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If a person has a specific mutation in a gene, is it more likely he has other mutations in that gene?

If a person has a specific mutation in a gene, is it more likely he has other mutations in that gene?


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If a person has a specific mutation in a gene (2281 del/ins in a single copy of the Bloom BLM gene), is he more likely than the general population to have other types of mutations in the same gene?


A priori, no! Why would it? Do you have any specific hypothesis in mind you would like to discuss?

Below are some expectations from a simple model and possible reasons for why this expectation may break down under more complicated models.

Simple model

Under a simple model (panmictic population and a few other simple assumptions), the number of mutations a given individual has in any sequence considered follows a poisson distribution. Assuming that all mutations occuring have a constance selection coefficient $s$, a constant dominance coefficient $h$ and that the mutation rate for the sequence of interest is $U$, then the number of mutations an individual carry comes from a Poisson distribution with mean $frac{U}{2hs}$ (Crow 1970).

This model is simple but is probably a pretty good approximation to reality. Below are three assumptions that are not necessarily true and that would yield to a higher variance in the number of mutations (that is a higher probability for an individual that already carry a mutation to get a second mutation).

Population structure

In reality, populations are often not panmictic. As the genetic load depends upon the population size. More specifically, the smaller the population, the higher the genetic load (or the higher the number of mutants alleles present in the population) (Kimura et al. 1963).

Past evolutionary and demographic history

Populations are not stable through time. Some population have recently gone through a bottleneck, others a quickly expanding, some are shrinking, some have recently suffered from a plague, etc… Such processes can all cause populations to differ in the number of mutations they carry and therefore would increase the variance in the distribution of number of mutations individuals carry.

Within a specific short enough sequence, physical linkage associated with specific past evolutionary process will create a relatively long lasting linkage disequilibrium.

Condition-dependent mutation rate

It has been shown in Drosophila melanogaster that individuals with poor genotype tend to have a higher mutation rate causing their lineage to accumulate even more mutations (Sharp and Agrawal 2012).


Bear in mind that the average mutation rate of DNA polymerase is about 1 error for every 1 x 10^6 bases. So the probability of mutation is independent at each base pair, but low - there's nothing that would prevent another mutation, but there also is nothing that says it is demanded.

There is, however, a phenomenon known as compensating mutations - a second mutation that compensates for a detrimental effect of an earlier mutation. For example, if I have a mutation in a gene that codes for a protein, and that mutation changes an amino acid that is a contact point for protein folding (or a similar structural component), the protein may not fold correctly until there is a compensating mutation in the region of sequence coding for the residue that interacts with that first amino acid. Compensating mutations would tend to be positively selected if the protein function is significantly affected…


The answer of course depends some on the details (e.g., whether or not the mutation is neutral), but in general, yes, polymorphisms should cluster along the genome. Roughly speaking, the presence of one polymorphism indicates that the most recent common ancestor of this individual's two copies of the gene probably lived pretty far in the past, so there's been a lot of time for them to accumulate additional mutations.

I'm being a little sloppy here about polymorphisms within an individual vs differences from the reference genome, but the logic is the same.


Mutations and Disease

DNA is constantly subject to mutations, accidental changes in its code. Mutations can lead to missing or malformed proteins, and that can lead to disease.

We all start out our lives with some mutations. These mutations inherited from your parents are called germ-line mutations. However, you can also acquire mutations during your lifetime. Some mutations happen during cell division, when DNA gets duplicated. Still other mutations are caused when DNA gets damaged by environmental factors, including UV radiation, chemicals, and viruses.

Few mutations are bad for you. In fact, some mutations can be beneficial. Over time, genetic mutations create genetic diversity, which keeps populations healthy. Many mutations have no effect at all. These are called silent mutations.

But the mutations we hear about most often are the ones that cause disease. Some well-known inherited genetic disorders include cystic fibrosis, sickle cell anemia, Tay-Sachs disease, phenylketonuria and color-blindness, among many others. All of these disorders are caused by the mutation of a single gene.

Most inherited genetic diseases are recessive, which means that a person must inherit two copies of the mutated gene to inherit a disorder. This is one reason that marriage between close relatives is discouraged two genetically similar adults are more likely to give a child two copies of a defective gene.

Diseases caused by just one copy of a defective gene, such as Huntington's disease, are rare. Thanks to natural selection, these dominant genetic diseases tend to get weeded out of populations over time, because afflicted carriers are more likely to die before reproducing.

Scientists estimate that every one of us has between 5 and 10 potentially deadly mutations in our genes-the good news is that because there's usually only one copy of the bad gene, these diseases don't manifest.

Cancer usually results from a series of mutations within a single cell. Often, a faulty, damaged, or missing p53 gene is to blame. The p53 gene makes a protein that stops mutated cells from dividing. Without this protein, cells divide unchecked and become tumors.


Genetics and CF

A gene is the basic unit of heredity. Genes are responsible for the physical characteristics that each person has (like eye color, facial features, and many health conditions). Each gene occupies a certain location on a chromosome (a thread-like material that is located in the nucleus of every single cell in the body). Chromosomes come in 23 pairs, and each chromosome carries thousands of genes.

What happens?

Each gene has a specific role in determining how a person's body is put together and how it functions. The role of a gene is determined by its individual DNA code (deoxyribonucleic acid, the chemical coding for a gene). DNA is made up of four building blocks called bases. These bases are joined in a specific order for each gene. When a change occurs in the arrangement of the bases, it can cause the gene not to work properly.

What are genetic disorders?

A structural gene change which can cause a disease or a birth defect is called a mutation. Genes are inherited in pairs, with one gene inherited from each parent to make the pair. Cystic fibrosis occurs when both genes in the pair have a mutation. A person with cystic fibrosis inherits one CF gene from each parent. Cystic fibrosis is a genetic disorder caused by inheriting a pair of genes that are mutated or not working properly.

The Cystic Fibrosis Gene

Everyone inherits two copies of the CFTR (cystic fibrosis transmembrane conductance regulator) gene. However, some of the inherited copies are mutations. To date, over 700 mutations of the CFTR gene have been identified. A person with CF inherits two mutated copies of the CFTR gene. These mutations can either be homozygous, the same, or heterozygous, different mutations. The most common mutation is delta F508, accounting for approximately 70% of all mutations. Those homozygous for this mutation tend to be pancreatic insufficient.

What Does the Mutation Do?

The CFTR gene is a protein that functions as a chloride channel. A chloride channel helps maintain the proper balance of salt and water within a cell. A mutation in CFTR causes a dysfunction of the salt and water balance. This causes dehydration of the secretions (thick mucous) and excessive loss of salt in sweat.

What is a carrier?

A carrier is a person who only has one copy of the mutated gene. The parents of a child with CF each carry one CF gene and one normal gene. They have no symptoms and no disease.

How does CF occur?

When each of the parents contributes a gene to their child, they could pass on either their CF gene or their non-CF gene. Each pregnancy could result in one of three outcomes:


Genes and Alzheimer's Disease

There are two types of Alzheimer's—early-onset and late-onset. Both types have a genetic component.

Late-Onset Alzheimer's Disease

Most people with Alzheimer's have the late-onset form of the disease, in which symptoms become apparent in their mid-60s and later.

Researchers have not found a specific gene that directly causes late-onset Alzheimer's disease. However, having a genetic variant of the apolipoprotein E (APOE) gene on chromosome 19 does increase a person's risk. The APOE gene is involved in making a protein that helps carry cholesterol and other types of fat in the bloodstream.

APOE comes in several different forms, or alleles. Each person inherits two APOE alleles, one from each biological parent.

  • APOE ε2 is relatively rare and may provide some protection against the disease. If Alzheimer's disease occurs in a person with this allele, it usually develops later in life than it would in someone with the APOE ε4 gene.
  • APOE ε3, the most common allele, is believed to play a neutral role in the disease—neither decreasing nor increasing risk.
  • APOE ε4 increases risk for Alzheimer's disease and is also associated with an earlier age of disease onset. Having one or two APOE ε4 alleles increases the risk of developing Alzheimer's. About 25 percent of people carry one copy of APOE ɛ4, and 2 to 3 percent carry two copies.

APOE ε4 is called a risk-factor gene because it increases a person's risk of developing the disease. However, inheriting an APOE ε4 allele does not mean that a person will definitely develop Alzheimer's. Some people with an APOE ε4 allele never get the disease, and others who develop Alzheimer's do not have any APOE ε4 alleles.

Recent research indicates that rare forms of the APOE allele may provide protection against Alzheimer’s disease. More studies are needed to determine how these variations might delay disease onset or lower a person’s risk.

Early-Onset Alzheimer's Disease

Early-onset Alzheimer’s disease is rare, representing less than 10 percent of all people with Alzheimer’s. It typically occurs between a person’s 30s and mid-60s. Some cases are caused by an inherited change in one of three genes.

The three single-gene mutations associated with early-onset Alzheimer’s disease are:

  • Amyloid precursor protein (APP) on chromosome 21
  • Presenilin 1 (PSEN1) on chromosome 14
  • Presenilin 2 (PSEN2) on chromosome 1

Mutations in these genes result in the production of abnormal proteins that are associated with the disease. Each of these mutations plays a role in the breakdown of APP, a protein whose precise function is not yet fully understood. This breakdown is part of a process that generates harmful forms of amyloid plaques, a hallmark of Alzheimer’s disease.

A child whose biological mother or father carries a genetic mutation for one of these three genes has a 50/50 chance of inheriting that mutation. If the mutation is in fact inherited, the child has a very strong probability of developing early-onset Alzheimer’s disease.

For other cases of early-onset Alzheimer’s, research has shown that other genetic components are involved. Studies are ongoing to identify additional genetic risk variants.

Having Down syndrome increases the risk of developing early-onset Alzheimer’s disease. Many people with Down syndrome develop Alzheimer’s as they get older, with symptoms appearing in their 50s or 60s. Researchers believe this is because people with Down syndrome are born with an extra copy of chromosome 21, which carries the APP gene.


The London and Berlin Patients

The controversy over He's studies suggests that it will be years before mainstream researchers are comfortable using gene editing technology to disable the normal CCR5 gene in embryos and create a generation with HIV immunity. But all eyes are still on this mutation, because it played a key role in the treatment received by both of the men now thought to have been cured of HIV.

The men -- referred to as the Berlin patient and the London patient, respectively -- received allogenic hematopoietic stem cell transplantation as a treatment for cancer. These transplants are designed to replace cells damaged by disease, infection, or chemotherapy with healthy cells from a donor so that the patient's body can essentially rebuild its immune system. In these cases, doctors chose donors with the CCR5 delta 32 mutation in the hopes that when the immune system rebuilt with the new cells, it could also fight off HIV without medication. The treatment, however, is very intense, as it requires patients first to kill the existing marrow cells with chemotherapy or radiation and to take drugs to suppress their immune system so that it does not attack the donor cells.

The Berlin patient was later identified as Timothy Ray Brown and has now been HIV-free without medication for 12 years. Brown, who was being treated for leukemia at the time, came close to death during his treatment and was even put into a medically induced coma at one point.

Researchers tried for years to replicate the success they had with Brown, but HIV kept returning in subsequent patients. Some worried that Brown's success was not proof that the CCR5 delta 32 mutation was the key to treating HIV as hoped, but instead just a fluke brought on by intense, nearly fatal, radiation.

Then, in March 2019, researchers announced the success of the London patient (who has asked not to be named). He received a bone marrow transplant to treat Hodgkin's lymphoma. His treatment was less intense than Brown's, and he was never as sick. He has now been HIV-free without medication for 18 months. The London patient is one of 38 patients who received similar treatment who are currently being followed by a group of researchers. A second patient in the group has been HIV-free for four months.

While experts are eager to see how those patients fare, there appears to be consensus that this treatment is too intense to ever become common, especially in an era when medication can make the virus undetectable and untransmittable.

Still, the London patient's success is significant, because it proves that Brown's case was not a fluke and, as such, it puts the focus squarely back on CCR5. Paula Cannon, Ph.D., a molecular microbiologist who studies HIV at the University of Southern California's Keck School of Medicine, told Wired magazine: "There's a nice menu of things that we could possibly do now. What these two patients have shown us is that attacking the reservoir of infected cells while at the same time providing shiny, new HIV-resistant immune cells can result in a cure."


Effects of Mutations

The majority of mutations have neither negative nor positive effects on the organism in which they occur. These mutations are called neutral mutations. Examples include silent point mutations, which are neutral because they do not change the amino acids in the proteins they encode.

Many other DNA damages or errors have no effects on the organism because they are repaired before protein synthesis occurs. Cells have multiple repair mechanisms to fix errors in DNA.

Beneficial Mutations

Some mutations have a positive effect on the organism in which they occur. They are referred to as beneficial mutations. They generally code for new versions of proteins that help organisms adapt to their environment. If they increase an organism&rsquos chances of surviving or reproducing, the mutations are likely to become more common over time. There are several well-known examples of beneficial mutations. Here are just two:

  1. Mutations have occurred in bacteria that allow the bacteria to survive in the presence of antibiotic drugs. The mutations have led to the evolution of antibiotic-resistant strains of bacteria.
  2. A unique mutation is found in people in a small town in Italy. The mutation protects them from developing atherosclerosis, which is the dangerous buildup of fatty materials in blood vessels. The individual in which the mutation first appeared has even been identified.

Harmful Mutations

Imagine making a random change in a complicated machine such as a car engine. The chance that the random change would improve the functioning of the car is very small. The change is far more likely to result in a car that does not run well or perhaps does not run at all. By the same token, any random change in a gene's DNA is likely to result in the production of a protein that does not function normally or may not function at all. Such mutations are likely to be harmful. Harmful mutations may cause genetic disorders or cancer.

  • A genetic disorder is a disease, syndrome, or other abnormal condition caused by a mutation in one or more genes or by a chromosomal alteration. An example of a genetic disorder is cystic fibrosis. A mutation in a single gene causes the body to produce thick, sticky mucus that clogs the lungs and blocks ducts in digestive organs.
  • Cancer is a disease in which cells grow out of control and form abnormal masses of cells called tumors. It is generally caused by mutations in genes that regulate the cell cycle. Because of the mutations, cells with damaged DNA are allowed to divide without restrictions.

Inherited mutations are thought to play a role in about 5 to 10 percent of all cancers. Specific mutations that cause many of the known hereditary cancers have been identified. Most of the mutations occur in genes that control the growth of cells or the repair of damaged DNA.

Genetic testing can be done to determine whether individuals have inherited specific cancer-causing mutations. Some of the most common inherited cancers for which genetic testing is available hereditary, breast, and ovarian cancer, caused by mutations in genes named BRCA1 and BRCA2. Besides breast and ovarian cancers, mutations in these genes may also cause pancreatic and prostate cancers. Genetic testing is generally done on a small sample of body fluid or tissue, such as blood, saliva, or skin cells. The sample is analyzed by a lab that specializes in genetic testing, and it usually takes at least a few weeks to get the test results.

Should you get genetic testing to find out whether you have inherited a cancer-causing mutation? Such testing is not done routinely just to screen patients for risk of cancer. Instead, the tests are generally done only when the following three criteria are met:

  1. The test can determine definitively whether a specific gene is mutation is present. This is the case with the BRCA1 and BRCA2 gene mutations, for example.
  2. The test results would be useful to help guide future medical care. For example, if you found out you had a mutation in the BRCA1 or BRCA2 gene, you might get more frequent breast and ovarian cancer screenings than are generally recommended.
  3. You have a personal or family history that suggests you are at risk of inherited cancer.

Criterion number 3 is based, in turn, on such factors as:

  • diagnosis of cancer at an unusually young age.
  • several different cancers occurring independently in the same individual.
  • several close genetic relatives having the same type of cancer (such as a maternal grandmother, mother, and sister all having breast cancer).
  • cancer occurring in both organs in a set of paired organs (such as both kidneys or both breasts).

If you meet the criteria for genetic testing and are advised to undergo it, genetic counseling is highly recommended. A genetic counselor can help you understand what the results mean and how to make use of them to reduce your risk of developing cancer. For example, a positive test result that shows the presence of a mutation may not necessarily mean that you will develop cancer. It may depend on whether the gene is located on an autosome or sex chromosome and whether the mutation is dominant or recessive. Lifestyle factors may also play a role in cancer risk even for hereditary cancers, and early detection can often be life-saving if cancer does develop. Genetic counseling can also help you assess the chances that any children you may have will inherit the mutation.


Mutations Occur Spontaneously and Can Be Induced

Mutations arise spontaneously at low frequency owing to the chemical instability of purine and pyrimidine bases and to errors during DNA replication. Natural exposure of an organism to certain environmental factors, such as ultraviolet light and chemical carcinogens (e.g., aflatoxin B1), also can cause mutations.

A common cause of spontaneous point mutations is the deamination of cytosine to uracil in the DNA double helix. Subsequent replication leads to a mutant daughter cell in which a T୺ base pair replaces the wild-type C·G base pair. Another cause of spontaneous mutations is copying errors during DNA replication. Although replication generally is carried out with high fidelity, errors occasionally occur. Figure 8-5 illustrates how one type of copying error can produce a mutation. In the example shown, the mutant DNA contains nine additional base pairs.

Figure 8-5

One mechanism by which errors in DNA replication produce spontaneous mutations. The replication of only one strand is shown the other strand is replicated normally, as shown at the top. A replication error may arise in regions of DNA containing tandemly (more. )

In order to increase the frequency of mutation in experimental organisms, researchers often treat them with high doses of chemical mutagens or expose them to ionizing radiation. Mutations arising in response to such treatments are referred to as induced mutations. Generally, chemical mutagens induce point mutations, whereas ionizing radiation gives rise to large chromosomal abnormalities.

Ethylmethane sulfonate (EMS), a commonly used mutagen, alkylates guanine in DNA, forming O 6 -ethylguanine (Figure 8-6a). During subsequent DNA replication, O 6 -ethylguanine directs incorporation of deoxythymidylate, not deoxycytidylate, resulting in formation of mutant cells in which a G୼ base pair is replaced with an A·T base pair (Figure 8-6b). The causes of mutations and the mechanisms cells have for repairing alterations in DNA are discussed further in Chapter 12.

Figure 8-6

Induction of point mutations by ethylmethane sulfonate (EMS), a commonly used mutagen. (a) EMS alkylates guanine at the oxygen on position 6 of the purine ring, forming O 6 -ethylguanine (Et-G), which base-pairs with thymine. (b) Two rounds of DNA replication (more. )


Diagnosis and Tests

How is factor V Leiden (FVL) diagnosed?

Your doctor can diagnose FVL by ordering special screening and confirmatory blood tests that are specific to detect the presence of the mutation.

Despite the fact that FVL can be diagnosed by simple blood tests, such testing is not necessary in every person with a personal or family history of DVT or PE. If you think that testing may be indicated for you, it is very important that you discuss your concerns with your doctor(s) prior to being tested.


Find a Specialist Find a Specialist

If you need medical advice, you can look for doctors or other healthcare professionals who have experience with this disease. You may find these specialists through advocacy organizations, clinical trials, or articles published in medical journals. You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments.

If you can’t find a specialist in your local area, try contacting national or international specialists. They may be able to refer you to someone they know through conferences or research efforts. Some specialists may be willing to consult with you or your local doctors over the phone or by email if you can't travel to them for care.

You can find more tips in our guide, How to Find a Disease Specialist. We also encourage you to explore the rest of this page to find resources that can help you find specialists.

Healthcare Resources

  • To find a medical professional who specializes in genetics, you can ask your doctor for a referral or you can search for one yourself. Online directories are provided by the American College of Medical Genetics and the National Society of Genetic Counselors. If you need additional help, contact a GARD Information Specialist. You can also learn more about genetic consultations from MedlinePlus Genetics.

If a person has a specific mutation in a gene, is it more likely he has other mutations in that gene? - Biology

Let’s begin with a question: What is a gene mutation and how do mutations occur?

A gene mutation is a permanent alteration in the DNA sequence that makes up a gene, such that the sequence differs from what is found in most people. Mutations range in size they can affect anywhere from a single DNA building block (base pair) to a large segment of a chromosome that includes multiple genes.

Gene mutations can be classified in two major ways:

  • Hereditary mutations are inherited from a parent and are present throughout a person’s life in virtually every cell in the body. These mutations are also called germline mutations because they are present in the parent’s egg or sperm cells, which are also called germ cells. When an egg and a sperm cell unite, the resulting fertilized egg cell receives DNA from both parents. If this DNA has a mutation, the child that grows from the fertilized egg will have the mutation in each of his or her cells.
  • Acquired (or somatic) mutations occur at some time during a person’s life and are present only in certain cells, not in every cell in the body. These changes can be caused by environmental factors such as ultraviolet radiation from the sun, or can occur if a mistake is made as DNA copies itself during cell division. Acquired mutations in somatic cells (cells other than sperm and egg cells) cannot be passed on to the next generation.

Genetic changes that are described as de novo (new) mutations can be either hereditary or somatic. In some cases, the mutation occurs in a person’s egg or sperm cell but is not present in any of the person’s other cells. In other cases, the mutation occurs in the fertilized egg shortly after the egg and sperm cells unite. (It is often impossible to tell exactly when a de novo mutation happened.) As the fertilized egg divides, each resulting cell in the growing embryo will have the mutation. De novo mutations may explain genetic disorders in which an affected child has a mutation in every cell in the body but the parents do not, and there is no family history of the disorder.

Somatic mutations that happen in a single cell early in embryonic development can lead to a situation called mosaicism. These genetic changes are not present in a parent’s egg or sperm cells, or in the fertilized egg, but happen a bit later when the embryo includes several cells. As all the cells divide during growth and development, cells that arise from the cell with the altered gene will have the mutation, while other cells will not. Depending on the mutation and how many cells are affected, mosaicism may or may not cause health problems.

Most disease-causing gene mutations are uncommon in the general population. However, other genetic changes occur more frequently. Genetic alterations that occur in more than 1 percent of the population are called polymorphisms. They are common enough to be considered a normal variation in the DNA. Polymorphisms are responsible for many of the normal differences between people such as eye color, hair color, and blood type. Although many polymorphisms have no negative effects on a person’s health, some of these variations may influence the risk of developing certain disorders.


Mutations have allowed humans to adapt to their environment. For instance, lactose tolerance is a specific external mutation that was advantageous in societies that raised cows and goats. Mutations have been responsible for antibiotic resistance in bacteria, sickle cell resistance to malaria, and immunity to HIV, among others. A rare gene mutation leading to unusual shortness of height has proven to be advantageous for a particular Ecuadorian community. National Public Radio's (NPR) Jon Hamilton writes how the Ecuadorian community with the rare gene mutation known as Laron syndrome are protected against cancer and diabetes.

In 2008, Professor Eiberg from the Department of Cellular and Molecular Biology stated, “Originally, we all had brown eyes but a genetic mutation affecting the OCA2 gene in our chromosomes resulted in the creation of a 'switch,' which literally 'turned off' the ability to produce brown eyes.” He explains that things like “hair color, baldness, freckles, and beauty spots” are all brought about by mutations.