BRITISH STANDARD |

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12683:1998
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Biotechnology Ð Modified |
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organisms for application in |
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the environment Ð Guidance |
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for the characterization of the |
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genetically modified organism |
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by analysis of the molecular |
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stability of the genomic |
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modification |
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The European Standard EN 12683:1998 has the status of a |
British Standard |
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ICS 07.080; |
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NO COPYING WITHOUT BSI PERMISSION EXCEPT AS PERMITTED BY COPYRIGHT LAW
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 BS EN 12683:1998

National foreword
This British Standard is the English language version of EN 12683:1998.
The UK participation in its preparation was entrusted to Technical Committee
CII/58, Biotechnology, which has the responsibility to:

Ð aid enquirers to understand the text;

Ð present to the responsible European committee any enquiries on the
interpretation, or proposals for change, and keep the UK interests informed;
Ð monitor related international and European developments and promulgate
them in the UK.

A list of organizations represented on this committee can be obtained on request to

its secretary.
Cross-references
The British Standards which implement international or European publications
referred to in this document may be found in the BSI Standards Catalogue under the
section entitled ªInternational Standards Correspondence Indexº, or by using the
ªFindº facility of the BSI Standards Electronic Catalogue.
A British Standard does not purport to include all the necessary provisions of a
contract. Users of British Standards are responsible for their correct application.
Compliance with a British Standard does not of itself confer immunity
from legal obligations.

Summary of pages
This document comprises a front cover, an inside front cover, the EN title page,
pages 2 to 8, an inside back cover and a back cover.

This British Standard, having Amendments issued since publication

been prepared under the
direction of the Sector Amd. No. Date Text affected
Committee for Materials and
Chemicals, was published under
the authority of the Standards
Committee and comes into effect
on 15 December 1998

 BSI 1998

ISBN 0 580 30177 X

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 EUROPEAN STANDARD EN 12683
NORME EUROPEÂENNE
EUROPAÈISCHE NORM July 1998

ICS 07.080

Descriptors: biotechnology, genetics, modified organisms, environments, environmental protection, analysis method, bioassay,
experimental design

English version

Biotechnology Ð Modified organisms for application in the

environment Ð Guidance for the characterization of the genetically
modified organism by analysis of the molecular stability of the
genomic modification

Biotechnologie Ð Organismes modifieÂs disseÂmineÂs Biotechnik Ð VeraÈnderte Organismen zum Einsatz

dans l'environnement Ð Guide pour la in der Umwelt Ð Leitfaden fuÈr die
caracteÂrisation de l'organisme geÂneÂtiquement Charakterisierung des gentechnisch veraÈnderten
modifie par l'analyse de la stabilite moleÂculaire de Organismus durch Untersuchung der molekularen
la modification geÂnomique StabilitaÈt der GenomveraÈnderung

This European Standard was approved by CEN on 1 July 1998.

CEN members are bound to comply with the CEN/CENELEC Internal Regulations
which stipulate the conditions for giving this European Standard the status of a
national standard without any alteration. Up-to-date lists and bibliographical
references concerning such national standards may be obtained on application to
the Central Secretariat or to any CEN member.
This European Standard exists in three official versions (English, French, German).
A version in any other language made by translation under the responsibility of a
CEN member into its own language and notified to the Central Secretariat has the
same status as the official versions.
CEN members are the national standards bodies of Austria, Belgium, Czech
Republic, Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Italy,
Luxembourg, Netherlands, Norway, Portugal, Spain, Sweden, Switzerland and
United Kingdom.

CEN
European Committee for Standardization
Comite EuropeÂen de Normalisation
EuropaÈisches Komitee fuÈr Normung

Central Secretariat: rue de Stassart 36, B-1050 Brussels

 1998 CEN All rights of exploitation in any form and by any means reserved worldwide for CEN national
Members.
Ref. No. EN 12683:1998 E
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 Page 2
EN 12683:1998

Foreword Contents
This European Standard has been prepared by Page
Technical Committee CEN/TC 233, Biotechnology, the
Secretariat of which is held by AFNOR. Foreword 2
This European Standard shall be given the status of a Introduction 3
national standard, either by publication of an identical 1 Scope 3
text or by endorsement, at the latest by January 1999, 2 Normative references 3
and conflicting national standards shall be withdrawn
at the latest by January 1999. 3 Definitions 3
This European Standard has been prepared under a 4 Molecular stability testing 4
mandate given to CEN by the European Commission 5 Materials 5
and the European Free Trade Association.
6 Considerations for experimental
According to the CEN/CENELEC Internal Regulations, procedures 5
the national standards organizations of the following
countries are bound to implement this European 7 Validity of data analysis 7
Standard: Austria, Belgium, Czech Republic, Denmark, 8 Documentation of results 7
Finland, France, Germany, Greece, Iceland, Ireland, Annex A (informative) Bibliography 8
Italy, Luxembourg, Netherlands, Norway, Portugal,
Spain, Sweden, Switzerland and the United Kingdom.

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 Page 3
EN 12683:1998

Introduction EN 12682:1998, Biotechnology Ð Modified organisms

This European Standard relates to part of the for application in the environment Ð Guidance for
characterization of genetically modified organisms the characterization of genetically modified organism
(GMOs). It is designed as a guideline for adaptation of by analysis of the functional expression of the
experimental procedures to the requirements of the genomic modification.
specific experimental design. The characterization of a
GMO can include the analysis of: 3 Definitions
Ð the genomic modification (see EN 12687); For the purposes of this standard, the following
Ð the functional expression of the genomic definitions apply:
modification (see EN 12682);
Ð the molecular stability of the genomic 3.1
modification. control
This European Standard deals with the analysis of the preparation of known characteristics used to
molecular stability of the genomic modification of standardize an analysis
GMOs. In principle, this European Standard refers to
the analysis of the molecular stability of GMOs during 3.2
their prerelease evaluation and in monitoring of data signal
experimental releases. If specific questions concerning output of a test system
molecular stability occur during or after the release, NOTE Data signals can be characterized:
especially if the release is scheduled for more than one Ð by binary decision: presence/absence (+/2);
generation, it is this standard that could apply (see Ð in relative terms by ordering the data signal strength with
Annex A [3], [4]). respect to (a) defined control(s);
The analysis of the molecular stability can be based Ð quantitatively by giving their output strength in absolute
on: terms;
Ð the physical analysis of the genetic modification Ð by position or movement;
of interest as it exists in the GMO (genomic Ð qualitatively by describing parameters not addressed by
modification) (see EN 12687); and/or strength or position.
Ð the analysis of the functional expression of the 3.3
genetic modification of interest (genomic
detection
modification) (see EN 12682).
recognition of the presence of an organism or of a
molecular structure within a sample
1 Scope
This European Standard provides guidance for factors 3.4
and criteria considered by the experimenter for the gene probe
valid design, execution and evaluation of an analysis of specific nucleic acid sequence used to identify certain
the molecular stability of the genomic modification DNA or RNA fragments by means of hybridization
with respect to life cycle, heritability and external
factors. It describes the steps in the characterization of 3.5
a GMO that should be followed to ensure the validity genetic modification of interest
of the analysis of the molecular stability of the
genomic modification. conceptual design for altering the genetic material
within an organism
The type of molecular stability analysis is dependent
NOTE 1 The genetic modification of interest can be described at
on the objectives of the experiment. different levels of molecular detail.
NOTE 2 The conceptual design can include insertion, substitution
2 Normative references or deletion of genetic material.
This European Standard incorporates by dated or 3.6
undated reference, provisions from other publications.
These normative references are cited at the genetically modified organism
appropriate places in the text and the publications are organism in which the genetic material has been
listed hereafter. For dated references, subsequent altered in a way that does not occur naturally by
amendments to or revisions of any of these mating and/or natural recombination
publications apply to this European Standard only NOTE Within the terms of this definition, genetic modification
when incorporated in it by amendment or revision. For occurs at least through the use of the techniques listed in the
undated references the latest edition of the publication Directive 90/220/EEC or its appropriate annexes (see annex A [2]).
referred to applies.
EN 12687:1998, Biotechnology Ð Modified organisms
for application in the environment Ð Guidance for
the characterization of genetically modified organism
by analysis of the genomic modification.
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EN 12683:1998

3.7 4.2 Types of molecular stability

genomic modification Molecular stability or instability of a genomic
actual physical structure of the genetic modification of modification can be observed at any of the following
interest as it exists in the genetically modified levels:
organism Ð the structural or genomic level;
3.8 Ð the transcriptional or RNA-level;
identification Ð the level of functional expression;
establishment of identity by comparison with a Ð phenotype such as morphology, resistance, host
reference specificity, colour.
NOTE 1 The reference could be an organism, a molecular 4.3 Factors influencing the molecular stability
structure or the genetic modification of interest.
Molecular stability of a genomic modification at the
NOTE 2 The certainty of identification is affected by the types
and/or number of characteristics investigated. structural or genomic level can depend on factors
which directly influence the genomic modification such
3.9 as:
molecular stability Ð mutation;
maintenance of the integrity of the desired structure Ð recombination and/or transposition;
and/or the desired function of the genomic
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Ð gene transfer;
modification with respect to time and/or generation
Ð copy number of accessory genetic elements like
3.10 plasmids;
organism Ð methylation.
biological entity capable of replication or of These factors influence mainly the genomic
transferring genetic material modification, the type of integration into, and/or the
3.11 localization within the genome.
reproducibility Molecular stability of the functional expression can
depend on factors which indirectly influence the
precision under reproducibility conditions [ISO 3534-1] genomic modification such as:
NOTE 1 Reproducibility conditions are conditions where test
results are obtained with the same method on identical test items Ð recipient organism;
in different laboratories with different operators using different Ð tissue and/or organ specificity;
equipment.
Ð dependence upon metabolic activity;
NOTE 2 Results should be expressed as reproducibility standard
deviation or reproducibility coefficient of variation. Ð developmental stage (e.g. germination,
senescence);
4 Molecular stability testing Ð external factors (e.g. wounding, UV- and visible
light, temperature, habitat).
4.1 General considerations Factors which influence the genomic modification can
The relative molecular stability of traits introduced by act either in cis or in trans.
genetic modification, over time and generation, can be Examples for factors acting in cis are:
important in order to ensure the performance of the
GMO under field conditions and/or for biosafety Ð integration site;
reasons. The design of an analysis for molecular Ð chromatin structure;
stability should take into account the natural variations Ð DNA structure;
on the one hand and the experimental objective with
Ð copy number;
respect to product performance and safety on the
other. Ð methylation.
Molecular stability analysis can be performed at either Examples for factors acting in trans are:
the structural or genomic level or at the functional or Ð life cycle;
phenotypic level depending on the objective of Ð heritability;
experiment. Testing for molecular stability between
generations should be carried out over an appropriate Ð external factors.
number of generations. 4.4 Analysis of molecular stability
Molecular stability testing could be required at various 4.4.1 General
points during the development and release of a GMO
into the environment. This generally starts in contained The molecular stability testing is the correlation of
systems, like the laboratory, microcosms, growth analytical data (structure and expression) from GMOs
chambers, greenhouses, animal houses and can or their genetic material between samplings taken at
continue during the release into the environment. different time points.

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EN 12683:1998

4.4.2 Methods at the structural or genomic level 6.2 Experimental design

The following is a list of methods appropriate to test The considerations for experimental procedures to
the molecular stability at the structural or genomic analyse the molecular stability of the genomic
level. Not all of these methods are necessarily modification should start with the definition and
applicable for the analysis of every genomic statement of the objective for this analysis followed by
modification. The method of choice and its the design of the experiment, which should be written
appropriateness or combination of methods depends down in a protocol, but keeping the flexibility needed
on the stated objectives of the analysis. As molecular to handle unexpected observations.
biology is a rapidly evolving field of research, the listed The reason for choosing a particular method or
methods are considered neither prioritized, restrictive methods should be stated in the experimental design.
nor exhaustive. The methods should be properly
The following points should be considered in the
assessed with regard to their information value:
design of an experiment to test the molecular stability
Ð restriction pattern analysis; of a genomic modification:
Ð nucleic acid hybridization methods; Ð objective of the molecular stability analysis;
Ð nucleic acid amplification methods; Ð type of molecular stability analysis: structural or
Ð sequencing methods; genomic, functional or phenotypic molecular
stability;
Ð analysis of the chromatin and/or chromosome
Ð choice of the method(s) to analyse molecular
structure such as nucleosome footprinting and FISH
stability;
(Fluorescent In Situ Hybridization).
Ð type of organism (micro-organism, plant, animal);
4.4.3 Methods at the functional or phenotypic Ð type of genetic modification (e.g. deletion,
level insertion, rearrangement);
The following methods can be appropriate to test the Ð part of the organism used for analysis;
molecular stability at the functional or phenotypic Ð numbers of samples during one generation;
level: Ð number of generations tested;
Ð biological tests (e.g. resistance and/or tolerance to Ð growth and senescence;
pests or pesticides); Ð population size to be tested;
Ð test of enzymatic activities; Ð external factors (e.g. light, temperature, humidity,
Ð immuno-detection; soil variables, other site factors);
Ð nuclear-run-on-assays and Northern Blot. Ð use of appropriate controls.
NOTE This list should not be considered as exhaustive.

5 Materials 6.3 Execution of the experimental protocol

If nucleic acids, gene probes, labelled gene probes are 6.3.1 General
used, they should be prepared in accordance with Methods of molecular stability testing at the functional
EN 12687:1998, clause 5. or phenotypic and at the molecular level are described
in 6.3.2 and 6.3.3.
6 Considerations for experimental Not all of the methods are necessarily applicable in
one experiment to analyse the molecular stability of
procedures the genomic modification. The choice of the method or
6.1 General the combination of methods depends on the
The main steps of the experimental procedures for the experimental design which itself is influenced by the
analysis of the molecular stability of the genomic factors described in 6.2.
modification are: 6.3.2 Functional or phenotypic analysis
a) precise statement of the objective for the intended If appropriate, phenotypic testing can be used to
analysis (see 6.2); analyse the molecular stability of the genetic
b) experimental design according to various criteria modification of interest. These tests combine the
(see 6.2); analysis of the performance of the GMO under the
experimental conditions with the molecular stability
c) execution of the analysis according to the
analysis. Mostly, the analysis is based on biological
experimental protocol (see 6.3);
tests. Examples for the appropriateness of these kinds
d) appropriate record keeping (see 6.4); of tests are based on phenotypic analysis, such as
e) evaluation of the validity of the results (see resistance tests against pests or pesticides. In general,
clause 7); phenotypic analysis is cost-effective and can be
f) documentation of the results (see clause 8). performed with a statistically relevant number of
organisms. Additionally or alternatively to biological
tests, biochemical analysis can be suitable (see
also 6.3.3.4).
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EN 12683:1998

6.3.3 Molecular analysis For all methods, a positive control should contain
the modified sequence, whose molecular stability is
6.3.3.1 General
being analysed. In the case of Southern
Molecular analysis of the stability of the genetic hybridization, the positive control should be
modification of interest can be performed at various obtained by digestion of the DNA with a restriction
levels, such as the structure of the genome, RNA- enzyme or combination of enzymes having at least
transcription, protein-expression. The various methods two cutting sites in the modified genetic sequence. A
are described in 6.3.3.2 to 6.3.3.5. negative control should be obtained by using the
6.3.3.2 Structural or genomic analysis nucleic acid of an organism which is identical to the
GMO except for the lack of the modified genetic
At this level, nucleic acid hybridization and DNA- or sequence.
RNA-fragment amplification methods can be applied. In
order to avoid misinterpretation of the results b) Nucleic acid amplification methods
appropriate controls should be included in all Various methods can be applied, depending on the
experiments. Methods for analysis structure or type of molecular stability question to be answered
genomic molecular stability include the following. (e.g. PCR, reverse transcriptase-PCR, inverse-PCR).
a) Nucleic acid hybridization methods Nucleic acid amplification methods are very sensitive
Slot/dot blot can be applied, if cultivation of the techniques. Therefore, special care should be given
GMO is not possible or necessary. The advantage of to the purity of the sample, the optimization of the
this method is that a higher number of samples can stringency during the amplification reaction and the
be screened within reasonable time and a more inclusion of appropriate controls. The detection
reasonable cost than with Southern hybridization should be done in such a way that false positive
analysis. However, as a disadvantage, false positive results are excluded. For example, this could include
results can often be obtained from closely-related a Southern analysis or restriction enzyme analysis of
sequences, if the hybridization stringency is not the amplified DNA. Additionally, crude DNA samples
sufficient. sometimes contain components that inhibit the
activity of the polymerase. Control amplification
Colony or plaque hybridization can be applied when reactions using a second pair of primers specific for
the molecular stability of a large number of an additional endogenous DNA sequence should be
micro-organisms has to be analysed. The specificity performed to ensure the purity of the DNA sample.
of the technique depends on the ability of the gene
probe to differentiate between the target sequence 6.3.3.3 Rate of transcription
and cross-reacting sequences. To identify artifacts, it Nuclear-run-on-assays, performed according to
is necessary to use duplicate filters. laboratory manuals (see annex A [7], [8]) can be
Slot/dot blot and colony and plaque hybridization applied to determine the molecular stability of the rate
give no information about the integrity of the of transcription. The following controls should be used:
structure. With these methods, only the presence or Ð a positive control corresponds to a host gene
absence of a certain genomic modification can be which has no homology with the genetic
determined. modification of interest and which is transcribed in
Southern hybridization is characterized by a higher the tissue of interest;
sensitivity and specificity than the previously Ð a negative control corresponds to an assay
described methods. However, as it is time- and performed in the presence of alpha-amanitin which
cost-intensive, generally only a smaller number of acts as an inhibitor of RNA polymerase II.
samples can be handled. The method is very time-consuming and laborious.
Therefore, it is usually used for diagnosis or
verification rather than for screening. The specificity 6.3.3.4 Steady state levels of RNA
of the technique depends mainly on the gene probe Methods to determine the steady state levels of the
used and the nature of the target nucleic acid. This transcribed RNA include RNA slot/dot blot, Northern
method is particularly suitable to detect hybridization, RNase-protection-assays and
rearrangements which can give rise to questions reverse-transcriptase PCR. The following controls
concerning molecular stability or instability of the should be used:
genomic modification. Ð a positive control corresponds to a host gene
Data signals from false positive hybridization are which has no homology with the genetic
recognized if a fragment other than the size modification of interest and which is transcribed in
predicted from the genetic modification of interest is the tissue of interest;
detected by the gene probe. However, in this case it Ð a negative control corresponds to RNA extracted
is also possible that a deletion or insertion has from the non-genetically modified organism.
occurred within the genomic modification. For the
case of hybridization analysis, degradation of nucleic
acid in the samples can also lead to unexpected
hybridization data signals.

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EN 12683:1998

6.3.3.5 Molecular stability of the expression of a h) a statistically relevant number, as determined by

protein the experimental design (see 6.2), of generations has
Various methods to detect and quantify the expression been analysed; and
level of a protein of interest can be applied. The i) appropriate external conditions have been taken
method of choice depends on the experimental design into account.
and especially on the type of a protein expressed due
to the genomic modification. Examples of applicable 7.2 Specific considerations
methods are Western blot analysis and other 7.2.1 Validity of data analysis based on nucleic
immuno-detection techniques. The applicability of acid hybridization methods
these methods depends on the availability of a specific Using slot/dot or colony blot, samples and controls
antibody or antiserum. should be applied or transferred to the same filter.
If an expressed protein has an enzymatic activity and a Using Southern or Northern hybridization methods,
suitable test system is available, the measurement of
samples and controls should be run on the same gel.
this enzymatic activity can be a suitable method.
As with slot-, dot- and colony-blot, the comparison
Positive and negative controls should be included in between the results of the positive and negative
order to detect false positive due to antibody controls indicates the suitability of the method to
cross-reactivity or non-specific enzymatic reactions. specifically analyse the molecular stability of the
Positive controls should be protein extracts from
genetic modification of interest. Gene probes should be
organisms which are known to express the protein to
suitably designed to be able to detect and identify
be detected or pure preparations of the protein to be
molecular stability or instability of the DNA.
detected. Negative controls should be protein extracts
from the non-modified organism. 7.2.2 Validity of data analysis based on nucleic
6.4 Record keeping acid amplification methods
A record should be kept of the execution of the Samples and controls should be amplified
experimental procedures. This should include: simultaneously. Verification of false positive results may
Ð identification of the experiment; be made by including a control where no nucleic acid
Ð person(s) performing the experiment; has been added. Verification of false negative results
Ð date of the experiment; can be performed by including an internal marker in
the sample. The length of the amplified fragment of the
Ð method chosen for the molecular stability
internal marker should be similar but clearly
analysis;
distinguishable from the length of the amplified
Ð origin of samples; fragment of interest. Comparisons between positive
Ð number of samples analysed; and negative controls and between controls and
Ð controls used; sample indicate the specificity of the analysis and
Ð deviations from the protocol; whether the modified sequence is present in the
Ð duration of the experiment; sample.
Ð key equipment used. 7.2.3 Validity of data analysis based on protein
NOTE This list should not be considered as exhaustive. analysis
Regardless of whether immuno-detection or enzymatic
7 Validity of data analysis activity methods are used, appropriate controls should
7.1 General considerations be included in the test and analysed simultaneously
The data analysis, regardless of the method(s) applied, (on the same filter in the case of Western blotting or in
should be regarded as valid if: the same batch in the case of ELISA or similar
a) the experimental design has been laid down in a methods for measurement of enzymatic activity).
written protocol; Antibodies or antisera should be specifically able to
b) the experiment has been performed according to detect the protein of interest and results should be
that written protocol, indicating deviations from the quantifiable, if required by the experimental design.
protocol;
c) samples and controls are analysed simultaneously 8 Documentation of results
using identical methods; A report of the analysis should be prepared which
d) all appropriate controls give the expected results; should include the experimental protocol, a clear
e) limits of detection and reproducibility of the description of sampling, a brief description of the
applied method(s) are appropriate; method(s) used for the molecular stability analysis and
f) results are expressed (see clause 8) and the raw data of the analysis (including
realistically assessed with regard to the information autoradiographs, pictures of the gels, ELISA-readouts,
value of the applied method; tables, figures). Additionally, a short written description
g) a statistically relevant number of samples has should be prepared that includes the test and any
been analysed according to the question asked (for unexpected results. This report should include a short
example molecular stability in the GMO or after interpretation of the results. The report should be kept
gene transfer); in an identified location.
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EN 12683:1998

Annex A (informative)
Bibliography
[1] Council Directive 90/219/EEC of 23 April 1990
on the contained use of genetically modified
micro-organisms. OJEC 08.05.1990,
no L 117, p 1.
[2] Council Directive 90/220/EEC of 23 April 1990
on the deliberate release into the environment
of genetically modified organisms. OJEC
08.05.1990, no L 117, p 15.
[3] EN 12468, Biotechnology Ð Modified
organisms for application in the
environment Ð Guidance for the monitoring
strategies for deliberate releases of genetically
modified plants.
[4] EN 12685, Biotechnology Ð Modified
organisms for application in the
environment Ð Guidance for the monitoring
strategies for deliberate releases of genetically
modified micro-organisms, including viruses.
[5] EN 12305, Biotechnology Ð Modified
organisms for application in the
environment Ð Guidance for the sampling
strategies for deliberate releases of genetically
modified plants.
[6] EN 12686, Biotechnology Ð Modified
organisms for application in the
environment Ð Guidance for the sampling
strategies for deliberate releases of genetically
modified micro-organisms, including viruses.
[7] Sambrook J., Fritsch E.F. and Maniatis T.
(1989). Molecular Cloning. A laboratory
manual, Second Edition, Cold Spring Harbor
Laboratory Press.
[8] Ausubel, F.A. et al. (eds. Greene). Current
Protocols in Molecular Biology. Publ. Wiley &
Sons.

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