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.

Biology & Chemistry  Map: Finding guide to terms in these glossaries  Site Map
Related Glossaries include
Applications Functional Genomics Pharmacogenomics, Biomarkers 
Informatics Algorithms, Bioinformatics
Technologies Chromatography & electrophoresis, Gene amplification & PCR, Microarrays Sequencing  
Biology Chemistry & biology Expression, Gene definitions, Maps- genomic & genetic, Sequences DNA & beyond 

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. 

Related terms: Gene amplification & PCR glossary

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, 1968

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: allelic variants, mutation, polymorphisms, SNP, 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'.

allelic imbalance: A situation where one member (allele) of a gene pair is lost (LOSS OF HETEROZYGOSITY) or amplified. MeSH, 1991

allelic variants:

alternative splicing: Gene definitions

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.   

Related term: intron SNPs

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.

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:  random genome-wide association studies. Related term: linkage

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.

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

biological markers, biomarkers: Biomarkers glossary 

biological variation: Studies of genetic architecture have historically focused on associations of genotype and phenotype (e.g., between DNA markers and a disease). However, an organism is a unique consequence of both genes and environment and is created by complex interactions of multiple events and forces. How genes are expressed depends on their cellular, developmental, physiological, and environmental context. Genetic Architecture, Biological Variation and Complex Phenotypes, PA-02-110, May 29, 2002- June 5, 2005 http://grants1.nih.gov/grants/guide/pa-files/PA-02-110.html

cSNPs: When SNPs are present in the actual gene-coding region of a chromosome, they are called cSNPs and have a higher probability of influencing propensity to disease or drug response than SNPs found outside gene regions. There are an estimated 200,000 cSNPs present in the human genome. CHA Cambridge Healthtech Advisors, Clinical Genomics: The Impact of Genomics on Clinical Trials and Medical Practice report, 2004 

Related/ equivalent? term: exon SNPs Broader term: SNP Narrower terms: non- synonymous SNPs, synonymous SNPs

Whitehead cSNP data: http://www-genome.wi.mit.edu/cvar_snps/

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 

Related term:  Gene categories candidate gene

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

coding SNPs: See cSNP

common variants: When a given SNP at a particular location on a chromosome occurs in at least 1% of the population, it is considered to be a common variant. CHA Cambridge Healthtech Advisors, Clinical Genomics: The Impact of Genomics on Clinical Trials and Medical Practice report, 2004

Copy Number Polymorphisms CNPs: Will become a valuable tool for defining relative phenotypes in a population. Insight Pharma Reports: Comparative Genomic Hybridization: Current State and Future Directions, 2006 

Copy-number polymorphisms (CNPs) represent a greatly underestimated aspect of human genetic variation. Recently, two landmark studies reported genome-wide analyses of CNPs in normal individuals and represent the beginning of an understanding of this type of large-scale variation.   Patrick G. Buckley^*, Kiran K. Mantripragada^*, Arkadiusz Piotrowski, Teresita Diaz de Ståhl and Jan P. Dumanski Copy-number polymorphisms: mining the tip of an iceberg, Trends in Genetics 21 (6): 315- 317, June 2005  http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TCY-4G1PKNS-1&_user=10&_coverDate=06%2F30%2F2

Another term for CNV

Google = about 16,300 Dec. 8, 2006

copy number variation CNV: All agree that copy number variation (CNV) contributes substantially to human genetic diversity. But to what extent? The resulting applications of newly developed whole-genome scanning technologies have catalyzed the appreciation of CNV in the genetic community. The range of these promising new technologies will, for the first time, allow scanning of the entire human genome for CNV in a single experiment. As these genome-wide scanning techniques become more widely used in diagnostic laboratories, the major challenge is how to accurately interpret which submicroscopic genomic imbalances are pathogenic in nature and which are benign. Comprehending Copy Number Variation Tools, Applications, and Results April 21-22, 2008 • San Diego, CA

We defined a CNV as a DNA segment that is 1kb or larger and present at variable copy number in comparison with a reference genome. A CNV can be simple in structure, such as tandem duplication, or may involve complex gains or losses of homologus sequences at multiple sites in the genome. Richard Redon et. al, Global Variaiton in copy number in the human genome, Nature 2006 Nov 23;444 (7118): 444- 454   

Google = about 67,900 Dec. 8, 2006 

Related terms: SNP, HapMap

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.

crossing over: See under genetic recombination.

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, 1991

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, 1996 (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.  

DNA marker: Biomarkers glossary 

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’, 1993 

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

Related terms: indels; Functional genomics Cre-lox 

detection technologies: See genetic variation - detection technologies

diagnostics: Molecular Medicine glossary

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

EST Expressed Sequence Tags Gene definitions

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

epigenetic: Genetic Manipulation & Disruption glossary

epigenome, epigenomics: -Omes & -omics glossary

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]

exon skipping: Gene definitions

exon SNPs, exonic SNPs: Are these the same as coding SNPs cSNPs?

fingerprinting: SEE DNA fingerprinting.

forensics: DNA glossary

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. 

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, 1991. 

Related term: reading frames.  Sequences, DNA & beyond.

functional cloning: Functional 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

functional variants: Genetic variation in the general population (not just patients and controls) that can potentially affect gene functional directly.  ... We would not need to know the disease status of the individuals sampled.  This rich catalogue of genetic changes ... would include SNPs that alter amino acids in proteins, and possibly gene-splicing or expression levels. Most would be rarer than those pursued by the HapMap.    Richard Gibbs, "Deeper into the genome" Nature 7063:1233- 1234, 27 Oct. 2005 

gene-based SNPs: Not just coding SNPs but also intron SNPs and promoter SNPs. 

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. 

Related term: association studies

gene duplication: See duplication

Genetic Annotation Initiative: Genomics glossary

genetic drift: Random fluctuations in gene frequencies, particularly in small populations. 

genetic enhancement: Molecular Medicine glossary

genetic markers: Biomarkers glossary 

genetic recombination: Genetic manipulation & disruption 

genetic variation - detection technologies: Includes microarrays, dHPLC, DNA fingerprinting, DNA footprinting, DNA ligase enzymes, endonucleases, ribotyping, SSCP, SSEP. Related terms: protein variations; Sequencing glossary genotype, haplotype, scanning, scoring.

genetic variation - human: In genome scan studies, evenly spaced sections - perhaps 100,000 or more - of the entire human genome are studied across samples from 500- 1,000 patients in order to search for the correlation between patient genotypes and a particular disease. ... There are no techniques now that can scan the entire genome or even a fraction of it. 

Compare  candidate gene studies

genomic biomarkers: Biomarkers glossary

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

genotyping, genotyping technologies: Sequencing glossary

haploinsufficiency: The situation in which an individual who is heterozygous for a certain gene mutation or hemizygous at a particular locus, often due to a deletion of the corresponding allele, is clinically affected because a single copy of the normal gene is incapable of providing sufficient protein production as to assure normal function.  Genetics Home Reference, National Library of Medicine, NIH   http://ghr.nlm.nih.gov/ghr/glossary/haploinsufficiency

haplotype, haplotyping, haplotyping technologies: Sequencing glossary 

haplotype blocks: Long blocks of DNA have traveled from one generation to the next with little genetic shuffling. Along any given stretch of chromosome, the genetic variation within these blocks comes in only four or five patterns in different people, according to a new study published online in Science Express May 23 [2002] and scheduled for the print version of Science June 21 [2002]. ... these genome segments often contain one or more genes that make important proteins, many gene regulatory segments, and many fragments with no known function. ... The block like structure of human haplotypes was first identified by co-author Mark Daly, a statistical geneticist at the Whitehead. ... The low diversity among distinct haplotype blocks opened up what may be an express lane to screening the whole genome. [The next big thing in mining the genome, Focus, Harvard Medical School, June 7, 2002]  http://focus.hms.harvard.edu/2002/June7_2002/genomics.html

Related terms: SNP haplotype Maps, genomic & genetic haplotype map, haplotype mapping, HapMap

HapMap Project: Maps glossary 

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. 

Human Genome Variation Society  http://www.genomic.unimelb.edu.au/mdi/   Planned Community Wide Database http://www.hgvs.org/centraldb.html 

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.

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.  Insertions and deletions can be hard to tell apart and are sometimes referred to collectively as “indels”.

International HapMap Project: Maps glossary

International SNP Map Working Group: Maps & mapping glossary

Related terms: SNP maps, SNPs.

intron SNPs, intronic SNPs: Are these the same as anonymous SNPs?  See also under gene based SNPs. 

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: 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: linkage analysis, linkage disequilibrium.

linkage analysis:  Early gene discovery methods centered on linkage analysis in families, wherein clusters of patients with a particular disease were identified and studies were expanded in large pedigrees. The association of microsatellite markers with disease pointed the way to genome loci likely to contain a disease gene. While this family linkage approach is adequate for high- penetrance variants, it is not very useful for polygenic diseases, which would require impractically large family clusters to yield meaningful data. 

Related terms linkage, linkage disequilibrium.

linkage disequilibrium: 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] 

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. 

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

localize, locus, loci (plural): Gene definitions

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

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]

Types of genetic maps are differentiated largely by the type of marker used.

Narrower terms: polymorphisms, DNA fingerprints, microsatellite markers, microsatellite repeats, microsatellites,  minisatellite repeats, RFLPs, restriction enzymes, SSRs, STRs, STSs, satellites Biomarkers biological markers, biomarkers, DNA markers, genetic markers, surrogate markers; DNA: ESTs; Related terms:  Maps- genomic & genetic

microsatellite markers: See microsatellites 

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. 

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, 1997   Also known as SSRs  

Related term/broader term?: tandem repeats. Broader term polymorphisms

minisequencing: Sequencing glossary 

Minorities, race and Genetics: Human Genome Project Information, DOE, US http://www.ornl.gov/TechResources/Human_Genome/elsi/minorities.html

missense mutation:  Wikipedia http://en.wikipedia.org/wiki/Missense_mutations 

molecular endophenotypes: http://www3.interscience.wiley.com/cgi-bin/abstract/112345248/ABSTRACT  

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,] 

multifactorial diseases: Disease that result from a complex interplay of multiple genes and the environment. CHA Cambridge Healthtech Advisors, Clinical Genomics: The Impact of Genomics on Clinical Trials and Medical Practice report, 2004

Compare multigenic, polygenic, oligogenic.

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

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

multiplicative: See under epistasis.

mutation:  Usually refers to a harmful genome variation that is associated with a specific human disease, and is often present in less than !% of people. CHA Cambridge Healthtech Advisors, Clinical Genomics: The Impact of Genomics on Clinical Trials and Medical Practice report, 2004

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]

Any detectable and heritable change in the genetic material not caused by genetic segregation or recombination, which is transmitted to daughter cells and to succeeding generations, providing it is not a dominant lethal factor. MeSH, 1964

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]  

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.

Related terms: alleles, polymorphisms, SNPs. Narrower terms: 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)   

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]

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

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

nonsense mutation: (also called STOP mutation) Any change in DNA that causes a (termination) codon to replace a codon representing an amino acid. W Fangman, Definitions of course terms, Genetics 372, Winter 2000   http://depts.washington.edu/genetics/courses/genet372/w2000Terms.html 

non- synonymous SNPs, nsSNPs: When the altered code doesn't correspond to the same amino acid as the "wild- type" sequence. Substitutions in coding regions that result in a different amino acid. 

Broader term: cSNP Related term: synonymous SNP

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.

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

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 report] 

promoter region SNPs:  Maxime Paris "Single nucleotide primer extensions to type SNPs in barley"  Proceedings of the 10th Australian Barley Technical Symposium, 2001 http://www.regional.org.au/au/abts/2001/t3/paris.htm

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

phenotype: Genomics glossary  Related term: genetic architecture

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 mutation caused by the substitution of one nucleotide for another. This results in the DNA molecule having a change in a single base pair. MeSH, 1993

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

 A point is a single nucleotide on a chromosome. [PhRMA]

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.  

polygenic: Genomics glossary Related terms:  multifactorial, multigenic, oligogenic, epistasis,

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

polymorphisms: 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]   

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.   Polymorphisms have  the sense of being more neutral than mutations.  

Related terms: alleles, association, linkage, mutations, population genetics, SNPs. Narrower terms: 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, 1966 Until recently, a small rather esoteric specialty.

population genomics: The study of the forces that determine patterns of neutral and adaptive variation in genomes. Michel Vieulle, Expression of interest for a network in population genomics, European Framework Programme 6  http://gdrevol.snv.jussieu.fr/pgmics.pdf 

positional cloning: Functional genomics glossary

promoter SNPs: See pSNPs

protein biomarkers: Biomarkers glossary

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

protein variations:  Discovering how cells respond to genetic instructions by creating millions of protein variations and figuring out what all those proteins do will be the next frontier of biomedical research. The ability to identify cellular proteins will be especially valuable in cancer research, because each type of cancer produces its own protein biomarkers, according to Samir M. Hanash, M.D., Ph.D., a professor of pediatrics and communicable diseases in the University of Michigan Medical School. Unfortunately, current technology is neither accurate nor sensitive enough to detect most of these proteins, which often exist only in trace amounts.  "New Protein Separation Technology, Univ. of Michigan press release, April 19, 2000 http://www.newswise.com/articles/2000/4/PROTEIN2.UMI.html

Related terms: genetic variants; Broader term: variants

rSNPs:  These SNPs affect regulatory regions that govern gene expression.  Thought to be relatively uncommon and potentially as valuable as cSNPs.  

rSNP guide http://wwwmgs.bionet.nsc.ru/mgs/systems/rsnp/help.html

RFLP Restriction Fragment Length Polymorphism:  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]  

Variation occurring within a species in the presence or length of DNA fragment generated by a specific endonuclease at a specific site in the genome. Such variations are generated by mutations that create or abolish recognition sites for these enzymes or change the length of the fragment. MeSH, 1995

Restriction fragment length polymorphism, which can be used in SNP genotyping. This method relies on enzymatic cleavage of DNA followed by electrophoresis. 

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. 

Broader term: association studies.

reassortment: The rearrangement of genes from two distinct strains to produce a novel viral strain. 

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 manipulation & disruption genetic recombination; recombinant DNA technology, recombinant antibodies, recombinant DNA, recombinant proteins, recombination 

reference SNP: A reference SNP ID, or 'rs' ID is an identification tag assigned by NCBI to SNPs that appear to be unique in the database. The rs ID number, or tag, is assigned at submission. dbSNP FAQ, NCBI, US, 2002 http://www.ncbi.nlm.nih.gov/SNP/get_html.cgi?whichHtml=faq#gs id

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. 

Related terms: Maps- genomic & genetic

regulatory SNPs: See rSNPs

repeats: Narrower terms:  include microsatellite repeats, minisatellite repeats, short tandem repeats, satellites, tandem repeats, VNTRs

restriction analysis: Uses naturally occurring enzymes that cut DNA at precise sites. The enzymes cut the DNA from different individuals in different places when individuals differ in the sequence of a site where the enzyme cuts. The cut fragments will therefore be different sizes, and the pattern of sizes will form a DNA pattern, or "DNA fingerprint" for the individual. CHA Cambridge Healthtech Advisors, Clinical Genomics: The Impact of Genomics on Clinical Trials and Medical Practice report, 2004

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.

ribotyping: RESTRICTION FRAGMENT LENGTH POLYMORPHISM analysis of rRNA genes that is used for differentiating between species or strains. [MeSH, 2001

SNP Single nucleotide polymorphism: The most common form of DNA variation, alterations to a single base. If the SNP is in a gene, it can disrupt the gene's function. Most \SNPs do not occur in genes, but can be associated with other types of DNA variation and so are used effectively as markers. CHA Cambridge Healthtech Advisors, Clinical Genomics: The Impact of Genomics on Clinical Trials and Medical Practice report, 2004  

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

A SNP is a position in the genome where some individuals have one DNA base (e.g., A), and others have a different base (e.g., C). 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. This distinction is pragmatic and reflects the fact that low- frequency mutations cannot be used effectively in genetic studies as genetic markers, while more common ones can.  

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. 

Narrower terms: SNPs- human, single amino acid polymorphisms SAPS;  anonymous SNPs, cSNPs, candidate SNP, exonic SNPs, intron SNPs, pSNP, promoter SNPs, 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 Consortium: Now the International HapMap Project http://www.hapmap.org/abouthapmap.html 

SNP discovery: Sequencing glossary

SNP haplotypes: Multilocus analysis of single-nucleotidepolymorphism (SNP) haplotypes may provide evidence of association with disease, even when the individual loci themselves do not. Haplotype-based methods are expected to outperform single-SNP analyses because (i) common genetic variation can be structured into haplotypes within blocks of strong linkage disequilibrium and (ii) the functional properties of a protein are determined by the linear sequence of amino acids corresponding to DNA variation on a haplotype. Andrew P Morris, A Flexible Bayesian Framework for Modeling Haplotype Association with Disease, Allowing for Dominance Effects of the Underlying Causative Variants, American Journal of Human Genetics,79 : 679– 694, 2006 DOI: 10.1086/508264 http://www.journals.uchicago.edu/cgi-bin/resolve?id=doi:10.1086/508264

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. 

SNP maps: Maps genomic & genetic 

SNP scans: See under genome scans.

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

SSEP Single Strand Electrophoretic Polymorphism: A technique for screening for 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:  Small regions of repeated bases throughout the human genome, which vary widely in length within the population.  These regions vary at much higher rates than SNPs, and in fact change too rapidly to be useful in identifying disease genes or propensity to disease.  However, they have proved very useful in identifying individuals by constructing a DNA fingerprint of the length of a set of STRs in the person's genome. CHA Cambridge Healthtech Advisors, Clinical Genomics: The Impact of Genomics on Clinical Trials and Medical Practice report, 2004

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: cloning, vectors 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 terms: microsatellite, minisatellite

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 (broader? narrower?).

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

Related terms: Sequencing genotyping, scoring methods

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: aggregate, Mendelian.

Single Amino acid Polymorphisms SAPs: Structurally expressed SNPs and mutations. Andrew CR Martin, Single Amino Acid Polymorphism Database http://www.bioinf.org.uk/saap/ 

Polymorphisms, which differ by a single amino acid.

Related term; SNP

‘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

splice variations: Gene definitions

suppression: Second mutation at a site distinct from the first mutation reverses, at least partially, the phenotypic expression of the first mutation. 

surrogate endpoint, surrogate markers: Biomarkers glossary 

synonymous SNP: 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

When the altered code still corresponds to the same amino acid as the "wild- type" sequence 

Narrower term: SAP single amino acid polymorphism Broader term: cSNP  
Related term: non- synonymous SNP

tag SNPs: The HapMap project has identified a further subset of 'tag' SNPs that are most useful in genetic association studies, because they link common haplotypes. Richard Gibbs, "Deeper into the genome" Nature 7063:1233- 1234, 27 Oct. 2005 

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

targeted mutation: Functional genomics glossary

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.

variants: Includes narrower terms: alleles, mutations, polymorphisms, SNPs and even narrower terms:    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

Narrower terms: genetic variations, protein variants

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

whole genome duplication: Gene duplication is an important source of evolutionary novelty. Most duplications are of just a single gene, but Ohno proposed that whole- genome duplication (polyploidy) is an important evolutionary mechanism. KH Wolfe, DC Shields "Molecular evidence for an ancient duplication of the entire yeast genome" Nature 387(6634): 708- 713, June 12, 1997

wild-type: The most frequently encountered genotype in natural breeding populations. [IUPAC Biotech]  

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

To what extent is wild-type a theoretical concept?  Is it as slippery and elusive as the concept of  "normal" in many cases in clinical medicine? 

Related terms:  Gene categories suppressor genes  Protein categories: wild- type proteins

Bibliography
Alpha glossary index

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

How to look for other unfamiliar  terms