Penetrance in
genetics
Genetics is the study of genes, genetic variation, and heredity in organisms.Hartl D, Jones E (2005) It is an important branch in biology because heredity is vital to organisms' evolution. Gregor Mendel, a Moravian Augustinian friar wor ...
is the proportion of individuals carrying a particular variant (or
allele
An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution.
::"The chro ...
) of a
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
(the
genotype
The genotype of an organism is its complete set of genetic material. Genotype can also be used to refer to the alleles or variants an individual carries in a particular gene or genetic location. The number of alleles an individual can have in a ...
) that also express an associated trait (the
phenotype
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...
). In
medical genetics
Medical genetics is the branch
tics in that human genetics is a field of scientific research that may or may not apply to medicine, while medical genetics refers to the application of genetics to medical care. For example, research on the caus ...
, 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 showin ...
s among all individuals with such mutation. For example, if a
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
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 effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
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 (NF) is a group of three conditions in which tumors grow in the nervous system. The three types are neurofibromatosis type I (NF1), neurofibromatosis type II (NF2), and schwannomatosis. In NF1 symptoms include light brown sp ...
– 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
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
,
dominance, and
co-dominance
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
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 that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...
due to mutations in the
BRCA1
Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the ''BRCA1'' () gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. ''BRCA1'' is a h ...
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 stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are "o ...
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 neoplasias, that affect the endocrine system through development of neoplastic lesions in pituitary, parathyroid gland and pancreas.
It was first d ...
, a hereditary disorder characterized by
parathyroid
Parathyroid glands are small 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 and secretes par ...
hyperplasia and
pancreatic
The pancreas is an Organ (anatomy), organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdominal cavity, abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine ...
islet-cell and
pituitary
In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The hypop ...
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 protein that in humans is encoded by the ''BRCA1'' () gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. ''BRCA1'' is a h ...
'' and ''
BRCA2
''BRCA2'' and BRCA2 () are a human gene and its protein product, respectively. The official symbol (BRCA2, italic for the gene, nonitalic for the protein) and the official name (originally breast cancer 2; currently BRCA2, DNA repair associated) ...
'' mutations, associated with an elevated risk of
breast
The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues.
In females, it serves as the mammary gland, which produces and secret ...
and
ovarian cancer
Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different c ...
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 genes that interact additively to influence a phenotypic trait, thus contributing to multiple-gene inheritance (polygenic inheritance, multigenic inheritance, quantitative inheritance), a type of ...
, 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 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 hemochromatosis (also spelled ''haemochromatosis'' in British English) indicates increased total accumulation of iron in the body from any cause and resulting organ damage. The most important causes are hereditary haemochromatosi ...
, 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, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
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 ...
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, sampling bias is a bias (statistics), bias in which a sample is collected in such a way that some members of the intended statistical population, population have a lower or higher sampling probability than others. It results in a bia ...
. 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 due to damage caused by liver disease. Damage causes tissue repai ...
.
Attributable risk
For alleles with incomplete penetrance, the penetrance of the allele is not the same as the
attributable risk In epidemiology, attributable risk or excess risk is a term synonymous to risk difference, that has also been used to denote attributable fraction among the exposed and attributable fraction for the population.
See also
* Population Impact Measure ...
. 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 stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are "o ...
expression. Only a statistical measure of association is possible with such
polygenic
A polygene is a member of a group of non-epistatic genes that interact additively to influence a phenotypic trait, thus contributing to multiple-gene inheritance (polygenic inheritance, multigenic inheritance, quantitative inheritance), a type of ...
traits.
See also
*
Expressivity
References
{{Reflist
External links
Tutorial about the different aspects of genetic penetrance.
Medical genetics