Haemophilia

From Wikipedia, the free encyclopedia

 

Haemophilia
Synonyms	Hemophilia
A drawing of clotting factor VIII
Pronunciation	/hiːməˈfɪliə/
Specialty	Haematology
Symptoms	Easy and prolonged bleeding
Usual onset	At birth
Causes	Usually genetic
Diagnostic method	Blood test
Prevention	Preimplantation screening
Treatment	Replace missing blood clotting factors
Frequency	1 in 7,500 males (haemophilia A), 1 in 40,000 males (haemophilia B)

Haemophilia, also spelt as hemophilia, is a mostly inherited genetic disorder that impairs the body's ability to make blood clots, a process needed to stop bleeding. This results in people bleeding longer after an injury, easy bruising, and an increased risk of bleeding inside joints or the brain. Those with a mild case of the disease may have symptoms only after an accident or during surgery. Bleeding into a joint can result in permanent damage while bleeding in the brain can result in long term headaches, seizures, or a decreased level of consciousness.

There are two main types of haemophilia: haemophilia A, which occurs due to not enough clotting factor VIII, and haemophilia B, which occurs due to not enough clotting factor IX. They are typically inherited from one's parents through an X chromosome with a nonfunctional gene. Rarely a new mutation may occur during early development or haemophilia may develop later in life due to antibodies forming against a clotting factor. Other types include haemophilia C, which occurs due to not enough factor XI, and parahaemophilia, which occurs due to not enough factor V. Acquired haemophilia is associated with cancers, autoimmune disorders, and pregnancy. Diagnosis is by testing the blood for its ability to clot and its levels of clotting factors.

Prevention may occur by removing an egg, fertilizing it, and testing the embryo before transferring it to the uterus. Treatment is by replacing the missing blood clotting factors. This may be done on a regular basis or during bleeding episodes. Replacement may take place at home or in hospital. The clotting factors are made either from human blood or by recombinant methods. Up to 20% of people develop antibodies to the clotting factors which makes treatment more difficult. The medication desmopressin may be used in those with mild haemophilia A. Studies of gene therapy are in early human trials.

Haemophilia A affects about 1 in 5,000–10,000, while haemophilia B affects about 1 in 40,000, males at birth. As haemophilia A and B are both X-linked recessive disorders, females are rarely severely affected. Some females with a nonfunctional gene on one of the X chromosomes may be mildly symptomatic. Haemophilia C occurs equally in both sexes and is mostly found in Ashkenazi Jews. In the 1800s haemophilia was common within the royal families of Europe. The difference between haemophilia A and B was determined in 1952. The word is from the Greek haima αἷμα meaning blood and philia φιλία meaning love.

Signs and symptoms

Characteristic symptoms vary with severity. In general symptoms are internal or external bleeding episodes, which are called "bleeds". People with more severe haemophilia suffer more severe and more frequent bleeds, while people with mild haemophilia usually suffer more minor symptoms except after surgery or serious trauma. In cases of moderate haemophilia symptoms are variable which manifest along a spectrum between severe and mild forms.

In both haemophilia A and B, there is spontaneous bleeding but a normal bleeding time, normal prothrombin time, normal thrombin time, but prolonged partial thromboplastin time. Internal bleeding is common in people with severe haemophilia and some individuals with moderate haemophilia. The most characteristic type of internal bleed is a joint bleed where blood enters into the joint spaces. This is most common with severe haemophiliacs and can occur spontaneously (without evident trauma). If not treated promptly, joint bleeds can lead to permanent joint damage and disfigurement. Bleeding into soft tissues such as muscles and subcutaneous tissues is less severe but can lead to damage and requires treatment.

Children with mild to moderate haemophilia may not have any signs or symptoms at birth especially if they do not undergo circumcision. Their first symptoms are often frequent and large bruises and haematomas from frequent bumps and falls as they learn to walk. Swelling and bruising from bleeding in the joints, soft tissue, and muscles may also occur. Children with mild haemophilia may not have noticeable symptoms for many years. Often, the first sign in very mild haemophiliacs is heavy bleeding from a dental procedure, an accident, or surgery. Females who are carriers usually have enough clotting factors from their one normal gene to prevent serious bleeding problems, though some may present as mild haemophiliacs.

Complications

Severe complications are much more common in cases of severe and moderate haemophilia. Complications may arise from the disease itself or from its treatment:

• Deep internal bleeding, e.g. deep-muscle bleeding, leading to swelling, numbness or pain of a limb.
• Joint damage from haemarthrosis (haemophilic arthropathy), potentially with severe pain, disfigurement, and even destruction of the joint and development of debilitating arthritis.
• Transfusion transmitted infection from blood transfusions that are given as treatment.
• Adverse reactions to clotting factor treatment, including the development of an immune inhibitor which renders factor replacement less effective.
• Intracranial haemorrhage is a serious medical emergency caused by the buildup of pressure inside the skull. It can cause disorientation, nausea, loss of consciousness, brain damage, and death.

Haemophilic arthropathy is characterized by chronic proliferative synovitis and cartilage destruction. If an intra-articular bleed is not drained early, it may cause apoptosis of chondrocytes and affect the synthesis of proteoglycans. The hypertrophied and fragile synovial lining while attempting to eliminate excessive blood may be more likely to easily rebleed, leading to a vicious cycle of hemarthrosis-synovitis-hemarthrosis. In addition, iron deposition in the synovium may induce an inflammatory response activating the immune system and stimulating angiogenesis, resulting in cartilage and bone destruction.

Genetics

X-linked recessive inheritance

Females possess two X-chromosomes, males have one X and one Y-chromosome. Since the mutations causing the disease are X-linked recessive, a female carrying the defect on one of her X-chromosomes may not be affected by it, as the equivalent allele on her other chromosome should express itself to produce the necessary clotting factors, due to X inactivation. However, the Y-chromosome in the male has no gene for factors VIII or IX. If the genes responsible for production of factor VIII or factor IX present on a male's X-chromosome are deficient there is no equivalent on the Y-chromosome to cancel it out, so the deficient gene is not masked and the disorder will develop.

Since a male receives his single X-chromosome from his mother, the son of a healthy female silently carrying the deficient gene will have a 50% chance of inheriting that gene from her and with it the disease; and if his mother is affected with haemophilia, he will have a 100% chance of being a haemophiliac. In contrast, for a female to inherit the disease, she must receive two deficient X-chromosomes, one from her mother and the other from her father (who must therefore be a haemophiliac himself). Hence, haemophilia is expressed far more commonly among males than females, while double-X females are far more likely to be silent carriers, survive childhood and to submit each of her genetic children to an at least 50% risk of receiving the deficient gene. However, it is possible for female carriers to become mild haemophiliacs due to lyonisation (inactivation) of the X-chromosomes. Haemophiliac daughters are more common than they once were, as improved treatments for the disease have allowed more haemophiliac males to survive to adulthood and become parents. Adult females may experience menorrhagia (heavy periods) due to the bleeding tendency. The pattern of inheritance is criss-cross type. This type of pattern is also seen in colour blindness.

A mother who is a carrier has a 50% chance of passing the faulty X-chromosome to her daughter, while an affected father will always pass on the affected gene to his daughters. A son cannot inherit the defective gene from his father. This is a recessive trait and can be passed on if cases are more severe with carrier. Genetic testing and genetic counselling is recommended for families with haemophilia. Prenatal testing, such as amniocentesis, is available to pregnant women who may be carriers of the condition.

As with all genetic disorders, it is of course also possible for a human to acquire it spontaneously through mutation, rather than inheriting it, because of a new mutation in one of their parents' gametes. Spontaneous mutations account for about 33% of all cases of haemophilia A. About 30% of cases of haemophilia B are the result of a spontaneous gene mutation.

If a female gives birth to a haemophiliac son, either the female is a carrier for the blood disorder or the haemophilia was the result of a spontaneous mutation. Until modern direct DNA testing, however, it was impossible to determine if a female with only healthy children was a carrier or not. Generally, the more healthy sons she bore, the higher the probability that she was not a carrier.
If a male is afflicted with the disease and has children with a female who is not a carrier, his daughters will be carriers of haemophilia. His sons, however, will not be affected with the disease. The disease is X-linked and the father cannot pass haemophilia through the Y-chromosome. Males with the disorder are then no more likely to pass on the gene to their children than carrier females, though all daughters they sire will be carriers and all sons they father will not have haemophilia (unless the mother is a carrier).

Severity

There are numerous different mutations which cause each type of haemophilia. Due to differences in changes to the genes involved, people with haemophilia often have some level of active clotting factor. Individuals with less than 1% active factor are classified as having severe haemophilia, those with 1-5% active factor have moderate haemophilia, and those with mild haemophilia have between 5-40% of normal levels of active clotting factor.

Diagnosis

Haemophilia can be diagnosed before, during or after birth if there is a family history of the condition. Several options are available to parents. If there is no family history of haemophilia, it is usually only diagnosed when a child begins to walk or crawl. They may experience joint bleeds or easy bruising.

Mild haemophilia may only be discovered later, usually after an injury or a dental or surgical procedure.

Before pregnancy

Genetic testing and counselling are available to help determine the risk of passing the condition onto a child. This may involve testing a sample of tissue or blood to look for signs of the genetic mutation that causes haemophilia.

During pregnancy

A pregnant woman with a history of haemophilia in her family can test for the haemophilia gene. Such tests include:

• chorionic villus sampling (CVS) – a small sample of the placenta is removed from the womb and tested for the haemophilia gene, usually during weeks 11-14 of pregnancy
• amniocentesis – a sample of amniotic fluid is taken for testing, usually during weeks 15-20 of pregnancy

There's a small risk of these procedures causing problems such as miscarriage or premature labour, so the woman may discuss this with the doctor in charge of her care.

After birth

If haemophilia is suspected after a child has been born, a blood test can usually confirm the diagnosis. Blood from the umbilical cord can be tested at birth if there's a family history of haemophilia. A blood test will also be able to identify whether a child has haemophilia A or B, and how severe it is.

Classification

There are several types of haemophilia: haemophilia A, haemophilia B, haemophilia C, parahaemophilia, and acquired haemophilia A.

Haemophilia A, is a recessive X-linked genetic disorder resulting in a deficiency of functional clotting Factor VIII. Haemophilia B, is also a recessive X-linked genetic disorder involving a lack of functional clotting Factor IX. Haemophilia C, is an autosomal genetic disorder involving a lack of functional clotting Factor XI. Haemophilia C is not completely recessive, as heterozygous individuals also show increased bleeding.

The type of haemophilia known as parahaemophilia is a mild and rare form and is due to a deficiency in factor V. This type can be inherited or acquired.

A non-genetic form of haemophilia is caused by autoantibodies against factor VIII and so is known as acquired haemophilia A. Acquired haemophilia can be associated with cancers, autoimmune disorders and following childbirth.

Management

There is no long-term cure. Treatment is by replacing the missing blood clotting factors.

Clotting factors

Commercially produced factor concentrates such as "Advate", a recombinant Factor VIII, come as a white powder in a vial which must be mixed with sterile water prior to intravenous injection.

Clotting factors are usually not needed in mild haemophilia. In moderate haemophilia clotting factors are typically only needed when bleeding occurs or to prevent bleeding with certain events. In severe haemophilia preventive use is often recommended two or three times a week and may continue for life. Rapid treatment of bleeding episodes decreases damage to the body.

Factor VIII is used in haemophilia A and factor IX in haemophilia B. Factor replacement can be either isolated from human blood serum, recombinant, or a combination of the two. Some people develop antibodies (inhibitors) against the replacement factors given to them, so the amount of the factor has to be increased or non-human replacement products must be given, such as porcine factor VIII.

If a person becomes refractory to replacement coagulation factor as a result of high levels of circulating inhibitors, this may be partially overcome with recombinant human factor VII.
In early 2008, the US Food and Drug Administration (FDA) approved anti-haemophilic factor, genetically engineered from the genes of Chinese hamster ovary cells. Since 1993 recombinant factor products (which are typically cultured in Chinese hamster ovary (CHO) tissue culture cells and involve little, if any human plasma products) have been available and have been widely used in wealthier western countries. While recombinant clotting factor products offer higher purity and safety, they are, like concentrate, extremely expensive, and not generally available in the developing world. In many cases, factor products of any sort are difficult to obtain in developing countries.

Clotting factors are either given preventively or on-demand. Preventive use involves the infusion of clotting factor on a regular schedule in order to keep clotting levels sufficiently high to prevent spontaneous bleeding episodes. On-demand (or episodic) treatment involves treating bleeding episodes once they arise. In 2007, a trial comparing on-demand treatment of boys (< 30 months) with haemophilia A with prophylactic treatment (infusions of 25 IU/kg body weight of Factor VIII every other day) in respect to its effect on the prevention of joint-diseases. When the boys reached 6 years of age, 93% of those in the prophylaxis group and 55% of those in the episodic-therapy group had a normal index joint-structure on MRI. Prophylactic treatment, however, resulted in average costs of $300,000 per year. The author of an editorial published in the same issue of the NEJM supports the idea that prophylactic treatment not only is more effective than on demand treatment but also suggests that starting after the first serious joint-related haemorrhage may be more cost effective than waiting until the fixed age to begin.

Other

Desmopressin (DDAVP) may be used in those with mild haemophilia A. Tranexamic acid or epsilon aminocaproic acid may be given along with clotting factors to prevent breakdown of clots.

Pain medicines, steroids, and physical therapy may be used to reduce pain and swelling in an affected joint.

Contraindications

Anticoagulants such as heparin and warfarin are contraindicated for people with haemophilia as these can aggravate clotting difficulties. Also contraindicated are those drugs which have "blood thinning" side effects. For instance, medicines which contain aspirin, ibuprofen, or naproxen sodium should not be taken because they are well known to have the side effect of prolonged bleeding.

Also contraindicated are activities with a high likelihood of trauma, such as motorcycling and skateboarding. Popular sports with very high rates of physical contact and injuries such as American football, hockey, boxing, wrestling, and rugby should be avoided by people with haemophilia. Other active sports like soccer, baseball, and basketball also have a high rate of injuries, but have overall less contact and should be undertaken cautiously and only in consultation with a doctor.

Prognosis

Like most aspects of the disorder, life expectancy varies with severity and adequate treatment. People with severe haemophilia who don't receive adequate, modern treatment have greatly shortened lifespans and often do not reach maturity. Prior to the 1960s when effective treatment became available, average life expectancy was only 11 years. By the 1980s the life span of the average haemophiliac receiving appropriate treatment was 50–60 years. Today with appropriate treatment, males with haemophilia typically have a near normal quality of life with an average lifespan approximately 10 years shorter than an unaffected male.

Since the 1980s the primary leading cause of death of people with severe haemophilia has shifted from haemorrhage to HIV/AIDS acquired through treatment with contaminated blood products. The second leading cause of death related to severe haemophilia complications is intracranial haemorrhage which today accounts for one third of all deaths of people with haemophilia. Two other major causes of death include hepatitis infections causing cirrhosis and obstruction of air or blood flow due to soft tissue haemorrhage.

Epidemiology

Haemophilia is rare, with only about 1 instance in every 10,000 births (or 1 in 5,000 male births) for haemophilia A and 1 in 50,000 births for haemophilia B. About 18,000 people in the United States have haemophilia. Each year in the US, about 400 babies are born with the disorder. Haemophilia usually occurs in males and less often in females. It is estimated that about 2500 Canadians have haemophilia A, and about 500 Canadians have haemophilia B.

History

"About seventy or eighty years ago, a woman by name of Smith, settled in the vicinity of Plymouth, New Hampshire, and transmitted the following idiosyncrasy to her descendants. It is one, she observed, to which her family is unfortunately subject, and had been the source not only of great solicitude, but frequently the cause of death. If the least scratch is made on the skin of some of them, as mortal a hemorrhagy will eventually ensue as if the largest wound is inflicted. (…) So assured are the members of this family of the terrible consequences of the least wound, that they will not suffer themselves to be bled on any consideration, having lost a relation by not being able to stop the discharge occasioned by this operation."

 

John C. Otto, 1803

Scientific discovery

The first medical professional to describe the disease was Abulcasis. In the tenth century he described families whose males died of bleeding after only minor traumas. While many other such descriptive and practical references to the disease appear throughout historical writings, scientific analysis did not begin until the start of the nineteenth century.

In 1803, John Conrad Otto, a Philadelphian physician, wrote an account about "a hemorrhagic disposition existing in certain families" in which he called the affected males "bleeders". He recognised that the disorder was hereditary and that it affected mostly males and was passed down by healthy females. His paper was the second paper to describe important characteristics of an X-linked genetic disorder (the first paper being a description of colour blindness by John Dalton who studied his own family). Otto was able to trace the disease back to a woman who settled near Plymouth, NH in 1720. The idea that affected males could pass the trait onto their unaffected daughters was not described until 1813 when John F. Hay, published an account in The New England Journal of Medicine.

In 1924, a Finnish doctor discovered a hereditary bleeding disorder similar to haemophilia localised in the Åland Islands, southwest of Finland. This bleeding disorder is called "Von Willebrand Disease".

The term "haemophilia" is derived from the term "haemorrhaphilia" which was used in a description of the condition written by Friedrich Hopff in 1828, while he was a student at the University of Zurich. In 1937, Patek and Taylor, two doctors from Harvard, discovered anti-haemophilic globulin. In 1947, Pavlosky, a doctor from Buenos Aires, found haemophilia A and haemophilia B to be separate diseases by doing a lab test. This test was done by transferring the blood of one haemophiliac to another haemophiliac. The fact that this corrected the clotting problem showed that there was more than one form of haemophilia.

European royalty

Queen Victoria passed haemophilia on to many of her descendants.

Haemophilia has featured prominently in European royalty and thus is sometimes known as 'the royal disease'. Queen Victoria passed the mutation for haemophilia B to her son Leopold and, through two of her daughters, Alice and Beatrice, to various royals across the continent, including the royal families of Spain, Germany, and Russia. In Russia, Tsarevich Alexei, the son and heir of Tsar Nicholas II, famously suffered from haemophilia, which he had gotten from his mother, Empress Alexandra, one of Queen Victoria's granddaughters. The haemophilia of Alexei would result in the rise to prominence of the Russian mystic Grigori Rasputin, at the imperial court.

It was claimed that Rasputin was successful at treating Tsarevich Alexei's haemophilia. At the time, a common treatment administered by professional doctors was to use aspirin, which worsened rather than lessened the problem. It is believed that, by simply advising against the medical treatment, Rasputin could bring visible and significant improvement to the condition of Tsarevich Alexei.

In Spain, Queen Victoria's youngest daughter, Princess Beatrice, had a daughter Victoria Eugenie of Battenberg, who later became Queen of Spain. Two of her sons were haemophiliacs and both died from minor car accidents. Her eldest son, Prince Alfonso of Spain, Prince of Asturias, died at the age of 31 from internal bleeding after his car hit a telephone booth. Her youngest son, Infante Gonzalo, died at age 19 from abdominal bleeding following a minor car accident in which he and his sister hit a wall while avoiding a cyclist. Neither appeared injured or sought immediate medical care and Gonzalo died two days later from internal bleeding.

Blood contamination issues

Ryan White was an American haemophiliac who became infected with HIV/AIDS through contaminated blood products.

Up until late-1985 many people with haemophilia received clotting factor products that posed a risk of HIV and hepatitis C infection, the plasma used to create the products was not screened or tested, neither had most of the products been subject to any form of viral inactivation.

Tens of thousands worldwide were infected as a result of contaminated factor products including more than 10,000 people in the United States, 3,500 British, 1,400 Japanese, 700 Canadians, 250 Irish, and 115 Iraqis.

Infection via the tainted factor products had mostly stopped by 1986 by which time viral inactivation methods had largely been put into place, although some products were shown to still be dangerous in 1987.

Research

Gene therapy

In those with severe haemophilia, gene therapy may reduce symptoms to those that a mild or moderate person with haemophilia might have. The best results have been found in haemophilia B. In 2016 early stage human research was ongoing with a few sites recruiting participants. In 2017 a gene therapy trial on nine people with haemophilia A reported that high doses did better than low doses. It is not currently an accepted treatment for haemophilia.

Mutation

From Wikipedia, the free encyclopedia

A tulip flower exhibiting a partially yellow petal because of a mutation in its genes.

In biology, a mutation is the permanent alteration of the nucleotide sequence of the genome of an organism, virus, or extrachromosomal DNA or other genetic elements.

Mutations result from errors during DNA replication (especially during meiosis) or other types of damage to DNA (such as may be caused by exposure to radiation or carcinogens), which then may undergo error-prone repair (especially microhomology-mediated end joining), or cause an error during other forms of repair, or else may cause an error during replication (translesion synthesis). Mutations may also result from insertion or deletion of segments of DNA due to mobile genetic elements. Mutations may or may not produce discernible changes in the observable characteristics (phenotype) of an organism. Mutations play a part in both normal and abnormal biological processes including: evolution, cancer, and the development of the immune system, including junctional diversity.

The genomes of RNA viruses are based on RNA rather than DNA. The RNA viral genome can be double stranded (as in DNA) or single stranded. In some of these viruses (such as the single stranded human immunodeficiency virus) replication occurs quickly and there are no mechanisms to check the genome for accuracy. This error-prone process often results in mutations.

Mutation can result in many different types of change in sequences. Mutations in genes can either have no effect, alter the product of a gene, or prevent the gene from functioning properly or completely. Mutations can also occur in nongenic regions. One study on genetic variations between different species of Drosophila suggests that, if a mutation changes a protein produced by a gene, the result is likely to be harmful, with an estimated 70 percent of amino acid polymorphisms that have damaging effects, and the remainder being either neutral or marginally beneficial. Due to the damaging effects that mutations can have on genes, organisms have mechanisms such as DNA repair to prevent or correct mutations by reverting the mutated sequence back to its original state.

Description

Mutations can involve the duplication of large sections of DNA, usually through genetic recombination. These duplications are a major source of raw material for evolving new genes, with tens to hundreds of genes duplicated in animal genomes every million years. Most genes belong to larger gene families of shared ancestry, known as homology. Novel genes are produced by several methods, commonly through the duplication and mutation of an ancestral gene, or by recombining parts of different genes to form new combinations with new functions.

Here, protein domains act as modules, each with a particular and independent function, that can be mixed together to produce genes encoding new proteins with novel properties. For example, the human eye uses four genes to make structures that sense light: three for cone cell or color vision and one for rod cell or night vision; all four arose from a single ancestral gene. Another advantage of duplicating a gene (or even an entire genome) is that this increases engineering redundancy; this allows one gene in the pair to acquire a new function while the other copy performs the original function. Other types of mutation occasionally create new genes from previously noncoding DNA.

Changes in chromosome number may involve even larger mutations, where segments of the DNA within chromosomes break and then rearrange. For example, in the Homininae, two chromosomes fused to produce human chromosome 2; this fusion did not occur in the lineage of the other apes, and they retain these separate chromosomes. In evolution, the most important role of such chromosomal rearrangements may be to accelerate the divergence of a population into new species by making populations less likely to interbreed, thereby preserving genetic differences between these populations.

Sequences of DNA that can move about the genome, such as transposons, make up a major fraction of the genetic material of plants and animals, and may have been important in the evolution of genomes. For example, more than a million copies of the Alu sequence are present in the human genome, and these sequences have now been recruited to perform functions such as regulating gene expression. Another effect of these mobile DNA sequences is that when they move within a genome, they can mutate or delete existing genes and thereby produce genetic diversity.

Nonlethal mutations accumulate within the gene pool and increase the amount of genetic variation. The abundance of some genetic changes within the gene pool can be reduced by natural selection, while other "more favorable" mutations may accumulate and result in adaptive changes.

Prodryas persephone, a Late Eocene butterfly

For example, a butterfly may produce offspring with new mutations. The majority of these mutations will have no effect; but one might change the color of one of the butterfly's offspring, making it harder (or easier) for predators to see. If this color change is advantageous, the chances of this butterfly's surviving and producing its own offspring are a little better, and over time the number of butterflies with this mutation may form a larger percentage of the population.

Neutral mutations are defined as mutations whose effects do not influence the fitness of an individual. These can increase in frequency over time due to genetic drift. It is believed that the overwhelming majority of mutations have no significant effect on an organism's fitness. Also, DNA repair mechanisms are able to mend most changes before they become permanent mutations, and many organisms have mechanisms for eliminating otherwise-permanently mutated somatic cells.

Beneficial mutations can improve reproductive success.

History

Hugo de Vries, making a painting of an evening primrose, the plant which had apparently produced new forms by large mutations in his experiments, by Thérèse Schwartze, 1918

Mutationism is one of several alternatives to evolution by natural selection that have existed both before and after the publication of Charles Darwin's 1859 book, On the Origin of Species. In the theory, mutation was the source of novelty, creating new forms and new species, potentially instantaneously, in a sudden jump. This was envisaged as driving evolution, which was limited by the supply of mutations.

Before Darwin, biologists commonly believed in saltationism, the possibility of large evolutionary jumps, including immediate speciation. For example, in 1822 Étienne Geoffroy Saint-Hilaire argued that species could be formed by sudden transformations, or what would later be called macromutation. Darwin opposed saltation, insisting on gradualism in evolution as in geology. In 1864, Albert von Kölliker revived Geoffroy's theory. In 1901 the geneticist Hugo de Vries gave the name "mutation" to seemingly new forms that suddenly arose in his experiments on the evening primrose Oenothera lamarckiana, and in the first decade of the 20th century, mutationism, or as de Vries named it mutationstheorie, became a rival to Darwinism supported for a while by geneticists including William Bateson, Thomas Hunt Morgan, and Reginald Punnett.

Understanding of mutationism is clouded by the mid-20th century portrayal of the early mutationists by supporters of the modern synthesis as opponents of Darwinian evolution and rivals of the biometrics school who argued that selection operated on continuous variation. In this portrayal, mutationism was defeated by a synthesis of genetics and natural selection that supposedly started later, around 1918, with work by the mathematician Ronald Fisher. However, the alignment of Mendelian genetics and natural selection began as early as 1902 with a paper by Udny Yule, and built up with theoretical and experimental work in Europe and America. Despite the controversy, the early mutationists had by 1918 already accepted natural selection and explained continuous variation as the result of multiple genes acting on the same characteristic, such as height.

Mutationism, along with other alternatives to Darwinism like Lamarckism and orthogenesis, was discarded by most biologists as they came to see that Mendelian genetics and natural selection could readily work together; mutation took its place as a source of the genetic variation essential for natural selection to work on. However, mutationism did not entirely vanish. In 1940, Richard Goldschmidt again argued for single-step speciation by macromutation, describing the organisms thus produced as "hopeful monsters", earning widespread ridicule. In 1987, Masatoshi Nei argued controversially that evolution was often mutation-limited. Modern biologists such as Douglas J. Futuyma conclude that essentially all claims of evolution driven by large mutations can be explained by Darwinian evolution.

Causes

Four classes of mutations are (1) spontaneous mutations (molecular decay), (2) mutations due to error-prone replication bypass of naturally occurring DNA damage (also called error-prone translesion synthesis), (3) errors introduced during DNA repair, and (4) induced mutations caused by mutagens. Scientists may also deliberately introduce mutant sequences through DNA manipulation for the sake of scientific experimentation.

One 2017 study claimed that 66% of cancer-causing mutations are random, 29% are due to the environment (the studied population spanned 69 countries), and 5% are inherited.

Humans on average pass 60 new mutations to their children but fathers pass more mutations depending on their age with every year adding two new mutations to a child.

Spontaneous mutation

Spontaneous mutations occur with non-zero probability even given a healthy, uncontaminated cell. They can be characterized by the specific change:

• Tautomerism — A base is changed by the repositioning of a hydrogen atom, altering the hydrogen bonding pattern of that base, resulting in incorrect base pairing during replication.
• Depurination — Loss of a purine base (A or G) to form an apurinic site (AP site).
• Deamination — Hydrolysis changes a normal base to an atypical base containing a keto group in place of the original amine group. Examples include C → U and A → HX (hypoxanthine), which can be corrected by DNA repair mechanisms; and 5MeC (5-methylcytosine) → T, which is less likely to be detected as a mutation because thymine is a normal DNA base.
• Slipped strand mispairing — Denaturation of the new strand from the template during replication, followed by renaturation in a different spot ("slipping"). This can lead to insertions or deletions.
• Replication slippage

Error-prone replication bypass

There is increasing evidence that the majority of spontaneously arising mutations are due to error-prone replication (translesion synthesis) past DNA damage in the template strand. Naturally occurring oxidative DNA damages arise at least 10,000 times per cell per day in humans and 50,000 times or more per cell per day in rats. In mice, the majority of mutations are caused by translesion synthesis. Likewise, in yeast, Kunz et al. found that more than 60% of the spontaneous single base pair substitutions and deletions were caused by translation synthesis.

Errors introduced during DNA repair

Although naturally occurring double-strand breaks occur at a relatively low frequency in DNA, their repair often causes mutation. Non-homologous end joining (NHEJ) is a major pathway for repairing double-strand breaks. NHEJ involves removal of a few nucleotides to allow somewhat inaccurate alignment of the two ends for rejoining followed by addition of nucleotides to fill in gaps. As a consequence, NHEJ often introduces mutations.

A covalent adduct between the metabolite of benzo[a]pyrene, the major mutagen in tobacco smoke, and DNA

Induced mutation

Induced mutations are alterations in the gene after it has come in contact with mutagens and environmental causes.

Induced mutations on the molecular level can be caused by:

• Chemicals
  • Hydroxylamine
  • Base analogs (e.g., Bromodeoxyuridine (BrdU))
  • Alkylating agents (e.g., N-ethyl-N-nitrosourea (ENU)). These agents can mutate both replicating and non-replicating DNA. In contrast, a base analog can mutate the DNA only when the analog is incorporated in replicating the DNA. Each of these classes of chemical mutagens has certain effects that then lead to transitions, transversions, or deletions.
  • Agents that form DNA adducts (e.g., ochratoxin A)
  • DNA intercalating agents (e.g., ethidium bromide)
  • DNA crosslinkers
  • 

• • This figure depicts the following processes of transcription, splicing, and translation of a eukaryotic gene.
    Oxidative damage
  • Nitrous acid converts amine groups on A and C to diazo groups, altering their hydrogen bonding patterns, which leads to incorrect base pairing during replication.
• Radiation
  • Ultraviolet light (UV) (non-ionizing radiation). Two nucleotide bases in DNA—cytosine and thymine—are most vulnerable to radiation that can change their properties. UV light can induce adjacent pyrimidine bases in a DNA strand to become covalently joined as a pyrimidine dimer. UV radiation, in particular longer-wave UVA, can also cause oxidative damage to DNA.
  • Ionizing radiation. Exposure to ionizing radiation, such as gamma radiation, can result in mutation, possibly resulting in cancer or death.

Classification of types

By effect on structure

Five types of chromosomal mutations.

 

Selection of disease-causing mutations, in a standard table of the genetic code of amino acids.

 

The sequence of a gene can be altered in a number of ways. Gene mutations have varying effects on health depending on where they occur and whether they alter the function of essential proteins. Mutations in the structure of genes can be classified into several types.

Small-scale mutations

Small-scale mutations affect a gene in one or a few nucleotides. (If only a single nucleotide is affected, they are called point mutations.) Small-scale mutations include:

• Insertions add one or more extra nucleotides into the DNA. They are usually caused by transposable elements, or errors during replication of repeating elements. Insertions in the coding region of a gene may alter splicing of the mRNA (splice site mutation), or cause a shift in the reading frame (frameshift), both of which can significantly alter the gene product. Insertions can be reversed by excision of the transposable element.
• Deletions remove one or more nucleotides from the DNA. Like insertions, these mutations can alter the reading frame of the gene. In general, they are irreversible: Though exactly the same sequence might in theory be restored by an insertion, transposable elements able to revert a very short deletion (say 1–2 bases) in any location either are highly unlikely to exist or do not exist at all.
• Substitution mutations, often caused by chemicals or malfunction of DNA replication, exchange a single nucleotide for another. These changes are classified as transitions or transversions. Most common is the transition that exchanges a purine for a purine (A ↔ G) or a pyrimidine for a pyrimidine, (C ↔ T). A transition can be caused by nitrous acid, base mis-pairing, or mutagenic base analogs such as BrdU. Less common is a transversion, which exchanges a purine for a pyrimidine or a pyrimidine for a purine (C/T ↔ A/G). An example of a transversion is the conversion of adenine (A) into a cytosine (C). A point mutation are modifications of single base pairs of DNA or other small base pairs within a gene. A point mutation can be reversed by another point mutation, in which the nucleotide is changed back to its original state (true reversion) or by second-site reversion (a complementary mutation elsewhere that results in regained gene functionality). As discussed below, point mutations that occur within the protein coding region of a gene may be classified as synonymous or nonsynonymous substitutions, the latter of which in turn can be divided into missense or nonsense mutations.

Large-scale mutations

Large-scale mutations in chromosomal structure include:

• Amplifications (or gene duplications) leading to multiple copies of all chromosomal regions, increasing the dosage of the genes located within them.
• Deletions of large chromosomal regions, leading to loss of the genes within those regions.
• Mutations whose effect is to juxtapose previously separate pieces of DNA, potentially bringing together separate genes to form functionally distinct fusion genes (e.g., bcr-abl).
• Large scale changes to the structure of chromosomes called chromosomal rearrangement that can lead to a decrease of fitness but also to speciation in isolated, inbred populations. These include:
  • Chromosomal translocations: interchange of genetic parts from nonhomologous chromosomes.
  • Chromosomal inversions: reversing the orientation of a chromosomal segment.
  • Non-homologous chromosomal crossover.
  • Interstitial deletions: an intra-chromosomal deletion that removes a segment of DNA from a single chromosome, thereby apposing previously distant genes. For example, cells isolated from a human astrocytoma, a type of brain tumor, were found to have a chromosomal deletion removing sequences between the Fused in Glioblastoma (FIG) gene and the receptor tyrosine kinase (ROS), producing a fusion protein (FIG-ROS). The abnormal FIG-ROS fusion protein has constitutively active kinase activity that causes oncogenic transformation (a transformation from normal cells to cancer cells).
• Loss of heterozygosity: loss of one allele, either by a deletion or a genetic recombination event, in an organism that previously had two different alleles.

By effect on function

• Loss-of-function mutations, also called inactivating mutations, result in the gene product having less or no function (being partially or wholly inactivated). When the allele has a complete loss of function (null allele), it is often called an amorph or amorphic mutation in the Muller's morphs schema. Phenotypes associated with such mutations are most often recessive. Exceptions are when the organism is haploid, or when the reduced dosage of a normal gene product is not enough for a normal phenotype (this is called haploinsufficiency).
• Gain-of-function mutations, also called activating mutations, change the gene product such that its effect gets stronger (enhanced activation) or even is superseded by a different and abnormal function. When the new allele is created, a heterozygote containing the newly created allele as well as the original will express the new allele; genetically this defines the mutations as dominant phenotypes. Several of Muller's morphs correspond to gain of function, including hypermorph and neomorph. In December 2017, the U.S. government lifted a temporary ban implemented in 2014 that banned federal funding for any new "gain-of-function" experiments that enhance pathogens "such as Avian influenza, SARS and the Middle East Respiratory Syndrome or MERS viruses."
• Dominant negative mutations (also called antimorphic mutations) have an altered gene product that acts antagonistically to the wild-type allele. These mutations usually result in an altered molecular function (often inactive) and are characterized by a dominant or semi-dominant phenotype. In humans, dominant negative mutations have been implicated in cancer (e.g., mutations in genes p53, ATM, CEBPA and PPARgamma). Marfan syndrome is caused by mutations in the FBN1 gene, located on chromosome 15, which encodes fibrillin-1, a glycoprotein component of the extracellular matrix. Marfan syndrome is also an example of dominant negative mutation and haploinsufficiency.
• Hypomorphs, after Mullerian classification, are characterized by altered gene products that acts with decreased gene expression compared to the wild type allele.
• Neomorphs are characterized by the control of new protein product synthesis.
• Lethal mutations are mutations that lead to the death of the organisms that carry the mutations.
• A back mutation or reversion is a point mutation that restores the original sequence and hence the original phenotype.

By effect on fitness

In applied genetics, it is usual to speak of mutations as either harmful or beneficial.

• A harmful, or deleterious, mutation decreases the fitness of the organism.
• A beneficial, or advantageous mutation increases the fitness of the organism. Mutations that promotes traits that are desirable, are also called beneficial. In theoretical population genetics, it is more usual to speak of mutations as deleterious or advantageous than harmful or beneficial.
• A neutral mutation has no harmful or beneficial effect on the organism. Such mutations occur at a steady rate, forming the basis for the molecular clock. In the neutral theory of molecular evolution, neutral mutations provide genetic drift as the basis for most variation at the molecular level.
• A nearly neutral mutation is a mutation that may be slightly deleterious or advantageous, although most nearly neutral mutations are slightly deleterious.

Distribution of fitness effects

Attempts have been made to infer the distribution of fitness effects (DFE) using mutagenesis experiments and theoretical models applied to molecular sequence data. DFE, as used to determine the relative abundance of different types of mutations (i.e., strongly deleterious, nearly neutral or advantageous), is relevant to many evolutionary questions, such as the maintenance of genetic variation, the rate of genomic decay, the maintenance of outcrossing sexual reproduction as opposed to inbreeding and the evolution of sex and genetic recombination. In summary, the DFE plays an important role in predicting evolutionary dynamics. A variety of approaches have been used to study the DFE, including theoretical, experimental and analytical methods.

• Mutagenesis experiment: The direct method to investigate the DFE is to induce mutations and then measure the mutational fitness effects, which has already been done in viruses, bacteria, yeast, and Drosophila. For example, most studies of the DFE in viruses used site-directed mutagenesis to create point mutations and measure relative fitness of each mutant. In Escherichia coli, one study used transposon mutagenesis to directly measure the fitness of a random insertion of a derivative of Tn10. In yeast, a combined mutagenesis and deep sequencing approach has been developed to generate high-quality systematic mutant libraries and measure fitness in high throughput. However, given that many mutations have effects too small to be detected and that mutagenesis experiments can detect only mutations of moderately large effect; DNA sequence data analysis can provide valuable information about these mutations.

The distribution of fitness effects (DFE) of mutations in vesicular stomatitis virus. In this experiment, random mutations were introduced into the virus by site-directed mutagenesis, and the fitness of each mutant was compared with the ancestral type. A fitness of zero, less than one, one, more than one, respectively, indicates that mutations are lethal, deleterious, neutral, and advantageous.

• Molecular sequence analysis: With rapid development of DNA sequencing technology, an enormous amount of DNA sequence data is available and even more is forthcoming in the future. Various methods have been developed to infer the DFE from DNA sequence data. By examining DNA sequence differences within and between species, we are able to infer various characteristics of the DFE for neutral, deleterious and advantageous mutations. To be specific, the DNA sequence analysis approach allows us to estimate the effects of mutations with very small effects, which are hardly detectable through mutagenesis experiments.

One of the earliest theoretical studies of the distribution of fitness effects was done by Motoo Kimura, an influential theoretical population geneticist. His neutral theory of molecular evolution proposes that most novel mutations will be highly deleterious, with a small fraction being neutral. Hiroshi Akashi more recently proposed a bimodal model for the DFE, with modes centered around highly deleterious and neutral mutations. Both theories agree that the vast majority of novel mutations are neutral or deleterious and that advantageous mutations are rare, which has been supported by experimental results. One example is a study done on the DFE of random mutations in vesicular stomatitis virus. Out of all mutations, 39.6% were lethal, 31.2% were non-lethal deleterious, and 27.1% were neutral. Another example comes from a high throughput mutagenesis experiment with yeast. In this experiment it was shown that the overall DFE is bimodal, with a cluster of neutral mutations, and a broad distribution of deleterious mutations.

Though relatively few mutations are advantageous, those that are play an important role in evolutionary changes. Like neutral mutations, weakly selected advantageous mutations can be lost due to random genetic drift, but strongly selected advantageous mutations are more likely to be fixed. Knowing the DFE of advantageous mutations may lead to increased ability to predict the evolutionary dynamics. Theoretical work on the DFE for advantageous mutations has been done by John H. Gillespie and H. Allen Orr. They proposed that the distribution for advantageous mutations should be exponential under a wide range of conditions, which, in general, has been supported by experimental studies, at least for strongly selected advantageous mutations.

In general, it is accepted that the majority of mutations are neutral or deleterious, with advantageous mutations being rare; however, the proportion of types of mutations varies between species. This indicates two important points: first, the proportion of effectively neutral mutations is likely to vary between species, resulting from dependence on effective population size; second, the average effect of deleterious mutations varies dramatically between species. In addition, the DFE also differs between coding regions and noncoding regions, with the DFE of noncoding DNA containing more weakly selected mutations.

By impact on protein sequence

• A frameshift mutation is a mutation caused by insertion or deletion of a number of nucleotides that is not evenly divisible by three from a DNA sequence. Due to the triplet nature of gene expression by codons, the insertion or deletion can disrupt the reading frame, or the grouping of the codons, resulting in a completely different translation from the original. The earlier in the sequence the deletion or insertion occurs, the more altered the protein produced is. (For example, the code CCU GAC UAC CUA codes for the amino acids proline, aspartic acid, tyrosine, and leucine. If the U in CCU was deleted, the resulting sequence would be CCG ACU ACC UAx, which would instead code for proline, threonine, threonine, and part of another amino acid or perhaps a stop codon (where the x stands for the following nucleotide).) By contrast, any insertion or deletion that is evenly divisible by three is termed an in-frame mutation.
• A point substitution mutation results in a change in a single nucleotide and can be either synonymous or nonsynonymous.
  • A synonymous substitution replaces a codon with another codon that codes for the same amino acid, so that the produced amino acid sequence is not modified. Synonymous mutations occur due to the degenerate nature of the genetic code. If this mutation does not result in any phenotypic effects, then it is called silent, but not all synonymous substitutions are silent. (There can also be silent mutations in nucleotides outside of the coding regions, such as the introns, because the exact nucleotide sequence is not as crucial as it is in the coding regions, but these are not considered synonymous substitutions.)
  • A nonsynonymous substitution replaces a codon with another codon that codes for a different amino acid, so that the produced amino acid sequence is modified. Nonsynonymous substitutions can in turn be classified as nonsense or missense mutations:
    • A missense mutation or changes a nucleotide is to cause substitution of a different amino acid. This in turn can render the resulting protein nonfunctional. Such mutations are responsible for diseases such as Epidermolysis bullosa, sickle-cell disease, and SOD1-mediated ALS. On the other hand, if a missense mutation occurs in an amino acid codon that results in the use of a different, but chemically similar, amino acid, then sometimes little or no change is rendered in the protein. For example, a change from AAA to AGA will encode arginine, a chemically similar molecule to the intended lysine. In this latter case the mutation will have little or no effect on phenotype and therefore be neutral.
    • A nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a nonsense codon in the transcribed mRNA, and possibly a truncated, and often nonfunctional protein product. This sort of mutation has been linked to different mutations, such as congenital adrenal hyperplasia. (See Stop codon.)

By inheritance

A mutation has caused this moss rose plant to produce flowers of different colors. This is a somatic mutation that may also be passed on in the germline.

In multicellular organisms with dedicated reproductive cells, mutations can be subdivided into germline mutations, which can be passed on to descendants through their reproductive cells, and somatic mutations (also called acquired mutations), which involve cells outside the dedicated reproductive group and which are not usually transmitted to descendants.

A germline mutation gives rise to a constitutional mutation in the offspring, that is, a mutation that is present in every cell. A constitutional mutation can also occur very soon after fertilisation, or continue from a previous constitutional mutation in a parent.

The distinction between germline and somatic mutations is important in animals that have a dedicated germline to produce reproductive cells. However, it is of little value in understanding the effects of mutations in plants, which lack dedicated germline. The distinction is also blurred in those animals that reproduce asexually through mechanisms such as budding, because the cells that give rise to the daughter organisms also give rise to that organism's germline. A new germline mutation not inherited from either parent is called a de novo mutation.

Diploid organisms (e.g., humans) contain two copies of each gene—a paternal and a maternal allele. Based on the occurrence of mutation on each chromosome, we may classify mutations into three types.

• A heterozygous mutation is a mutation of only one allele.
• A homozygous mutation is an identical mutation of both the paternal and maternal alleles.
• Compound heterozygous mutations or a genetic compound consists of two different mutations in the paternal and maternal alleles.

A wild type or homozygous non-mutated organism is one in which neither allele is mutated.

Special classes

• Conditional mutation is a mutation that has wild-type (or less severe) phenotype under certain "permissive" environmental conditions and a mutant phenotype under certain "restrictive" conditions. For example, a temperature-sensitive mutation can cause cell death at high temperature (restrictive condition), but might have no deleterious consequences at a lower temperature (permissive condition). These mutations are non-autonomous, as their manifestation depends upon presence of certain conditions, as opposed to other mutations which appear autonomously. The permissive conditions may be temperature, certain chemicals, light or mutations in other parts of the genome. In vivo mechanisms like transcriptional switches can create conditional mutations. For instance, association of Steroid Binding Domain can create a transcriptional switch that can change the expression of a gene based on the presence of a steroid ligand. Conditional mutations have applications in research as they allow control over gene expression. This is especially useful studying diseases in adults by allowing expression after a certain period of growth, thus eliminating the deleterious effect of gene expression seen during stages of development in model organisms. DNA Recombinase systems like Cre-Lox Recombination used in association with promoters that are activated under certain conditions can generate conditional mutations. Dual Recombinase technology can be used to induce multiple conditional mutations to study the diseases which manifest as a result of simultaneous mutations in multiple genes. Certain inteins have been identified which splice only at certain permissive temperatures, leading to improper protein synthesis and thus, loss of function mutations at other temperatures. Conditional mutations may also be used in genetic studies associated with ageing, as the expression can be changed after a certain time period in the organism's lifespan.
• Replication timing quantitative trait loci affects DNA replication.

Nomenclature

In order to categorize a mutation as such, the "normal" sequence must be obtained from the DNA of a "normal" or "healthy" organism (as opposed to a "mutant" or "sick" one), it should be identified and reported; ideally, it should be made publicly available for a straightforward nucleotide-by-nucleotide comparison, and agreed upon by the scientific community or by a group of expert geneticists and biologists, who have the responsibility of establishing the standard or so-called "consensus" sequence. This step requires a tremendous scientific effort. Once the consensus sequence is known, the mutations in a genome can be pinpointed, described, and classified. The committee of the Human Genome Variation Society (HGVS) has developed the standard human sequence variant nomenclature, which should be used by researchers and DNA diagnostic centers to generate unambiguous mutation descriptions. In principle, this nomenclature can also be used to describe mutations in other organisms. The nomenclature specifies the type of mutation and base or amino acid changes.

• Nucleotide substitution (e.g., 76A>T) — The number is the position of the nucleotide from the 5' end; the first letter represents the wild-type nucleotide, and the second letter represents the nucleotide that replaced the wild type. In the given example, the adenine at the 76th position was replaced by a thymine.
  • If it becomes necessary to differentiate between mutations in genomic DNA, mitochondrial DNA, and RNA, a simple convention is used. For example, if the 100th base of a nucleotide sequence mutated from G to C, then it would be written as g.100G>C if the mutation occurred in genomic DNA, m.100G>C if the mutation occurred in mitochondrial DNA, or r.100g>c if the mutation occurred in RNA. Note that, for mutations in RNA, the nucleotide code is written in lower case.
• Amino acid substitution (e.g., D111E) — The first letter is the one letter code of the wild-type amino acid, the number is the position of the amino acid from the N-terminus, and the second letter is the one letter code of the amino acid present in the mutation. Nonsense mutations are represented with an X for the second amino acid (e.g. D111X).
• Amino acid deletion (e.g., ΔF508) — The Greek letter Δ (delta) indicates a deletion. The letter refers to the amino acid present in the wild type and the number is the position from the N terminus of the amino acid were it to be present as in the wild type.

Mutation rates

Mutation rates vary substantially across species, and the evolutionary forces that generally determine mutation are the subject of ongoing investigation

Harmful mutations

Changes in DNA caused by mutation can cause errors in protein sequence, creating partially or completely non-functional proteins. Each cell, in order to function correctly, depends on thousands of proteins to function in the right places at the right times. When a mutation alters a protein that plays a critical role in the body, a medical condition can result. Some mutations alter a gene's DNA base sequence but do not change the function of the protein made by the gene. One study on the comparison of genes between different species of Drosophila suggests that if a mutation does change a protein, this will probably be harmful, with an estimated 70 percent of amino acid polymorphisms having damaging effects, and the remainder being either neutral or weakly beneficial. Studies have shown that only 7% of point mutations in noncoding DNA of yeast are deleterious and 12% in coding DNA are deleterious. The rest of the mutations are either neutral or slightly beneficial.

If a mutation is present in a germ cell, it can give rise to offspring that carries the mutation in all of its cells. This is the case in hereditary diseases. In particular, if there is a mutation in a DNA repair gene within a germ cell, humans carrying such germline mutations may have an increased risk of cancer. A list of 34 such germline mutations is given in the article DNA repair-deficiency disorder. An example of one is albinism, a mutation that occurs in the OCA1 or OCA2 gene. Individuals with this disorder are more prone to many types of cancers, other disorders and have impaired vision. On the other hand, a mutation may occur in a somatic cell of an organism. Such mutations will be present in all descendants of this cell within the same organism, and certain mutations can cause the cell to become malignant, and, thus, cause cancer.

A DNA damage can cause an error when the DNA is replicated, and this error of replication can cause a gene mutation that, in turn, could cause a genetic disorder. DNA damages are repaired by the DNA repair system of the cell. Each cell has a number of pathways through which enzymes recognize and repair damages in DNA. Because DNA can be damaged in many ways, the process of DNA repair is an important way in which the body protects itself from disease. Once DNA damage has given rise to a mutation, the mutation cannot be repaired. DNA repair pathways can only recognize and act on "abnormal" structures in the DNA. Once a mutation occurs in a gene sequence it then has normal DNA structure and cannot be repaired.

Beneficial mutations

Although mutations that cause changes in protein sequences can be harmful to an organism, on occasions the effect may be positive in a given environment. In this case, the mutation may enable the mutant organism to withstand particular environmental stresses better than wild-type organisms, or reproduce more quickly. In these cases a mutation will tend to become more common in a population through natural selection.

For example, a specific 32 base pair deletion in human CCR5 (CCR5-Δ32) confers HIV resistance to homozygotes and delays AIDS onset in heterozygotes. One possible explanation of the etiology of the relatively high frequency of CCR5-Δ32 in the European population is that it conferred resistance to the bubonic plague in mid-14th century Europe. People with this mutation were more likely to survive infection; thus its frequency in the population increased. This theory could explain why this mutation is not found in Southern Africa, which remained untouched by bubonic plague. A newer theory suggests that the selective pressure on the CCR5 Delta 32 mutation was caused by smallpox instead of the bubonic plague.

An example of a harmful mutation is sickle-cell disease, a blood disorder in which the body produces an abnormal type of the oxygen-carrying substance hemoglobin in the red blood cells. One-third of all indigenous inhabitants of Sub-Saharan Africa carry the gene, because, in areas where malaria is common, there is a survival value in carrying only a single sickle-cell gene (sickle cell trait). Those with only one of the two alleles of the sickle-cell disease are more resistant to malaria, since the infestation of the malaria Plasmodium is halted by the sickling of the cells that it infests.

Prion mutations

Prions are proteins and do not contain genetic material. However, prion replication has been shown to be subject to mutation and natural selection just like other forms of replication. The human gene PRNP codes for the major prion protein, PrP, and is subject to mutations that can give rise to disease-causing prions.

Somatic mutation

A change in the genetic structure that is not inherited from a parent, and also not passed to offspring, is called a somatic mutation. Somatic mutations are not inherited because they do not affect the germline. These types of mutations are usually prompted by environmental causes, such as ultraviolet radiation or any exposure to certain harmful chemicals, and can cause diseases including cancer.
With plants, some somatic mutations can be propagated without the need for seed production, for example, by grafting and stem cuttings. These type of mutation have led to new types of fruits, such as the "Delicious" apple and the "Washington" navel orange.

Human and mouse somatic cells have a mutation rate more than ten times higher than the germline mutation rate for both species; mice have a higher rate of both somatic and germline mutations per cell division than humans. The disparity in mutation rate between the germline and somatic tissues likely reflects the greater importance of genome maintenance in the germline than in the soma.

Amorphic mutations

An amorph, a term utilized by Muller in 1932, is a mutated allele, which has lost the ability of the parent (whether wild type or any other type) allele to encode any functional protein. An amorphic mutation may be caused by the replacement of an amino acid that deactivates an enzyme or by the deletion of part of a gene that produces the enzyme.

Cells with heterozygous mutations (one good copy of gene and one mutated copy) may function normally with the unmutated copy until the good copy has been spontaneously somatically mutated. This kind of mutation happens all the time in living organisms, but it is difficult to measure the rate. Measuring this rate is important in predicting the rate at which people may develop cancer.

Point mutations may arise from spontaneous mutations that occur during DNA replication. The rate of mutation may be increased by mutagens. Mutagens can be physical, such as radiation from UV rays, X-rays or extreme heat, or chemical (molecules that misplace base pairs or disrupt the helical shape of DNA). Mutagens associated with cancers are often studied to learn about cancer and its prevention.

Hypomorphic and hypermorphic mutations

A hypomorphic mutation is a replacement of amino acids that would hinder enzyme activity, which would reduce the enzyme level but not to the point of complete loss. Usually, hypomorphic mutations are recessive, but haploinsufficiency causes some alleles to be dominant.

A hypermorphic mutation changes the regulation of the gene and causes it to overproduce the gene produce causing a greater than normal enzyme levels. These type of alleles are dominant gain of function type of alleles.