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Penetrance in
genetics Genetics is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, ...

genetics
is the proportion of individuals carrying a particular variant (or
allele An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is one of two, or more, forms of a given gene In biology, a gene (from ''genos'' "...Wilhelm Johannsen coined the word gene to describe the Mendelian_inheritance ...
) of a
gene In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mecha ...

gene
(the
genotype The genotype of an organism is its complete set of genetic material. Genotype can also be used to refer to the or variants an individual carries in a particular gene or genetic location. The number of alleles an individual can have in a specific ...
) that also express an associated trait (the
phenotype In genetics Genetics is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular inter ...

phenotype
). In
medical genetics Medical genetics is the branch of medicine Medicine is the science Science () is a systematic enterprise that builds and organizes knowledge Knowledge is a familiarity, awareness, or understanding of someone or something, such as ...
, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical
symptom Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality show ...
s among all individuals with such mutation. For example, if a
mutation In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mechan ...
in the gene responsible for a particular
autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The first ...

autosomal dominant
disorder has 95% penetrance, then 95% of those with the mutation will develop the disease, while 5% will not. A condition, most commonly inherited in an autosomal dominant manner, is said to show complete penetrance if clinical symptoms are present in all individuals who have the disease-causing mutation. A condition which shows complete penetrance is
neurofibromatosis type 1 Neurofibromatosis type I (NF-1) is a complex multi-system human disorder caused by the mutation of a gene In biology, a gene (from ''genos'' "...Wilhelm Johannsen coined the word gene to describe the Mendelian_inheritance#History, Mendeli ...
– every person who has a mutation in the gene will show symptoms of the condition. The penetrance is 100%. Common examples used to show degrees of penetrance are often highly penetrant. There are several reasons for this: *Highly penetrant alleles, and highly heritable symptoms, are easier to demonstrate, because if the allele is present, the phenotype is generally expressed. Mendelian genetic concepts such as recessiveness, dominance, and
co-dominance In genetics Genetics is a branch of biology concerned with the study of genes, genetic variation, and heredity in organisms.Hartl D, Jones E (2005) Though heredity had been observed for millennia, Gregor Mendel, Moravia, Moravian scientis ...
are fairly simple additions to this principle. *Alleles which are highly penetrant are more likely to be noticed by clinicians and geneticists, and alleles for symptoms which are highly heritable are more likely to be inferred to exist, and then are more easily tracked down.


Degrees

* Complete and incomplete or reduced penetrance: An allele is said to have complete penetrance if all individuals who have the disease-causing mutation have clinical symptoms of the disease. In incomplete or reduced penetrance, some individuals will not express the trait even though they carry the allele. An example of an autosomal dominant condition showing incomplete penetrance is familial
breast cancer Breast cancer is cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumor A benign tumor is a mass of cells Cell most o ...

breast cancer
due to mutations in the
BRCA1 Breast cancer type 1 susceptibility protein is a that in humans is encoded by the ''BRCA1'' () . s are common in other species, whereas genomes may encode a more distantly related gene. ''BRCA1'' is a human (also known as a ) and is responsi ...

BRCA1
gene. Females with a mutation in this gene have an 80% lifetime risk of developing breast cancer. The penetrance of the condition is therefore 80%. * High and low penetrance: If an allele is highly penetrant, then the trait it produces will almost always be apparent in an individual carrying the allele. An allele with low penetrance will only occasionally produce the trait with which it is associated. In cases of low penetrance, it can be difficult to distinguish environmental from genetic factors.


Determination

Penetrance can be difficult to determine reliably, even for genetic diseases that are caused by a single polymorphic allele. For many hereditary diseases, the onset of symptoms is age related, and is affected by environmental factors such as nutrition and smoking, as well as genetic cofactors and
epigenetic In biology, epigenetics is the study of heritability, heritable phenotype changes that do not involve alterations in the DNA sequence. The Ancient Greek, Greek prefix ''wikt:epi-, epi-'' ( "over, outside of, around") in ''epigenetics'' implies f ...
regulation of expression: * Age-related cumulative frequency: Penetrance is often expressed as a frequency of disease at different ages. For example,
multiple endocrine neoplasia type 1 Multiple endocrine neoplasia type 1 (MEN-1) is one of a group of disorders, the multiple endocrine neoplasia The term multiple endocrine neoplasia encompasses several distinct syndromes featuring Endocrine gland neoplasm, tumors of endocrine glan ...
, a hereditary disorder characterized by
parathyroid Parathyroid glands are small endocrine system, endocrine glands in the neck of humans and other tetrapods. Humans usually have four parathyroid glands, located on the back of the thyroid gland in variable locations. The parathyroid gland produces ...

parathyroid
hyperplasia and
pancreatic The pancreas is an organ of the digestive system The human digestive system consists of the human gastrointestinal tract, gastrointestinal tract plus the accessory organs of digestion (the tongue, salivary glands, pancreas, liver, and gallb ...
islet-cell and
pituitary In vertebrate Vertebrates () comprise all species of animal Animals (also called Metazoa) are multicellular eukaryotic organisms that form the Kingdom (biology), biological kingdom Animalia. With few exceptions, animals Hetero ...
adenomas, is caused by a mutation in the menin gene (''MEN1'') on human chromosome 11q13. In one study the age-related penetrance of ''MEN1'' was 7% by age 10 but nearly 100% by age 60. * Environmental modifiers: Penetrance may be affected by environmental factors. For example, several studies of ''
BRCA1 Breast cancer type 1 susceptibility protein is a that in humans is encoded by the ''BRCA1'' () . s are common in other species, whereas genomes may encode a more distantly related gene. ''BRCA1'' is a human (also known as a ) and is responsi ...

BRCA1
'' and ''
BRCA2 ''BRCA2'' and BRCA2 () are a human gene In biology, a gene (from ''genos'' "...Wilhelm Johannsen coined the word gene to describe the Mendelian_inheritance#History, Mendelian units of heredity..." (Greek language, Greek) meaning ' ...

BRCA2
'' mutations, associated with an elevated risk of
breast The breast is one of two prominences located on the upper ventral Standard anatomical terms of location deal unambiguously with the of s, including s. Terms used generally derive from or roots and used to describe something in its . Th ...

breast
and
ovarian cancer Ovarian cancer is a cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumor A benign tumor is a mass of cells Cell most ...
in women, have examined associations with environmental and behavioral modifiers such as pregnancies, history of breast feeding, smoking, diet, and so forth. * Genetic modifiers: Penetrance at a given allele may be
polygenic A polygene is a member of a group of non-epistatic gene In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, ...
, modified by the presence or absence of polymorphic alleles at other gene loci. Genome association studies may assess the influence of such variants on the penetrance of an allele. * Epigenetic regulation: Epigenetics can affect the penetrance of genes through
genomic imprinting #REDIRECT Genomic imprinting#REDIRECT Genomic imprinting Genomic imprinting is an epigenetic phenomenon that causes gene In biology, a gene (from ''genos'' "...Wilhelm Johannsen coined the word gene to describe the Mendelian_inheritance#His ...

genomic imprinting
by the paternal or maternal allele or epigenetic regulation resulting from environmental or other personal factors.


Ascertainment bias

A consensus definition of what constitutes the presence of a phenotype is essential for determining the penetrance of an allele. For hereditary
hemochromatosis Iron overload or haemochromatosis (also spelled ''hemochromatosis'' in American English American English (AmE, AE, AmEng, USEng, en-US), sometimes called United States English or U.S. English, is the set of variety (linguistics), varietie ...
, a disease caused by excess intestinal iron absorption, the degree of penetrance has been a subject of controversy for many years and illustrates the challenges facing investigators seeking a quantitative measure of penetrance. Individuals who are
homozygote Zygosity (the noun, zygote A zygote (from Greek ζυγωτός ''zygōtos'' "joined" or "yoked", from ζυγοῦν ''zygoun'' "to join" or "to yoke") is a eukaryotic cell formed by a fertilization event between two gamete A gamete ( /ˈ ...
s for the C282Y allele of the
HFE gene Human homeostatic iron regulator protein also known as the HFE protein (High FE2+) is a protein which in humans is encoded by the ''HFE'' gene. The ''HFE'' gene is located on short arm of chromosome 6 at location 6p22.2 Function The protein en ...
are at risk for developing lethal concentrations of iron, particularly in the liver. Typically patients develop clinical disease in late-middle age. Determining the penetrance of the C282Y allele can be influenced when the medical community evaluates homozygotes. Many of those afflicted do not seek treatment until symptoms are advanced, and with age-related conditions, some individuals die first of other causes. This dilemma is known as an
ascertainment bias In statistics Statistics is the discipline that concerns the collection, organization, analysis, interpretation, and presentation of data. In applying statistics to a scientific, industrial, or social problem, it is conventional to begin with ...
. There can be a bias favoring only the ascertainment of the most severely affected, or there can be a bias in the other direction, deeming that a homozygote is ''affected'' with the disease if they simply have elevated blood iron levels, but no physiological evidence of organ disease such as
cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis Fibrosis, also known as fibrotic scarring, is a pathological wo ...
.


Attributable risk

For alleles with incomplete penetrance, the penetrance of the allele is not the same as the
attributable riskIn epidemiology Epidemiology is the study and analysis of the distribution (who, when, and where), patterns and risk factor, determinants of health and disease conditions in defined populations. It is a cornerstone of public health, and shapes pol ...
. For example, many alleles have been shown, through association studies, to cause some form of cancer, often with low penetrance. But cases of the cancer would arise even without the presence of the allele. Attributable risk is that proportion of total risk that can be attributed to the presence of the allele.


Polygenic traits

Most biological traits (such as height or intelligence in humans) are multifactorial, influenced by many genes as well as environmental conditions and
epigenetic In biology, epigenetics is the study of heritability, heritable phenotype changes that do not involve alterations in the DNA sequence. The Ancient Greek, Greek prefix ''wikt:epi-, epi-'' ( "over, outside of, around") in ''epigenetics'' implies f ...
expression. Only a statistical measure of association is possible with such
polygenic A polygene is a member of a group of non-epistatic gene In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, ...
traits.


See also

* Expressivity


References

{{Reflist


External links


Tutorial about the different aspects of genetic penetrance.
Medical genetics