:10.1038/nature08250. PMC 2844771. PMID 19684571.
  5. ^ a b c 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. doi:10.1073/pnas.0910672106. PMC 2768590. PMID 19861545.
  6. ^ Reference, Genetics Home. "What are whole exome sequencing and whole genome sequencing?". Genetics Home Reference. Retrieved 2019-11-07.
  7. ^ Yang, Yaping; Muzny, Donna M.; Reid, Jeffrey G.; Bainbridge, Matthew N.; Willis, Alecia; Ward, Patricia A.; Braxton, Alicia; Beuten, Joke; Xia, Fan; Niu, Zhiyv; Hardison, Matthew (2013-10-17). "Clinical Whole-Exome Sequencing for the Diagnosis of Mendelian Disorders". New England Journal of Medicine. 369 (16): 1502–1511. doi:10.1056/NEJMoa1306555. ISSN 0028-4793. PMC 4211433. PMID 24088041.{{cite journal}}: CS1 maint: PMC format (link)
  8. ^ Edelson, P. Kaitlyn; Dugoff, Lorraine; Bromley, Bryann (2019-01-01), Norton, Mary E.; Kuller, Jeffrey A.; Dugoff, Lorraine (eds.), "Chapter 11 - Genetic Evaluation of Fetal Sonographic Abnormalities", Perinatal Genetics, Content Repository Only!, pp. 105–124, ISBN 9780323530941, retrieved 2019-10-31
  9. ^ Nagele, Peter (2013-11). "Exome sequencing: one small step for malignant hyperthermia, one giant step for our specialty--why exome sequencing matters to all of us, not just the experts". Anesthesiology. 119 (5): 1006–1008. doi:10.1097/ALN.0b013e3182a8a90c. ISSN 1528-1175. PMC 3980570. PMID 24195944. {{cite journal}}: Check date values in: |date= (help)
  10. ^ Belkadi, Aziz; Bolze, Alexandre; Itan, Yuval; Cobat, Aurélie; Vincent, Quentin B.; Antipenko, Alexander; Shang, Lei; Boisson, Bertrand; Casanova, Jean-Laurent; Abel, Laurent (2015-04-28). "Whole-genome sequencing is more powerful than whole-exome sequencing for detecting exome variants". Proceedings of the National Academy of Sciences. 112 (17): 5473–5478. doi:10.1073/pnas.1418631112. ISSN 0027-8424. PMC 4418901. PMID 25827230.{{cite journal}}: CS1 maint: PMC format (link)
  11. ^ Gaff, C. L.; Macciocca, I. (2016-01-01), Kumar, Dhavendra; Antonarakis, Stylianos (eds.), "Chapter 15 - Genomic Perspective of Genetic Counseling", Medical and Health Genomics, Academic Press, pp. 201–212, doi:10.1016/b978-0-12-420196-5.00015-0, ISBN 9780124201965, retrieved 2019-11-07
  12. ^ Overall, researchers believe that whole exome sequencing has allowed healthcare providers to diagnose 30-50% of patients who were thought to have rare genetic disorders.
  13. ^ Zhu, X., Petrovski, S., Xie, P. et al. Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios. Genet Med 17, 774–781 (2015) doi:10.1038/gim.2014.191
  14. ^ Reference, Genetics Home. "Bartter syndrome". Genetics Home Reference. Retrieved 2019-11-19.
  15. ^ Frésard, L., & Montgomery, S. B. (2018). Diagnosing rare diseases after the exome. Cold Spring Harbor molecular case studies, 4(6), a003392. doi:10.1101/mcs.a003392
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