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 term index Related Glossaries include
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
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
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.
Related terms: allelic variants, copy number variations, mutation, polymorphisms, SNP, bi-allelic, di-
allelic, multiple- allelism, tri- allelic.
Narrower term: slightly deleterious
allele.
Broader term: variants
allelic imbalance:
A situation where one member (allele) of a gene pair is lost (LOSS OF HETEROZYGOSITY) or amplified.
MeSH, 1991
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 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
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.
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
chimerism:
The
occurrence in an individual of two or more cell populations of different
chromosomal constitutions, derived from different individuals. This
contrasts with MOSAICISM in which the different cell populations are
derived from a single individual.
MeSH Year introduced: 2005
coding SNPs 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
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
complex trait:
Complex traits
are defined as those where inheritance does not follow a Mendelian (that is,
simple) pattern. The best definition of a complex trait is: where “one or more
genes acting alone or in concert increase or reduce the risk of that trait”.3
This definition allows for all of the above possibilities (oligogenic,
polygenic, and multifactorial), as well as non-Mendelian single gene disease,
and has three important details. Firstly, genetic variations (mutations or
polymorphisms (see box 2)) result in differences in the risk of disease; the
disease causing mutations (DCMs) or alleles do not by themselves confer disease,
they simply increase or reduce the likelihood that a trait will be expressed in
a given individual. The second detail concerns the term “trait” as opposed
to “disease”. Most diseases are heterogeneous syndromes and the clinical
phenotypes are often extremely variable. Using the term “trait” allows for
this variation in the disease phenotype and the prospect that DCMs not only
determine which diseases we are more likely to develop but also may determine
the severity of the clinical syndrome that follows.
Previously
complex traits were called “polygenic” (involving more than one gene),
multifactorial (depending on the interaction of the host genome and one or more
environmental factors), or oligogenic (whereby individual mutations in several
different genes in one or more common pathways lead to the same clinical
syndrome but each patient with the disease may possess a single disease causing
mutation only)
P
T Donaldson, Genetics
of liver disease: immunogenetics and disease pathogenesis, Gut.
2004
April; 53(4):
599–608 doi:
http://gut.bmj.com/content/53/4/599
Copy
Number Polymorphisms CNPs:
Will become a valuable tool
for defining relative phenotypes in a population.
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
https://www.ncbi.nlm.nih.gov/pubmed/15922827
Another term for CNV
copy
number variations CNVs:
large-scale structural changes in DNA that vary from individual to individual.
These include insertions, deletions, duplications and complex multi-site
variants that range from kilobases to megabases in size. CNV can influence gene
expression, phenotypic variation and alter gene dosage, and in certain instances
may be associated with developmental disorders, cause disease or confer
susceptibility to complex disease traits.
Commonly used Genome Terms, NCBI
https://www.ncbi.nlm.nih.gov/projects/genome/glossary.shtml
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 Related terms: copy
number polymorphisms, SNP
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
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.
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
di-allelic: See under bi-allelic.
direct approach:
See candidate gene approach. Alternative
to shotgun sequencing. Sequencing
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
epiallele:
Wiktionary http://en.wiktionary.org/wiki/epiallele
See related epigenetics
epigenetic:
Descriptive term for processes that change the phenotype
without altering the genotype. IUPAC Biotech epigenetics: Epigenetics
refers to the study of heritable changes in gene expression that occur without a
change in DNA sequence. Epigenetic mechanisms are multifaceted and complex, and
they provide an additional layer of transcriptional control to regulate how
genes are expressed.
Covers a broad range of effects, and several are
discussed in this special issue. But how did epigenetic regulation arise? For
RNA- mediated silencing and DNA methylation there is evidence that they
have evolved as part of a host defense mechanism against viruses and parasitic
DNA. The substrate - double- stranded RNA (dsRNA) - for both posttranscriptional
gene silencing (PTGS) [or RNA interference (RNAi)] and transcriptional gene
silencing (TGS) seen in plants is a common intermediate in the life cycle of
many viruses and transposons. Guy Riddihough and Elizabeth Pennisi, "The
Evolution of Epigenetics" Science 293 (5532): Aug. 20, 2001
Given that there
are several existing definitions of epigenetics, it might be felt that
another is the last thing we need. Conversely, there might be a place for
a view of epigenetics that keeps the sense of the prevailing usages but
avoids the constraints imposed by stringently requiring heritability. The
following could be a unifying definition of epigenetic events: the
structural adaptation of chromosomal regions so as to register, signal or
perpetuate altered activity states. This definition is inclusive of
chromosomal marks, because transient modifications associated with both
DNA repair or cell-cycle phases and stable changes maintained across
multiple cell generations qualify. It focuses on chromosomes and genes,
implicitly excluding potential three-dimensional architectural templating
of membrane systems and prions, except when these impinge on chromosome
function. Also included is the exciting possibility that epigenetic
processes are buffers of genetic variation, pending an epigenetic (or
mutational) change of state that leads an identical combination of genes
to produce a different developmental outcome17. An implicit feature of
this proposed definition is that it portrays epigenetic marks as
responsive, not proactive. In other words, epigenetic systems of this kind
would not, under normal circumstances, initiate a change of state at a
particular locus but would register a change already imposed by other
events. Perceptions of epigenetics - Code Biology
www.codebiology.org/database/Epigenetic%20Code/Bir07.pdf
Epigenetics: a web supplement Science Aug. 10, 2001 http://www.sciencemag.org/content/vol293/issue5532/#specialintro
Epigenetics 101, Guardian http://www.theguardian.com/science/occams-corner/2014/apr/25/epigenetics-beginners-guide-to-everything
International Human Epigenetic
Consortium
http://ihec-epigenomes.org/
epigenome:
A set of what may
be hundreds of genes whose function is determined by [genetic] imprinting.
[Post Gazette News Bar Harbor, Maine genetics seminar, July 26, 2000]
http://www.post-gazette.com/healthscience/20000726heredity1.asp
epigenomics:
The
Common Fund's Epigenomics Program includes a series of complementary initiatives
aimed at generating new research tools, technologies, datasets, and
infrastructure to accelerate our understanding of the role of epigenetics - the
study of how chemical "marks" on DNA regulate gene activity and
expression without altering the DNA sequence itself - in human health and
disease. Initiatives include Reference
Epigenome Mapping Centers , Epigenomics Data Analysis and Coordination Center ,
Technology Development in Epigenetics , Discovery of Novel Epigenetic Marks in
Mammalian Cells, Epigenomics of Human Health and Disease. Epigenomics, NIH
Common Fund http://commonfund.nih.gov/epigenomics/
A whole genome approach
to epigenesis and epigenetics. “An approach that views these [imprinting,
metabolic networks, genetic hierarchies in embryonic development, and epigenetic
mechanisms of gene activation in cancer] and other complex phenotypes from
the genomic level down, rather than from the genetic level up, can provide
powerful insights into the functional interrelationships of genes in health
and disease. S Beck, A Olek and J Walter “From genomics to epigenomics”
Nature Biotechnology 17 (12):1144 Dec 1999
Takes a
whole-genome approach to studying environmental or developmental epigenetic
effects, primarily DNA methylation, on gene function. Thus, epigenomics focuses
on those genes whose function is determined by external factors. Brush
up on your 'omics, Chemical & Engineering News, 81(49): 20, Dec. 2003 http://pubs.acs.org/cen/coverstory/8149/8149genomics1.html
Related terms: Expression; Gene
definitions epigenetics
epigenotype:
Patients with disorders involving imprinted genes such
as Angelman syndrome (AS) and Prader- Willi syndrome (PWS) can have a mutation in
the imprinting mechanism. Previously, we identified an imprinting center (IC)
within chromosome 15q11-ql3 and proposed that IC mutations block resetting of
the imprint, fixing on that chromosome the parental imprint (epigenotype) on
which the mutation arose. S Saitoh, "Minimal definition of the imprinting
center and fixation of chromosome 15q11-q13 epigenotype by imprinting
mutations" Proceedings of the National Academy of Sciences U S
A PNAS 93 (15) :7... CH Waddington
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]
eSNPs
expression SNPs:
We present the first empiric study to systematically
characterize the set of single nucleotide polymorphisms associated with
expression (eSNPs) in liver, subcutaneous fat, and omental fat tissues,
demonstrating these eSNPs are significantly more enriched for SNPs that
associate with type 2 diabetes (T2D) in three large-scale GWAS than a matched
set of randomly selected SNPs. Zhong H, Beaulaurier J, Lum PY, Molony C, Yang X,
et al. (2010) Liver and Adipose Expression Associated SNPs Are Enriched for
Association to Type 2 Diabetes. PLoS Genet 6(5): e1000932.
doi:10.1371/journal.pgen.1000932 http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1000932
exon
skipping: As many as half of the disease- associated single- nucleotide
mutations in the coding regions of genes do not alter specific amino acids in
the protein, but rather affect RNA splicing; for example, by inactivating or
creating a splice site. And more often than not, these mutations result in the
exclusion of exons from mRNA, a process known as exon skipping. So finding a way
to correct these mutations and reinstate these exons into the transcript could
be an effective route to treating the underlying cause of a wide range of
diseases. Simon
Frantz The Essence of Correction, Nature Reviews Drug Discovery 2: 170 April
2003
One of the major forms of
alternative splicing, which generates multiple mRNA isoforms differing in the
precise combinations of their exon sequences, is exon skipping. While in
constitutive splicing all exons are included, in the skipped pattern(s) one or
more exons are skipped. The regulation of this process is still not well
understood; so far, cis- regulatory elements (such as exonic splicing enhancers)
were identified in individual cases. We therefore set to investigate the
possibility that exon skipping is controlled by sequences in the adjacent
introns. Conserved
sequence elements associated with exon skipping E. Miriami, H. Margalit, R.
Sperling Nucleic Acids Research 31 (7) : 1974- 1983, Apr 1, 2003
Differential exon use is a hallmark of
alternative splicing, a prevalent mechanism for generating protein isoform
diversity. Many disease- associated mutations also affect pre- mRNA splicing,
usually causing inappropriate exon skipping. Correction
of disease- associated exon skipping by synthetic exon- specific activators L.
Cartegni, AR Krainer Nat Structural Biology Feb. 2003 10 (2) :120 -125
exon SNPs, exonic SNPs:
Are these the same as coding SNPs cSNPs?
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 polymorphisms:
To understand the mechanistic basis by which a
polymorphism is associated with a particular phenotype or behavioural outcome,
it is necessary to know whether that polymorphism is functional (i.e., whether
it alters the function of a gene or set of genes). In most cases, the function
of an associated polymorphism is not defined and must be surmised or
extrapolated as an effect on the gene that contains this polymorphism. In rare
cases, a polymorphism may be a nonsynonymous coding region variation that alters
the gene product protein structure. What is a functional genetic polymorphism?
Defining classes of functionality. J Psychiatry Neurosci. 2011;36(6):363-5.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3201989/
Assessing
the functionality of a given polymorphism is not a straightforward process. Most
genes have several polymorphic sites, many of which may impact on gene
expression; SNPs are inherited as haplotypes and the potential for
post-translational modification of expressed genes means that simply assessing
gene transcription is not evidence of a biological effect. Even if an SNP is
associated with a “functional” effect, there is no guarantee that the
associated function will have a biological consequence. Most biological systems
have a degree of built-in redundancy to cope with relative differences in key
components. P
T Donaldson, Genetics
of liver disease: immunogenetics and disease pathogenesis, Gut.
2004 April; 53(4):
599–608 doi: 10.1136/gut.2003.031732.
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
gene mapping: describes
the methods used to identify the locus of
a gene and the distances between genes.[2]
. Wikipedia accessed 2018 Nov 8
https://en.wikipedia.org/wiki/Gene_mapping
genetic drift: Random fluctuations
in gene frequencies, particularly in small populations.
genetic mapping:
also called linkage mapping -
can offer firm evidence that a disease transmitted from parent to child is
linked to one or more genes. Mapping also provides clues about which
chromosome contains the gene and precisely where the gene lies on that
chromosome. Genetic maps have been used successfully to find the gene
responsible for relatively rare, single-gene inherited disorders such as
cystic fibrosis and Duchenne muscular dystrophy. Genetic maps are also
useful in guiding scientists to the many genes that are believed to play a
role in the development of more common disorders such as asthma, heart
disease, diabetes, cancer, and psychiatric conditions. NHGRI Genetic
Mapping
https://www.genome.gov/10000715/
genetic variants:
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.
genetic variation - detection technologies:
Includes microarrays,
dHPLC, DNA fingerprinting, DNA footprinting, DNA ligase enzymes, endonucleases,
ribotyping, SSCP, SSEP.
Related terms: protein variations; Sequencing
genotype, haplotype,
scanning, scoring.
genome mapping:
The essence of all genome mapping
is to place a collection of molecular markers onto their respective
positions on the genome. Molecular
markers come in all forms. Genes can
be viewed as one special type of genetic markers in the construction of
genome maps, and mapped the same way as any other markers. Wikipedia
accessed 2018 Nov 8
https://en.wikipedia.org/wiki/Gene_mapping
There are two distinctive types of "Maps" used
in the field of genome mapping: genetic maps and physical maps. While both
maps are a collection of genetic
markers and gene loci, genetic maps'
distances are based on the genetic linkage information, while physical
maps use actual physical distances usually measured in number of base
pairs. While the physical map could be a more "accurate" representation of
the genome, genetic maps often offer insights into the nature of different
regions of the chromosome, e.g. the genetic distance to physical distance
ratio varies greatly at different genomic regions which reflects different
recombination rates, and such rate is often indicative of euchromatic
(usually gene-rich) vs heterochromatic (usually gene poor) regions of the
genome. …Genome sequencing is sometimes mistakenly referred to as "genome
mapping" by non-biologists. The process of "shotgun sequencing" resembles
the process of physical mapping: it shatters the genome into small
fragments, characterizes each fragment, then puts them back together (more
recent sequencing technologies are drastically different). While the
scope, purpose and process are totally different, a genome assembly can be
viewed as the "ultimate" form of physical map, in that it provides in a
much better way all the information that a traditional physical map can
offer. Wikipedia accessed 2018 Nov 8
https://en.wikipedia.org/wiki/Gene_mapping#Genetic_mapping_vs_physical_mapping
genotype: Sequencing
GWAS
Central
provides a centralized compilation of summary level findings from genetic
association studies, both large and small. We actively gather datasets
from public domain projects.
https://www.gwascentral.org/
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
Wikipedia
https://en.wikipedia.org/wiki/Haploinsufficiency
haplotype, haplotyping, haplotyping technologies: Sequencing
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.
heritability:
Before we attempt to identify disease genes, we need to have some
estimate of the heritable component of the disease so that we can determine the
best and most pragmatic means of investigating it. Simple measures of
heritability include: concordance in monozygotic and dizygotic twins, the degree
of familial aggregation, and calculations such as sibling relative risk.
P T Donaldson, Genetics
of liver disease: immunogenetics and disease pathogenesis, Gut.
2004 April; 53(4):
599–608 doi: 10.1136/gut.2003.031732
HGVbase now
GWAS Central
Human Genome
Variation Society http://www.hgvs.org/
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.
indel:
HGVS:
confusing term, do not use
Sometimes:
a sequence change where, compared to a reference sequence, one or more
nucleotides are replaced by one or more other nucleotides
Sometimes:
a variant which is a deletion or an insertion.
MESH
a length difference between
two alleles where it is unknowable if the difference was originally caused
by a sequence insertion or a sequence deletion.
Human Genome Variation
Society, Sequence Variant Glossary
http://varnomen.hgvs.org/bg-material/glossary/
See
also insertion
INDEL Mutation:
A mutation named with the blend of insertion and deletion. It refers to a
length difference between two ALLELES where it is unknowable if the
difference was originally caused by a SEQUENCE INSERTION or by a SEQUENCE
DELETION. If the number of nucleotides in the insertion/deletion is not
divisible by three, and it occurs in a protein coding region, it is also a
FRAMESHIFT MUTATION. MeSH 2008
indirect approach: See random genome-wide association studies.
informative polymorphisms:
Within candidate genes, the number of common polymorphisms is
finite, but direct assay of all existing common polymorphism is inefficient,
because genotypes at many of these sites are strongly correlated. Thus, it is
not necessary to assay all common variants if the patterns of allelic
association between common variants can be described. We have developed an
algorithm to select the maximally informative set of common single-nucleotide
polymorphisms (tagSNPs) to assay in candidate-gene association studies,
such that all known common polymorphisms either are directly assayed or exceed a
threshold level of association with a tagSNP.
Am
J Hum Genet. 2004
Jan;74(1):106-20. Epub 2003 Dec 15. Selecting a maximally informative set of
single-nucleotide polymorphisms for association analyses using linkage
disequilibrium. Carlson
CS, Eberle
MA, Rieder
MJ, Yi
Q, Kruglyak
L, Nickerson
DA. http://www.ncbi.nlm.nih.gov/pubmed/14681826
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”.
intra-genic
sequence variants:
HGBASE is not designed to include gene `mutations', but instead is a catalog of
intra-genic (promoter to transcription end point) sequence variants found in
`normal' individuals. Although the distinction between `mutation' and
`variation' can be somewhat blurred, the general idea is that the content of
HGBASE concerns frequently occurring `normal polymorphisms', whether or not they
are suspected to increase the risk of developing a particular phenotype. This is
in contrast to `mutant sequences' which are known to cause genetic disease.
Despite its name, HGBASE contains all types of intra-genic variation and is not
limited to bi-allelic polymorphisms (though these do represent most of the
database content). Both functional polymorphisms (e.g. promoter and non-silent
codon changes) and non-functional polymorphisms (e.g. intron sequence
differences) are included. This is for two reasons. Firstly, it is often
difficult to be certain about the functional consequence of a variation.
Secondly, regardless of functional relevance, any intra-genic polymorphism can
usually be employed as an effective surrogate marker for an unknown functional
variant in an association study, due to close proximity and linkage
disequilibrium. Human Genetic Bi-allelic Sequences, HGBASE, a Database of Intra-genic
Polymorphisms 1998
http://www.bioline.org.br/request?oc98131
http://www.scielo.br/pdf/mioc/v93n5/12m.pdf
Now HGVBase http://www.hgvbaseg2p.org/index
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
https://www.ndsu.edu/pubweb/~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
https://www.ndsu.edu/pubweb/~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
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
missense
mutation: Wikipedia http://en.wikipedia.org/wiki/Missense_mutations
molecular variants: Narrower terms: alleles, mutations, polymorphisms,
SNPs.
Broader term: variants.
mosaicism:
The
occurrence in an individual of two or more cell populations of different
chromosomal constitutions, derived from a single ZYGOTE, as opposed to
CHIMERISM in which the different cell populations are derived from more
than one zygote. MeSH Year introduced: 1967(1964)
multifactorial:
As
polygenic but requires environmental
input for disease genesis. P T Donaldson, Genetics
of liver disease: immunogenetics and disease pathogenesis, Gut.
2004 April; 53(4):
599–608 doi: 10.1136/gut.2003.031732
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
alleles: The state of having three or more alleles,
or distinctive forms of a gene.
Wiktionary accessed Jan 12 2011 http://en.wiktionary.org/wiki/multiple_allelism
ABO
blood groups are a good example of multiple allelism.
Individuals have only two alleles, but there are a number of different
combinations and phenotypes.
multiplicative: See under
epistasis.
mutation:
Genetic
variation present in less than 1% of the population. P T Donaldson,
Genetics of liver disease: immunogenetics and disease pathogenesis, Gut.
2004 April; 53(4):
599–608 doi:
10.1136/gut.2003.031732
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 targeted mutation. Mutation databases see Databases & software directory under
'variations'.
mutation detection: See genetic variation detection
technologies 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
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:
Single
mutations in each case or family but several different genes make up the
disease. P T Donaldson, Genetics
of liver disease: immunogenetics and disease pathogenesis, Gut.
2004 April; 53(4):
599–608
doi: 10.1136/gut.2003.031732.
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
penetrance: Genomics
phene: See Databases &
software directory under OMIA Online Mendelian Inheritance in Animals
phenotype: Genomics
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:
Single
genes produce multiple, seemingly unrelated phenotypic effects.
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 gene
mutation, one allele of
a gene changes into a different allele. Because such a change takes place
within a single gene and maps to one chromosomal locus (“point”), a gene
mutation is sometimes called a point
mutation. This terminology
originated before the advent of DNA sequencing
and therefore before it was routinely possible to discover the molecular
basis for a mutational event. Nowadays, point mutations typically refer to
alterations of single base pairs of DNA or of a small number of adjacent
base pairs NCBI Resources, Molecular Basis of Mutation
https://www.ncbi.nlm.nih.gov/books/NBK21322/
Point mutations
affect only one or a few nucleotides within a gene University of
Evansville http://faculty.evansville.edu/de3/b10004/PDFs/13b_Sources_variation.pdf
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:
involves multiple genes
that interact to create a permissive gene pool for disease genesis. P T
Donaldson, Genetics
of liver disease: immunogenetics and disease pathogenesis, Gut.
2004 April; 53(4):
599–608
doi: 10.1136/gut.2003.031732.
Related
terms: multifactorial, multigenic, oligogenic, epistasis,
positional candidates: Functional
genomics
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. 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, alleles, association, linkage, mutations, population genetics,
sequence variants, SNPs.
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
Guidelines for referring populations in publications and presentations,
https://www.coriell.org/0/Sections/Support/NHGRI/NHGRI_Pop_Ref.aspx?PgId=688
promoter SNPs 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.
protein polymorphisms: Polymorphisms in exons (protein coding
DNA). cSNPs are a subset of protein polymorphisms.
protein variants:
Variations in proteins have very large number of
diverse effects affecting sequence, structure, stability, interactions,
activity, abundance and other properties. Although protein-coding exons cover
just over 1 % of the human genome they harbor a disproportionately large portion
of disease-causing variants… Protein variants can be of genetic origin or emerge
at protein level. Types and effects of protein variants Vihinen, M. Hum Genet
(2015) 134: 405.
https://doi.org/10.1007/s00439-015-1529-6
https://link.springer.com/article/10.1007/s00439-015-1529-6
Broader terms: genetic variants, variants
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 recombination; recombinant DNA technology,
recombinant antibodies, recombinant DNA, recombinant proteins,
recombination
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 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
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 RFLP: 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, can be used in SNP
genotyping. This method relies on enzymatic cleavage of DNA followed by electrophoresis. Broader term: marker
ribotyping:
RESTRICTION FRAGMENT LENGTH POLYMORPHISM analysis of rRNA genes that is used for differentiating between species or strains.
MeSH, 2001
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.
sequence
variant: following
recommendations of the Human Genome Variation Society, “sequence variant”
is a more inclusive term than “polymorphism. What is a functional genetic
polymorphism? Defining classes of functionality. J Psychiatry Neurosci.
2011;36(6):363-5.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3201989/
Single Amino acid Polymorphisms SAAPs:
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.
‘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
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
This
involves exchange of one nucleotide base (ACT or G) for another. P T Donaldson,
Genetics
of liver disease: immunogenetics and disease pathogenesis, Gut.
2004 April; 53(4):
599–608
doi: 10.1136/gut.2003.031732.
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 Consortium:
Became International HapMap Project
https://en.wikipedia.org/wiki/International_HapMap_Project
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
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1592560/
SNP - human:
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.
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. 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
structural
variants:
No two genomes are alike; instead, each displays structural variability in the
form of single-nucleotide polymorphisms (SNPs), deletions or insertions of
various sizes, which are collectively called copy number variants (CNVs) and
inversions, which are copy number neutral structural variants. Nicole
Rusk, Finding copy-number variants, Nature Methods 5(11):917 Nov 2008
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 positional cloning Functional
genomics.
STS databases see Databases &
software directory
suppression:
Second mutation at
a site distinct from the first mutation reverses, at least partially, the
phenotypic expression of the first mutation.
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 targeted mutation: Functional
genomics
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.
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
Genetic variations resources
Background on
Comparative Genomic Analysis, NHGRI, 2012 http://www.genome.gov/10005835
DDBJ/ EMBL/ GenBank Feature Table, Version 6.7, 2016 http://www.ebi.ac.uk/embl/Documentation/FT_definitions/feature_table.html
Den
Dunnen et al. (2016) HGVS
recommendations for the description of sequence variants: 2016 update.
Hum.Mutat. 25: 37: 564-569 although the examples on these pages mainly give examples for human (Homo
sapiens), the recommendations can be
applied to all species. Genetic Epidemiology Glossary, M Tevfik Dorak 2017 http://www.dorak.info/epi/glosge.html
Human
Genome Variation Society, Sequence Variant Glossary
http://varnomen.hgvs.org/bg-material/glossary/ Human Genome Variation Society, Sequence Variant Nomenclature
http://varnomen.hgvs.org/ Philip McLean, Genes and
Mutations, North Dakota State University, 1999
https://www.ndsu.edu/pubweb/~mcclean/plsc431/mutation/mutation1.htm
NCBI Commonly used Genome
Terms
https://www.ncbi.nlm.nih.gov/projects/genome/glossary.shtml
NCBI
Variations
https://www.ncbi.nlm.nih.gov/guide/variation/
NHGRI (National Human Genome Research Institute), Talking Glossary of Genetic
Terms, 100+ definitions.
https://www.genome.gov/genetics-glossary
Includes extended audio definitions.
NIH, Understanding Human Genetic Variation;
Biological Sciences Curriculum Study. Bethesda (MD): National
Institutes of Health (US); 2007.
https://www.ncbi.nlm.nih.gov/books/NBK20363/ IUPAC definitions are reprinted with the
permission of the International Union of Pure and Applied Chemistry.
How
to look for other unfamiliar terms
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