All experts agree that sequencing technologies have developed at a revolutionary speed over the last five years. The “$1000 genome” seems just to be around the corner and, according to experts, the trend towards further miniaturisation and cost degression will continue.
Next-generation sequencing (NGS) is currently replacing Frederick Sanger’s method of DNA sequencing developed in the 1980s. Basically, high-throughput DNA analysis methods enable miniaturisation and optimisation, which enables individual sequencing reactions to be carried out in a highly parallel manner. At present, 107 to 1010 nucleotides can be sequenced per day and system, surpassing the sequencing capacity of existing technologies by several magnitudes.
State-of-the-art NGS systems are able to sequence and compare four human genomes within two weeks, not including data analysis. Experts believe that a 100-fold per-base coverage is required to provide a high enough level of precision. This in turn reduces the throughput rate. The NGS market is currently dominated by three companies offering different though basically comparable technologies. The most innovative approach is single-molecule sequencing.
Norwegian pilot project: genome-wide tumour analysis
State-of-the-art sequencing technologies are already playing a major role in basic research and help to explain the pathogenesis of diseases on the molecular level as well as detecting microbes such as those that caused the EHEC epidemics in Germany in summer 2011. Oncology centres in the USA are looking into several hundred tumour genes in their effort to correlate genomics with therapy response. And yet another example: a pilot programme was recently started in Norway that aims to bring next-generation DNA sequencing into the country’s national healthcare system to personalise cancer treatments and increase the chances of curing cancer (Theurillat, Jean-Philippe).
That said, NGS technologies still suffer from one major drawback in that they produce high false-positive rates (Timmermann, Bernd). All whole-genome sequencers produce their own specific errors. Although these errors are difficult to quantify, their number (error rates of up to one percent) is nevertheless too high for them to be used for medical purposes.
The German Ethics Council has announced that a comprehensive report on genetic diagnostics is to be published in 2013 and believes that this report will fuel the discussion on genetic testing. In fact, the vast majority of experts believe that the German Genetic Diagnostics Act needs to be amended. Many people have criticised the fact that research that leads to huge quantities of genetic information does not fall under the scope of this law. Another controversial aspect relates to the information study volunteers need to be given before and after testing. Calls for guidelines for researchers, clinicians and patients are getting louder.
In addition to medically questionable lifestyle genetic tests (so-called direct-to-consumer tests), the economic dimension of genetic diagnostics is another controversial issue. So for example the question as to whether insurance companies should pay for genome sequencing services in cases when lifestyle changes might prevent or improve the diagnosed or predicted condition. The Netherlands are evaluating the introduction of a targeted exome test (which comprises 1200 genes) to assess the disease risk of seriously ill children.
Up until the end of the year, the interdisciplinary Genetic Diagnostic Commission will provide information about the current price of genome sequencing. Human geneticists are keen to find out about the counselling requirements associated with newborn hearing disorder screening, which has recently been implemented in all German states. Approximately 50% of all hearing disorders in children have a genetic basis (Henn, in: Duttge et al., p. 27).
And there is yet another unsolved serious problem that needs to be dealt with, namely the problem of quality assurance. A survey on human molecular genetic testing laboratories published in 2012 (Berwouts, S. et al.) concluded that the quality practices vary widely in European genetic testing laboratories and that this is associated with potential risks for patients as well as compromising patient care and treatment. Human geneticists are also calling for measures that ensure the quality of genetic counselling (Henn, in Duttge et al., p. 30) and for the approval of genetic tests that enable people who have been tested to take the necessary steps to improve their health.
Recent genome research results might have disproved the dogma of the exceptionality of genes. However, the bioethical debate needs to be continued as it is governments’ responsibility to regulate the use of the flood of genetic data while respecting basic individual rights. However, it is safe to assume that if something is technically feasible, it will be put into practice – now and in the future; the detailed knowledge of a person’s genome will not be an exception to this rule.
wp - 23.11.2012
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Abecasis, GR: The 1000 Genomes Project Consortium, An integrated map of genetic variation from 1,092 human genomes, Nature, 491, 1st November 2012, doi: 10.1038/nature11632.
Berwouts, S. et al.: Quality assurance practices in Europe: a survey of molecular genetic testing laboratories, European Journal of Human Genetics (2012), 20, p. 118-1126, doi: 10.1038/ejhg.2012.125 online 27th June 2012.
Goldsmith, L. et al.: Direct-to-consumer genomic testing: systematic review of the literature on user perspectives, European Journal of Human Genetics (2012), 20, 811-816, doi:10.1038/ejhg.2012.18.
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Mullard, A.: Consumer gene tests poised for regulatory green light, Nature Medicine, Vol. 18, No. 9, September 2012, p. 1306.
Roberts, Nicholas J.: The Predictive Capacity of Personal Genome Sequencing, Science Translational Medicine Rapid Publication on April 2 2012, Sci. Transl. Med. DOI: 10.1126/scitranslmed.3003380
Challenges associated with the Encode project, e.g.:
Ward, L./Kellis, M.: Interpreting noncoding genetic variation in complex traits and human disease, in: Nature Biotechnology, Vol. 30, No. 11, Nov. 2012, p. 1095-1106, doi: 10.1038/nbt.2422.
Articles in German:
Theurillat, Jean-Philippe, NZZ, 23.5.2012, https://www.gesundheitsindustrie-bw.denzz.ch/wissen/wissenschaft/die-krebstherapie-der-zukunft_1.16997844.html
Timmermann, Bernd, MPI for Molecular Genetics, March 2012, public hearing of the German Ethics Council.
Orth, M. et al.: Praktische Umsetzung des Gendiagnostikgesetzes (GenDG) in der Laboratoriumsmedizin, dem humangenetischen Laboratorium und der humangenetischen Beratung/Practical Implications oft he German Genetic Diagnostics Act (GenDG) for Laboratory Medicine, the Human Genetics Laboratory for Genetic Counseling, in: LaboratoriumsMedizin, Vol. 35, H. 5, p. 243ff.
Schulze, Bernt: Gendiagnostikgesetz und genetische Beratung I: Geschichte eines Irrwegs, Dt. Ärzteblatt, H. 16, 20. April 2012
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Duttge, G./Engel, W./Zoll, B. (Eds.): Das Gendiagnostikgesetz im Spannungsfeld von Humangenetik und Recht, Göttingen 2012 (Göttinger Schriften zum Medizinrecht Vol. 11).
Klinkhammer, G.: Arbeitskreis medizinischer Ethikkommissionen: Eine klare Vereinbarung treffen, Dt. Ärzteblatt, H. 33-34, 17.8.2012.
Public discussion of the Berlin-Brandenburg Academy of Sciences on genetic diagnostics, German title: 'Schicksal Gendiagnostik', 'Gentechnologiebericht' work group, 10th September 2012, Berlin: (audio recording) https://www.gesundheitsindustrie-bw.dewww.bbaw.de/mediathek/schicksal_gendiagnostik/?searchterm=schicksal_gendiagnostik
Public hearing of the German Ethics Council, 3rd May 2012: Opportunities and limits of predictive genetic diagnostics of multifactorial diseases
Public hearing of the German Ethics Council, 22nd March 2012: Scientific and technological developments in the field of multiplex and high-throughput diagnostics
Opinion of the German Society of Human Genetics on the qualification related to "human genetic diagnostics and consultation" as stipulated in § 7 paragraph 3 of the German Genetic Diagnostics Act, 15th Feb. 2012, and others relating to the GEKO guidelines, https://www.gesundheitsindustrie-bw.dewww.gfhev.de/de/leitlinien/gfh.htm?Submit2=Liste+anzeigen#GEKO
German Society of Human Genetics/Association of German Human Geneticists (HG): S2k guideline "Human genetic diagnostics" and genetic counselling, online publication 21st June 2011, doi: 10.1007/s11825-011-0284-x, guideline available through: https://www.gesundheitsindustrie-bw.dewww.awmf.org/uploads/tx_szleitlinien/078-015l_S2k_Humangenetische_Diagnostik_genetische_Beratung.pdf
Genetic Diagnostics Commission at the Robert Koch Institute:
German Academy of Natural Scientists Leopoldina/acatech/Berlin-Brandenburg Academy of Sciences: Opinion on predictive genetic diagnostics as a tool for disease prevention, November 2010