A gene variant is a permanent change in the DNA sequence that makes up a gene. This type of genetic change used to be known as a gene mutation, but because changes in DNA do not always cause disease, it is thought that gene variant is a more accurate term. Variants can affect one or more DNA building blocks (nucleotides) in a gene.

Gene variants can be inherited from a parent or occur during a person’s lifetime:

• Inherited (or hereditary) variants are passed from parent to child and are present throughout a person’s life in virtually every cell in the body. These variants are also called germline variants 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 contains DNA from both parents. Any variants that are present in that DNA will be present in the cells of the child that grows from the fertilized egg.
• Non-inherited variants occur at some time during a person’s life and are present only in certain cells, not in every cell in the body. Because non-inherited variants typically occur in somatic cells (cells other than sperm and egg cells), they are often referred to as somatic variants. These variants cannot be passed to the next generation. Non-inherited variants can be caused by environmental factors such as ultraviolet radiation from the sun or can occur if an error is made as DNA copies itself during cell division.

Some genetic changes are described as new (de novo) variants; these variants are recognized in a child but not in either parent. In some cases, the variant occurs in a parent’s egg or sperm cell but is not present in any of their other cells. In other cases, the variant occurs in the fertilized egg shortly after the egg and sperm cells unite. (It is often impossible to tell exactly when a de novo variant happened.) As the fertilized egg divides, each resulting cell in the growing embryo will have the variant. De novo variants are one explanation for genetic disorders in which an affected child has a variant in every cell in the body, but the parents do not, and there is no family history of the disorder.

Variants acquired during development can lead to a situation called mosaicism, in which a set of cells in the body has a different genetic makeup than others. In mosaicism, the genetic change is not present in a parent’s egg or sperm cells, or in the fertilized egg, but happens later, anytime from embryonic development through adulthood. As cells grow and divide, cells that arise from the cell with the altered gene will have the variant, while other cells will not. When a proportion of somatic cells have a gene variant and others do not, it is called somatic mosaicism. Depending on the variant and how many cells are affected, somatic mosaicism may or may not cause health problems. When a proportion of egg or sperm cells have a variant and others do not, it is called germline mosaicism. In this situation, an unaffected parent can pass a genetic condition to their child.

Most variants do not lead to development of disease, and those that do are uncommon in the general population. Some variants occur often enough in the population to be considered common genetic variation. Several such variants are responsible for differences between people such as eye color, hair color, and blood type. Although many of these common variations in the DNA have no negative effects on a person’s health, some may influence the risk of developing certain disorders.

The gene is the basic physical unit of inheritance. Genes are passed from parents to offspring and contain the information needed to specify traits. Genes are arranged, one after another, on structures called chromosomes. A chromosome contains a single, long DNA molecule, only a portion of which corresponds to a single gene. Humans have approximately 20,000 genes arranged on their chromosomes.

A gene could be as short as a few hundred base pairs or as long as many thousands. The BRCA1 and BRCA2 genes, for instance, are very long and huge. The beta-globin gene, on the other hand, is only a few hundred of these nucleotides. A gene, in a common way of thinking about it, is a packet of information coding generally for a protein. Of course, [in] DNA, the gene doesn't do the work. It's the protein that's produced from that that carries out the function. It's gotten [a] little messy in that one gene doesn't just make one protein. Oftentimes, because of alternative splicing, one gene can produce multiple proteins. And of course there are genes that don't even make proteins at all. They make RNAs that have some other functional role. And some people have begun to question whether the term "gene" is useful because it's gotten so complicated. Not to worry, it is still a very useful term. Geneticists wouldn't know how to have a conversation without using the word.

Francis S. Collins, M.D., Ph.D.

Double helix is the description of the structure of a DNA molecule. A DNA molecule consists of two strands that wind around each other like a twisted ladder. Each strand has a backbone made of alternating groups of sugar (deoxyribose) and phosphate groups. Attached to each sugar is one of four bases: adenine (A), cytosine (C), guanine (G), or thymine (T). The two strands are held together by bonds between the bases, adenine forming a base pair with thymine, and cytosine forming a base pair with guanine.

A double helix has become the icon for many, many kinds of discussions about where science has been and where it's going. This really is an amazing structure. You can't stare at the double helix for very long without having a sense of awe about the elegance of this information molecule DNA, with its double helical form basically being the way in which all living forms are connected to each other, because they all use this same structure for conveying that information. Of course, this is Watson and Crick's incredible realization back in 1953, but it will stand in history as probably one of the most significant scientific moments of all time.

Francis S. Collins, M.D., Ph.D.

A mutation is a change in a DNA sequence. Mutations can result from DNA copying mistakes made during cell division, exposure to ionizing radiation, exposure to chemicals called mutagens, or infection by viruses. Germ line mutations occur in the eggs and sperm and can be passed on to offspring, while somatic mutations occur in body cells and are not passed on.

Mutation has been the source of many Hollywood movies, but it's really a simple process of a mistake made in a DNA sequence as it's being copied. Some of that's just the background noise that DNA copying is not perfect, and we should be glad of that or evolution couldn't operate. But mutation can also be induced by things like radiation or carcinogens in a way that can increase the risk of cancers or birth defects. But it's pretty simple; it's basically an induced misspelling of the DNA sequence. That's a mutation.

Francis S. Collins, M.D., Ph.D.

An allele is one of two or more versions of DNA sequence (a single base or a segment of bases) at a given genomic location. An individual inherits two alleles, one from each parent, for any given genomic location where such variation exists. If the two alleles are the same, the individual is homozygous for that allele. If the alleles are different, the individual is heterozygous.

"Allele" is the word that we use to describe the alternative form or versions of a gene. People inherit one allele for each autosomal gene from each parent, and we tend to lump the alleles into categories. Typically, we call them either normal or wild-type alleles, or abnormal, or mutant alleles.

A carrier, as related to genetics, is an individual who “carries” and can pass on to its offspring a genomic variant (allele) associated with a disease (or trait) that is inherited in an autosomal recessive or sex-linked manner, and who does not show symptoms of that disease (or features of that trait). The carrier has inherited the variant allele from one parent and a normal allele from the other parent. Any offspring of carriers is at risk of inheriting a variant allele from their parents, which would result in that child having the disease (or trait).

Carrier. The key to understanding carrier in the genetic sense is that, even though we all have two copies of each gene, for some genes you can have only one working copy and essentially have no major medical issues. The challenge arises when you have a child with another person who is also a carrier for the same autosomal recessive disorder, and the child inherits both nonworking copies from each parent. There's a 25% chance of this happening with every pregnancy. Most often, people don't know that they are carriers. As a result, it's now possible to genetically screen prospective parents to determine whether they are carriers for any of the more commonly seen autosomal recessive disorders.

Neil A. Hanchard, M.B.B.S., D.Phil., Senior Investigator, Center for Precision Health Research

To function correctly, each cell depends on thousands of proteins to do their jobs in the right places at the right times. Sometimes, gene variants (also known as mutations) prevent one or more proteins from working properly. By changing a gene’s instructions for making a protein, a variant can cause a protein to malfunction or to not be produced at all. When a variant alters a protein that plays a critical role in the body, it can disrupt normal development or cause a health condition. A condition caused by variants in one or more genes is called a genetic disorder.

In some cases, gene variants 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 variants 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 variants that alter or eliminate a gene’s function. For example, when people say that someone has “the cystic fibrosis gene,” they are usually referring to a version of the CFTR gene that contains a variant that causes the disease. All people, including those without cystic fibrosis, have a version of the CFTR gene.

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

Often, gene variants 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 errors in DNA. Because DNA can be changed or damaged in many ways, DNA repair is an important process by which the body protects itself from disease.

A very small percentage of all variants actually have a positive effect. These variants lead to new versions of proteins that help an individual better adapt to changes in his or her environment. For example, a beneficial variant 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 many variants with no effect on health, diagnosing genetic disorders can be difficult.

When determining if a gene variant is associated with a genetic disorder, the variant is evaluated using scientific research to date, such as information on how the variant affects the function or production of the protein that is made from the gene and previous variant classification data. The variant is then classified on a spectrum based on how likely the variant is to lead to the disorder.

Gene variants, as they relate to genetic disorders, are classified into one of five groups:

• Pathogenic: The variant is responsible for causing disease. There is ample scientific research to support an association between the disease and the gene variant. These variants are often referred to as mutations.
• Likely pathogenic: The variant is probably responsible for causing disease, but there is not enough scientific research to be certain.
• Variant of uncertain significance (VUS or VOUS): The variant cannot be confirmed to play a role in the development of disease. There may not be enough scientific research to confirm or refute a disease association or the research may be conflicting.
• Likely benign: The variant is probably not responsible for causing disease, but there is not enough scientific research to be certain.
• Benign: The variant is not responsible for causing disease. There is ample scientific research to disprove an association between the disease and the gene variant.

Evaluation needs to be done for each variant. Just because a gene is associated with a disease, does not mean that all variants in that gene are pathogenic. Additionally, evaluation of a variant needs to be done for all diseases with which it is thought to be associated. A variant that is pathogenic for one disease, is not necessarily pathogenic for a different disease. It is important to re-evaluate variants periodically; the classification of a variant can change over time as more information about the effects of variants becomes known through additional scientific research.

The DNA sequence of a gene can be altered in a number of ways. Gene variants (also known as mutations) can have varying effects ­­on health, depending on where they occur and whether they alter the function of essential proteins. Variant types include the following:

Substitution

This type of variant replaces one DNA building block (nucleotide) with another. Substitution variants can be further classified by the effect they have on the production of protein from the altered gene.

Missense

A missense variant is a type of substitution in which the nucleotide change results in the replacement of one protein building block (amino acid) with another in the protein made from the gene. The amino acid change may alter the function of the protein.

Nonsense

A nonsense variant is another type of substitution. Instead of causing a change in one amino acid, however, the altered DNA sequence results in a stop signal that prematurely signals the cell to stop building a protein. This type of variant results in a shortened protein that may function improperly, be nonfunctional, or get broken down.

Insertion

An insertion changes the DNA sequence by adding one or more nucleotides to the gene. As a result, the protein made from the gene may not function properly.

Deletion

A deletion changes the DNA sequence by removing at least one nucleotide in a gene. Small deletions remove one or a few nucleotides within a gene, while larger deletions can remove an entire gene or several neighboring genes. The deleted DNA may alter the function of the affected protein or proteins.

Deletion-Insertion

This variant occurs when a deletion and insertion happen at the same time in the same location in the gene. In a deletion-insertion variant, at least one nucleotide is removed and at least one nucleotide is inserted. However, the change must be complex enough to differ from a simple substitution. The resulting protein may not function properly. A deletion-insertion (delins) variant may also be known as an insertion-deletion (indel) variant.

Duplication

A duplication occurs when a stretch of one or more nucleotides in a gene is copied and repeated next to the original DNA sequence. This type of variant may alter the function of the protein made from the gene.

Inversion

An inversion changes more than one nucleotide in a gene by replacing the original sequence with the same sequence in reverse order.

Frameshift

A reading frame consists of groups of three nucleotides that each code for one amino acid. A frameshift variant occurs when there is an addition or loss of nucleotides that shifts the grouping and changes the code for all downstream amino acids. The resulting protein is usually nonfunctional. Insertions, deletions, and duplications can all be frameshift variants.

Repeat expansion

Some regions of DNA contain short sequences of nucleotides that are repeated a number of times in a row. For example, a trinucleotide repeat is made up of sequences of three nucleotides, and a tetranucleotide repeat is made up of sequences of four nucleotides. A repeat expansion is a variant that increases the number of times that the short DNA sequence is repeated. This type of variant can cause the resulting protein to function improperly.

ACGT is an acronym for the four types of bases found in a DNA molecule: adenine (A), cytosine (C), guanine (G), and thymine (T). A DNA molecule consists of two strands wound around each other, with each strand held together by bonds between the bases. Adenine pairs with thymine, and cytosine pairs with guanine. The sequence of bases in a portion of a DNA molecule, called a gene, carries the instructions needed to assemble a protein.

Genetic code is the term we use for the way that the four bases of DNA--the A, C, G, and Ts--are strung together in a way that the cellular machinery, the ribosome, can read them and turn them into a protein. In the genetic code, each three nucleotides in a row count as a triplet and code for a single amino acid. So each sequence of three codes for an amino acid. And proteins are made up of sometimes hundreds amino acids, so the code that would make one protein could have hundreds, sometimes even thousands, of triplets contained in it.

Deletion is a type of mutation involving the loss of genetic material. It can be small, involving a single missing DNA base pair, or large, involving a piece of a chromosome.

Deletion really means that something is missing. And as a geneticist talking about deletion it means something is missing of the genetic material. And it can be something small, just a base pair; it can be something larger; it can be part of a gene; it can be even larger; it can be an entire gene; or yet larger again, it can be part of the chromosome. And depending upon what it is, you have to look at it in different ways. You can find a deletion in a chromosome just by doing a cytogenetic or chromosome analysis, or a deletion in a gene you can find out by sequencing the DNA. So when you have a deletion, depending upon the size, it can have different effects. What was the most surprising to me was that just by having a deletion of one base pair, you can have the most severe birth defect, and sometimes by missing an entire chromosome, you don't even see all that much compared to just having a deletion of a small base pair. Different deletions can lead to different findings, and they can affect just behavior; they can affect how a child, how a person looks; they can affect a very severe problem that the child may die at birth; or they can affect something that just has to do with eye color, hair color, with weight or height of the person.

Maximilian Muenke, M.D.

Duplication is a type of mutation that involves the production of one or more copies of a gene or region of a chromosome. Gene and chromosome duplications occur in all organisms, though they are especially prominent among plants. Gene duplication is an important mechanism by which evolution occurs.

Duplications occur when there is more than one copy of a specific stretch of DNA. This can occur in several different contexts. During a disease process, extra copies of the gene can contribute to a cancer. Genes can also duplicate through evolution, where one copy can continue the original function and the other copy of the gene produces a new function. On occasion, whole chromosomes are duplicated. In humans this causes disease. Throughout evolution, there have been several occasions, both in fish and plants, where whole genomes have been duplicated.

Lawrence C. Brody, Ph.D.

A frameshift mutation is a type of mutation involving the insertion or deletion of a nucleotide in which the number of deleted base pairs is not divisible by three. "Divisible by three" is important because the cell reads a gene in groups of three bases. Each group of three bases corresponds to one of 20 different amino acids used to build a protein. If a mutation disrupts this reading frame, then the entire DNA sequence following the mutation will be read incorrectly.

A frameshift mutation is a particular type of mutation that involves either insertion or deletion of extra bases of DNA. Now, what's important here is the number three. The number of bases that are either added or subtracted can't be divisible by three. And that's important because the cell reads a gene in groups of three bases. Every group of three bases corresponds to one of the 20 different amino acids that are used by your body to make proteins. And keep in mind your body has a lot of proteins; everything from the material that makes up your skin, to the material that makes up your hair, to the digestive juices that help you digest that yummy lunch you just had. If a mutation disrupts one of those reading frames, so that the wrong amino acid is put in place, then the entire DNA sequence following the mutation will be disrupted or read incorrectly. Very often, what we see is a premature termination. Instead of the encoded protein being of a certain particular size, it'll end up being much shorter, and it won't be able to accomplish the role that's been set out for it.

Elaine A. Ostrander, Ph.D.

Insertion is a type of mutation involving the addition of genetic material. An insertion mutation can be small, involving a single extra DNA base pair, or large, involving a piece of a chromosome.

Insertion really means that something has been stuck in there. And again, as a geneticist, when we think of an insertion, we think of a piece of DNA, and that can be small or large, being stuck in at a place where it really doesn't belong. So an insertion of just one base pair could lead to something that we call a frameshift. It shifts the reading of the three-base pair code and by that can throw off the entire protein, and by that can lead, for example, to a birth defect. Insertion can be larger, that, for example, there is an insertion of three base pairs, and then it will not throw off the frame, or it will not lead to a frameshift, and potentially is less harmful than having the insertion of just one base pair. And of course you can have an insertion of huge pieces of DNA. They can be so large that you could actually see it on the chromosome analysis, where all of the smaller insertions you would see only by sequencing the stretch of DNA.

Maximilian Muenke, M.D.

A missense mutation is when the change of a single base pair causes the substitution of a different amino acid in the resulting protein. This amino acid substitution may have no effect, or it may render the protein nonfunctional.

A missense mutation is a mistake in the DNA which results in the wrong amino acid being incorporated into a protein because of change, that single DNA sequence change, results in a different amino acid codon which the ribosome recognizes. Changes in amino acid can be very important in the function of a protein. But sometimes they make no difference at all, or very little difference. Sometimes missense mutations cause amino acids to be incorporated, which make the protein more effective in doing its job. More frequently, it causes the protein to be less effective in doing its job. But this is really the grist of evolution, when missense mutations happen, and therefore small changes, frequently small changes in proteins, happen, and it happens to be that it improves the function of a protein. That will sometimes give the organism that has it a competitive advantage over its colleagues and be maintained in the population.

Christopher P. Austin, M.D.

A nonsense mutation occurs in DNA when a sequence change gives rise to a stop codon rather than a codon specifying an amino acid. The presence of the new stop codon results in the production of a shortened protein that is likely non-functional.

A nonsense mutation, or its synonym, a stop mutation, is a change in DNA that causes a protein to terminate or end its translation earlier than expected. This is a common form of mutation in humans and in other animals that causes a shortened or nonfunctional protein to be expressed.

A point mutation is when a single base pair is altered. Point mutations can have one of three effects. First, the base substitution can be a silent mutation where the altered codon corresponds to the same amino acid. Second, the base substitution can be a missense mutation where the altered codon corresponds to a different amino acid. Or third, the base substitution can be a nonsense mutation where the altered codon corresponds to a stop signal.

Point mutations are a large category of mutations that describe a change in single nucleotide of DNA, such that that nucleotide is switched for another nucleotide, or that nucleotide is deleted, or a single nucleotide is inserted into the DNA that causes that DNA to be different from the normal or wild type gene sequence.

Leslie G. Biesecker, M.D.

Substitution, as related to genomics, is a type of mutation in which one nucleotide is replaced by a different nucleotide. The term can also refer to the replacement of one amino acid in a protein with a different amino acid.

Substitution. It's always fascinated me how tiny changes in one's genome, like a simple substitution, can have such profound effects on human health. Changing a single nucleotide will change the amino acid sequence, which can impact how the protein it forms will look and act. Most of these small changes don't have a meaningful impact on human health or appearance, but we're quickly learning how to find the ones that are important. Knowing how small genetic changes work can then help us to discover new treatments for diseases. The differences between people's appearance comes from these seemingly miniscule changes in our genetic code, which I think should remind us that all humans share nearly all of our genetic material.

Benjamin E. Berkman, J.D., M.P.H., Deputy Director, NHGRI Bioethics Core

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 have one, three, or more copies of particular genes. Less commonly, both copies of a gene may be missing. These types of genetic difference are known as copy number variations (CNV).

Copy number variation results from insertions, deletions, and duplications of large segments of DNA that are at least one thousand nucleotides (also called 1 kilobase or 1kb) in length. These segments are often big enough to include whole genes. Variation in gene copy number can influence the activity of genes and the functioning of proteins made from them, which may affect body processes.

Copy number variation accounts for a significant amount of genetic difference between people. More than 10 percent of the human genome appears to contain differences in gene copy number. While much of this variation does not affect health or development, some differences influence a person’s risk of disease, particularly some types of cancer, or response to certain drugs.

Human cells normally contain 23 pairs of chromosomes, for a total of 46 chromosomes in each cell. 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 in the number 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 (also known as trisomy 21) is an example of a condition caused by trisomy. 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 (also known as monosomy X) is a condition caused by monosomy. 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. 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’s cells differ in their chromosomal makeup, it is known as chromosomal mosaicism. 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.

A chromosome is an organized package of DNA found in the nucleus of the cell. Different organisms have different numbers of chromosomes. Humans have 23 pairs of chromosomes--22 pairs of numbered chromosomes, called autosomes, and one pair of sex chromosomes, X and Y. Each parent contributes one chromosome to each pair so that offspring get half of their chromosomes from their mother and half from their father.

A chromosome is the structure housing DNA in a cell. Chromosomes are structurally quite sophisticated, containing elements necessary for processes such as replication and segregation. Each species has a characteristic set of chromosomes with respect to number and organization. For example, humans have 23 pairs of chromosomes--22 pairs of numbered chromosomes called autosomes, 1 through 22, and one pair of sex chromosomes, X and Y. Each parent contributes one chromosome of each pair to an offspring.

Eric D. Green, M.D., Ph.D.

Monosomy is the state of having a single copy of a chromosome pair instead of the usual two copies found in diploid cells. Monosomy can be partial if a portion of the second chromosome copy is present. Monosomy, or partial monosomy, is the cause of some human diseases such as Turner syndrome and Cri du Chat syndrome.

Monosomy is used to refer to a status of an autosomal gene, when normally two copies are supposed to be present and instead only a single copy of a gene is present. This word can also refer to multiple genes or segments, or even an entire chromosome, where an individual is supposed to have two copies of this gene or chromosome, and they only have a single copy. The loss of one of two copies of an autosomal gene or segment of genes, or an entire chromosome, is a cause of human genetic disease.

Leslie G. Biesecker, M.D.