Phenotype characteristics (harmful phenotype, significant clinical pathological phenotype)

Source

Non-harmful / below threshold / severity degree 0 Mild / severity degree 1 Moderate / severity degree 2 Severe / severity degree 3
Directive 2010/63/EU, Annex VIII

Breeding genetically altered animals which are expected to have no clinically detectable adverse phenotype. Breeding of genetically altered animals which is expected to result in a phenotype with mild effects. Breeding of genetically altered animals which is expected to result in a phenotype with moderate effects.

Breeding animals with genetic disorders that are expected to experience severe and persistent impairment of general condition.

Examples: Huntington’s disease. Muscular dystrophy. Chronic relapsing neuritis models.
Home Office (2014 b)

Animals can be considered sub-threshold if: they are born and no harmful phenotype actually manifested; or the phenotype was subtle and of no welfare significance; or because of the management conditions the phenotype caused no welfare concern to the animal.

Common examples of likely sub-threshold severity classification: Categories of GAAs that are likely to be sub-threshold given the nature of the genetic alteration: established heterozygotes carrying recessive alleles; reporter gene expressing strains, where there is no adverse phenotype; Cre expressing lines where they do not have other defects, for example, due to cross breeding to generate multi-gene manipulations. An animal of any strain that has not had a formal welfare assessment carried out and is bred under project licence authority if it does not show any noticeable adverse effects and has not been genotyped by a regulated method. Immunodeficient animals that do not during their lifetime suffer infections and remain otherwise healthy. Animals killed prior to the onset of any harmful phenotype in strains where the phenotype progresses over time but animals are overtly normal for the early part of their life. However, if the line is known to have a disease that has onset from birth, then, regardless of appearance, a sub-threshold assessment cannot be given because the disease will already be present, for example, diabetes with onset of disease or pre-diabetic state from birth. These must be assigned a mild severity or higher.

Unknown phenotype, but not expected to be harmful. Known phenotype that can be kept so that actual severity is sub-threshold or mild provided certain conditions are met. These conditions will be mandated through the project authorisation.
A mild severity classification is appropriate when animals show a distinct phenotype but this does not: reduce lifespan compared with the background strain; prevent normal feeding and movement; result in systemic disease, but does lead to an observable difference in a parameter such as growth rate, size, anatomy or behaviour.

A mild severity classification might be given to: Animals killed at the onset of a disease phenotype, provided it has not materially affected wellbeing. Neonatal mice and rats lost due to the phenotype within the first five days after birth (note: this relates only to phenotype-related deaths, other procedure-related harms should be considered separately).
Animals bred on moderate severity limit protocols will be expected to develop a phenotype that is sufficient to cause a disease comparable with the moderate severity description (see separate Home Office document Advisory notes on recording and reporting the actual severity of regulated procedures). Disease is not expected to be fatal, and animals will be killed before any disease becomes life-threatening.
A severity classification of moderate could be given: for most harmful phenotypes that do not result in animals becoming severely ill, moribund or result in death. For most neoplasia if left beyond first detection but animals are killed within conventional limits (see Workman et al., British Journal of Cancer (2010) 102, pp 1555–1577). If animals show evidence of: weight loss; reduced weight gain compared with appropriate controls (for example, wild-type litter mates); impairment of feeding sufficient to reduce body weight; excessive body weight gain sufficient to induce disease; significant compromise of normal movement; or clinical evidence of systemic illness within the limits of the moderate severity classification (see separate Home Office document Advisory notes on recording and reporting the actual severity of regulated procedures).

The most common examples will be breeding of heterozygous animals that will result in severe phenotypes in homozygous offspring, including:
paralysis; seizures; fractures; or birth of living offspring with severe developmental abnormalities or expected pre-weaning death.
Breeding stock, or offspring, that are retained to a point where they show a disease phenotype in the severe category (see separate Home Office document Advisory notes on retrospective recording and reporting of actual severity of regulated procedures) will be classed as severe.
Any animals found dead on a breeding protocol, unless an informed decision (see separate Home Office document Advisory notes on recording and reporting the actual severity of regulated procedures) can be made that it is unlikely the death was preceded by severe suffering.

Offspring of rats and mice found dead or cannibalised after postnatal day five, or death of neonates in other species caused by aggressive maternal behaviour where offspring are well developed at birth (for example, pigs), where this is phenotype- and not husbandry-related. A husbandry-related cause of cannibalism would be facilities failure leading to stress in the parents, and therefore unrelated to that specific breeding programme.

Federal Food Safety and Veterinary Office FSVO (2018)

Genetically modified line (spontaneous mutation or genetically altered) used for animal experiments without an impaired phenotype and Genetically modified lines whose well-being is likely to be impaired not by the genetic modification but by the animal experiment.

Examples: Reporter lines such as EGFP-expressing lines. Conditional and non-induced inducible genetically modified lines.

Genetically modified line (spontaneous mutation or genetically altered) with a mildly impaired phenotype Examples: Deafness. Blindness. Dental abnormalities not affecting feed intake. Isolated gait abnormalities. Mild coordination disorders. Immunodecient animals in SPF housing.

Genetically modified lines (spontaneous mutation or genetically altered) with a moderately impaired phenotype.

Examples: Alzheimer's disease. Parkinson's disease.

Genetically modified lines (spontaneous mutation or genetically altered) with a severely impaired phenotype. Examples: Mammary carcinoma. Colitis. Osteoporosis. Kidney disease. Atherosclerosis. Ageing. Arthritis. Sceletal abnormalities. Motor restrictions. Acetylcholinesterase. Amyotrophic lateral sclerosis. Experimental allergic encephalomyelitis. Huntington’s chorea.

Working Group of Berlin Animal Welfare Officers (2010)*
* Since apart from the desired changes there can also be side-effects, the phenotype, with every line, is to be assessed comprehensively.

Phenotype does not differ from wild type.

Phenotype with mild disorders and mild clinical pictures, e.g. change in blood lipids.

Phenotype with moderate disorders and moderate clinical pictures, e.g. increase in aggression, anxiety.

Phenotype with severe disorders and severe clinical pictures, e.g. haemophilia.

 

More information on phenotypes and severity classification can be found in Guidelines on severity assessment and classification of genetically altered mice and rat lines.

GA animal model in the experiment

Source

Non-harmful / below threshold / severity degree 0 Mild / severity degree 1 Moderate / severity degree 2 Severe / severity degree 3
Federal Food Safety and Veterinary Office FSVO (2018)

Mutants (spontaneous mutation or genetically altered) without any clinically manifest diseases, disorders or abnormalities.

Mutants (spontaneous mutation or genetically altered) with mild clinically manifest diseases, disorders or abnormalities.

Examples: Immunodeficient mice in SPF housing. obese mouse without diabetes mellitus. Rats with hypertension.

Mutants (spontaneous mutation or genetically altered) with clinically manifest diseases and/or disorders which are compensated by means of appropriate therapeutic measures.

Examples: Obese mouse with diabetes mellitus. Muscular atrophy. Spontaneous diabetes mellitus.

Mutants (spontaneous mutation or genetically altered) with severe clinically manifest diseases or disorders without therapy to reduce constraint.

Examples: Autoimmune arthritis. Knockout animals with severe failure symptoms. Harlequin mouse with cardiovascular disorders. Amyotrophic lateral sclerosis. Fronto-temporal lobar degeneration.

 

Generation of GA animals

Source

Non-harmful / below threshold / severity degree 0 Mild / severity degree 1 Moderate / severity degree 2 Severe / severity degree 3
Directive 2010/63/EU, Annex VIII

    Creation of genetically altered animals through surgical procedures.  

 

Tissue sampling for genotyping

Source

Non-harmful / below threshold / severity degree 0 Mild / severity degree 1 Moderate / severity degree 2 Severe / severity degree 3
Directive 2010/63/EU, Annex VIII

  Superficial procedures, e.g. ear and tail biopsies.    
Home Office (2014 b)   Invasive genotyping carried out using a method that causes only transient pain, even if the phenotype is not harmful.    
Federal Food Safety and Veterinary Office FSVO (2018)

Experimental marking and genotyping using non-invasive methods.

Examples: Marking with dye. Genotyping by hair sample.

Experimental marking using invasive methods and tissue collection under anaesthesia for the genotyping of adult animals.

Examples: Tattooing. Ear punching, Microchips in rodents and rabbits. Experimental tail tip biopsy up to 0.5 cm. Toe tip amputation up to the age of 3 weeks.

Experimental interventions to regulate reproduction or for genotyping of adult animals.

Examples: Vasectomy. Castration.
 

 

This page was updated on 01 January 2021

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