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Authors
Benjamin A Raby, MD, MPH
Robert D Blank, MD, PhD
Section Editor
Anne Slavotinek, MBBS, PhD
Deputy Editor
Jennifer S Tirnauer, MD
Disclosures: Benjamin A Raby, MD, MPH Employment (spouse): Paraxel [hematology (CRO)]. Robert D Blank,
MD, PhDConsultant/Advisory Boards: Bristol-Myers-Squibb [obesity, metabolic bone disease (FGF21
analogue)]. Anne Slavotinek, MBBS, PhD Other Financial Interest: Oxford University Press [royalties for book on
growth charts]. Jennifer S Tirnauer, MDNothing to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be provided
to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate
standards of evidence.
Conflict of interest policy
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Aug 2015. | This topic last updated: Jul 22, 2015.
INTRODUCTION One of the greatest obstacles clinicians experience in reading about and
understanding genetics is the extensive use of technical language and jargon. It should be noted
that genetic terms are frequently used imprecisely in published clinical literature. The following is
a compilation of some of the most important technical terms.
A more extensive discussion of terms can be accessed in standard genetics reference texts [1]. In
addition, a guide for the conventions regarding the proper names of genes and alleles in humans
can be found atwww.genenames.org/guidelines.html.
Glossaries of epidemiological terms and terms that apply to systematic reviews and metaanalyses are presented separately in UpToDate. (See "Glossary of common biostatistical and
epidemiological terms" and"Systematic review and meta-analysis", section on 'Glossary of
terms'.)
GLOSSARY
Allele One of a series of alternative forms at a specific region of a chromosome. At the
DNA level, different alleles have different base sequences.
Allele frequency The proportion of chromosomes in a population harboring a specific
allele. "Minor allele frequency" typically refers to the less common variant at a biallelic locus
and is usually used to refer to the frequency of a single nucleotide polymorphism (SNP).
Allelic heterogeneity Common occurrence of multiple mutations in one gene that all
result in the same disease or syndrome. As an example, more than 1500 mutations in the
cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis.
Note that this term differs from genetic heterogeneity.
Aneuploidy The state of having an abnormal number of chromosomes. A euploid
human karyotype has 46 chromosomes (figure 1). Aneuploidy can affect the entire somatic
cell population, as in trisomy 21, or it can affect a subset of cells, as in a tumor.
DNA barcoding can also refer to the addition of unique labels to DNA samples for
identification. As an example, this type of barcoding may be used to label DNA from different
individuals when next-generation sequencing is used.
Dominant negative Alleles that cause an abnormal phenotype or disease by a
mechanism that depends on the presence of an abnormal gene product interfering with the
function of the products from a normal gene.
Double heterozygote An individual who is heterozygous for two mutations at two
separate genetic loci that together are sufficient to manifest a phenotype. Differs from
compound heterozygote.
Embryonic stem cell A pluripotential cell derived from the inner cell mass of an earlystage embryo that is capable of differentiating into cells derived from all three germ layers.
Epigenetic change A modification of a chromosome that does not alter the nucleotide
base sequence, but alters the expression of a gene. Epigenetic changes may be stable in
an individual, but may be reversed during gametogenesis or early development. DNA
methylation and histone acetylation are common epigenetic changes. Epigenetic changes
form the mechanistic basis of imprinting.
Epistasis The process by which variations at two or more genetic loci interact to
produce phenotypes different from the individual effects of each variant. This process is
often referred to as either a gene-gene interaction or a genetic modifier effect.
Exome The portion of the genome that consists of exons.
Exome sequencing A sequencing strategy that provides the DNA sequence
corresponding to all exons (~1 percent of the genome), excluding introns and non-coding
genomic sequence. Though the complete exome includes non-coding 5 and 3 Untranslated
Regions (UTRs), most exome sequencing assays are enriched for the coding exons and
largely exclude the non-coding regions.
Exon A segment of DNA that is transcribed and present in mature messenger RNA
(mRNA). Many exons encode a portion of a protein, but non-coding exons also exist. This is
in contrast to an intron, the DNA sequence between exons that does not become part of
mature mRNA. Exons constitute only a small percent of the genome (about 1 to 2 percent).
Expressivity A parameter used in genetic models that quantifies the degree to which
an inherited characteristic is expressed in an organism.
Frameshift mutation A mutation that results from an insertion or deletion of a number
of bases that is not divisible by three, resulting in a shift of the reading frame (figure 4) and
thus altering the protein.
Fusion gene A functional gene product that results from the fusion of DNA segments
from two physically distinct genes. The fusion occurs as a consequence of chromosomal
rearrangements such as translocations, inversions, segmental deletions, or duplications.
Examples include the BCR-ABL and the FIP1L1-PDGFRA oncogenes.
Gene A unit of DNA sequence that encodes specific function. Classical definitions limit
genes to those elements that code for protein. However, non-protein coding genes (such as
non-coding RNAs or pseudogenes) are also genes.
Genetic heterogeneity Mutations in different genes resulting in the same phenotype or
disease. Examples include the multiple genetic causes of sensorineural deafness. This
differs from allelic heterogeneity.
offspring. Examples include the Prader-Willi syndrome and Angelman Syndrome locus and
a gene involved in pseudohyperparathyroidism. (See "Epidemiology and genetics of PraderWilli syndrome" and "Congenital cytogenetic abnormalities".)
Indel A class of common polymorphisms defined by an extra copy or a missing copy of
a short genetic or chromosomal sequence.
Induced pluripotent stem cell (iPSC) A pluripotent cell capable of differentiation to
mature lineages that is derived by in vitro reprogramming of a somatic cell.
Intron A segment of DNA between two exons that is transcribed to pre-mRNA but is
removed through the process of splicing and is therefore not part of mature mRNA.
Inversion A chromosomal rearrangement characterized by rotation and reintegration of
a DNA segment, resulting in an inverted orientation of the segment relative to its typical
state.
Linkage The relationship that exists between two loci that violate the Mendelian law of
independent assortment and therefore segregate in families in a non-random fashion. Nonindependent assortment results because linked loci reside together on the same
chromosome (ie, they are syntenic). However, most syntenic loci are not linked due to
mandatory recombination during meiosis. Linkage therefore implies the linked loci are in
close physical proximity to each other. The genetic linkage distance is expressed by
recombination fraction as expressed in centiMorgans (cM). Note that this is not necessarily
proportional to the physical distance (base pairs) separating the loci.
Linkage analysis Method of gene mapping that tests for the non-random segregation
of disease phenotypes with discrete chromosomal segments. Identification of linked regions
implies the existence of disease-causing mutations within or proximal to the linked region.
The process of disease-gene identification within this region is termed positional cloning.
Linkage disequilibrium The non-random association of alleles at two or more loci in a
population. Linkage disequilibrium is present when the observed haplotype distribution of
two or more markers in a population is significantly different from the expected haplotype
distribution (which can be derived from the cross-product of observed allele frequencies)
(figure 6).
Locus A specific chromosomal or genomic location. Plural = loci.
LOD score Logarithm of the odds score. A quantitative measure of the statistical
evidence of linkage between two genes. The LOD score depends on both the probability of
cosegregation of the two genes during meiosis and the size and structure of the population
in which the linkage analysis is performed. By convention, LOD scores >3 are considered to
be evidence of linkage in human studies. In some studies, the threshold LOD scores for
linkage can be established via permutation testing.
Lyonization See X-inactivation.
Manhattan plot A type of plot used to display results of a GWAS study. Genomic
coordinates are shown on the X-axis and the negative logarithm of the P-value for each
SNP on the Y-axis. SNPs with the strongest association will have the lowest P-values, and
hence the tallest profiles. Named for the appearance of the skyline in Manhattan in the
United States (figure 7).
Marker A locus with alternative alleles that can be used in genetic mapping
experiments.
Meiosis The cell division process in germline cells by which the chromosomal
complement is reduced from the diploid to the haploid number (figure 8).
Mendelian inheritance A trait is said to have Mendelian inheritance if its genetic
transmission can be explained by a Mendelian model of inheritance, such as autosomal
dominant, autosomal recessive, or X-linked recessive inheritance. This is in contrast to
digenic and quantitative traits.
Methylation The addition of methyl groups to cytosine in DNA. Methylation, when
followed by deamination, is a major pathway for mutation to thymine. Methylation also
correlates with reduced gene transcription and is an important mechanism for gene
imprinting and X-inactivation.
Micro-RNA (miR) A small, non-coding RNA that regulates the stability or translation of a
set of mRNAs.
Microsatellite A tandem array of short sequences of DNA (typically two to four bases).
Microsatellites are numerous and widely distributed in the genome. There is often
polymorphism in their length, making them useful markers in genetic studies, including
genome mapping and family-based linkage analysis. Microsatellites are also known as short
tandem repeat markers (STRs).
Mitochondrial genome The genetic material carried within mitochondria. At
fertilization, all the mitochondria are derived from the egg, so mitochondrial genes display
maternal inheritance.
Mitosis The process of cell division occurring in somatic cells, in which each daughter
cell receives a full chromosome complement.
Monogenic trait/monogenic disease Trait or disease with inheritance that can be
explained by a single gene, in contrast to polygenic and complex diseases.
Mutation, mutant An altered version of a gene. These terms are used in several
different senses, depending on context:
A genetic variant of low population frequency, in contrast to a polymorphism (often a
single nuclear polymorphism, or SNP) with an allele frequency of 1 percent or greater.
Types of gene mutations include nonsense (creates premature stop codon) (figure 3);
missense (creates amino acid change) (figure 2); silent (no associated change in
protein sequence); and frameshift (shifts the reading frame of the DNA and alters
protein translation, resulting in an entirely new protein sequence downstream of the
mutation) (figure 4).
Implication of abnormal function (eg, sickle cell mutation of the hemoglobin beta
chain).
Implication of recent sequence change (either germline or somatic), in contrast to
inheritance from a carrier parent.
An organism or population can harbor a specific mutation (eg, antibiotic-resistant
mutants).
Next-generation sequencing Any of several high-throughput DNA sequencing
methods that rely on parallel analysis of multiple DNA fragments (eg, whole genome
sequencing, exome sequencing). These methods have resulted in dramatic decreases in
the cost and time needed for sequencing projects and are used in some clinical settings.
Non-coding variant Genetic variation that does not map to gene regions that code for
protein. These variants can be functional if they reside in and disrupt functional elements,
such as non-coding RNA sequences or regulatory sites (eg, promoters, enhancers,
suppressors, or splice-sites).
Oncogene Gene that contributes to the production of cancer. Oncogenes typically act
in a dominant manner (ie, an oncogenic mutation at one allele is sufficient to promote
tumorigenesis).
Pedigree A diagram or other graphic representation of a family that shows the family
relationships, sex of each family member, and presence or absence of one or more
diseases in each individual (figure 9).
Penetrance The probability that an individual harboring a disease-causing mutation will
develop the associated disease or condition. Incomplete (or variable) penetrance occurs
when an individual with a disease-causing mutation does not manifest features of the
disorder. There are many causes of incomplete penetrance, including absence of
environmental or genetic co-factors, epigenetic effects such as imprinting, sex-specific
effects, or age-related expression differences.
Phenotype A characteristic of an organism (as opposed to the organisms genotype).
Phenotypes are sensitive to the assays used to assign or measure them. They may be
categorical, such as presence or absence of a disease; or quantitative, such as systolic
blood pressure. Further complexities in phenotypic description involve the physiological
state of the organism at the time of measurement, age, or use of provocative stimuli. Most
phenotypes are variable, and this variability leads to the concepts of penetrance and
expressivity.
Pleiotropy The association of variant(s) in a single gene with multiple phenotypic
effects, often in different tissues or organs. An example is Marfan syndrome, in which
mutations in the fibrillin 1 (FBN1) gene can cause cardiac, ocular, and connective tissue
findings.
Ploidy The number of sets of chromosomes present in an organism or cell. Ploidy
varies among different organisms, including those that are always haploid (eg, bacteria),
either haploid or diploid (eg, Saccharomyces species [yeast]), consistently diploid (eg,
mammals), or polyploid (eg, hexaploid wheat). Different tissues in multicellular organisms
may have different ploidies (eg, mammalian hepatocytes may be tetraploid). The
designation of ploidy is based on the predominant ploidy of cells in the organism.
Polymorphism A genetic region for which there are at least two different alleles present
in at least one population. Most commonly refers to a common single base-pair change or
single nucleotide polymorphism (SNP). By definition, a SNP has a population frequency of
at least 1 percent, in contrast to a mutation, which has a frequency of less than 1 percent.
A polymorphism also refers to any biologic marker (DNA, RNA, or protein) with two or more
states. Protein polymorphisms (varying amino acid sequence) can result from differences in
DNA sequence (ie, DNA polymorphisms) or from differential RNA splicing (ie, isoforms),
which in turn can result from sequence variation, epigenetic phenomenon,
or temporal/spatial/environmental differences.
Polygenic trait/polygenic disease In contrast to monogenic diseases, polygenic
diseases are those for which the inherited trait(s) is explained by more than one gene.
Tumor suppressor gene Gene that protects against the development or growth of
tumors. Tumor suppressor genes typically act in a recessive manner (ie, both normal copies
must be lost for a tumor to develop).
Uniparental disomy The inheritance of two copies of a chromosome (or part of a
chromosome) from one parent, and no copy from the other parent, due either to nondisjunction errors during either the first or second phases of meiosis, or to chromosomal
alterations in early fetal development. Non-disjunction during the first phase of meiosis
(meiosis I) will result in inheritance of each of the grandparental chromosomes from one
parent, termed heterodisomy. In contrast, non-disjunction during meiosis II results in
inheritance of two identical copies of one grandparental chromosome, termed isodisomy.
Variant See genetic polymorphism/genetic variant.
Variant of unknown significance (VUS) A classification term used in clinical DNA
sequencing reports to signify genetic polymorphisms for which the pathogenicity (likelihood
of causing disease) cannot be determined easily. VUS are variants that cannot be readily
classified as pathogenic, likely pathogenic, or benign.
Whole genome sequencing A sequencing strategy that provides the DNA sequence
for the entire genome, including exons, introns, and other non-coding sequence. In contrast,
exome sequencing only determines the sequence of gene coding regions.
1.