View a Printer-Friendly Version of this Web Page!

Our knowledge of genetic variations has been so profoundly influenced by Mendelian  genetics that it is difficult to speculate about the ways in which our thinking will need to change with further insights into genomics. We have far to go in teasing apart the multiple variables of complex traits and diseases, the relationships between hereditary, somatic and environmental factors, and in making the transition from focusing on monogenic diseases with high penetrance to polygenic conditions with greatly varying degrees of penetrance. In addition some fairly common words (allele, polymorphism, wild- type) may carry an explicit (or more frequently implicit) connotation of "normal" and/ or functional, dating from the early days of genetics when only mutant phenotypes revealed the presence of genetic variations.  

Currently identified disease related genetic variations are relatively rare.  Gene expression studies are giving some insight into clusters of alleles which may be linkable to diseases and phenotypes. Recent work on SNPs seems promising, but powerful new methods for integrating data and detecting variants undetectable by current technologies are still needed.

Related Glossaries include Applications Functional Genomics Pharmacogenomics  Sequencing Informatics Algorithms, Bioinformatics Technologies Chromatography & electrophoresis, Gene amplification & PCR, Microarrays Biology Expression, Gene definitions, Maps- genomic & genetic, Sequences DNA & beyond Additional definitions appear in the In-depth glossary, after the Bibliography.

alleles: One of several alternate forms of a gene which occur at the same locus on homologous chromosomes and which become separated during meiosis and can be recombined following fusion of gametes. [IUPAC Biotech, IUPAC Compendium]

Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [MeSH]

A related individual or strain contains stable, alternative forms of the same gene which differs from the presented sequence at this location (and perhaps others). superceded by 'Variation'. Allele will become illegal from April 15th, 2000 [DDBJ/ EMBL/ GenBank Feature Table]  http://www.ebi.ac.uk/embl/Documentation/FT_definitions/feature_table.html     

Related terms mutation, polymorphisms, SNP ; In-depth bi-allelic, di- allelic, multiple- allelism, tri- allelic. Narrower term slightly deleterious allele. Broader term variants

From alleomorph, which is from the Greek meaning one another form, used by Bateson & Saunders 1902 [OED]  The word gene didn't come along until 1911, coined by W. Johanssen.

Alleles databases See Databases & software directory under 'variations'.

association studies: Looking at particular genes or variations in two groups (e.g., affected patients and controls or responders and nonresponders) to establish an association with a phenotype by finding significant variations in the two groups. [CHI SNPs Update] 

In human genetic linkage studies frequently involve the comparison of allele frequencies for a marker locus between a disease population and in a control population. When statistically significant differences in the frequency of an allele(s) are found between a disease and control population, the disease and allele(s) are said to be in association. [NHLBI]  

Narrower term In-depth random genome-wide association studies. Related term linkage

bioinformatics: Bioinformatics glossary

biological markers: Measurable and quantifiable biological parameters (e.g. specific enzyme concentration, specific hormone concentration, specific gene phenotype distribution in a population, presence of biological substances) which serve as indices for health - and physiology related assessments, such as disease risk, psychiatric disorders, environmental exposure and its effects, disease diagnosis, metabolic processes, substance abuse, pregnancy, cell line development, epidemiologic studies, etc. [MeSH] Also referred to as "biomarkers".

biomarkers: Pharmacogenomics glossary Related term surrogate markers  

Related terms biological markers, genetic markers; Broader term markers.

crossing over: See under genetic recombination.

DNA marker: A cloned chromosomal locus with allelic variation that can be followed directly by a DNA- based assay such as Southern blotting or PCR. [NHLBI]

detection technologies: See genetic variation - detection technologies.

EST Expressed Sequence Tags Gene definitions

fingerprinting: SEE In-depth DNA fingerprinting.

forensics: Genomics glossary

functional polymorphisms: Promoter and non- silent codon changes. http://www.cgr.ki.se/cgb/groups/brookes/Articles/Human%20Genetic%20Bi.pdf  

Compare non-functional polymorphisms.

gene-based SNPs: Not just coding SNPs but also intron SNPs and promoter SNPs. [CHI SNPs Update]

gene-disease associations: The discovery of gene- disease associations requires scanning these same hundreds of thousands of SNPs in as many as 1,000 individuals, possibly using microarray technology.. Validation of gene- disease association studies requires measuring very few SNPs in thousands of individuals. [CHI SNPs Update]

genetic architecture: The full range of genetic effects on a trait, with emphasis on the context dependence of the expression of those genes in manifesting a phenotype. A full cataloging of the genetic architecture of complex phenotypes consists of a description of all of the genetic and environmental factors that affect the phenotype, along with the magnitude of their individual effects and the magnitudes of interactions among the factors. It is, in principle, possible to describe the genetic components in terms of Mendelian segregation and location along a genetic map. Environmental factors are, in general, much less easily partitioned into separate factors whose individual effects and interactions can be sorted out. ... Genetic architecture is less a fundamental biological property of the phenotype than a characteristic of a phenotype in a particular population. The genetic architecture is a moving target that changes according to gene and genotype frequencies, the distributions of environmental factors, and such biological properties as age and sex. The implication of the population dependence is that the predominant genetic factors contributing to a complex phenotype may seem to differ from population to population. This is one explanation for the apparent heterogeneity sometimes found in the results of genetic linkage studies in different populations. Alternative explanations include insufficient statistical power in the linkage tests and the possibility that superficially identical complex phenotypes in different populations may actually have different biological causes. It is not now possible, in most cases, to differentiate among these various explanations. [NIH Program Announcement Genetic architecture of complex phenotypes, June 9, 1998] . http://grants.nih.gov/grants/guide/pa-files/PA-98-078.html 

Related term complex traits

genetic markers: A phenotypically recognizable genetic trait which can be used to identify a genetic locus, a linkage group, or a recombination event [MeSH]

Consist of specific nucleotide patterns. [NHLBI] Related term ESTs Gene definitions UniGene (database) has marker information

genetic recombination:  Happens during the cell division (meiosis) that occurs during the formation of sperm and egg cells. In this process, chromosomes pair up and may swap portions of genetic material in a phenomenon known as crossing over. The chromosomes then reassemble and separate, with each containing some material from the other. The chromosomes are then divvied out into individual sex cells. During crossing over, it is more likely that far- apart genes will be separated by a break than those that are close together. The genes that tend to stay together are said to be linked and therefore may serve as markers for one another — a pattern that is of particular interest when, for example, one of the genes is a disease gene. [CHI SNPs Update]

Production of new arrangements of genes by various mechanisms such as assortment and segregation, crossing over, gene conversion, transformation, conjugation, transduction, F-duction, or mixed infection of viruses. [MeSH]  

Related terms recombinant, recombination

genetic variation - detection technologies: Includes microarrays, In-depth: dHPLC, DNA fingerprinting, DNA footprinting, DNA ligase enzymes, endonucleases, SSCP, SSEP Related terms: Genomics glossary genotype, haplotype, scanning, scoring.

genetic variation - human: The race is on to secure worthwhile information from the published Human Genome. As the emphasis shifts from de novo sequencing to understanding differences in individuals, a variety of approaches will be used to most quickly unlock the value of genomics. While there are many finishing lines across wide- ranging boundaries, to claim the prize it is still imperative to get there first. That there are fewer genes than supposed has ironically increased complexity, rather than reducing it. More than ever technological feats must be united with clinical significance. This area of study has evolved into a science that impacts daily lives Human Genetic Variation September 17-18, 2001, Cambridge MA

genome scan: A traditional genome scan uses microsatellite markers and linkage analysis to scan genomic DNA. Now being combined with genome- wide SNP scans (using hundreds of thousands of markers in thousands of patients) and large-scale association studies [CHI SNPs]  Compare In-depth candidate gene studies

genotype: Genomics glossary  Narrower terms: genetic variation detection, mutation detection

genotyping, genotyping technologies: Sequencing glossary

haplotype: Genomics glossary

haplotyping, haplotyping technologies: Sequencing glossary

idiomorphism:  A polymorphism or any type of variation in DNA sequence occurring with less than 1% frequency.  [Nicholas Schork to Malorye Branca, personal communication Sept. 1999] Compare with SNP.

linkage: Two loci are physically connected to one another on the same chromosome at a distance that is measured at less than 50% recombination.  Two traits are linked when they fail to be transmitted to offspring independently from one another.  The more closely linked two loci are to one another, the greater the chance that both loci will be transmitted to offspring together. The tendency for genes that are located close to each other on the same chromosome to be inherited together. [NHLBI]

The proximity of two or more markers (e.g. genes, RFLP markers) on a chromosome; the closer together the markers are, the lower the probability that they will be separated during DNA repair or replication processes (binary fission in prokaryotes, mitosis or meiosis in eukaryotes), and hence the greater the probability that they will be inherited together. [DOE]  Related terms In-depth linkage analysis, linkage disequilibrium.

localize: Gene definitions

locus, loci (plural): Gene definitions

markers: 1. (DNA) A fragment of known size used as reference for analytical purposes. 2. (genetic) A gene with known phenotype and mapped position. 3. (chromatography) A reference substance co- chromatographed with the sample to assist in identifying the components. [IUPAC Compendium]

A segment of DNA with an identifiable physical location on a chromosome whose inheritance can be followed. A marker can be a gene, or it can be some section of DNA with no known function. Because DNA segments that lie near each other on a chromosome tend to be inherited together, markers are often used as indirect ways of tracking the inheritance patterns of genes that have not yet been identified, but whose approximate locations are known. [NHGRI]

Narrower terms biological markers, biomarkers, DNA markers, ESTs, genetic markers, polymorphisms, In-depth  DNA fingerprints, microsatellite markers, microsatellite repeats, microsatellites,  minisatellite repeats, RFLPs, restriction enzymes, SSRs, STRs, STSs, satellites Related terms Maps- genomic & genetic Types of genetic maps are differentiated largely by the type of marker used.

minisequencing: Sequencing glossary  In-depth

molecular variants: Narrower terms alleles, mutations, polymorphisms, SNPs. Broader term variants.

multifactorial: Two or more genes, together with an environmental effect, work together to lead to a phenotype. [NHLBI Glossary,] Compare multigenic, polygenic, oligogenic.

multigenic: Traits controlled by more than one allele. Compare multifactorial, oligogenic, polygenic.

multiplicative: See under epistasis.

mutation: A heritable change in the nucleotide sequence of genomic DNA (or RNA in RNA viruses), or in the number of genes or chromosomes in a cell, which may occur spontaneously or be brought about by chemical mutagens or by radiation (induced mutation). [IUPAC Bioinorganic]

A related strain has an abrupt, inheritable change in the sequence at this location Mutation superceded by 'Variation' Mutation will become illegal from April 15th, 2000. [DDBJ/ EMBL/ GenBank Feature Table] http://www.ebi.ac.uk/embl/Documentation/FT_definitions/feature_table.html

Any type of change (including insertions, deletions, point mutations, and rearrangements in the nucleotide sequence of DNA) which leads to variations in the population. Genetic changes that have been associated with disease risk or were caused by damage inflicted by external agents (such as radiation) are particularly described as mutations. [CHI SNPs]

A change, deletion, or rearrangement in the DNA sequence that may lead to the synthesis of an altered inactive protein the loss of the ability to produced the protein. If a mutation occurs in a germ cell, then it is a heritable change in that it can be transmitted from generation to generation. Mutations may also be in somatic cells and are not heritable in the traditional sense of the word, but are transmitted to all daughter cells. [NHLBI]  

Related terms alleles, polymorphisms, SNPs. Narrower terms  In-depth deletions,  duplications, frame shift mutations, leaky mutations, loss of function mutations, null mutations, neutral mutations, point mutations, suppressor mutations; Functional genomics glossary  targeted mutation.

Mutation databases see Databases & software directory under 'variations'.

HUGO MUTATION DATABASE INITIATIVE: Issues, Databases, and Perspectives for the New Millennium  (special issue)  Human Mutation Vol.15 (1) January 2000 http://www.wiley.com/products/subject/life/genetics/genetics_humu_mdi.html

Special issue Mutation Research DNA Repair  40 years of DNA Repair Volume 485 Issue 1 (25 February 2001)   http://www.mutationresearch.com/mutat/show/

mutation detection: See genetic variation detection.

mutation rate: The frequency with which a mutation occurs within an organism or gene. In general, rates of spontaneous mutation vary between one in 10⁴ and one in 10⁸ per gene per generation, and can be considerably increased by mutagens. [IUPAC Biotech]

non-functional polymorphisms: Intron sequence differences. http://www.cgr.ki.se/cgb/groups/brookes/Articles/Human%20Genetic%20Bi.pdf

oligogenic: A trait is considered to be oligogenic when two or more genes work together to produce the phenotype. Implies that ‘few’ genes are involved and should be contrasted with a polygenic trait, which implies that many genes are involved in phenotype expression. [NHLBI] Compare multifactorial, multigenic, polygenic

phene: See Databases & software directory under OMIA Online Mendelian Inheritance in Animals

phenotype: Genomics glossary  Related term genetic architecture.

pleiotropy: Gene definitions

polygenic: Genomics glossary Related terms  multifactorial, multigenic, oligogenic In-depth epistasis,

polymorphisms: Genetic variations, broadly encompassing any of the many types of variations in DNA sequence that are found within a given population. Specific subtypes of polymorphisms include mutations, point mutations, and SNPs. [CHI SNPs] 

A term formulated by population geneticists to describe loci at which there are two or more alleles that are each present at a frequency of at least 1% in a population of animals. The term has been co- opted for use in transmission genetics to describe any locus at which at least two alleles are available for use in breeding studies, irrespective of their actual frequencies in natural populations. [NHLBI]

A gene that exists in more than one version (allele), and where the rare allele can be found in more than 2% of the population. [NHGRI]   Polymorphisms have the sense of being more neutral than mutations.  

Related terms alleles, association, linkage, mutations, population genetics, SNPs. Narrower terms: In-depth functional polymorphisms, idiomorphisms, non- functional polymorphisms; SNP- human, microsatellite repeat polymorphisms, RFLPs, SSRs simple sequence repeats, STRs, tandem repeats. Related terms: CEPH, International SNP Map Working Group, linkage analysis, SSCP, SSEP. Broader term: variants

population genetics: The study of the genetic composition of populations and of the effects of factors such as selection, population size, mutation, migration, and genetic drift on the frequencies of various genotypes and phenotypes. [MeSH] Until recently, a small rather esoteric specialty.

population genomics: From genomic polymorphisms, to changes in gene expression, to altered protein activity there is a probabilistic link between misspellings in the genetic code and changes in biological function. In some cases, this link is strong and depends on a single gene but often it is weak and multigenic.The hypothesis driving many population studies is that my carefully phenotyping and genotyping large populations will allow these associations to be elucidated. We are investigating this hypothesis in our collaboration with large epidemiological studies (e.g the Channing Laboratory) and in developing efficient algorithms for exploring genetic association (e.g. Bayesian model induction). [Children's Hospital, Boston, US Informatics Program "Population studies using genomic data, 2001]  http://www.chip.org/chip/research/population.html

positional cloning: Functional genomics glossary

primer extension: Gene amplification & PCR glossary

protein polymorphisms: Polymorphisms in exons (protein coding DNA). cSNPs are a subset of protein polymorphisms. 

recombinant: The result of a crossover in a doubly heterozygous parent such that alleles at two loci that were present on opposite homologs are brought together on the same homolog.  The term is used to describe the chromosome as well as the animal in which it is present. [NHLBI]  Related  terms genetic recombination; recombinant DNA technology Technology & instrumentation overview; recombinant antibodies, recombinant DNA, recombinant proteins Pharmaceutical biology.

recombination: The formation of new combinations and arrangements of genes during meiosis; recombination is achieved by crossing over, independent assortment, and segregation. [NHLBI] Narrower ? term genetic recombination.

repeats: Narrower terms: In-depth include microsatellite repeats, minisatellite repeats, short tandem repeats, satellites, tandem repeats, VNTRs.

SNP Single nucleotide polymorphism: SNPs involve the change of one DNA base to another. SNPs and point mutations are structurally identical, differing only in their frequency. Variations that occur in 1% or less of a population are considered point mutations, and those occurring in more than 1% are SNPs. SNPs can occur in coding regions of the genome (cSNPs), in regulatory regions (rSNPs), or, most commonly, in "junk DNA" regions, in which case they are referred to as anonymous SNPs. [CHI SNP Update]

SNPs are single base pair positions in genomic DNA at which different sequence alternatives (alleles) exist in normal individuals in some population(s), wherein the least frequent allele has an abundance of 1% or greater.  Thus single base insertion/ deletion variants (indels) would not formally be considered to be SNPs. ... In practice, the term SNP is typically used more loosely than required by the above definition. ... Complications with the above definition also exist. Specifically, some people might not want to consider disease predisposing single base variants to be SNPs - but the above definition would encompass such things as recessively acting, low penetrance, dominant, quantitative trait loci, or risk associated alleles, since all of these will occur in some normal (non- diseased) individual.  Also the 'some population' component of the definition is limited by practical challenges of attaining and surveying representative global population samples. Consequently, claims of non- polymorphic sequences should always be accompanies by statements of the actual populations and the numbers of chromosomes tested. Overall, it is therefore apparent that the term 'SNP' is being widely and imprecisely used as a catch-all label for many different types of subtle sequence variation. [Anthony Brooks "The essence of SNPs" Gene 234: 177-186, 1999]  http://www.cgr.ki.se/cgb/groups/brookes/Articles/essence_of_snps_article.pdf.

Narrower terms SNPs- human, single amino acid polymorphisms SAPS; In-depth anonymous SNPs, cSNPs, candidate SNP, pSNP, rSNP, SNP haplotypes, synonymous SNP.  Related terms idiomorphism, protein polymorphisms SNP Consortium, SNP discovery, SNP scans,

SNP databases See Database & software directory under 'variations'.

SNP discovery: Sequencing glossary

SNP discovery - commercialization: One of the fastest- growing areas of genomic research. This field has advanced much more rapidly than ever anticipated, and extensive progress has been made in mapping SNPs both in the public (The SNP Consortium) and private arenas. Also, throughput capacity is rapidly increasing in this field. Now, the focus is shifting to validating SNPs and to using SNP data to identify novel disease targets. Commercial Implications of Advances in the Identification, Mapping, and Application of Single Nucleotide Polymorphisms, CHI Genomic Reports, Oct. 2001. http://www.chireports.com/content/reports/snpupdate01.asp

SNPs - human: Human Mutation- Special Issue SNP 2000:Third International Meeting on Single Nucleotide Polymorphism and Complex Genome Analysis Vol. 17 (4) April 2001  http://www.wiley.com/products/subject/life/genetics/genetics_humu_snp2000.html

A single site in a nucleotide sequence that contains two to four allelic variations within a population at relatively high frequencies (1.0% by convention). [S. Sunyaev "SNP frequencies in human genes" Trends in Genetics 16:8): 335-337 August 2000]

About 30 million SNPs are thought to exist, making them much better markers than alternative markers, such as micro- satellite repeats or short tandem repeats. But it has been the discovery that some SNPs are linked to particular diseases that has fueled the rising interest in this field. ... to determine whether and how particular SNPs correlate to specific conditions, one may need to study hundreds of thousands of SNPs in thousands of patients. At this point in time, this remains a costly prospect. Also, the software tools are only now emerging to deal with the analysis challenges.  [CHI Bioinformatics]

SNP scans: See under genome scans.

scanning: Technology used to discover new or unknown SNPs. [M Phillips CHI Nucleic Acid Detection Technologies conference, June 7-9, 2000] Related term genome scan.

scoring: Determining, by comparison the base pairs (genotypes) at the locus for many individuals for particular SNPs that have already been discovered.

Related terms: genotyping

Single Amino acid Polymorphisms SAPs: Additional factors of complexity are polymorphisms at the protein sequence level. While some of these polymorphisms are linked to disease states, most are not, yet have in many cases a direct or indirect effect on the activities of the proteins. [Rolf Apweiler, Amos Bairoch "The Human Proteomics Initiative of SIB and EBI" Bioinformer 5:3 Autumn 1999] http://bioinformer.ebi.ac.uk/newsletter/archives/5/hpi.html

Polymorphisms, which differ by a single amino acid. Related term: cSNPs  

surrogate markers: Pharmacogenomics glossary

variants: Includes narrower terms: alleles, mutations, polymorphisms, SNPs and even narrower terms  In-depth glossary deletions, duplications, enhancements, frame- shift mutations, idiomorphisms, indels, insertions, leaky mutations, loss of function mutations, null mutations, point mutations, reassortments, VNTRs. Variants seems to be replacing these terms in sequencing databases.

There is no single technology at present that will detect all the types of abnormality (large deletions, rearrangements, base substitutions, small insertions and deletions, amplifications, and epigenetic changes such as methylation) that are present in cancer cells. [PSA. Futreal et. al "Cancer and genomics" Nature 409: 850-852, 15 Feb. 2001]

validation of gene-disease associations: See under gene- disease associations

wild-type: The most frequently encountered genotype in natural breeding populations. [IUPAC Biotech]  To what extent is this a theoretical concept?  Is it as slippery and elusive as the concept of  "normal" in many cases in clinical medicine?

The term "wild-type" was fixed in the lexicon in the early days of fruit-fly genetics, when one could go out and catch one; now it means the original line of normally functioning individuals. [HF Judson, Eighth Day of Creation Cold Spring Harbor Laboratory Press 1996 p. 276] 

Related term: Proteins glossary wild- type proteins

Bibliography

[CHI SNP Update] Commercial Implications of Advances in the Identification, Mapping, and Application of Single Nucleotide Polymorphisms, CHI Genomic Reports, Oct. 2001. http://www.chireports.com/content/reports/snpupdate01.asp

[CHI SNPs]  Single Nucleotide Polymorphisms: Commercial and Scientific Prospects  Cambridge Healthtech Institute, Malorye Branca and Kenneth Rubenstein Report 2, Genomic Technologies, 1999.  

[SNP Consortium] Glossary, 2001. 30+ definitions. http://snp.cshl.org

Alpha glossary index

IUPAC definitions are reprinted with the permission of the International Union of Pure and Applied Chemistry.

In-depth Genetic variations glossary

aggregate: Related term segregation

allele-specific hybridization (ASH): A method of SNP detection. ASH technologies use oligonucleotides that differ at a single base position corresponding to the SNP to be detected. In some instances, two oligos are provided, one for a "wild-type" or normal allele and the other for the SNP. In other instances, four oligos, corresponding to each of the four possible bases at the SNP position, are provided. ASH technology shows up in several microarray products. [CHI SNP Update] Related terms Gene amplification & PCR glossary

anonymous SNPs : SNPs that have no known effect on gene function.  Thought to be the most common type of  SNPs and possibly valuable as markers for linkage disequilibrium studies, when they are relatively close to the gene being sought.  [CHI SNPs]

bi-allelic: In principle, SNPs could be bi-, tri-, or tetra-allelic polymorphisms.  However, in humans, tri- allelic and tetra- allelic SNPs are rare almost to the point of non- existence, and so SNPs are sometimes simply referred to as bi- allelic markers (or di- allelic to be etymologically correct).  This is somewhat misleading because SNPs are only a subset of all possible bi- allelic polymorphisms (e.g., multiple base variations). [Anthony Brooks "The essence of SNPs" Gene 234: 177-186, 1999]  http://www.cgr.ki.se/cgb/groups/brookes/Articles/essence_of_snps_article.pdf.

Variant of di-allelic. Related terms allele, SNPs.

cSNPs:  Located within protein coding sequences and may interfere with gene and related protein function by altering the protein’s amino acid composition.  Generally thought to be the least common and most valuable type of  SNP.  At least 200,000 are estimated to be found.  Many companies are patenting these for use in the candidate gene approach.  [CHI SNPs] Broader term SNP

CEPH: Centre d’Etude du Polymorphism Humain, Paris FRANCE. Collects pedigrees appropriate for reference genetic mapping.  These are characterized by the availability of a large number of offspring (average 8.5) and both sets of paternal and maternal grandparents.  The structure of these pedigrees renders them “linkage phase known”. [NHLBI].

candidate gene studies:  These studies, in contrast to genomewide scans, focus on particular SNPs thought to have a functional effect or to be involved in specific conditions. They are generally considered more practical than genomewide scans [CHI SNPs Update] Related term  Gene definitions candidate gene

candidate SNP:  Particular SNPs thought to have a functional effect.

correlation studies:  For SNPs will likely be attempts to correlate phenotype or drug response with candidate SNPs.  May or may not be carried out with population validation studies. [CHI SNPs]

DGGE: Chromatography & electrophoresis glossary

dHPLC Denaturing HPLC: Chromatography & electrophoresis glossary 

DNA fingerprinting: A procedure in which multilocus band patterns of a DNA sample are generated by digestion of the DNA with restriction enzymes followed by electrophoresis and visualization by hybridization with  probes specific for repetitive sequences. In forensic medicine the probes used are "core" sequences specific for simple tandem repetitive sequences (MINISATELLITE REPEATS or VNTRs). The multilocus band patterns, known as DNA fingerprints, are evaluated for similarities with DNA from an individual. [MeSH] Related term Genomics glossary forensic applications

DNA footprinting: A method for determining the sequence specificity of DNA- binding proteins. DNA footprinting utilizes a DNA damaging agent which cleaves DNA at every base pair; DNA cleavage is inhibited where the ligand binds to DNA. [MeSH (Rieger et al., Glossary of Genetics: Classical and Molecular, 5th ed)]

DNA ligase enzymes: Can link two adjacent oligonucleotide probes that are hybridized to a template.  A SNP detection technology.  [CHI SNP]

deletions:  A genetic rearrangement through loss of segments of DNA or RNA, bringing sequences which are normally separated into close proximity.  This deletion may be detected using cytogenetic techniques and can also be inferred from the phenotype, indicating a deletion at one specific locus. [MeSH ‘gene deletion’] 

A type of mutation caused by loss of one or more nucleotides from a DNA segment. Deletions can be very large, encompassing many genes and megabases of DNA, to the point of producing a visible cytological abnormality in a chromosome. Small deletions within a gene can alter the reading frame, and thus the amino acid sequence of the encoded protein  [Mouse Genome Informatics, Jackson Lab]

If a particular nucleotide (or series of nucleotides) is not copied during DNA replication deletions arise. Deletions may have no effect, results in disease, or in rare cases be beneficial. [CHI SNPs] Related term indels; Functional genomics In-depth Cre-lox 

di-allelic: See under bi-allelic.

direct approach: See candidate gene approach. Alternative to shotgun sequencing. Sequencing glossary

duplication: A particular kind of mutation: production of one or more copies of any piece of DNA,  including a gene or even an entire chromosome. [NHGRI]

An additional copy of a DNA segment present in the genome. Gene duplication is the source of paralogous genes.  [Mouse Genome Informatics]

Narrower term: whole genome duplication [need definition]

endonucleases: A high throughput fragment analysis SNP scanning technology [M Phillips CHI Nucleic Acid Technologies conference, June 2000]

epigenetic: Gene definitions

epistasis: : Two or more genes interacting with one another in a multiplicative (the effects of alleles at loci which together contribute to a phenotype when their combination is not equal to the sum of the individual contribute of each allele by itself) fashion. [NHLBI]

founder populations: Those in which an identifiable current population derives from a relatively small group of founders. The small size of the founder group suggests that one will find fewer genes and fewer alleles involved in susceptibility to a given disease within the population. [CHI SNPs Update]

frame-shift mutation: A type of mutation in which a number of nucleotides not divisible by three is deleted from or inserted into a coding sequence, thereby causing an alteration in the reading frame of the entire sequence downstream of the mutation. These mutations may be induced by certain types of mutagens or may occur spontaneously. [MeSH]. Related term reading frames.  Sequences, DNA & beyond.

functional cloning: Functional genomics glossary

Genetic Annotation Initiative: Until recently, genetic dissection of  phenotypes has been limited largely to investigations in model organisms. However, advances in genomic technologies have provided an important opportunity to identify cancer genes through genetic analysis. A key to performing such analyses is the ability to detect variation, which will facilitate the tracking of transmission and identification of alternative forms of a gene.  The NCI has established the Genetic Annotation Initiative (GAI) to delineate, characterize, and validate gene variants. The GAI is part of the Cancer Genome Anatomy Project (CGAP), National Cancer Institute, US.  http://www.nci.nih.gov/initiatives/gai.html  See also Bioinformatics glossary  annotation

genetic drift: Random fluctuations in gene frequencies, particularly in small populations. [CHI SNP].

Hardy-Weinberg law: A principle of population genetics that predicts genetic equilibrium in large populations, assuming standard variables.  GH Hardy was a British mathematician and Wilhelm Weinberg a German physician. 

HUGO Mutation Database Initiative:  http://ariel.unimelb.edu.au/~cotton/mdi.htm  Variation databases and related sites

indels: See under insertion.

indirect approach: See random genome-wide association studies.

insertion: Several nucleotides can be added to a sequence, resulting in an insertion.  Effects of an insertion are variable.  [CHI SNPs]  Insertions and deletions can be hard to tell apart and are sometimes referred to collectively as “indels”.

International SNP Map Working Group: Identifies and localizes 1.42. millions SNPs in the human genome. ["A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms" International SNP Map Working Group Nature 409:928-933, 15 Feb. 2001] Related terms SNP maps, SNPs. http://www.nature.com/cgi-taf/DynaPage.taf?file=/nature/journal/v409/n6822/full/409928a0_fs.html

leaky mutation: Some function remains, but not at the level of the wild type allele. [Philip McClean , Intermediate Genetics PLSC 431, North Dakota State University, 2000]   http://www.ndsu.nodak.edu/instruct/mcclean/plsc431/mutation/mutation4.htm

linkage analysis: Studying the genetics of families to find out where in the genome there are particular genes that may be associated with a disease. This approach is most effective with monogenic disorders that have high penetrance. Tallies up within family associations at a particular locus. In cases of genes with many functional polymorphisms, linkage analysis with a linked marker can identify the gene, but association analysis will not. May require large numbers of affected families, often many thousands, to achieve statistically significant results for complex diseases. [CHI SNPs] Related terms linkage, linkage disequilibrium.

linkage disequilibrium: The tendency of closely spaced alleles to be inherited together. Linkage disequilibrium reduces the number of polymorphic markers that must be studied when using random markers to detect association between a gene and a trait. In the absence of linkage disequilibrium, only a causative polymorphism shows any appreciable difference between the case and the control group. However, in the presence of linkage disequilibrium, polymorphisms that are physically near a causal polymorphism will also show a difference in frequency between cases and controls, and an enhanced association with the trait in questions. [CHI Breaking Bottlenecks]

When alleles at two distinctive loci occur in gametes more frequently than expected given the known allele frequencies and recombination fraction between the two loci, the alleles are said to be in linkage disequilibrium.  Evidence for linkage disequilibrium can be helpful in mapping disease genes since it suggests that the two may be very close to one another. [NHLBI] 

Related terms haplotype, haplotyping technologies, linkage, linkage analysis.

loss of function mutation: Wild type alleles typically encode a product necessary for a specific biological function. If a mutation occurs in that allele, the function for which it encodes is also lost. The general term for these mutations is loss-of-function mutations. [Philip McClean , Intermediate Genetics PLSC 431, North Dakota State University, 2000]    http://www.ndsu.nodak.edu/instruct/mcclean/plsc431/mutation/mutation4.htm

microsatellite markers: See microsatellite repeat polymorphisms

microsatellites: Consist of tandem repeats, which contain repetitive runs of the same short base sequence (e.g., GTA, GTA, GTA…). Among individuals, these sections of DNA may vary in the number of repeats they contain and can serve as markers and signs of genetic variation. [CHI SNPs Update]

minisatellite repeats: Tandem arrays of moderately repetitive (5- 50 repeats) short (10- 60 bases) DNA sequences found dispersed throughout the genome and clustered near telomeres. Their degree of repetition is two to several hundred at each locus. Loci number in the thousands but each locus shows a distinctive repeat unit. Minisatellite repeats are often called variable number of tandem repeats [VNTRs]. [MeSH] Also known as SSRs Related terms tandem repeats. Broader term polymorphisms

multiple allelism: The existence of several known alleles of a gene. [Schwindlein]

negative selection: Many mutations are deleterious to the fitness of an organism. These will be selected against and eventually lost from the population.  [S. Sunyaev “SNP frequencies in human genes” Trends in Genetics 16:8): 335-337 August 2000]

neutral mutation: Substitutions that have no selective advantage or disadvantage. [S. Sunyaev  “SNP frequencies in human genes” Trends in Genetics 16:8): 335-337 August 2000]

nucleotide diversity: The number of base differences between two genomes, divided by the number of base pairs compared.  A sensitive indicator of biological and historical factors that have affected the human genome. [A. Chakravarti "...to a future of genetic medicine" Nature 409: 822-823, 15 Feb. 2001]

Related terms population genetics, population genomics

null mutation: A mutation where function is totally lost.

pSNPs:  If a cSNP or an rSNP leads to an altered amino acid, which in turn leads to altered protein function or expression and an observable change in the organism’s phenotype, the  SNP may be labeled a pSNP. [CHI SNPs] Broader term SNP

phenocopy: A phenotype that is not genetically controlled but looks like a genetically controlled phenotype. An  environmentally induced phenotype that resembles the phenotype produced by a mutation. [Edinburgh]

pleiotropism or pleiotropy: Gene definitions.

point mutations: A variation in just a single nucleotide. These are the most common type of genetic variation. Point mutations that occur in greater than 1% of the members of a group or species are called SNPs. [CHI SNPs] A point is a single nucleotide on a chromosome. [PhRMA]

In classical genetics, a point mutation was originally defined as a change in an inherited trait that was not accompanied by any chromosomal change that could be seen with a light microscope (even in the giant polytene chromosomes of Drosophila larval salivary glands). In current usage, point mutations are usually understood to involve only one base pair, but to include both substitutions (transitions and transversions), and the addition or deletion of a single base pair. A point mutation can result in missense (amino acid substitution), nonsense (insertion of a stop codon), or frameshift (either positive or negative). [Richard Ham, Molecular Basis for Mutation, Univ. of Colorado, US Fall 2000] http://www.colorado.edu/MCDB/MCDB2150Fall/notes00/L0006.html

positional candidates: Functional genomics glossary Not to be confused with the candidate gene strategy.

rSNPs:  These SNPs affect regulatory regions that govern gene expression.  Thought to be relatively uncommon and potentially as valuable as cSNPs.  Limited commercial activity at this time.  [CHI SNPs] Broader term SNP

RFLP Restriction Fragment Length Polymorphism: Restriction fragment length polymorphism, which can be used in SNP genotyping. This method relies on enzymatic cleavage of DNA followed by electrophoresis. [CHI SNPs Update]

A variant among individual organisms in the size and number of DNA fragments generated by the actions of restriction enzymes. These variations can be detected by the differences in the distribution of DNA fragments during electrophoresis. [NHLBI]  Broader term marker. 

random genome-wide association studies: Looks at many random SNPs in the hope that some will be in linkage disequilibrium with a particular gene or genes. [CHI SNPs] Broader term association studies.

reassortment: The rearrangement of genes from two distinct strains to produce a novel viral strain. [CHI SNPs Update]

regional scanning:  Developed by Genset.  Used linkage studies to identify sequence regions from the public domain and their own studies to narrow the parts of the genome they would subsequently scan.  Then using high-density mapping, making a first pass using a map with SNPs every 30- 40 kb in the regions of interest and then increasing the density to every 5-10 kb as they closed in on the genes of interest.  Can only be used for studies of disease genes for which family linkage data is available.  [CHI SNPs] See also Maps- genomic & genetic

restriction enzymes: Endonucleases which recognize specific base sequences within a DNA helix, creating a double- strand break of DNA. Type I restriction enzymes bind to these recognition sites but subsequently cut the DNA at different sites. Type II restriction enzymes both bind and cut within their recognition or target sites. [IUPAC Biotech]  

A group of enzymes isolated from bacteria that cut DNA molecules at specific sites characterized by certain nucleotide sequences. [NHLBI] Broader term markers.

restriction fragment length polymorphism: See RFLP.

The SNP Consortium (TSC): Established (April 1999) to identify SNPs and add them to the public domain rather than patenting them for commercial use. A joint enterprise of  pharmaceutical companies (AstraZeneca, Bayer, Bristol-Myers Squibb, F. Hoffmann-La Roche, Glaxo Wellcome, Aventis/Hoechst Marion Rouse, Novartis, Pfizer, Searle, and SmithKline Beecham) and the Wellcome Trust, with sequencing carried out by three public genomics institutes (Sanger Centre, Washington University School of Medicine, and the Whitehead Institute) with Stanford University Human Genome Center contributing mapping and Cold Spring Harbor Laboratory coordinating bioinformatics activities. [CHI SNP] Motorola joined in October 1999 and IBM in March 2000. SNP Consortium http://snp.cshl.org     http://www.wellcome.ac.uk/en/1/biovensnp.html

Within two years of its establishment, the consortium had far exceeded its initial goals, and its final map will have one SNP for every 5,000 to 10,000 base pairs. The technology used in this project was finely tuned, and 95% of the SNPs called (i.e., identified) on the consortium map can be validated using a gold standard. [CHI Bioinformatics]

SNP haplotypes: There has been much interest in the recent publication of the single nucleotide polymorphism (SNP) map of the human genome, particularly with reference to the role it might play in disease gene mapping and developing a better understanding of patterns of linkage disequilibrium (LD) across chromosomes. For these types of analyses with samples of population data, SNP haplotypes are essential. However, current genotyping technology cannot determine phase. This has prompted the development of statistical methodology to infer phase, allowing haplotypes to be reconstructed from the available genotype data. Existing methods utilise parsimony and maximum likelihood, implemented via the E-M algorithm. The disadvantage of these approaches is that they do not assign uncertainty to phase assignment, leading to over- confidence in the inferences made by subsequent analyses using the extracted haplotype data. [Andrew Morris "A Bayesian MCMC method for extracting phase information from SNP genotypes" Statistics & Probability Seminars, Univ. of Bristol, 16 Nov. 2001] http://www.stats.bris.ac.uk/Seminars/Abstracts/morris.html

SNP maps: Maps genomic & genetic 

SSCP  Single Strand Conformational Polymorphism: High throughput fragment analysis, a technique for screening for SNPs. [CHI SNPs]

SSEP Single Strand Electrophoretic Polymorphism: A technique for screening for SNPs. [CHI SNPs]

SSRs Simple Sequence Repeats: Stretches of 1 to 6 nucleotide units repeated in tandem and randomly spread in eukaryotic genomes. SSR are very polymorphic due to the high mutation rate affecting the number of repeat units. Such length-polymorphisms can be easily detected on high resolution gels (e. g. sequencing gels), by running PCR amplified fragments obtained using a unique pair of primers flanking the repeat (Weber and May 1989). SSR have several advantages over other molecular markers. For example, (i) microsatellites allow the identification of many alleles at a single locus, (ii) they are evenly distributed all over the genome, (iii) they are co-dominant, (iv) little DNA is required and (v) the analysis can be semi-automated and performed without the need of radioactivity. In our  lab as well as in others (Gianfranceschi et al. 1998, Guilford et al. 1997, Maliepaard et al. 1998) SSRs for the genetic analysis of apple have been developed. We focused on the isolation and characterisation of (GA)n repeats, since those are the most abundant class of repeats in plants, after (TA)n, which have some technical disadvantages that hinder the selection of TA rich sequences. [Luca Gianfranceschi "Simple Sequence Repeats: Markers of Choice in Apple Breeding, ETHZ, Switzerland, INRA France] http://www.inra.fr/Internet/Projets/DARE/textes/focus/genetics/geneticspublication/ssr.htm

STRs Short Tandem Repeats : Often serve as polymorphic markers. [CHI SNPs]

STSs Sequence-Tagged Sites:  Unique short sequence of DNA, typically less than 400 bases long.  Detected by PCR.  Allows identification of where in the genome the studied sequence is localized.  ESTs are STSs derived from cDNA.  Useful for orienting the physical mapping and sequence data reported from different laboratories.  [DOE]

A short DNA segment that occurs only once in the human genome and whose exact location and order of bases are known. Because each is unique, STSs are helpful for chromosome placement of mapping and sequencing data from many different laboratories. STSs serve as landmarks on the physical map of the human genome. [NHGRI]

Related terms vectors, cloning Cell biology glossary positional cloning Functional genomics.

STS databases see Databases & software directory.

satellite: Many tandem repeats (identical or related) of a short basic repeating unit;  many have a base composition or other property different from the genome average  that allows them to be separated from the bulk (main band) genomic DNA. [DDBJ/ EMBL/ GenBank Feature Table]
http://www.ebi.ac.uk/embl/Documentation/FT_definitions/feature_table.html  Narrower term microsatellite, minisatellite.

segregation:  The principle that the two partners of a chromosome pair are separated during meiosis and distributed randomly to the germ cells.  Each germ cell has an equal chance of receiving either chromosome.  [NHLBI].  Related terms Mendelian, aggregate.

‘slightly’ deleterious alleles: An allelic variant subject to negative selection, but the selection coefficient is relatively low. The frequency of a slightly deleterious allele in a population is subject both to the stochastic fluctuations of genetic drift, depending on population size, and to a very weak negative selection.  Unlike strongly deleterious alleles, which are quickly eliminated by selection, slightly deleterious alleles can be kept in a population for a long time owing to drift. Due to selective pressure, they are predominantly observed at low frequencies (in comparison to purely neutral alleles. [S. Sunyaev  “SNP frequencies in human genes” Trends in Genetics 16:8): 335-337 August 2000]

suppression: Second mutation at a site distinct from the first mutation reverses, at least partially, the phenotypic expression of the first mutation. [CHI Functional Genomics]

The restoration of the wild- type phenotype in an organism possessing a mutationally altered genotype.  The effects of the mutation may be suppressed by a second ‘suppressor’ mutation on a different gene, by a suppressor mutation on the same gene but located at a distance from the site of the primary mutation, or by the presence of a cytoplasmic suppressor due to a change in non chromosomal DNA. [Metathesaurus]

suppressor mutation: A reversion to original phenotype but by a mutation in another gene. [Kenneth G. Wilson, Genetics, Miami Univ. US] http://www.cas.muohio.edu/~wilsonkg/genetics/Gene_code/mutation/mutation.htm

synonymous SNP:  When, despite the substitution of a base in a cSNP, the cSNP still codes for the same amino acid.  [CHI SNPs]

Substitutions in coding regions that result in the same amino acid. [S. Sunyaev  “SNP frequencies in human genes” Trends in Genetics 16:8): 335-337 August 2000]

Narrower term: SAP single amino acid polymorphism

tandem repeats:  Multiple copies of the same base sequence on a chromosome; used as a marker in physical mapping. [DOE] Related term microsatellite repeat polymorphisms, STR, satellite

tri-allelic:  Blood groups (A, B, O) are an example of tri-allelism. Related terms allele, bi-allelic.

VNTRs Variable Number of Tandem Repeats: See minisatellite repeats.