Autosomal dominance

'''Autosomal dominance in Genetics, describes a specific relationship between the effects of different versions of a gene (alleles) on a trait or phenotype. Animals (including humans) and plants are ‘diploid’ (see ploidy), with two copies of each gene, one inherited from each parent. If the two copies are not identical (not the same allele), their combined effect may be different than the effect of having two identical copies of one or the other allele. But if the combined effect is the same as the effect of having two copies of one of the alleles, we say that allele’s effect is dominant over the other.

For example, having two copies of one allele of the EYCL3 gene causes the eye’s iris to be brown, and having two copies of another allele causes the iris to be blue. But having one copy of each allele leads to a brown iris, thus the brown allele is said to be dominant over the blue allele (and the blue allele is said to be recessive to the brown allele).

We now know that in most cases a dominance relationship is seen when the recessive allele is defective. In these cases a single copy of the normal allele produces enough of the gene’s product to give the same effect as two normal copies, and so the normal allele is described as being dominant to the defective allele. This is the case for the eye color alleles described above, where a single functional copy of the ‘brown’ allele causes enough melanin to be made in the iris that the eyes appear brown even when paired with the non-melanin-producing ‘blue’ allele.

Dominance was discovered by Mendel, who introduced the use of uppercase letters to denote ‘dominant alleles’ and lowercase to denote ‘recessive alleles’, as is still commonly used in introductory genetics courses (e.g. B b for alleles causing brown and blue eyes). Although this usage is convenient it is misleading, because dominance is not a property of an allele considered in isolation but of a relationship between the effects of two alleles. When geneticists loosely refer to a dominant allele or a recessive allele, they mean that the allele is dominant or recessive to the standard allele.

Geneticists often use the term dominance in other contexts, distinguishing between simple or complete dominance as described above, and other relationships. Relationships described as incomplete or partial dominance are usually more accurately described as giving an intermediate or blended phenotype. The relationship described as codominance describes a relationship where the distinct phenotypes caused by each allele are both seen when both alleles are present.

Nomenclature
Genes are indicated in shorthand by a combination of one or a few letters - for example, in cat coat genetics the alleles Mc and mc (for "mackerel tabby") play a prominent role. Alleles producing dominant traits are denoted by initial capital letters; those that confer recessive traits are written with lowercase letters. The alleles present in a locus are usually separated by a slash; in the Mc - mc case, the dominant trait is the "mackerel-stripe" pattern, and the recessive one the "classic" or "oyster" tabby pattern, and thus a classical-pattern tabby cat would carry the alleles mc/mc, whereas a mackerel-stripe tabby would be either Mc/mc or Mc/Mc.

Relationship to other genetics concepts
Humans have 23 homologous chromosome pairs (22 pairs of autosomal chromosomes and two distinct sex chromosomes, X and Y). It is estimated that the human genome contains 20,000-25,000 genes "". Each chromosomal pair has the same genes, although it is generally unlikely that homologous genes from each parent will be identical in sequence. The specific variations possible for a single gene are called alleles: for a single eye-color gene, there may be a blue eye allele, a brown eye allele, a green eye allele, etc. Consequently, a child may inherit a blue eye allele from their mother and a brown eye allele from their father. The dominance relationships between the alleles control which traits are and are not expressed.

An example of an autosomal dominant human disorder is Huntington's disease, which is a neurological disorder resulting in impaired motor function. The mutant allele results in an abnormal protein, containing large repeats of the amino acid glutamine. This defective protein is toxic to neural tissue, resulting in the characteristic symptoms of the disease. Hence, one copy suffices to confer the disorder.

A list of human traits that follow a simple inheritance pattern can be found in human genetics. Humans have several genetic diseases, often but not always caused by recessive alleles.

Punnett square
The genetic combinations possible with simple dominance can be expressed by a diagram called a Punnett square. One parent's alleles are listed across the top and the other parent's alleles are listed down the left side. The interior squares represent possible offspring, in the ratio of their statistical probability. In the previous example of flower color, P represents the dominant purple-colored allele and p the recessive white-colored allele. If both parents are purple-colored and heterozygous (Pp), the Punnett square for their offspring would be:

In the PP and Pp cases, the offspring is purple colored due to the dominant P. Only in the pp case is there expression of the recessive white-colored phenotype. Therefore, the phenotypic ratio in this case is 3:1, meaning that F2 generation offspring will be purple-colored three times out of four, on average.

Dominant allele
Dominant trait refers to a genetic feature that hides the recessive trait in the phenotype of an individual. A dominant trait is a phenotype that is seen in both the homozygous AA and heterozygous Aa genotypes. Many traits are determined by pairs of complementary genes, each inherited from a single parent. Often when these are paired and compared, one allele (the dominant) will be found to effectively shut out the instructions from the other, recessive allele. For example, if a person has one allele for blood type A and one for blood type O, that person will always have blood type A. For a person to have blood type O, both their alleles must be O (recessive).

When an individual has two dominant alleles (AA), the condition is referred to as homozygous dominant; an individual with two recessive alleles (aa) is called homozygous recessive. An individual carrying one dominant and one recessive allele is referred to as heterozygous.

A dominant trait when written in a genotype is always written before the recessive gene in a heterozygous pair. A heterozygous genotype is written Aa, not aA.

Simple dominance or complete dominance
Consider the simple example of flower color in peas, first studied by Gregor Mendel. The dominant allele is purple and the recessive allele is white. In a given individual, the two corresponding alleles of the chromosome pair fall into one of three patterns:


 * both alleles purple (PP)
 * both alleles white (pp)
 * one allele purple and one allele white (Pp)

If the two alleles are the same (homozygous), the trait they represent will be expressed. But if the individual carries one of each allele (heterozygous), only the dominant one will be expressed. The recessive allele will simply be suppressed.

Simple dominance in pedigrees
Dominant traits are recognizable by the fact that they do not skip generations, as recessive traits do. It is therefore quite possible for two parents with purple flowers to have white flowers among their progeny, but two such white offspring could not have purple offspring (although very rarely, one might be produced by mutation). In this situation, the purple individuals in the first generation must have both been heterozygous (carrying one copy of each allele).

Incomplete dominance
Discovered by Karl Correns, incomplete dominance (sometimes called partial dominance) is a heterozygous genotype that creates an intermediate phenotype. In this case, only one allele (usually the wild type) at the single locus is expressed, and the expression is doseage dependent. Two copies of the gene produce full expression, while one copy of the gene produces partial expression in an intermediate phenotype. A cross of two intermediate phenotypes (= monohybrid heterozygotes) will result in the reappearance of both parent phenotypes and the intermediate phenotype. There is a 1:2:1 phenotype ratio instead of the 3:1 phenotype ratio found when one allele is dominant and the other is recessive. This lets an organism's genotype be diagnosed from its phenotype without time-consuming breeding tests.

The classic example of this is the color of carnations.

R is the allele for red pigment. R' is the allele for no pigment.

Thus, RR offspring make a lot of red pigment and appear red. R'R' offspring make no red pigment and appear white. Both RR' and R'R offspring make some pigment and therefore appear pink.

A readily visible example of incomplete dominance is the color modifier Merle in dogs.

Codominance
In codominance, neither phenotype is completely dominant. Instead, the heterozygous individual expresses both phenotypes. A common example is the ABO blood group system. The gene for blood types has three alleles: A, B, and i. i causes O type and is recessive to both A and B. The A and B alleles are codominant with each other. When a person has both an A and a B allele, the person has type AB blood.

When two persons with AB blood type have children, the children can be type A, type B, or type AB. There is a 1A:2AB:1B phenotype ratio instead of the 3:1 phenotype ratio found when one allele is dominant and the other is recessive. This is the same phenotype ratio found in matings of two organisms that are heterozygous for incomplete dominant alleles.

Example Punnett square for a father with A and i, and a mother with B and i:

Amongst the very few codominant genetic diseases in humans, one relatively common one is A1AD, in which the genotypes Pi00, PiZ0, PiZZ, and PiSZ all have their more-or-less characteristic clinical representations.

Most molecular markers are considered to be codominant.

A roan horse has codominant follicle genes, expressing individual red and white follicles.

Dominant negative
Most loss-of-function mutations are recessive. However, some are dominant and are called "dominant negative" or antimorphic mutations. Typically, a dominant negative mutation occurs when the gene product adversely affects the normal, wild-type gene product within the same cell. This usually occurs if the product can still interact with the same elements as the wild-type product, but block some aspect of its function. Such proteins may be competitive inhibitors of the normal protein functions.

Types:


 * A mutation in a transcription factor that removes the activation domain, but still contains the DNA binding domain. This product can then block the wild-type transcription factor from binding the DNA site leading to reduced levels of gene activation.
 * A protein that is functional as a dimer. A mutation that removes the functional domain, but retains the dimerization domain would cause a dominate negative phenotype, because some fraction of protein dimers would be missing one of the functional domains.

Autosomal dominant gene
An autosomal dominant gene is one that occurs on an autosomal (non-sex determining) chromosome. As it is dominant, the phenotype it gives will be expressed even if the gene is heterozygous. This contrasts with recessive genes, which need to be homozygous to be expressed.

The chances of an autosomal dominant disorder being inherited are 50% if one parent is heterozygous for the mutant gene and the other is homozygous for the normal, or 'wild-type', gene. This is because the offspring will always inherit a normal gene from the parent carrying the wild-type genes, and will have a 50% chance of inheriting the mutant gene from the other parent. If the mutant gene is inherited, the offspring will be heterozygous for the mutant gene, and will suffer from the disorder. If the parent with the disorder is homozygous for the gene, the offspring produced from mating with an unaffected parent will always have the disorder. See Mendelian inheritance.

The term vertical transmission refers to the concept that autosomal dominant disorders are inherited through generations. This is obvious when you examine the pedigree chart of a family for a particular trait. Because males and females are equally affected, they are equally likely to have affected children.

Although the mutated gene should be present in successive generations in which there are more than one or two offspring, it may appear that a generation is skipped if there is reduced penetrance.

Autosomal dominant disorders

 * Achondroplasia
 * Alexander disease
 * Antithrombin deficiency
 * Brugada syndrome
 * Charcot-Marie-Tooth Syndrome
 * Ectrodactyly
 * Cleft Chin
 * Ehlers-Danlos Syndrome
 * Familial hypercholesterolemia
 * Facioscapulohumeral muscular dystrophy
 * Fatal Familial Insomnia
 * Fibrodysplasia Ossificans Progressiva
 * FOXP2 Gene
 * Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu Syndrome)
 * Hereditary multiple exostoses
 * Hereditary spherocytosis
 * Huntington's Disease
 * Hypertrophic cardiomyopathy
 * Kabuki syndrome (potentially)
 * Lactase Persistence
 * Malignant hyperthermia
 * Mandibulofacial dysostosis (Treacher Collins syndrome)
 * Marfan Syndrome
 * Mowat-Wilson Syndrome
 * Multiple endocrine neoplasia
 * Neurofibromatosis
 * Osteogenesis Imperfecta
 * Pfeiffer syndrome
 * Polycystic Kidney Disease
 * Tuberous Sclerosis
 * Von Hippel-Lindau disease
 * Familial adenomatous polyposis
 * Noonan Syndrome

Recessive allele
The term "recessive allele" refers to an allele that causes a phenotype (visible or detectable characteristic) that is only seen in homozygous genotypes (organisms that have two copies of the same allele) and never in heterozygous genotypes. Every diploid organism, including humans, has two copies of every gene on autosomal chromosomes, one from the mother and one from the father. The dominant allele of a gene will always be expressed while the recessive allele of a gene will be expressed only if the organism has two recessive forms. Thus, if both parents are carriers of a recessive trait, there is a 25% chance with each child to show the recessive trait.

The term "recessive allele" is part of the laws of Mendelian inheritance formulated by Gregor Mendel. Examples of recessive traits in Mendel's famous pea plant experiments include the color and shape of seed pods and plant height.

Autosomal recessive allele


Autosomal recessive is a mode of inheritance of genetic traits located on the autosomes (the pairs of non-sex determining chromosomes - in humans 22).

In opposition to autosomal dominant trait, a recessive trait only becomes phenotypically apparent when two similar alleles of a gene are present. In other words, the subject is homozygous for the trait.

The frequency of the carrier state can be calculated by the Hardy-Weinberg formula: $$ p^2+2pq+q^2=1 $$ (p is the frequency of one pair of alleles, and q = 1 &minus; p is the frequency of the other pair of alleles.)

Recessive genetic disorders occur when both parents are carriers and each contributes an allele to the embryo, meaning these are not dominant genes. As both parents are heterozygous for the disorder, the chance of two disease alleles landing in one of their offspring is 25% (in autosomal dominant traits this is higher). 50% of the children (or 2/3 of the remaining ones) are carriers. When one of the parents is homozygous, the trait will only show in his/her offspring if the other parent is also a carrier. In that case, the chance of disease in the offspring is 50%.

Nomenclature of recessiveness
Technically, the term "recessive gene" is imprecise because it is not the gene that is recessive but the phenotype (or trait). It should also be noted that the concepts of recessiveness and dominance were developed before a molecular understanding of DNA and before molecular biology, thus mapping many newer concepts to "dominant" or "recessive" phenotypes is problematic. Many traits previously thought to be recessive have mild forms or biochemical abnormalities that arise from the presence of the one copy of the allele. This suggests that the dominant phenotype is dependent upon having two dominant alleles and the presence of one dominant and one recessive allele creates some blending of both dominant and recessive traits.

Pea Plant
Gregor Mendel performed many experiments on pea plant (Pisum sativum) while researching traits, chosen because of the simple and low variety of characteristics, as well as the short period of germination. He experimented with color (green vs. yellow), size (short vs. tall), pea texture (smooth vs. wrinkled), and many others. By good fortune, the characteristics displayed by these plants clearly exhibited a dominant and recessive form. This is not true for many organisms.

For example, when testing the color of the pea plants, he chose two yellow plants, since yellow was more common than green. He mated them, and examined the offspring. He continued to mate only those that appeared yellow, and eventually, the green ones would stop being produced. He also mated the green ones together and determined that only green ones were produced.

Mendel determined that this was because green was a recessive trait which only appeared when yellow, the dominant trait, was not present. Also, he determined that the dominant trait would be displayed whether or not the recessive trait was there.

Autosomal recessive disorders
Dominance/recessiveness refers to phenotype, not genotype. An example to prove the point is sickle cell anemia. The sickle cell genotype is caused by a single base pair change in the beta-globin gene: normal=GAG (glu), sickle=GTG (val). There are several phenotypes associated with the sickle genotype:-

This example demonstrates that one can only refer to dominance/recessiveness with respect to individual phenotypes.
 * 1) anemia (a recessive trait)
 * 2) blood cell sickling (co-dominant)
 * 3) altered beta-globin electrophoretic mobility (co-dominant)
 * 4) resistance to malaria (dominant)

Other recessive disorders: -


 * Cystic fibrosis
 * Tay-Sachs disease
 * Chronic granulomatous disease
 * Thalassemia
 * Bloom's Syndrome
 * Alpha 1-antitrypsin deficiency
 * Haemochromatosis types 1-3
 * Wilson's disease
 * Most types of Mucopolysaccharidosis
 * Most Glycogen storage diseases
 * Homocystinuria
 * Congenital adrenal hyperplasia
 * Dubin-Johnson syndrome
 * Fanconi anemia
 * Galactosemia
 * Glucose-6-phosphate dehydrogenase deficiency
 * Phenylketonuria
 * Albinism
 * Rotor syndrome
 * Familial Mediterranean fever
 * Pendred syndrome
 * Certain forms of Spinal muscular atrophy
 * Xeroderma pigmentosum
 * Friedreich's ataxia
 * Dry (otherwise known as "rice-bran") earwax

Mechanisms of dominance
Many genes code for enzymes. Consider the case where someone is homozygous for some trait. Both alleles code for the same enzyme, which causes a trait. Only a small amount of that enzyme may be necessary for a given phenotype. The individual therefore has a surplus of the necessary enzyme. Let's call this case "normal". Individuals without any functional copies cannot produce the enzyme at all, and their phenotype reflects that. Consider a heterozygous individual. Since only a small amount of the normal enzyme is needed, there is still enough enzyme to show the phenotype. This is why some alleles are dominant over others.

In the case of incomplete dominance, the single dominant allele does not produce enough enzyme, so the heterozygotes show some different phenotype. For example, fruit color in eggplants is inherited in this manner. A purple color is caused by two functional copies of the enzyme, with a white color resulting from two non-functional copies. With only one functional copy, there is not enough purple pigment, and the color of the fruit is a lighter shade, called violet.

Some non-normal alleles can be dominant. The mechanisms for this are varied, but one simple example is when the functional enzyme is composed of several subunits. In this case, if any of the subunits are nonfunctional, the entire enzyme is nonfunctional. In the case of a single subunit with a functional and nonfunctional allele (heterozygous individual), the concentration of functional enzymes is 50% of normal. If the enzyme has two identical subunits, the concentration of functional enzyme is 25% of normal. For four subunits, the concentration of functional enzyme is about 6% of normal. This may not be enough to produce the wild type phenotype. There are other mechanisms for dominant mutants.

Other factors
It is important to note that most genetic traits are not simply controlled by a single set of alleles. Often many alleles, each with their own dominance relationships, contribute in varying ways to complex traits.

Some medical conditions may have multiple inheritance patterns, such as in centronuclear myopathy or myotubular myopathy, where the autosomal dominant form is on chromosome 19 but the sex-linked form is on the X chromosome.