Genetic Variation: the phenotypic and genotypic differences observed among individuals in a population. (MeSH) Can refer to differences between individuals or to differences between populations. Mutation is the ultimate source of genetic variation, but mechanisms such as sexual reproduction and genetic drift contribute to it as well. (NHGRI)

Variation in the genetic program causes variation in the outcome (for example, what a person looks like). (Mitchell, 5) Variation occurs whenever the order of the “bases” in a “DNA sequence” changes. Variations can involve only one base or many bases. If the two “strands” of a “chromosome” are thought of as “nucleotides” threaded on a string, then, for example, a string can break and the order of the beads can vary. One or more nucleotides may be changed, added, or removed. In chromosomes, these changes are called “polymorphisms,” “insertions,” and “deletions.” (NCI16, slide 8) Charles Darwin noted that some of the variation of a trait is due to inborn differences in populations, and some to differences in “environmental” influences. (Lewis, 137) “Diabetes,” “cancer,” “heart disease,” “Huntington's disease,” and “hemophilia” all result from variations that cause harmful effects. In a ‘simple’ disease such as hemophilia, variation in one gene is sufficient to cause disease symptoms. By contrast, in a ‘complex’ disease like cancer, symptoms are seen only after many variations have occurred in different genes in the same cell. (NCI16, slide 11) However, much variation seems to be neutral in its effects. (Ridley, 139) An amazing aspect of the “human genome” is that there is so little variation in the "DNA sequence" when the "genome" of one person is compared to that of another. Of the 3.2 billion bases, roughly 99.9 percent are the same between any two people. It is the variation in the remaining tiny fraction of the genome, 0.1 percent - roughly several million bases - that makes a person unique. This small amount of variation determines attributes such as how a person looks, or the diseases he or she develops. (NCI16, slide 7) Genetic variation in a population is derived from a wide assortment of genes and “alleles.” The persistence of populations over time through changing environments depends on their capacity to adapt to shifting external conditions. Sometimes the addition of a new allele to a population makes it more able to survive; sometimes the addition of a new allele to a population makes it less able. Still other times, the addition of a new allele to a population has no effect at all, yet the new allele will persist over generations because its contribution to survival is neutral. (Nature Education) Also referred to as 'variation,' 'genetic variance,' and 'genetic diversity.’

Genetic Drift: a mechanism of “evolution.” It refers to random fluctuations in the “frequencies” of alleles from generation to generation due to chance events. Genetic drift can cause “traits” to be “dominant” or disappear from a population. The effects of genetic drift are most pronounced in small populations. (NHGRI) Random changes in gene frequency in small isolated populations owing to factors other than natural selection. (Lawrence)

Gene Mutation(s): an alteration in the DNA sequence of a gene. (Batiza, 173) A gene is made up of a normal sequence of letters. Mutations change that sequence. (Dorsey, 24) Range from single base changes to entire extra sets of chromosomes. (Lewis, 236) A recent discovery (showed) that not all mutations are present in the genomes of our parents. Some mutations arise spontaneously in the sperm of adult men. (Kandel4, 49) Can result from DNA copying mistakes made during “cell division,” exposure to “ionizing radiation,” exposure to chemicals called “mutagens,” or “infection” by “viruses.” (NHGRI) Occur randomly and any part of the DNA present in an “organism” may mutate. The rate at which mutation takes place can be increased by exposure to various mutagens. (Indge, 117). Mutations can be harmful, beneficial, or have no effect. If they occur in cells that make “eggs” or “sperm,” they can be inherited; if mutations occur in other types of cells, they are not inherited. Certain mutations may lead to cancer or other diseases. (NCI1) A change in the “genetic material” of organisms. A mutation may alter the traits of organisms in a way that increases their chances of survival or reproduction. When a mutation causes such a beneficial change, the mutation is more likely to increase in a population over the course of many generations, a process called “natural selection.” (Brooker, 6) Verb - ‘mutate.’

Copy Number Variation (CNV): difference in the structure of our chromosomes. We may be missing a small bit of DNA from a chromosome or we may have an extra bit of DNA in a chromosome. Copy number variations my decrease or increase the number of genes on a chromosome by twenty to thirty genes. (Kandel4, 46) The number of copies of a particular gene. Varies from one individual to the next. Following the completion of the “Human Genome Project,” it became apparent that the genome experiences gains and losses of genetic material. The extent to which copy number variation contributes to human disease is not yet known. It has long been recognized that some cancers are associated with elevated copy numbers of particular genes. (NHGRI) Repeated short DNA sequences. May explain behavioral disorders that arise in someone without a family history. (Lewis, 151) Genetic variants, including insertions, deletions, and duplications of (sequences) of DNA, are also collectively referred to as copy number variants. Copy number variants account for a significant proportion of the genetic variation between individuals. (NCI3) Also referred to as ‘copy number variants.’

Copy Number Deletion: missing a small bit of DNA from a chromosome. (Kandel4, 46) 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. (NHGRI) Absence of a segment of DNA. (GeneReviews) A loss of part of the DNA from a chromosome; can lead to a disease or abnormality. (HGPIA) Also referred to as a ‘deletion.’

Copy Number Duplication: having an extra bit of DNA in a chromosome. (Kandel4, 46) A chromosome abnormality in which a piece of DNA is incorporated into a gene and thereby disrupts the gene's normal function. (HGPIA) 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. (NHGRI) Also referred to as an ‘insertion.’

De Novo Mutations: those that arise spontaneously in the sperm of adult men. A father can transmit them to his children. Studies have found that de novo mutations markedly increase the risk of “autism.” The number of de novo mutations increases with paternal age. The reason de novo mutations increase with age is that sperm “precursor cells” divide every fifteen days. This continued division and copying of DNA leads to errors. Thus, a father who is twenty years old will have, on average, twenty-five de novo mutations in his sperm, whereas a father who is forty years old will have sixty-five mutations. Most of these mutations are harmless, but some are not. We also have evidence that de novo mutations in an older father’s sperm contribute to schizophrenia and to bipolar disorder. (Kandel4, 49-50) Also referred to as ‘new mutations.”

Frameshift: a 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. (NHGRI) An insertion or deletion involving a number of base pairs that is not a multiple of three, which consequently disrupts the triplet reading frame of a DNA sequence. Such mutations usually lead to the creation of a premature “stop codon,” and result in a shorter-than-normal protein product. (NCI3) Also referred to as ‘frameshift mutation,’ ’out-of-frame deletion,'  and 'out-of-frame mutation.’

Hot Spot: in genetics, a (region) of DNA that is likely to mutate (change). (NCI1) Regions (on a DNA strand) where sequences are repetitive. Mutations are more likely to occur in these regions. (Lewis, 217) DNA sequences of high susceptibility to mutation due to some inherent instability, tendency toward unequal "crossing over," or chemical predisposition to single nucleotide substitutions; region where mutations are observed with greater frequency. (GeneReviews) Also referred to as ‘hot spot mutation region.’

Point Mutation: a change in a single DNA base. (Lewis, 220) An alteration in a DNA sequence caused by the substitution of a single nucleotide for another nucleotide. (NCI13) A point mutation is when a single base pair is altered. Point mutations can have one of three effects. (NHGRI)

Missense Mutation: 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. (NHGRI) A single base pair substitution that alters the genetic code in a way that produces an amino acid that is different from the usual amino acid at that position. Some missense mutations will alter the function of the protein. (NCI3) Converts an amino acid-specific codon to a stop codon. (MeSH)

Nonsense Mutation: the substitution of a single base pair that leads to the appearance of a “stop codon” where previously there was a codon specifying an amino acid. The presence of this premature stop codon results in the production of a shortened, and likely nonfunctional, protein. (NHGRI) Its occurrence is abnormal causing premature termination of protein translation and results in production of truncated and non-functional proteins. (MeSH) The altered protein may be partially or completely inactivated, resulting in a change or loss of protein function. (NCI13)

Silent Mutation: base substitution where the altered codon corresponds to the same amino acid. (NHGRI) A mutation that alters DNA sequence, but has no apparent detectable effect on a phenotype or a function. (GHR)

Mutant: refers to "phenotype." The nature of a mutant phenotype depends upon how the mutation affects the gene's "product" or activity and usually connotes an abnormal or unusual characteristic.  However, a mutant phenotype may also be an uncommon variant that is nevertheless ‘normal,’ such as red hair. (Lewis, 212) Also referred to as 'mutant allele.’

Polymorphism: a genetic change (similar to a mutation). Present in more than 1% of the population. (Lewis, 212) Difference in DNA sequence among individuals that may underlie differences in health. Genetic variations occurring in more than 1% of a population would be considered useful polymorphisms for genetic “linkage analysis.” (HGPIA) Involves one of two or more variants of a particular DNA sequence. The most common type of polymorphism involves variation at a single base pair. Polymorphisms can also be much larger in size and involve long stretches of DNA. (NHGRI) Adjective - ‘polymorphic.’ 

Restriction Fragment Length Polymorphism (RFLP): variation occurring within a “species” in the presence or length of a DNA fragment generated at a specific site in the genome. Such variations are generated by mutations that create or abolish ‘recognition sites’ for “enzymes” or change the length of the fragment. (MeSH)

Single Nucleotide Polymorphisms (SNPs): tiny variations in the human genome. (NCI16, slide 3) DNA sequence variations that occur when a single nucleotide in the “genome sequence” is altered. (HGPIA) The single base is replaced by any of the other three bases. (NCI16, slide 13) Can occur in genes as well as in “noncoding regions.” Slight variations in our DNA sequences can have a major impact on whether or not we develop a disease and on our particular responses to such environmental insults as “bacteria,” viruses, and “toxins.” (ORNL) Scientists are studying how SNPs in the human genome correlate with disease, drug response, and other phenotypes. (NHGRI) Editor’s note - an example disorder is “sickle cell disease.”

Spontaneous Mutation: mutations that arise spontaneously, rather than being inherited. (Lewis, 151) An alteration in a gene that is present for the first time in one family member as a result of a mutation in an egg or sperm of one of the parents, or a mutation that arises in the fertilized egg itself during early “embryogenesis.” (NCI13) Also referred to as ‘de novo mutation’ and ‘new mutation.’

Substitution: a type of mutation where one base pair is replaced by a different base pair. The term also refers to the replacement of one amino acid in a protein with a different amino acid. (NHGRI) A type of mutation due to replacement of one nucleotide in a DNA sequence by another nucleotide, or replacement of one amino acid in a protein by another amino acid. (HGPIA)

Thymine Dimer: “thymine” bases damaged by “UVB radiation.” Causes an extra “covalent bond” between thymine bases. The extra bond kinks the “double helix” enough to disrupt “replication” or disrupt “transcription.” (Lewis, 228)

Gene Variant: a variation in the nucleic acid sequence of a specific gene. (NCIt) An alteration in the normal sequence of a gene, the significance of which is unclear until further study of the genotype and corresponding phenotype in a sufficiently large population. Complete gene sequencing often identifies numerous (sometimes hundreds) allelic variants for a given gene. (GeneReviews) Also referred to as an ‘variant’ and ‘allelic variant.’

Silent Variation: most variations in the human genome have no known effect at all because they occur in “noncoding regions” of the DNA. In addition, there are some changes that do occur in “coding regions,” yet they have no known effect. All these are silent variations. (NCI16)