Mutations and Health

A gene mutation is a permanent change in the DNA sequence that makes up a gene. Mutations range in size from a single DNA building block (DNA base) to a large segment of a chromosome.

Gene mutations occur in two ways: they can be inherited from a parent or acquired during a person’s lifetime. Mutations that are passed from parent to child are called hereditary mutations or germline mutations (because they are present in the egg and sperm cells, which are also called germ cells). This type of mutation is present throughout a person’s life in virtually every cell in the body.

Mutations that occur only in an egg or sperm cell, or those that occur just after fertilization, are called new (de novo) mutations. De novo mutations may explain genetic disorders in which an affected child has a mutation in every cell, but has no family history of the disorder.

Acquired (or somatic) mutations occur in the DNA of individual cells at some time during a person’s life. 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.

Mutations may also occur in a single cell within an early embryo. As all the cells divide during growth and development, the individual will have some cells with the mutation and some cells without the genetic change. This situation is called mosaicism.

Some genetic changes are very rare; others are common in the population. Genetic changes 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.

For more information about mutations:

The National Cancer Institute offers a discussion of hereditary mutations and information about acquired mutations.

The Centre for Genetics Education provides a fact sheet discussing changes to the genetic code.

More basic information about genetic mutations is available from GeneEd.

Additional information about genetic changes is available from the University of Utah fact sheet “What is a Mutation?”

To function correctly, each cell depends on thousands of proteins to do their jobs in the right places at the right times. Sometimes, gene mutations prevent one or more of these proteins from working properly. By changing a gene’s instructions for making a protein, a mutation can cause the protein to malfunction or to be missing entirely. When a mutation alters a protein that plays a critical role in the body, it can disrupt normal development or cause a medical condition. A condition caused by mutations in one or more genes is called a genetic disorder.

In some cases, gene mutations are so severe that they prevent an embryo from surviving until birth. These changes occur in genes that are essential for development, and often disrupt the development of an embryo in its earliest stages. Because these mutations have very serious effects, they are incompatible with life.

It is important to note that genes themselves do not cause disease—genetic disorders are caused by mutations that make a gene function improperly. For example, when people say that someone has “the cystic fibrosis gene,” they are usually referring to a mutated version of the CFTR gene, which causes the disease. All people, including those without cystic fibrosis, have a version of the CFTR gene.

For more information about mutations and genetic disorders:

The National Cancer Institute provides additional information about how gene mutations can trigger disease:

• Gene Mutations and Disease

• Altered DNA, Altered Protein

The Centre for Genetics Education offers a fact sheet about genetic changes that lead to disorders.

No; only a small percentage of mutations cause genetic disorders—most have no impact on health or development. For example, some mutations alter a gene’s DNA sequence but do not change the function of the protein made by the gene.

Often, gene mutations that could cause a genetic disorder are repaired by certain enzymes before the gene is expressed and an altered protein is produced. Each cell has a number of pathways through which enzymes recognize and repair mistakes in DNA. Because DNA can be damaged or mutated in many ways, DNA repair is an important process by which the body protects itself from disease.

A very small percentage of all mutations actually have a positive effect. These mutations lead to new versions of proteins that help an individual better adapt to changes in his or her environment. For example, a beneficial mutation could result in a protein that protects an individual and future generations from a new strain of bacteria.

Because a person’s genetic code can have a large number of mutations with no effect on health, diagnosing genetic conditions can be difficult. Sometimes, genes thought to be related to a particular genetic condition have mutations, but whether these changes are involved in development of the condition has not been determined; these genetic changes are known as variants of unknown significance (VOUS). Sometimes, no mutations are found in suspected disease-related genes, but mutations are found in other genes whose relationship to a particular genetic condition is unknown. It is difficult to know whether these variants are involved in the disease.

For more information about DNA repair and the health effects of gene mutations:

The University of Utah Genetic Science Learning Center provides information about genetic disorders that explains why some mutations cause disorders but others do not.

Additional information about DNA repair is available from the National Center for Biotechnology Information’s (NCBI) Science Primer. In the chapter called What Is A Cell?, scroll down to the heading “DNA Repair Mechanisms.”

The Yale Cancer Center describes the implications of finding variants of unknown significance (VOUS). The information applies to VOUS in cancer and other genetic conditions.

The DNA 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. The types of mutations include:

Missense mutation (illustration)

This type of mutation is a change in one DNA base pair that results in the substitution of one amino acid for another in the protein made by a gene.

Nonsense mutation (illustration)

A nonsense mutation is also a change in one DNA base pair. Instead of substituting one amino acid for another, however, the altered DNA sequence prematurely signals the cell to stop building a protein. This type of mutation results in a shortened protein that may function improperly or not at all.

Insertion (illustration)

An insertion changes the number of DNA bases in a gene by adding a piece of DNA. As a result, the protein made by the gene may not function properly.

Deletion (illustration)

A deletion changes the number of DNA bases by removing a piece of DNA. Small deletions may remove one or a few base pairs within a gene, while larger deletions can remove an entire gene or several neighboring genes. The deleted DNA may alter the function of the resulting protein(s).

Duplication (illustration)

A duplication consists of a piece of DNA that is abnormally copied one or more times. This type of mutation may alter the function of the resulting protein.

Frameshift mutation (illustration)

This type of mutation occurs when the addition or loss of DNA bases changes a gene’s reading frame. A reading frame consists of groups of 3 bases that each code for one amino acid. A frameshift mutation shifts the grouping of these bases and changes the code for amino acids. The resulting protein is usually nonfunctional. Insertions, deletions, and duplications can all be frameshift mutations.

Repeat expansion (illustration)

Nucleotide repeats are short DNA sequences that are repeated a number of times in a row. For example, a trinucleotide repeat is made up of 3-base-pair sequences, and a tetranucleotide repeat is made up of 4-base-pair sequences. A repeat expansion is a mutation that increases the number of times that the short DNA sequence is repeated. This type of mutation can cause the resulting protein to function improperly.

For more information about the types of gene mutations:

The National Human Genome Research Institute offers a Talking Glossary of Genetic Terms. This resource includes definitions, diagrams, and detailed audio descriptions of several of the gene mutations listed above.

People have two copies of most genes, one copy inherited from each parent. In some cases, however, the number of copies varies—meaning that a person can be born with one, three, or more copies of particular genes. Less commonly, one or more genes may be entirely missing. This type of genetic difference is known as copy number variation (CNV).

Copy number variation results from insertions, deletions, and duplications of large segments of DNA. These segments are big enough to include whole genes. Variation in gene copy number can influence the activity of genes and ultimately affect many body functions.

Researchers were surprised to learn that copy number variation accounts for a significant amount of genetic difference between people. More than 10 percent of human DNA appears to contain these differences in gene copy number. While much of this variation does not affect health or development, some differences likely influence a person’s risk of disease and response to certain drugs. Future research will focus on the consequences of copy number variation in different parts of the genome and study the contribution of these variations to many types of disease.

For more information about copy number variation:

The Howard Hughes Medical Institute discusses the results of recent research on copy number variation in the news release, Genetic Variation: We’re More Different Than We Thought.

For people interested in more technical data, several institutions provide databases of structural differences in human DNA, including copy number variation:

• Database of Genomic Variants

• The Sanger Institute: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources (DECIPHER)

Human cells normally contain 23 pairs of chromosomes, for a total of 46 chromosomes in each cell (illustration). A change in the number of chromosomes can cause problems with growth, development, and function of the body’s systems. These changes can occur during the formation of reproductive cells (eggs and sperm), in early fetal development, or in any cell after birth. A gain or loss of chromosomes from the normal 46 is called aneuploidy.

A common form of aneuploidy is trisomy, or the presence of an extra chromosome in cells. “Tri-” is Greek for “three”; people with trisomy have three copies of a particular chromosome in cells instead of the normal two copies. Down syndrome is an example of a condition caused by trisomy (illustration).  People with Down syndrome typically have three copies of chromosome 21 in each cell, for a total of 47 chromosomes per cell.

Monosomy, or the loss of one chromosome in cells, is another kind of aneuploidy. “Mono-” is Greek for “one”; people with monosomy have one copy of a particular chromosome in cells instead of the normal two copies. Turner syndrome is a condition caused by monosomy (illustration). Women with Turner syndrome usually have only one copy of the X chromosome in every cell, for a total of 45 chromosomes per cell.

Rarely, some cells end up with complete extra sets of chromosomes.  Cells with one additional set of chromosomes, for a total of 69 chromosomes, are called triploid (illustration).  Cells with two additional sets of chromosomes, for a total of 92 chromosomes, are called tetraploid.  A condition in which every cell in the body has an extra set of chromosomes is not compatible with life.

In some cases, a change in the number of chromosomes occurs only in certain cells.  When an individual has two or more cell populations with a different chromosomal makeup, this situation is called chromosomal mosaicism (illustration).  Chromosomal mosaicism occurs from an error in cell division in cells other than eggs and sperm. Most commonly, some cells end up with one extra or missing chromosome (for a total of 45 or 47 chromosomes per cell), while other cells have the usual 46 chromosomes. Mosaic Turner syndrome is one example of chromosomal mosaicism.  In females with this condition, some cells have 45 chromosomes because they are missing one copy of the X chromosome, while other cells have the usual number of chromosomes.

Many cancer cells also have changes in their number of chromosomes. These changes are not inherited; they occur in somatic cells (cells other than eggs or sperm) during the formation or progression of a cancerous tumor.

For more information about chromosomal disorders:

A discussion of how chromosomal abnormalities happen is provided by the National Human Genome Research Institute.

The Centre for Genetics Education offers a fact sheet about changes in chromosome number or size.

Information about chromosomal changes, including changes in the number of chromosomes, is available from EuroGentest.

The National Organization for Rare Disorders offers an overview of triploid syndrome.

Chromosomal Mosaicism, a web site provided by the University of British Columbia, offers detailed information about mosaic chromosomal abnormalities.

MedlinePlus offers an encyclopedia article about chromosomal mosaicism.

Changes that affect the structure of chromosomes can cause problems with growth, development, and function of the body’s systems. These changes can affect many genes along the chromosome and disrupt the proteins made from those genes.

Structural changes can occur during the formation of egg or sperm cells, in early fetal development, or in any cell after birth. Pieces of DNA can be rearranged within one chromosome or transferred between two or more chromosomes. The effects of structural changes depend on their size and location, and whether any genetic material is gained or lost.  Some changes cause medical problems, while others may have no effect on a person’s health.

Changes in chromosome structure include:

Translocations (illustration: balanced), (illustration: unbalanced)

A translocation occurs when a piece of one chromosome breaks off and attaches to another chromosome.  This type of rearrangement is described as balanced if no genetic material is gained or lost in the cell.  If there is a gain or loss of genetic material, the translocation is described as unbalanced. 

Deletions (illustration)

Deletions occur when a chromosome breaks and some genetic material is lost.  Deletions can be large or small, and can occur anywhere along a chromosome.

Duplications (illustration)

Duplications occur when part of a chromosome is copied (duplicated) too many times.  This type of chromosomal change results in extra copies of genetic material from the duplicated segment.

Inversions (illustration)

An inversion involves the breakage of a chromosome in two places; the resulting piece of DNA is reversed and re-inserted into the chromosome.  Genetic material may or may not be lost as a result of the chromosome breaks.  An inversion that involves the chromosome’s constriction point (centromere) is called a pericentric inversion.  An inversion that occurs in the long (q) arm or short (p) arm and does not involve the centromere is called a paracentric inversion.

Isochromosomes (illustration)

An isochromosome is a chromosome with two identical arms.  Instead of one long (q) arm and one short (p) arm, an isochromosome has two long arms or two short arms.  As a result, these abnormal chromosomes have an extra copy of some genes and are missing copies of other genes.

Dicentric chromosomes (illustration)

Unlike normal chromosomes, which have a single constriction point (centromere), a dicentric chromosome contains two centromeres.  Dicentric chromosomes result from the abnormal fusion of two chromosome pieces, each of which includes a centromere.  These structures are unstable and often involve a loss of some genetic material.

Ring chromosomes (illustration)

Ring chromosomes usually occur when a chromosome breaks in two places and the ends of the chromosome arms fuse together to form a circular structure.  The ring may or may not include the chromosome’s constriction point (centromere).  In many cases, genetic material near the ends of the chromosome is lost.

Many cancer cells also have changes in their chromosome structure. These changes are not inherited; they occur in somatic cells (cells other than eggs or sperm) during the formation or progression of a cancerous tumor.

For more information about structural changes to chromosomes:

The National Human Genome Research Institute provides a list of questions and answers about chromosome abnormalities, including a glossary of related terms.

Chromosome Deletion Outreach offers a fact sheet on this topic titled Introduction to Chromosomes. This resource includes illustrated explanations of several chromosome abnormalities.

The Centre for Genetics Education provides fact sheets about changes in chromosome number or size and chromosomal rearrangements (translocations).

EuroGentest offers fact sheets about chromosome changes and chromosome translocations.

More technical information is available from the textbook Human Molecular Genetics (second edition, 1999) in the section about structural chromosome abnormalities.

The Atlas of Genetics and Cytogenetics in Oncology and Haematology provides a technical introduction to chromosomal aberrations and a detailed discussion of ring chromosomes, particularly their role in cancer.

Mitochondria (illustration) are structures within cells that convert the energy from food into a form that cells can use. Although most DNA is packaged in chromosomes within the nucleus, mitochondria also have a small amount of their own DNA (known as mitochondrial DNA or mtDNA). In some cases, inherited changes in mitochondrial DNA can cause problems with growth, development, and function of the body’s systems. These mutations disrupt the mitochondria’s ability to generate energy efficiently for the cell.

Conditions caused by mutations in mitochondrial DNA often involve multiple organ systems. The effects of these conditions are most pronounced in organs and tissues that require a lot of energy (such as the heart, brain, and muscles). Although the health consequences of inherited mitochondrial DNA mutations vary widely, frequently observed features include muscle weakness and wasting, problems with movement, diabetes, kidney failure, heart disease, loss of intellectual functions (dementia), hearing loss, and abnormalities involving the eyes and vision.

Mitochondrial DNA is also prone to somatic mutations, which are not inherited. Somatic mutations occur in the DNA of certain cells during a person’s lifetime and typically are not passed to future generations. Because mitochondrial DNA has a limited ability to repair itself when it is damaged, these mutations tend to build up over time. A buildup of somatic mutations in mitochondrial DNA has been associated with some forms of cancer and an increased risk of certain age-related disorders such as heart disease, Alzheimer disease, and Parkinson disease. Additionally, research suggests that the progressive accumulation of these mutations over a person’s lifetime may play a role in the normal process of aging.

For more information about conditions caused by mitochondrial DNA mutations:

Genetics Home Reference provides background information about mitochondria and mitochondrial DNA written in consumer-friendly language.

The Cleveland Clinic offers a basic introduction to mitochondrial disease.

An overview of mitochondrial disorders is available from GeneReviews.

The Muscular Dystrophy Association offers an introduction to mitochondrial disorders as part of their fact sheet called Mitochondrial Myopathies.

The Neuromuscular Disease Center at Washington University provides an in-depth description of many mitochondrial conditions.

Researchers are learning that nearly all conditions and diseases have a genetic component. Some disorders, such as sickle cell anemia and cystic fibrosis, are caused by mutations in a single gene. The causes of many other disorders, however, are much more complex. Common medical problems such as heart disease, diabetes, and obesity do not have a single genetic cause—they are likely associated with the effects of multiple genes in combination with lifestyle and environmental factors. Conditions caused by many contributing factors are called complex or multifactorial disorders.

Although complex disorders often cluster in families, they do not have a clear-cut pattern of inheritance. This makes it difficult to determine a person’s risk of inheriting or passing on these disorders. Complex disorders are also difficult to study and treat because the specific factors that cause most of these disorders have not yet been identified. By 2010, however, researchers predict they will have found the major contributing genes for many common complex disorders.

For more information about complex disorders:

A fact sheet about the inheritance of multifactorial disorders is available from the Centre for Genetics Education.

If you would like information about a specific complex disorder such as diabetes or obesity, MedlinePlus will lead you to fact sheets and other reliable medical information. In addition, the Centers for Disease Control and Prevention provides a detailed list of diseases and conditions that links to additional information.

Statistical data can provide general information about how common a condition is, how many people have the condition, or how likely it is that a person will develop the condition. Statistics are not personalized, however—they offer estimates based on groups of people. By taking into account a person’s family history, medical history, and other factors, a genetics professional can help interpret what statistics mean for a particular patient.

Some statistical terms are commonly used when describing genetic conditions and other disorders. These terms include:

For more information about understanding and interpreting statistics:

The New York Department of Health provides a basic explanation of statistical terms, including incidence, prevalence, morbidity, and mortality.

Information about interpreting cancer statistics is available from the Centers for Disease Control and Prevention (CDC) as part of an educational module for students. Although this information focuses on cancer, information about health statistics can also apply to other disorders. The National Cancer Institute offers additional tools for understanding cancer statistics.

Naming genetic conditions

Genetic conditions are not named in one standard way (unlike genes, which are given an official name and symbol by a formal committee). Doctors who treat families with a particular disorder are often the first to propose a name for the condition. Expert working groups may later revise the name to improve its usefulness. Naming is important because it allows accurate and effective communication about particular conditions, which will ultimately help researchers find new approaches to treatment.

Disorder names are often derived from one or a combination of sources:

• The basic genetic or biochemical defect that causes the condition (for example, alpha-1 antitrypsin deficiency);

• One or more major signs or symptoms of the disorder (for example, hypermanganesemia with dystonia, polycythemia, and cirrhosis);

• The parts of the body affected by the condition (for example, craniofacial-deafness-hand syndrome);

• The name of a physician or researcher, often the first person to describe the disorder (for example, Marfan syndrome, which was named after Dr. Antoine Bernard-Jean Marfan);

• A geographic area (for example, familial Mediterranean fever, which occurs mainly in populations bordering the Mediterranean Sea); or

• The name of a patient or family with the condition (for example, amyotrophic lateral sclerosis, which is also called Lou Gehrig disease after the famous baseball player who had the condition).

Disorders named after a specific person or place are called eponyms. There is debate as to whether the possessive form (e.g., Alzheimer’s disease) or the nonpossessive form (Alzheimer disease) of eponyms is preferred. As a rule, medical geneticists use the nonpossessive form, and this form may become the standard for doctors in all fields of medicine.

Naming genes

The HUGO Gene Nomenclature Committee (HGNC) designates an official name and symbol (an abbreviation of the name) for each known human gene. Some official gene names include additional information in parentheses, such as related genetic conditions, subtypes of a condition, or inheritance pattern. The HGNC is a non-profit organization funded by the U.K. Medical Research Council and the U.S. National Institutes of Health. The Committee has named more than 13,000 of the estimated 20,000 to 25,000 genes in the human genome.

During the research process, genes often acquire several alternate names and symbols. Different researchers investigating the same gene may each give the gene a different name, which can cause confusion. The HGNC assigns a unique name and symbol to each human gene, which allows effective organization of genes in large databanks, aiding the advancement of research. For specific information about how genes are named, refer to the HGNC’s Guidelines for Human Gene Nomenclature.