Thompson & Thompson Genetics in Medicine, 8th Edition


Acceptor splice site The boundary between the 3′ end of an intron and the 5′ end of the following exon. Also called 3′ splice site.

Acrocentric A type of chromosome with the centromere near one end. The human acrocentric chromosomes (13, 14, 15, 21, and 22) have satellited short arms that carry genes for ribosomal RNA.

Active chromatin hub Nuclear domain where the proteins bound to the locus control region and the β-globin locus colocalize to permit globin gene expression.

Adjacent segregation Pattern of chromosome segregation in a cell with a balanced reciprocal translocation following synapsis of a quadrivalent in which unbalanced gametes are formed that have only one copy of each of the centromeres of the translocated chromosomes (adjacent-1) or have two copies of one or the other of the translocated chromosomes but not both (adjacent-2) (see Fig. 5-12).

Adverse selection A term used in the insurance industry to describe the situation in which individuals with private knowledge of having an increased risk for illness, disability, or death buy disproportionately more coverage than those at a lower risk. As a result, insurance premiums, which are based on averaging risk across the population, are inadequate to cover future claims.

Allele One of the alternative versions of a gene or DNA sequence at a given locus.

Allele-specific oligonucleotide (ASO) An oligonucleotide probe synthesized to match a particular DNA sequence precisely and allow the discrimination of alleles that differ by only a single base.

Allelic heterogeneity In a population, there may be a number of different mutant alleles at a single locus. In an individual, the same or similar phenotypes may be caused by different mutant alleles rather than by identical alleles at the locus.

Allelic imbalance Unequal expression of the two alleles of a gene. The most extreme example is monoallelic expression, which can be random, as in X-inactivation, or determined by parent of origin of the allele (genomic imprinting).

Allogenic In transplantation, denotes individuals (or tissues) that are of the same species but have different antigens (alternative spelling: allogeneic).

Alpha-fetoprotein (AFP) A fetal glycoprotein excreted into the amniotic fluid that reaches abnormally high concentration in amniotic fluid (and maternal serum) when the fetus has certain abnormalities, especially an open neural tube defect.

Alternate segregation Pattern of chromosome segregation in a cell with a balanced reciprocal translocation following synapsis of a quadrivalent in which balanced gametes are formed that have either a normal chromosome complement or contain the two reciprocal balanced translocation chromosomes.

Alu family of repetitive DNA In the human genome, approximately 10% of the DNA is made up of a set of approximately 1,000,000 dispersed, related sequences, each approximately 300 base pairs long, so named because they are cleaved by the restriction enzyme AluI.

Amniocentesis A procedure used in prenatal diagnosis to obtain amniotic fluid, which contains cells of fetal origin that can be cultured for analysis. Amniotic fluid is withdrawn from the amniotic sac by syringe after insertion of a hollow needle into the amnion through the abdominal wall and uterine wall.

Analytic validity In reference to a clinical laboratory test, the ability of that test to perform correctly, that is, measure what it is designed to measure.

Anaphase Stage in mitosis when chromosomes separate at the centromere and sister chromatids become independent daughter chromosomes, which move to opposite poles of the dividing cell. Immediately follows metaphase.

Ancestry informative markers Loci with alleles that show large differences in frequency among populations originating in different parts of the world.

Aneuploidy Any chromosome number that is not an exact multiple of the haploid number. The common forms of aneuploidy in humans are trisomy (the presence of an extra chromosome) and monosomy (the absence of a single chromosome).

Anomalies Birth defects resulting from malformations, deformations, or disruptions.

Anticipation The progressively earlier onset and increased severity of certain diseases in successive generations of a family. Anticipation is caused by expansion of the number of repeats that constitute a dynamic mutation within the gene responsible for the disease.

Anticodon A three-base segment of transfer RNA (tRNA) complementary to a codon in messenger RNA (mRNA).

Antisense oligonucleotides (ASOs) Synthetic short (usually 12 to 35 nucleotides) single-stranded molecules that can hybridize to corresponding sequences in a specific target pre-mRNA or microRNA, causing its degradation, inhibiting its translation, or modulating its splicing. Excellent therapeutic potential.

Antisense strand of DNA The noncoding DNA strand, which is complementary to mRNA and serves as the template for RNA synthesis. Also called the transcribed strand.

Apoenzyme The protein component of an enzyme that also requires a cofactor to become active. The apoenzyme with the cofactor is termed the holoenzyme.

Apoptosis Programmed cell death characterized by a stereotypic pattern of mitochondrial breakdown and chromatin degradation.

Array CGH Comparative genome hybridization performed by hybridizing to a wafer (“chip”) made of glass, plastic, or silicon onto which a large number of different nucleic acids have been individually spotted in a matrix pattern. See microarray.

Ascertainment The method of selection of individuals for inclusion in a genetic study.

Ascertainment bias A difference in the likelihood that affected relatives of affected individuals will be identified, compared with similarly affected relatives of controls. A possible source of error in family studies.

Association 1. In genetic epidemiology, describes the situation in which a particular allele is found either significantly more or significantly less frequently in a group of affected individuals than would be expected from the frequency of the allele in the general population from which the affected individuals were drawn; not to be confused with linkage. 2. In dysmorphology, a group of abnormalities of unknown etiology and pathogenesis that is seen together more often than would be expected by chance.

Assortative mating Selection of a mate with preference for a particular genotype; that is, nonrandom mating. Usually positive (preference for a mate of the same genotype), less frequently negative (preference for a mate of a different genotype).

Assortment The random distribution of different combinations of the parental chromosomes to the gametes. Nonallelic genes assort independently, unless they are linked.

Autologous Refers to grafts in the same animal from one part to another or to malignant cells and the cells of the individual in which they have arisen.

Autosome Any nuclear chromosome other than the sex chromosomes; 22 pairs in the human karyotype. A disease caused by mutation in an autosomal gene or gene pair shows autosomal inheritance.

Balanced polymorphism A polymorphism maintained in the population by heterozygote advantage, allowing an allele, even one that is deleterious in the homozygous state, to persist at a relatively high frequency in the population.

Barr body The sex chromatin as seen in female somatic cells, representing an inactive X chromosome.

Base pair (bp) A pair of complementary nucleotide bases, as in double-stranded DNA. Used as the unit of measurement of the length of a DNA sequence.

Bayesian analysis A mathematical method widely used in genetic counseling to calculate recurrence risks. The method combines information from several sources (genetics, pedigree information, and test results) to determine the probability that a specific individual might develop or transmit a certain disorder.

Beneficence The ethical principle of behaving in a way that promotes the well-being of others. See maleficence.

Binomial expansion When there are two alternative classes, one with probability p and the other with probability 1 − p = q, the frequencies of the possible combinations of p and q in a series of n trials is (p + q)n.

Biochemical genetics The study of the genetic basis for phenotype at the level of proteins, biochemical pathways, and metabolism.

Bioinformatics Computational analysis and storage of biological and experimental data, widely applied to genomic and proteomic studies.

Birth defect An abnormality present at birth, not necessarily genetic.

Bivalent A pair of homologous chromosomes in association, as seen at metaphase of the first meiotic division.

Blastocyst A stage in early embryogenesis in which the initial ball of cells derived from the fertilized egg (the morula) secrete fluid and form a fluid-filled internal cavity within which is a separate group of cells, the inner cell mass.

Blood group The phenotype produced by genetically determined antigens on a red blood cell. The antigens formed by a set of allelic genes make up a blood group system.

Body mass index (BMI) A measure of weight used for classifying individuals as underweight, appropriate for weight, overweight, or obese that is corrected for height. Expressed as weight divided by square of the height (kg/m2).

5′-Cap A modified nucleotide added to the 5′ end of a growing mRNA chain, required for normal processing, stability, and translation of mRNA.

Caretaker genes Tumor-suppressor genes that are indirectly involved in controlling cellular proliferation by repairing DNA damage and maintaining genomic integrity, thereby protecting proto-oncogenes and gatekeeper tumor-suppressor genes from mutations that could lead to cancer.

Carrier An individual heterozygous for a particular mutant allele. The term is used for heterozygotes for autosomal recessive alleles, for females heterozygous for X-linked alleles, or, less commonly, for an individual heterozygous for an autosomal dominant allele but not expressing it (e.g., a heterozygote for a Huntington disease allele in the presymptomatic stage).

Case-control study An epidemiological method in which patients with a disease (the cases) are compared with suitably chosen individuals without the disease (the controls) with respect to the relative frequency of various putative risk factors.

cDNA See complementary DNA.

Cell cycle The stages between two successive mitotic divisions, described in the text. Consists of the G1, S, G2, and M stages.

Cell-free DNA DNA detectable in body fluids that is not packaged in chromatin inside the nucleus of a cell.

Centimorgan (cM) The unit of distance between genes along chromosomes, named for Thomas Hunt Morgan. Two loci are 1 cM apart if recombination is detected between them in 1% of meioses.

Centromere The primary constriction on the chromosome, a region at which the sister chromatids are held together and at which the kinetochore is formed. Required for normal segregation in mitosis and meiosis.

Centrosomes A pair of centers that organize the growth of the microtubules of the mitotic spindle; visible at the poles of the dividing cell in late prophase.

CGH See comparative genome hybridization.

Chain termination mutation See termination codon.

Checkpoint Positions in the cell cycle, usually at the junction between the G1 and S or the G2 and M stages, at which the cell determines whether to proceed to the next stage of the cycle.

Chemical individuality A term coined by Archibald Garrod to describe the naturally occurring differences in the genetic and biochemical makeup of each individual.

Chemical library An annotated collection of hundreds to tens of thousands of small molecules, increasingly used in drug discovery. High-throughput screening against a drug target may identify a compound that interacts with the target, for example to restore activity to a mutant protein. Such chemicals, or derivatives of them, may then be developed into drugs.

Chimera An individual composed of cells derived from two genetically different zygotes. In humans, blood group chimeras result from exchange of hematopoietic stem cells by dizygotic twins in utero; dispermic chimeras, which are very rare, result from fusion of two zygotes into one individual. Chimerism is also an inevitable result of transplantation.

Chorionic villus sampling (CVS) A procedure used for prenatal diagnosis at 8 to 10 weeks of gestation. Fetal tissue for analysis is withdrawn from the villous area of the chorion either transcervically or transabdominally under ultrasonographic guidance.

Chromatids The two parallel strands of chromatin (referred to as sister chromatids), connected at the centromere, that constitute a chromosome after DNA synthesis.

Chromatin The complex of DNA and proteins of which chromosomes are composed. See also nucleosome.

Chromatin remodeling DNA packaged in nucleosomes is subject to remodeling between chromatin states through the activity of enzymatic chromatin remodeling complexes. Packaged DNA can thereby be made accessible to facilitate the regulation of transcription, DNA repair, recombination, and replication.

Chromosomal satellite A small mass of chromatin containing genes for ribosomal RNA, at the end of the short arm of each chromatid of an acrocentric chromosome; not to be confused with satellite DNA.

Chromosome One of the threadlike structures in the cell nucleus; consists of chromatin. Each contains a single molecule of DNA in the interphase nucleus.

Chromosome arm The portion of a chromosome from the centromere to the telomere. Each chromosome has two arms of varying sizes. See p and q.

Chromosome disorder A clinical condition caused by an abnormal chromosome constitution in which there is duplication, loss, or rearrangement of chromosomal material.

Chromosome instability syndrome Hereditary condition that predisposes to a high frequency of chromosome breakage and rearrangements. Often associated with markedly increased risk for a variety of cancers.

Chromosome mutation Mutation that leaves a chromosome intact but changes the number of chromosomes in a cell.

Chromosome segregation The separation of chromosomes or chromatids in cell division so that each daughter cell gets an equal number of chromosomes.

Chromosome shattering Phenomenon seen in some cancer cells in which novel and complex chromosome rearrangements occur because the chromosomes break into numerous pieces and rejoin. The mechanism is unknown.

Chromosome spread The chromosomes of a dividing cell as seen under the microscope in metaphase or prometaphase.

Cis Refers to the relationship between two sequences that are on the same chromosome, literally meaning “on the near side of.” Contrast with trans.

Clinical heterogeneity The term describing the occurrence of clinically different phenotypes from mutations in the same gene.

Clinical utility In reference to a clinical laboratory test, the ability of that test to improve the medical care that an individual receives.

Clinical validity In reference to a clinical laboratory test, the ability of that test to detect the disease that the test was designed to detect.

Clonal evolution The multistep process of successive genetic changes that occur in a developing tumor cell population.

Clone 1. A cell line derived by mitosis from a single ancestral diploid cell; in embryology, a cell lineage in which the cells have remained geographically close to each other. 2. In molecular biology, a recombinant DNA molecule containing a gene or other DNA sequence of interest. Also, the act of generating such a cell line or clone.

CNP See copy number variant.

CNV See copy number variant.

Coding strand In double-stranded DNA, the strand that has the same 5′ to 3′ sense (and sequence, except that in mRNA, U substitutes for T) as mRNA. The coding strand is the strand that is not transcribed by RNA polymerase. Also called the sense strand.

Codominant If both alleles of a pair are expressed in the heterozygous state, then the alleles (or the traits determined by them, or both) are codominant.

Codon A triplet of three bases in a DNA or RNA molecule, specifying a single amino acid.

Cohort study A random sample of the entire population is analyzed for whether the subjects currently have or, after being followed over time, develop a particular disease.

Colinearity The parallel relationship between the base sequence of the DNA of a gene (or the RNA transcribed from it) and the amino acid sequence of the corresponding polypeptide.

Commitment The transition of an embryonic cell from pluripotency to its particular fate.

Comparative genome hybridization (CGH) A fluorescence hybridization technique used to compare two different DNA samples with respect to their relative content of a particular DNA segment or segments. CGH can be used with fluorescence in situ hybridization (FISH) of metaphase chromosomes or with hybridization to large numbers of DNA fragments fixed to a solid support (CGH array).

Complementarity The complementary nature of base pairing in DNA.

Complementary DNA (cDNA) DNA synthesized from a messenger RNA template, through the action of the enzyme reverse transcriptase. See genomic DNA for comparison.

Complex inheritance A pattern of inheritance that is not mendelian. A trait with complex inheritance usually results from alleles at more than one locus interacting with environmental factors.

Compound (compound heterozygote) An individual, or a genotype, with two different mutant alleles at the same locus. Not to be confused with homozygote, in which the two mutant alleles are identical.

Concordance Describes a pair of relatives in which (1) both members of the pair have a certain qualitative trait or (2) both members have values of a quantitative trait that are similar in magnitude. See discordance.

Conditional probability 1. In Bayesian analysis, this is the chance of an observed outcome given that a consultand has a particular genotype. The product of the prior and conditional probabilities is the joint probability. 2. More generally, a synonym for Bayesian analysis.

Confined placental mosaicism Mosaicism in a chorionic villus sampling (CVS) specimen obtained from the placenta that is not present in the fetus itself.

Congenital Present at birth; not necessarily genetic.

Consanguinity Related by descent from a common ancestor (the adjective is consanguineous).

Consensus sequence In genes or proteins, an idealized sequence in which each base or amino acid residue represents the one most frequently found at that position when many actual sequences are compared; for example, the consensus sequence for splice donor or acceptor sites.

Consultand In genetic counseling, anyone who consults a genetic counselor for genetic information.

Contiguous gene syndrome A syndrome resulting from a microdeletion of chromosomal DNA extending over two or more contiguous loci. Also called segmental aneusomy.

Copy number variant (CNV) A variation in DNA sequence defined by the presence or absence of a segment of DNA, ranging from approximately 200 bp to approximately 2 Mb. Copy number variants may also have alleles that are tandem duplications of two, three, four, or more copies of a DNA segment. If a variant has an allele frequency greater than 1%, it is referred to as a copy number polymorphism (CNP).

Cordocentesis A procedure used in prenatal diagnosis to obtain a sample of fetal blood directly from the placenta.

Correlation A statistical tool applied to a set of paired measurements. A positive correlation exists when the larger the first measurement in the pair is, the larger the second measurement of the pair is. A negative correlation is the opposite, that is, the larger the first measurement, the smaller the second. Measured by the correlation coefficient r.

Coupling Describes the phase of two alleles at two different but syntenic loci, in which one allele at one of the loci is on the same chromosome as the allele at the second locus. See phase and repulsion.

CpG island Segments of genomic DNA that are particularly rich in the dinucleotide 5′-CG-3′ and are found in the promoters of many housekeeping genes. The “p” in CpG refers to the phosphate of the DNA backbone connecting the cytidine and guanidine nucleosides.

Crossover, crossing over The reciprocal exchange of segments between chromatids of homologous chromosomes, a characteristic of prophase of the first meiotic division. See also recombination. Unequal crossing over between misaligned chromatids can lead to duplication of the involved segment on one chromatid and deletion on the other and is a frequent cause of mutation.

Cryptic splice site A DNA sequence similar to the consensus splice site but not normally used. It is used when the normal splice site is altered by mutation or when a mutation in the cryptic site increases its use by the splicing apparatus. May be in a coding or a noncoding sequence.

Cytogenetics The study of chromosomes.

Cytokinesis Cleavage of cytoplasm at the end of mitosis, resulting in two separate cells, each with a full complement of 46 chromosomes.

Cytotrophoblast The fetal cells of the chorionic villi that are sampled for karyotyping and DNA analysis.

Daughter chromosomes The two individual chromosomes formed when a single chromosome composed of paired chromatids separates at the centromere in anaphase of cell division.

Deformation syndrome A recognizable pattern of dysmorphic features caused by extrinsic factors that affect the fetus in utero.

Degeneracy of the code The genetic code is described as degenerate because most of the 20 amino acids are specified by more than 1 of the 64 codons.

Degree of relationship The distance between two individuals in a pedigree. First-degree relatives include parents, siblings, and children. Second-degree relatives are aunts and uncles, nephews and nieces, grandparents and grandchildren.

Deletion The loss of a sequence of DNA from a chromosome. The deleted DNA may be of any length, from a single base to a large part of chromosome. A chromosome deletion may occur at the end of a chromosome (terminal deletion) or within a chromosome arm (interstitial).

Deoxyribonucleic acid See DNA.

Determination During development, the second stage of commitment in which a cell follows its developmental program regardless of whether it is transplanted to a different region of the embryo.

Developmental disorder Disorder resulting from disruption of the normal developmental program. Usually prenatal in onset but can first present postnatally.

Developmental program The process by which a cell in an embryo achieves its fate.

Deviation (D) Extent to which haplotype frequencies diverge from the expected based on the allele frequencies. A measure of linkage disequilibrium, usually normalized to allele frequencies using the D′ metric.

Dicentric A structurally abnormal chromosome with two centromeres. If a dicentric chromosome segregates as if it has only one centromere, it is referred to as pseudodicentric.

Dictyotene The stage of the first meiotic division in which a human oocyte remains from late fetal life until ovulation.

Differentiation The process whereby a cell acquires a tissue-specific pattern of expression of genes and proteins and a characteristic phenotype.

Diploid The number of chromosomes in most somatic cells, which is double the number found in the gametes. In humans, the diploid chromosome number is 46.

Discordance The situation in which (1) one member of the pair has a certain qualitative trait and the other does not or (2) the relatives have values of a quantitative trait that are at opposite ends of the distribution. See concordance.

Disjunction See nondisjunction.

Disomy See uniparental disomy.

Disorder of sexual development (DSD) A phenotype reflecting a mismatch between chromosomal sex and phenotypic sex.

Disruption A birth defect caused by destruction of tissue; may be caused by vascular occlusion, a teratogen, or rupture of the amniotic sac with entrapment.

Dizygotic (DZ) twins Twins produced by two separate ova, separately fertilized. Also called fraternal twins.

DNA (deoxyribonucleic acid) The molecule that encodes the genes responsible for the structure and function of living organisms and allows the transmission of genetic information from generation to generation.

DNA fingerprint A set of genotypes at a sufficient number of loci (e.g., at 13 STRP loci in the Combined DNA Index System [CODIS] used by the Federal Bureau of Investigation [FBI] in the United States) to unambiguously and uniquely specify the individual from which the DNA was obtained (except for monozygotic twins).

DNA methylation In eukaryotes, the addition of a methyl residue to the 5-position of the pyrimidine ring of a cytosine base in DNA to form 5-methylcytosine.

DNA polymerase An enzyme that can synthesize a new DNA strand by use of a previously synthesized DNA strand as a template.

DNA proofreading Recognition and removal of a noncomplementary DNA base inserted during replication, followed by its replacement by the correct complementary base.

Dominant A trait is dominant if it is phenotypically expressed in heterozygotes. If heterozygotes and homozygotes for the variant allele have the same phenotype, the disorder is a pure dominant (rare in human genetics). If homozygotes have a more severe phenotype than do heterozygotes, the disorder is termed semidominant or incompletely dominant.

Dominant negative A disease-causing allele, or the effect of such an allele, that disrupts the function of a wild-type allele in the same cell.

Donor splice site The boundary between the 3′ end of an exon and the 5′ end of the next intron. Also called 5′ splice site.

Dosage compensation As a consequence of X inactivation, the amount of product formed by the two copies of an X-linked gene in females is equivalent to the amount formed by the single gene in males. See X inactivation.

Double heterozygote An individual who is heterozygous at each of two different loci. Contrast with compound heterozygote.

Double minutes Very small accessory chromosomes, a form of gene amplification.

Driver gene A gene that has been found repeatedly to carry somatic mutations in many samples of the same type of cancer or even in multiple different types of cancers. The mutations are far too frequent to be simply the product of random events. These genes are thus presumed to be involved in the development or progression of the cancer itself. See passenger gene mutation.

Dynamic mutation Mutations caused by amplification of a simple nucleotide repeat sequence. They tend to increase in size from one generation to the next, thus the term dynamic. Most commonly, the nucleotide unit involved in the expansion contains three nucleotides (triplet repeat expansion), as with CAG in Huntington disease or CGG in fragile X syndrome.

Dysmorphic features Morphological developmental abnormalities, as seen in many syndromes of genetic or environmental origin.

Ecogenetic disorder A disorder resulting from the interaction of a genetic predisposition to a specific disease with an environmental factor.

Ectoderm One of the three primary germ layers of the early embryo. It begins as the layer farthest from the yolk sac and ultimately gives rise to the nervous system, the skin, and neural crest derivatives such as craniofacial structures and melanocytes.

Ectopic expression Expression of a gene in places where it is not normally expressed.

Embryonic stem cell A cell derived from the inner cell mass that is self-renewing in culture and, when reintroduced into the inner cell mass of a blastocyst, can repopulate all the tissues of the embryo.

Empirical risk In human genetics, the probability that a familial trait will occur in a family member, based on observed numbers of affected and unaffected individuals in family studies rather than on knowledge of the causative mechanism.

ENCODE Project Acronym for Encyclopedia oDNA Elements, a large-scale effort to identify and map all of the regulatory elements and epigenetic regulators of gene expression in a wide spectrum of cell types and tissues.

Endoderm One of the three primary germ layers of the early embryo. Ultimately gives rise to the gut, liver, and portions of the urogenital system.

Endophenotype A heritable quantitative biological trait that is a marker of risk for a genetically complex disorder. The concept is commonly used in psychiatric genetics but is used widely in genetic epidemiology.

Enhancer A DNA sequence that acts in cis (i.e., on the same chromosome) to increase transcription of a gene. The enhancer may be upstream or downstream to the gene and may be in the same or the reverse orientation. Contrast with silencer.

Enzymopathy A metabolic disorder resulting from deficiency or abnormality of a specific enzyme.

Epigenetic The term that refers to any factor that can affect gene function without change in the genotype. Some typical epigenetic factors involve alterations in DNA methylation, chromatin structure, histone modifications, and transcription factor binding that change genome structure and affect gene expression without changing the primary DNA sequence.

Episome A DNA element that either can exist as an autonomously replicating sequence in the cytoplasm or can integrate into chromosomal DNA. Adeno-associated viral vectors, used in gene therapy, are episomes that exist in the cytoplasm for long periods and can, although rarely, be inserted into the nuclear genome.

Euchromatin The major component of chromatin. It stains lightly with G banding, decondensing and becoming light-staining during interphase. Contrast with heterochromatin.

Eugenics Refers to increasing the prevalence of desirable traits in a population by decreasing the frequency of deleterious alleles at relevant loci through controlled, selective breeding. The opposite is dysgenics.

Eukaryote A unicellular or multicellular organism in which the cells have a nucleus with a nuclear membrane and other specialized characteristics.

Euploid Any chromosome number that is an exact multiple of the number in a haploid gamete (n). Most somatic cells are diploid (2n). Contrast with aneuploid.

Exon A transcribed region of a gene that is present in mature messenger RNA.

Exon skipping The use of molecular interventions to exclude an exon from a pre-mRNA that encodes a reading frame–disrupting mutation, thereby rescuing expression of the mutant gene.

Expression profile A quantitative assessment of the mRNAs present in a cell type, tissue, or tumor. Often used to characterize a cell, tissue, or tumor in comparison to the expression profile of another cell, tissue, or tumor.

Expressivity The extent to which a genetic defect is expressed. If there is variable expressivity, the trait may vary in expression from mild to severe but is never completely unexpressed in individuals who have the corresponding genotype. Contrast with penetrance.

Familial Any trait that is more common in relatives of an affected individual than in the general population, whether the cause is genetic, environmental, or both.

Fate The ultimate destination for a cell that has traveled down a developmental pathway. The embryonic fate map is a complete description of all the fates of all the different parts of the embryo.

Fetal cells Placental cells, obtained by chorionic villus sampling; skin, respiratory, and urinary tract cells obtained from amniotic fluid by amniocentesis; or fetal blood cells obtained by cordocentesis.

Fetal phase Stage of intrauterine development from weeks 9 to 40.

Fibroblast Normal cells derived from subcutaneous tissue that can be easily obtained from a skin biopsy specimen and grown for many generations in culture.

FISH Fluorescence in situ hybridization. See in situ hybridization.

Fitness (f) The probability of transmitting one's genes to the next generation compared with the average probability for the population.

Flanking sequence A region of DNA preceding or following a transcribed region or, more generally, preceding or following any segment of DNA or chromosome.

Founder effect A high frequency of a mutant allele in a population founded by a small ancestral group when one or more of the founders was a carrier of the mutant allele.

Fragile site Nonstaining gap in the chromatin of a metaphase chromosome, such as the fragile site at Xq27 in fragile X syndrome.

Frameshift mutation A mutation involving a deletion or insertion that is not an exact multiple of three base pairs and thus changes the reading frame of the gene downstream of the mutation.

G banding (Giemsa staining) Method of staining chromosomes to generate reproducible alternating light and dark bands.

Gain-of-function mutation A mutation associated with an increase in one or more of the normal functions of a protein. To be distinguished from novel property mutation.

Gamete A mature reproductive cell (ovum or sperm) with the haploid chromosome number.

Gene A hereditary unit; in molecular terms, a sequence of chromosomal DNA that is required for the production of a functional product.

Gene dosage The number of copies of a particular gene in the genome.

Gene family A set of genes containing similarly sized exons and containing highly similar DNA sequences, indicating that the genes have evolved from an ancestral gene by duplication and subsequent divergence.

Gene flow Gradual diffusion of genes from one population to another across a barrier. The barrier may be physical or cultural and may be breached by migration or mixing.

Gene map The characteristic arrangement of the genes on the chromosomes.

Gene mutation Alteration of the sequence of DNA involving as little as one nucleotide up to an arbitrarily set limit of 100 kilobase pairs.

Gene pool All the alleles present at a given locus or, more broadly, at all loci in the population.

Gene transfer therapy (gene therapy) Treatment of a disease by introduction of DNA sequences that will have a therapeutic benefit.

Genetic Determined by genes; not to be confused with congenital.

Genetic admixture The merging into the gene pool of an immigrant population with allele frequencies different from the already existing population, which, if there is random mating, results in new allele frequencies reflecting the mixing of the two populations.

Genetic code The 64 triplets of bases that specify the 20 amino acids found in proteins (see Table 3-1).

Genetic counseling The provision of information and assistance to affected individuals or family members at risk for a disorder that may be genetic, concerning the consequences of the disorder, the probability of developing or transmitting it, and the ways in which it may be prevented or ameliorated.

Genetic disorder A defect wholly or partly caused by a gene abnormality.

Genetic drift Random fluctuation of allele frequencies in small populations.

Genetic epidemiology A branch of public health research concerned with characterizing and quantifying the influence of genetic variation in the population on the incidence, prevalence, and causation of disease.

Genetic heterogeneity The production of the same or similar phenotypes by different genetic mechanisms. See allelic heterogeneity, clinical heterogeneity, locus heterogeneity.

Genetic lethal A mutant allele or genetically determined trait that leads to failure to reproduce, although not necessarily to death before reproduction.

Genetic load The sum total of death and disease caused by mutant genes.

Genetic map The relative positions of the genes on the chromosomes, as shown by linkage analysis.

Genetic marker A locus that has readily classifiable alleles and can be used in genetic studies. It may be a gene variant or a single nucleotide polymorphism (SNP) or short tandem repeat polymorphism (STRP) or any characteristic of DNA that allows different versions of a locus (or its product) to be distinguished one from another and followed through families. See polymorphism.

Genetic screening Testing of family members of an affected proband or of the population as a whole to identify individuals at risk for developing or transmitting a specific disorder.

Genocopy A genotype that determines a phenotype closely similar to that determined by a different genotype.

Genome The complete DNA sequence, containing the entire genetic information, of a gamete, an individual, a population, or a species.

Genome editing A new technology that uses proteins adapted from bacteria or plants (e.g., CRISPR/Cas9) to target a particular site within the genome of a cell with high efficiency and specificity. Once the site is targeted, it can be mutated, undergo repair of a preexisting mutation, or undergo alteration of an epigenetic imprint.

Genome-wide association study (GWAS) A genetic association study using hundreds of thousands to millions of polymorphic variants distributed throughout the genome.

Genomic DNA The chromosomal DNA sequence of a gene or segment of a gene, including the DNA sequence of noncoding as well as coding regions. Also, DNA that has been isolated directly from cells or chromosomes or the cloned copies of all or part of such DNA.

Genomic imprinting Monoallelic expression in which the choice of the allele to be expressed is determined by the parental origin of each allele. See Prader-Willi syndrome and Angelman syndrome in the text for examples.

Genomic medicine The practice of medicine based on large-scale genomic information, such as sequencing of large gene panels, exomes, or whole genomes; expression profiling to characterize tumors or to define prognosis in cancer; genotyping of variants in genes involved in drug metabolism or action to determine an individual's correct therapeutic dosage; or analysis of multiple protein biomarkers to monitor therapy or to provide predictive information in presymptomatic individuals.

Genomics The field of genetics concerned with structural and functional studies of the genome.

Genotype 1. The genetic constitution of an individual, as distinguished from the phenotype. 2. More specifically, the alleles present at one or more loci.

Germ layer One of three distinct layers of cells that arise in the inner cell mass, the ectoderm, mesoderm, and endoderm, each of which develops into a distinctly different tissue in the embryo.

Germline The cell line from which gametes are derived.

Germline mosaicism In an individual, the presence of two or more genetically different germline cells, resulting from mutation during the proliferation and differentiation of the germline.

Gonadal dysgenesis Disorder in which chromosomal and phenotypic sex do not match and normal gonads fail to develop. In complete gonadal dysgenesis, external genitalia are normal, whereas in incomplete gonadal dysgenesis, the external genitalia are ambiguous. Mixed gonadal dysgenesis has a range of phenotypes from male to Turner syndrome–like, resulting from 45,X/46,XY mosaicism.

Haploid The chromosome number of a normal gamete, with only one member of each chromosome pair. In humans, the haploid number is 23.

Haploinsufficiency A cause of genetic disease in which the contribution from a normal allele is insufficient to prevent disease because of a loss-of-function mutation at the other allele.

Haplotype A group of alleles in coupling at closely linked loci, usually inherited as a unit.

Hardy-Weinberg law The law that relates allele frequency to genotype frequency, used in population genetics to determine allele frequency and heterozygote frequency when the incidence of a disorder is known.

Hemizygous A term for the genotype of an individual with only one representative of a chromosome or chromosome segment, rather than the usual two; refers especially to X-linked genes in the male but also applies to genes on any chromosome segment that is deleted on the homologous chromosome.

Hemoglobin switching Change in expression of the various globin genes during development of hematopoiesis.

Heritability (h2) The fraction of total phenotypic variance of a quantitative trait that is due to genotypic differences. May be viewed as a statistical estimate of the hereditary contribution to a quantitative trait.

Heterochromatin Chromatin that stains darkly throughout the cell cycle, even in interphase. Generally thought to be late replicating and genetically inactive. Satellite DNA in regions such as centromeres, acrocentric short arms, and 1qh, 9qh, 16qh, and Yqh constitute constitutive heterochromatin, whereas the chromatin of the inactive X chromosome is referred to as facultative heterochromatin. Contrast with euchromatin.

Heterodisomy See uniparental disomy.

Heterogeneity See allelic heterogeneityclinical heterogeneitygenetic heterogeneitylocus heterogeneity.

Heteroplasmy The presence of more than one type of mitochondrial DNA in the mitochondria of a single individual. Contrast with homoplasmy.

Heteroploid Any chromosome number other than the normal.

Heterozygote (heterozygous) An individual or genotype with two different alleles, one of which is wild-type, at a given locus on a pair of homologous chromosomes. See compound heterozygote.

Heterozygote advantage Situation in which heterozygotes for some mendelian diseases have increased fitness not only over homozygotes for the mutant allele but even over homozygotes for the normal allele. See balanced polymorphism.

Histocompatibility A host will accept a particular graft only if it is histocompatible—that is, if the graft contains no antigens that the host lacks.

Histones Proteins associated with DNA in the chromosomes that are rich in basic amino acids (lysine or arginine) and virtually invariant throughout eukaryote evolution. Covalent modifications of histones are important epigenetic regulators of gene expression. The pattern of histones and their modifications constitute the epigenetic “histone code.”

Holoenzyme The functional compound formed by the binding of an apoenzyme and its appropriate coenzyme.

Homeobox gene A gene that contains a conserved 180–base pair sequence termed a homeobox in its coding region, encoding a protein motif known as the homeodomain. The 60 amino acid residues of the homeodomain are a DNA-binding motif, which is consistent with the role of homeodomain proteins in transcriptional regulation of genes involved in development.

Homogeneously staining regions (HSRs) Chromosome regions that stain uniformly and represent amplified copies of a DNA segment.

Homology A commonly used term in genetics but with different meanings in different contexts. 1. In bioinformatics, homologous sequences are DNA or protein sequences that have similar nucleotide or amino acid sequences, as seen between orthologous or paralogous genes. 2. In cytogenetics, homologous chromosomes are a pair of chromosomes, one inherited paternally, the other maternally, that are generally of similar size and shape when they are viewed under the microscope and contain the same loci, except for the two sex chromosomes in males (X and Y), which are only partially homologous. Homologous chromosomes pair with each other during meiosis I, undergo crossing over, and separate at anaphase I of meiosis. 3. In evolution, structures in different organisms are termed homologous if they evolved from a structure present in a common ancestor.

Homoplasmy The presence of only one type of mitochondrial DNA in the mitochondria of a single individual. Contrast with heteroplasmy.

Homozygote (homozygous) An individual or genotype with identical alleles at a given locus on a pair of homologous chromosomes.

Housekeeping genes Genes expressed in most or all cells because their products provide basic functions.

Housekeeping proteins Proteins expressed in virtually every cell that have fundamental roles in the maintenance of cell structure and function (versus specialty proteins).

Human Genome Project A major research project, international in scope, that took place in 1990 to 2003 and resulted in the sequencing and assembly of a representative human genome and the genomes of many model organisms.

Human leukocyte antigen (HLA) See major histocompatibility complex.

Hybridization In molecular biology, the bonding of two complementary single-stranded nucleic acid molecules according to the rules of base pairing. See comparative genome hybridization and fluorescence in situ hybridization.

Hydatidiform mole An abnormality of the placenta in which it grows to resemble a hydatid cyst or bunch of grapes, associated with very abnormal fetal development. In a complete mole, the karyotype is usually 46,XX, but can be 46,XY, representing duplication of the chromosomes of the sperm with no maternal contribution. A partial mole is triploid, usually with an extra paternal chromosome set.

Immunoglobulin gene superfamily A family of evolutionarily related genes composed of human leukocyte antigen (HLA) class I and class II genes, immunoglobulin genes, T-cell receptor genes, and other genes encoding cell surface molecules.

Imprinting See genomic imprinting.

Imprinting center Segment of DNA located in and around imprinted genes that regulates genomic imprinting and causes the imprinting of genes on a chromosome inherited from a parent of one sex to switch to the appropriate imprint in the germline of a child of the opposite sex.

In situ hybridization Mapping a gene or segment of DNA by molecular hybridization to a chromosome spread or cell nucleus on a slide by use of a labeled DNA sequence as a probe corresponding to the gene or DNA segment to be mapped. Usually involves fluorescently labeled probes, in which case it is referred to as fluorescence in situ hybridization (FISH).

In vitro fertilization A reproductive technology in which sperm are allowed to fertilize an egg in tissue culture and the fertilized eggs are then introduced back into the uterus to allow implantation.

Inborn error of metabolism A genetically determined biochemical disorder in which a specific protein defect disturbs a metabolic pathway that may have pathological consequences.

Inbreeding The mating of closely related individuals. The progeny of close relatives are said to be inbred. (Note that some consider the term inbreeding to be pejorative when it is applied to human populations.)

Inbreeding, coefficient of (F) The probability that a child of a consanguineous mating will be homozygous at any given locus for an allele inherited through each parent from a common ancestor.

Incompletely dominant A trait that is inherited in a dominant manner but is more severe in a homozygote than in a heterozygote (synonym: semidominant).

Indel A polymorphism defined by the presence or absence of a segment of DNA, ranging from one base to a few hundred base pairs. Includes simple indels, microsatellites, and minisatellite polymorphisms. Sometimes abbreviated in/del.

Index case The family member affected with a genetic disorder who is the first to draw attention to a pedigree. See proband.

Induced pluripotent stem cells (iPS cells) Pluripotent stem cells derived not from embryonic cells but from differentiated adult somatic cells that have been induced to lose their differentiated state and revert to pluripotency by artificially expressing a small number of specific transcription factors in these cells.

Induction The determination of the fate of one region of an embryo by extracellular signals from a second, usually neighboring, region.

In-frame deletion A deletion that does not destroy the normal reading frame of the gene.

Initiator codon The codon for methionine (AUG) that signals the start of translation in a mRNA. See messenger RNA.

Inner cell mass A small group of cells within the preimplantation mammalian embryo that will become the primitive ectoderm (or epiblast) after implantation and, ultimately, give rise to the embryo proper and not the placenta.

Insertion A chromosomal abnormality in which a DNA segment from one chromosome, or from an exogenous source such as a retrovirus, is inserted into another chromosome.

Intergenic DNA The mostly untranscribed DNA of unknown function that makes up a large proportion of the total DNA in the genome.

Interphase The stage of the cell cycle between two successive mitoses.

Intervening sequence See intron.

Intron A segment of a gene that is initially transcribed but then removed from within the primary RNA transcript by splicing together the sequences (exons) on either side of it.

Inversion A chromosomal rearrangement in which a segment of a chromosome is reversed end to end. If the centromere is included in the inversion, the inversion is pericentric; if not, it is paracentric.

Isochromosome An abnormal chromosome in which one arm is duplicated (forming two arms of equal length, with the same loci in reverse sequence) and the other arm is missing.

Isodisomy See uniparental disomy.

Isolate A subpopulation in which matings take place exclusively or usually with other members of the same subpopulation.

Isolated case An individual who is the only member of his or her kindred affected by a genetic disorder, either by chance or by new mutation. See also sporadic.

Karyotype The chromosome constitution of an individual. The term is also used for a photomicrograph of the chromosomes of an individual systematically arranged as well as to describe the process of preparing such a photomicrograph.

kb (kilobase or kilobase pair) A unit of 1000 bases in a DNA or RNA sequence.

Kindred An extended family.

Kinetochore A structure at the centromere to which the spindle fibers are attached.

LINE sequences A class of repetitive DNA made up of long interspersed DNA segments, up to 6 kb in length, occurring in several hundred thousand copies in the genome (also called L1 family).

Lineage The progeny of a cell, generally determined by experimentally labeling the cell so that all of its descendants can be identified. See clone.

Linkage Genes on the same chromosome are linked if they are transmitted together in meiosis more frequently than chance would allow. Compare with synteny.

Linkage analysis A statistical method in which the genotypes and phenotypes of parents and offspring in families are studied to determine whether two or more loci are assorting independently or exhibiting linkage during meiosis.

Linkage disequilibrium (LD) The occurrence of specific combinations of alleles in coupling phase at two or more linked loci (haplotypes) more frequently than expected by chance from the frequency of the alleles in the population. Opposite is linkage equilibrium.

Linkage disequilibrium block (LD block) A set of polymorphic markers forming a haplotype whose alleles are in strong linkage disequilibrium with each other. Usually occupies a region of the genome from a few kilobases to a few dozen kilobases in length.

Linkage map A chromosome map showing the relative positions of genes and other DNA markers on the chromosomes, as determined by linkage analysis.

lncRNA See noncoding RNA.

Locus The position occupied by a gene on a chromosome. Different forms of the gene (alleles) may occupy the locus.

Locus control region (LCR) A DNA domain, situated outside a cluster of structural genes, responsible for the appropriate expression of the genes within the cluster.

Locus heterogeneity The production of identical phenotypes by mutations at two or more different loci.

LOD score A statistical method that tests genetic marker data in families to determine whether two loci are linked. The LOD score is the logarithm of the odds in favor of linkage. By convention, a LOD score of 3 (odds of 1000:1 in favor) is accepted as proof of linkage, and a LOD score of −2 (100:1 against) as proof that the loci are unlinked.

Loops Three-dimensional arrangement of chromatin, packaged as solenoids, attached to the chromosome scaffold. Thought to be a structural or functional unit of chromosomes.

Loss of heterozygosity (LOH) Loss of a normal allele from a region of one chromosome of a pair, allowing a defective allele on the homologous chromosome to be clinically manifest. A feature of many cases of retinoblastoma, breast cancer, and other tumors due to mutation in a tumor-suppressor gene.

Loss-of-function mutation A mutation associated with a reduction or a complete loss of one or more of the normal functions of a protein.

Lymphoblastoid cells B-lymphocytes immortalized in culture by infection with Epstein-Barr virus.

Lyon's law (or hypothesis) Basic features of the phenomenon of X inactivation, which was first described by the late British geneticist Mary Lyon. Originally called the Lyon hypothesis, but upgraded to a law at the 50th anniversary of her discovery. Silencing of gene expression is sometimes referred to as lyonization. See X inactivation.

Major histocompatibility complex (MHC) The complex locus on chromosome 6p that includes the highly polymorphic human leukocyte antigen (HLA) genes.

Maleficence Behavior that harms others. Avoidance of maleficence is one of the cardinal principles of ethics. See beneficence.

Male to male transmission A pattern of inheritance of a trait from a father to all of his sons and none of his daughters (also referred to as holandric inheritance).

Malformation syndrome A recognizable pattern of dysmorphic features having a single cause, either genetic or environmental.

Manhattan plot A graph of all of the P values for an association between a trait and all of the single nucleotide polymorphism (SNPs) used in a genome-wide association study (GWAS) study. The SNPs are placed on the x-axis based on their location in the genome, starting with the tip of chromosome 1p on the left and going through each arm of the 22 autosomes. The P values are given as −log10 on the y-axis so that the more significant the association, the greater the value. It is called a Manhattan plot because the peaks of strong association resemble the tips of skyscrapers seen in the Manhattan skyline (see Fig. 10-11for example).

Manifesting heterozygote A female heterozygous for an X-linked disorder in whom, because of nonrandom X inactivation, the trait is expressed clinically, although usually not to the same degree of severity as in hemizygous affected males.

Map distance A theoretical concept that is based on how often recombination between the loci is observed. Measured in units of centimorgans, defined as the genetic length over which recombination occurs in 1% of meioses.

Marker chromosome A small unidentified chromosome seen in a chromosome preparation. Also referred to as a supernumerary chromosome or extra structurally abnormal chromosome.

Maternal inheritance The transmission of genetic information only through the mother.

Maternal serum screening Laboratory test that relies on measurement of the levels of particular substances, such as alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol, in a pregnant woman's blood to screen for fetuses affected with certain trisomies or with neural tube defects.

Mb (megabase or megabase pair) A unit of 1,000,000 bases or base pairs in genomic DNA.

Meiosis The type of cell division occurring in the germ cells, by which gametes containing the haploid chromosome number are produced from diploid cells. Two meiotic divisions occur: meiosis I and meiosis II. Reduction in chromosome number takes place during meiosis I.

Mendelian Patterns of inheritance that follow the classic laws of Mendel: autosomal dominant, autosomal recessive, and X-linked. See single-gene disorder.

Mesoderm The middle germ layer in the early embryo; the source of cells that go on to make bones, muscles, connective tissue, heart, hematopoietic system, kidney, and other organs.

Mesonephric duct Structure in the genital ridges of the early embryo that will develop into male internal sexual organs in the male. Also called the Wolffian duct.

Messenger RNA (mRNA) An RNA, transcribed from the DNA of a gene, that directs the sequence of amino acids of the encoded polypeptide. Contrast with noncoding RNA.

Metacentric A type of chromosome with a central centromere and arms of apparently equal length.

Metaphase The stage of mitosis or meiosis in which the chromosomes have reached their maximal condensation and are lined up on the equatorial plane of the cell, attached to the spindle fibers. This is the stage at which chromosomes are most easily examined. Immediately follows prometaphase.

Metastasis Spread of malignant cells to other sites in the body.

Methemoglobin The oxidized form of hemoglobin, containing iron in the ferric rather than the ferrous state, which is incapable of binding oxygen.

Microarray Miniaturized wafer (“chip”) made of glass, plastic, or silicon onto which a large number of different nucleic acids have been individually spotted. See also comparative genome hybridization, expression profile.

Microdeletion A chromosomal deletion that is too small to be seen under the microscope. See also contiguous gene syndrome.

MicroRNAs (miRNAs) A class of several thousand small single-stranded RNAs of only approximately 22 bases, constituting one of the most abundant classes of gene regulatory molecules. They suppress gene expression post-transcriptionally, by targeting specific mRNAs for cleavage or by suppressing mRNA translation.

Microsatellite See short tandem repeat polymorphism (STRP).

Microsatellite instability (MSI) A phenotype of cancer cells in which loss of function of mismatch repair genes causes errors such as slipped mispairing to go unrepaired when microsatellite sequences are replicated. These errors lead to tissue mosaicism so that the cancer appears to contain more than two alleles at many short tandem repeat polymorphic loci.

Minisatellite See VNTR.

Missense mutation A mutation that changes a codon specific for one amino acid to specify another amino acid.

Mitochondrial bottleneck A step in oogenesis in which only a small sample of the total number of mitochondria in an oocyte precursor is passed on to daughter cells, thereby allowing significant variation in the proportions of mutant and wild-type mitochondria inherited by the daughter cells.

Mitochondrial DNA (mtDNA) The DNA in the circular chromosome of the mitochondria. Mitochondrial DNA is present in many copies per cell, is maternally inherited, and evolves 5 to 10 times as rapidly as genomic DNA.

Mitochondrial inheritance The inheritance of a trait encoded in the mitochondrial genome. Because the mitochondrial genome is strictly maternally inherited, mitochondrial inheritance occurs solely through the female line.

Mitosis The process of ordinary cell division, resulting in the formation of two cells genetically identical to the parent cell.

Mitotic spindle Microtubular structure inside a mitotic cell to which centromeres attach. Guides the separation of sister chromatids to opposite poles during anaphase of mitosis.

Modifier gene A gene whose alleles alter the phenotype associated with mutations in a nonallelic gene. Often applied to the effect on the expressivity of mendelian disorders caused by variants at other loci.

Monosomy A chromosome constitution in which one member of a chromosome pair is missing, as in 45,X Turner syndrome.

Monozygotic (MZ) twins Twins derived from a single zygote and thus genetically identical. Also termed identical twins.

Morphogen A substance produced during development in a localized region of the organism that diffuses out to form a concentration gradient and directs cells into two or more specific developmental pathways, depending on its concentration.

Morphogenesis The process whereby changes in cell shape, adhesion, movement, and number lead to a three-dimensional structure.

Mosaic development Embryological development in which different regions of the embryo develop independently from surrounding regions. See regulative development.

Mosaicism Describes an individual or tissue with at least two cell lines, differing in genotype or karyotype, that were derived from a single zygote; not to be confused with chimera.

Multifactorial disease Disorders resulting from a combination of multiple factors, genetic and environmental. Demonstrate complex inheritance rather than mendelian inheritance patterns.

Multiple hypothesis testing A cause of false-positive statistically significant tests when one hypothesis among many being tested shows statistical significance by chance alone and not because the result is truly significant.

Multiplex ligation-dependent probe amplification A laboratory technique that allows the simultaneous measurement of the copy number of various segments of a gene through repeated rounds of ligation and polymerase chain reaction (PCR). Used to detect deletions and duplications within genes.

Mutagen An agent that increases the spontaneous mutation rate by causing changes in DNA.

Mutant A gene that has been altered by mutation; also used to refer to a nonhuman organism carrying a mutant gene.

Mutation Any permanent heritable change in the sequence of genomic DNA. See variant.

Mutation rate (µ) The frequency of mutation at a given locus, expressed as mutations per locus per gamete (or per generation, which is the same).

Negative predictive value With respect to a clinical test for a disease, the extent to which testing negative indicates that one does not have or will not develop the disease.

Neoplasia An abnormal growth produced by imbalance between normal cellular proliferation and normal cellular attrition. May be benign or malignant (cancer).

Noncoding gene See noncoding RNA.

Noncoding RNA (ncRNA) After transcription, an RNA product that will not be translated to a protein product. Contrast with messenger RNA. To avoid confusion with short ncRNAs such as miRNAs or siRNAs, sometimes referred to as long noncoding RNAs or lncRNAs. For example, see XIST RNA, under X inactivation.

Noncoding strand See antisense strand of DNA.

Nondisjunction The failure of two members of a chromosome pair to disjoin during meiosis I, or of two chromatids of a chromosome to disjoin during meiosis II or mitosis, so that both pass to one daughter cell and the other daughter cell receives neither. Also called chromosome missegregation.

Noninvasive prenatal screening (NIPS) Use of cell-free DNA of fetal origin in maternal blood to screen for fetal aneuploidy.

Nonsense-mediated mRNA decay A mechanism for quality control of mRNAs that recognizes and degrades mRNAs carrying mutant premature translation termination (nonsense) codons, thereby preventing the translation of truncated proteins.

Nonsense mutation A single-base substitution in DNA resulting in a termination codon.

Nonsynonymous Describes a single nucleotide variant (SNV) that alters a codon and therefore the resulting amino acid sequence of the encoded peptide.

Normal distribution The symmetrical, bell-shaped curve describing the frequency of particular values of a measured quantity in a population.

Novel property mutation A mutation that confers a new property on the protein.

Nuchal translucency An ultrasonographic finding of an echo-free space between the skin line and the soft tissue overlying the cervical spine in the subcutaneous tissue of the fetal neck. Associated with fetal aneuploidy.

Nucleoside Nitrogenous base plus a five-carbon sugar. Adenosine, cytosine, guanosine, and thymidine (in DNA) or uridine (in RNA).

Nucleosome The primary structural unit of chromatin, consisting of 146 base pairs of DNA wrapped twice around a core of eight histone molecules.

Nucleotide A molecule composed of a nitrogenous base and a five-carbon sugar (nucleoside) with a phosphate group attached to the 5′ carbon of the sugar molecule. A nucleic acid is a polymer of many nucleotides.

Null allele An allele that results either in the total absence of the gene product or in the total loss of function of the product.

Obligate heterozygote An individual who may be clinically unaffected but on the basis of pedigree analysis must carry a specific mutant allele.

Odds A ratio of probabilities or risks. Often calculated as a ratio of the probability of an event's occurring versus the probability of the event's not occurring, as one way to assess the relative chance of the event. Odds can vary in value from 0 to infinity.

Odds ratio A comparison of the odds that individuals who share a particular feature or factor (e.g., a genotype, an environmental exposure, or a drug) will have a disease or trait versus the odds for individuals who lack the factor.imageAmong individuals in whom the factor is present, the odds of being affected = (a/b). Among individuals in whom the factor is absent, the odds of being affected = (c/d), and the odds ratio = (a/b)/(c/d) = ad/bc. [Strictly speaking, this definition of odds ratio is a disease odds ratio. A more traditional odds ratio used in epidemiology is an exposure odds ratio, which is a comparison of the odds that individuals affected with a particular disease were exposed to a particular factor = (a/c) versus the odds that unaffected individuals were exposed = (b/d), giving an odds ratio of (a/c)/(b/d). Note that both formulations result in the same ratio = ad/bc. Using a disease odds ratio formulation makes it easier to show arithmetically that a disease odds ratio approximates the relative risk ratio when the disease is rare (c ≪ d and a ≪ b)]. See relative risk.

Oligonucleotide A short DNA molecule (usually 8 to 50 base pairs), synthesized for hybridization or for use in the polymerase chain reaction.

Oncogene A dominantly acting gene responsible for tumor development. When activated by mutation, overexpression, or amplification, oncogenes in somatic cells may lead to neoplastic transformation. Contrast with proto-oncogenedriver gene, and tumor-suppressor gene.

Oogonia Cells derived from primordial germ cells in females that develop into primary oocytes at the end of the third month of fetal life. Primary oocytes enter prophase of meiosis I and then stop and only complete meiosis and their differentiation into mature ova at the time of ovulation and fertilization.

Open reading frame The interval between the start and stop codons of a nucleotide sequence that encodes a protein.

Origin of replication One of the hundreds of thousands of sites along each chromosome at which DNA replication begins during the S phase of the cell cycle.

Orphan disease A disease is considered to be a rare or orphan disease if it affects less than 200,000 Americans or, in Europe, less than 1 in 2000 persons. The majority of genetic orphan diseases are monogenic.

Orthologous Refers to genes in different species that are similar in DNA sequence and also encode proteins that have the same function—at least at the biochemical level—in each species. Orthologous genes originate from the same gene in a common ancestor. Contrast with paralogous.

p 1. In cytogenetics, the short arm of a chromosome (from the French petit). 2. In population genetics, the frequency of the more common allele of a pair. 3. In biochemistry, abbreviation of protein (e.g., p53 is a 53-kD protein).

Pachytene Stage in meiosis I following synapsis when meiotic recombination takes place.

Paralogous Refers to two or more genes in a single species that are similar in DNA sequence and are likely to encode proteins with similar and perhaps overlapping but not identical functions. Paralogous genes are likely to have originated from a common ancestral gene. Examples are α- and β-globin genes.

Paramesonephric duct Structure in the genital ridges of the early embryo that will develop into female internal sexual organs in the female. Also called the müllerian duct.

Parental haplotype A haplotype in a gamete that is also present in the parent (i.e., no crossing over occurred in meiosis during gametogenesis to disrupt the haplotype). Also referred to as a nonrecombinant haplotype. The opposite is a nonparental or recombinant haplotype.

Parental transmission bias A phenomenon seen with the inheritance of unstable repeat expansion mutations in which expansions of the repeat occur preferentially when the mutation is transmitted by one parent versus the other.

Partial monosomy Subchromosomal mutation leading to loss of one copy of a segment of a chromosome.

Partial trisomy Subchromosomal mutation leading to gain of a third, extra copy of a segment of a chromosome.

Passenger gene mutation The vast majority of somatic mutations in cancers, which appear to be random, are not recurrent in particular cancer types, and probably occurred as the cancer developed, rather than directly causing the cancer to develop or progress. Compare with driver gene.

PAX gene family A family of transcription factors that share a DNA-binding motif originally described in the Drosophila “paired gene.”

PCR See polymerase chain reaction.

Pedigree In medical genetics, a family history of a hereditary condition, or a diagram of a family history indicating the family members, their relationship to the proband, and their status with respect to a particular hereditary condition.

Penetrance The fraction of individuals with a genotype known to cause a disease who have any signs or symptoms of the disease. Contrast with expressivity.

Pharmacodynamics The effects of a drug or its metabolites on physiological function and metabolic pathways.

Pharmacogenetics The area of biochemical genetics concerned with the impact of genetic variation on drug response and metabolism.

Pharmacogenomics The application of genomic information or methods to pharmacogenetic problems.

Pharmacokinetics The rate at which the body absorbs, transports, metabolizes, or excretes a drug or its metabolites.

Phase In an individual heterozygous at two syntenic loci, the designation of which allele at the first locus is on the same chromosome as which allele at the second locus. Not to be confused with the phases (stages) of the cell cycle. See coupling and repulsion.

Phenocopy A mimic of a phenotype that is usually determined by a specific genotype, produced instead by the interaction of some environmental factor with a normal genotype.

Phenotype The observed biochemical, physiological, and morphological characteristics of an individual, as determined by his or her genotype and the environment in which it is expressed. Also, in a more limited sense, the abnormalities resulting from a particular mutant gene.

Phenotypic threshold In mitochondrial genetics, the level of heteroplasmy for a given mutant mitochondrial genome at which phenotypic expression or disease occurs.

Philadelphia chromosome (Ph1) The structurally abnormal chromosome 22 that typically occurs in a proportion of the bone marrow cells in most patients with chronic myelogenous leukemia. The abnormality is a reciprocal translocation between the distal portion of 22q and the distal portion of 9q that fuses the BCR region of 9 to the ABL1 oncogene on 22.

Pleiotropy Multiple phenotypic effects of a single allele or pair of alleles. The term is used particularly when the effects are not obviously related.

Pluripotent Describes an embryonic cell that is capable of giving rise to different types of differentiated tissues or structures, depending on its location and environmental influences.

Point mutation See SNV.

Polar bodies One of two cells generated during meiosis I and one of two cells generated in meiosis II in oogenesis that receive very little cytoplasm and are not functional ova.

Polyadenylation site In the synthesis of mature mRNA, a site at which a sequence of 20 to 200 adenosine residues (the polyA tail) is added to the 3′ end of an RNA transcript, aiding its transport out of the nucleus and, usually, its stability.

Polygenic Inheritance determined by many genes at different loci, with small additive effects; to be distinguished from the complex inheritance seen with multifactorial disease in which environmental as well as genetic factors may be involved.

Polymerase chain reaction (PCR) The molecular genetic technique by which a short DNA or RNA sequence is amplified enormously by means of two flanking oligonucleotide primers used in repeated cycles of primer extension and DNA synthesis with DNA polymerase.

Polymorphism The occurrence together in a population of two or more alternative genotypes, each at a frequency greater than that which could be maintained by recurrent mutation alone. A locus is arbitrarily considered to be polymorphic if the rarer allele has a frequency of at least 0.01, so that the heterozygote frequency is at least 0.02. By convention, any allele rarer than this is a rare variant.

Population genetics The quantitative study of the frequencies of genetic variants in populations and of how these frequencies change over time both within and between populations.

Positive predictive value With respect to a clinical test for a disease, the extent to which testing positive indicates that one has or will develop the disease.

Preimplantation diagnosis A type of prenatal diagnosis in which one or more cells are removed, either at the blastomere or blastocyst stage, from a multicellular embryo that had been generated by in vitro fertilization and tested for the presence of a disease-causing mutation. An unaffected embryo can then be implanted in the uterus to establish a pregnancy. Avoids the need for considering abortion of an affected fetus that occurs with chorionic villus sampling (CVS) or amniocentesis.

Premature ovarian failure Loss of normal ovarian function before age 40.

Premutation In unstable repeat disorders (e.g., fragile X syndrome), a moderate expansion of the number of repeats that is at increased risk for undergoing further expansion during meiosis and causing the full disorder in the offspring. Premutations can be asymptomatic, as in Huntington disease, or they may be associated with a distinct syndrome, such as the fragile X–associated tremor/ataxia syndrome in individuals with triplet repeat expansions in their FMR1 gene in the premutation range.

Primary constriction See centromere.

Primary transcript The initial, unprocessed RNA transcript of a gene that is collinear with the genomic DNA, containing introns as well as exons.

Proband The affected family member through whom the family is ascertained. Also called the propositus or index case.

Prometaphase The stage of mitosis in which the nuclear membrane dissolves and chromosomes attach to the mitotic spindle. Immediately follows prophase.

Promoter A DNA sequence located in the 5′ end of a gene at which transcription is initiated.

Pronuclei The chromosomes of sperm and egg enclosed in separate nuclear membranes immediately following fertilization. After the first mitotic cell division, at which point the two sets of chromosomes join in a single nuclear membrane.

Prophase The first stage of cell division, during which the chromosomes become visible as discrete structures and subsequently thicken and shorten. Prophase of the first meiotic division is further characterized by pairing (synapsis) of homologous chromosomes.

Propositus See proband.

Proteome The collection of all proteins present in a cell, tissue, or organism at a particular time. Contrast with transcriptome, the collection of all RNA transcripts, and genome, the collection of all DNA sequences.

Proteomics A field of biochemistry encompassing the comprehensive analysis and cataloguing of the structure and function of all the proteins present in a given cell or tissue (see proteome). Parallels genomics, a similarly comprehensive approach to the analysis of DNA sequence and mRNA expression.

Proto-oncogene A normal gene involved in cell division or proliferation that may become activated by mutation or other mechanism to become an oncogene.

Pseudoautosomal region Segment of the X and Y chromosome, located at the most distal portion of their respective p and q arms, at which crossing over occurs during male meiosis. Traits due to alleles at pseudoautosomal loci will appear to be inherited as autosomal traits despite the physical location of these loci on the sex chromosomes.

Pseudodeficiency allele A clinically benign allele that has a reduction in functional activity detected by in vitro assays but that has sufficient activity in vivo to prevent haploinsufficiency.

Pseudogene 1. An inactive gene within a gene family, derived by mutation of an ancestral active gene and frequently located in the same region of the chromosome as its functional counterpart (nonprocessed pseudogene). 2. A DNA copy of an mRNA, created by retrotransposition and inserted randomly in the genome (processed pseudogene). Processed pseudogenes are probably never functional.

Pseudomosaicism The occurrence of a cytogenetically abnormal cell that arose after the tissue was put into culture; generally considered to be artifactual and of no clinical significance.

Purines One of the two types of nitrogen-containing bases (the other being pyrimidine) in DNA and RNA (adenine and guanine).

Pyrimidine One of the two types of nitrogen-containing bases (the other being purines) in DNA and RNA (cytosine and thymine in DNA, cytosine and uracil in RNA).

q 1. In cytogenetics, the long arm of a chromosome. 2. In population genetics, the frequency of the less common allele of a pair. Compare with p.

Quadrivalent In a cell with a balanced translocation, the complex of four chromosomes that forms in meiosis I synapsis consisting of the two translocated chromosomes paired with the two normal chromosomes corresponding to the chromosomes involved in the translocation.

Qualitative trait A trait that an individual either has or does not have. Contrast with quantitative trait.

Quantitative trait A measurable quantity that differs among different individuals, often following a normal distribution in the population. Contrast with qualitative trait.

Random mating Selection of a mate without regard to the genotype of the mate. In a randomly mating population, the frequencies of the various matings are determined solely by the frequencies of the alleles concerned.

Reading frame One of the three possible ways of reading a nucleotide sequence as a series of triplets. An open reading frame contains no termination codons and thus is potentially translatable into protein.

Rearrangement Chromosome breakage followed by reconstitution in an abnormal combination. If unbalanced, the rearrangement can produce an abnormal phenotype.

Recessive A trait that is expressed only in homozygotes, compound heterozygotes, or hemizygotes.

Reciprocal translocation See translocation.

Recombinant An individual who has a new combination of alleles in a haplotype not present in either parent.

Recombinant chromosome A chromosome that results from exchange of reciprocal segments by crossing over between a homologous pair of parental chromosomes during meiosis.

Recombination The formation of new combinations of alleles in coupling by crossing over between their loci.

Recombination fraction (θ) The fraction of offspring of a parent heterozygous at two loci who have inherited a chromosome carrying a recombination between the loci. Usually symbolized by the Greek letter θ.

Recurrence risk The probability that a genetic disorder present in one or more members of a family will recur in another member of the same or a subsequent generation.

Reduction division The first meiotic division, so-called because at this stage the chromosome number per cell is reduced from diploid to haploid.

Redundancy The situation in which genes (often paralogous) have overlapping functions.

Regulative development A developmental stage during which removal or destruction of a particular region of the embryo is compensated for by other embryonic regions, thereby allowing normal development.

Regulatory element A DNA segment, such as a promoter, insulator, enhancer, or locus control region, within or near a gene that regulates the expression of the gene.

Regulatory gene A gene that codes for an RNA or protein molecule that regulates the expression of other genes.

Relative risk A comparison of the risk for a disease or trait in individuals who share a particular factor (e.g., genotype, an environmental exposure, or a drug) versus the risk among individuals who lack the factor.imageThe risk for being affected in individuals who have the factor = (a/a + b), the risk for being affected when the factor is absent = (c/c + d), and the relative risk = (a/a + b)/(c/c + d) = a(c + d)/c(a + b). Note that relative risk ≈ ad/bc, the odds ratio, when the disease is relatively rare (c ≪ d and a ≪ b). See odds ratio.

Relative risk ratio (λr) In complex disorders, the risk that a disease will occur in a relative of an affected person compared with the risk for disease in any random person in the general population.

Repetitive DNA (repeats) DNA sequences that are present in multiple copies in the genome.

Replicative segregation Random distribution of mitochondria into daughter cells.

Repulsion Describes the phase of two alleles at two different but syntenic loci, in which one allele at one of the loci is not on the same chromosome as the allele at the second locus. See phase and coupling.

Retroposition A process by which a molecule of RNA, often derived from transcription of a repetitive element such as Alu or LINE, is transcribed by reverse transcriptase into a molecule of DNA, which is then inserted into another site in the genome.

Retrovirus A virus, with an RNA genome, that propagates by conversion of the RNA into DNA by the enzyme reverse transcriptase.

Reverse transcriptase An enzyme, RNA-dependent DNA polymerase, that catalyzes the synthesis of DNA on an RNA template.

Ribonucleic acid See RNA.

Ribosome A cytoplasmic organelle composed of ribosomal RNA and protein, on which polypeptides are synthesized based on the sequences of messenger RNA.

Ring chromosome A structurally abnormal chromosome in which the telomere of each chromosome arm has been deleted and the broken arms have reunited in ring formation.

Risk The probability of an event's occurring. Often calculated as the number of times the event occurs divided by the total number of opportunities there were for the event to occur. As with all probabilities, risk varies from 0 to 1.

RNA (ribonucleic acid) A nucleic acid formed on a DNA template, containing ribose instead of deoxyribose. Messenger RNA (mRNA) is the template on which polypeptides are synthesized. Transfer RNA (tRNA),in cooperation with the ribosomes, brings activated amino acids into position along the mRNA template. Ribosomal RNA (rRNA), a component of the ribosomes, functions as a nonspecific site of polypeptide synthesis. Noncoding RNAs (ncRNAs) are transcribed RNA molecules that do not encode proteins or directly carry out translation, as tRNA or rRNA do, but instead have a variety of roles in the regulation of gene expression. Some ncRNAs are very long (such as the XIST gene product involved in X-inactivation) and referred to as long ncRNA or lncRNA.

RNA editing Post-transcriptional modification of RNA transcripts, thereby changing certain codons in the mRNA so they differ from the codon specified in the original DNA template. Most frequently occurs through deamination of adenine to generate an inosine, which is read by the translational machinery as a guanine.

RNA polymerase An enzyme that synthesizes RNA on a DNA template. Different RNA polymerases synthesize different RNA molecules; for example, mRNAs are transcribed by RNA polymerase II.

RNA splicing The excision of introns from primary RNA transcripts and splicing together of exons in the generation of mature mRNA from the primary transcript.

RNAi RNA interference. A system for regulating gene expression in which short RNA segments, approximately 22 bases in length, form double-stranded structures with an mRNA and either target it for destruction or block its translation. (See microRNA.) Scientists have taken advantage of this normal, endogenous system of gene regulation to design new and powerful technologies for gene silencing by use of exogenously supplied RNAi sequences.

Robertsonian translocation A translocation between two acrocentric chromosomes by fusion at or near the centromere, with loss of the short arms.

Satellite DNA DNA containing many tandem repeats of a short basic repeating unit; not to be confused with chromosomal satellite, the chromatin at the distal end of the short arms of the acrocentric chromosomes.

Scaffold The nonhistone structure observed when histones are experimentally removed from chromosomes. Believed to represent a structural component of the nucleus and of chromosomes.

Segmental aneusomy Loss or gain of a small segment from one chromosome of a pair, resulting either in hemizygosity or partial trisomy for genes in that segment on the homologous chromosome. See also contiguous gene syndrome.

Segmental duplication Blocks of homologous sequences distributed across a region of the genome that mediate duplication and deletion of the segments of DNA located between them.

Segregation In genetics, the distribution of genetic material into daughter cells. For chromosomes, it is the orderly disjunction of the appropriate haploid set of homologous chromosomes at meiosis I or sister chromatids at meiosis II. For mitochondria, refers to distribution of newly formed mitochondria into daughter cells during mitosis. See nondisjunction and replicative segregation.

Selection In population genetics, the operation of forces that determine the relative fitness of a genotype in the population, thus affecting the frequency of particular alleles. The coefficient of selection, s, is a measure of the proportion of mutant alleles at a locus that are not passed on to the next generation and is given by 1-f, where f is the coefficient of fitness.

Sense strand See coding strand.

Sensitivity In diagnostic tests, the frequency with which the test result is positive when the disorder is present. Not to be confused with positive predictive value.

Sequence 1. In genomics and molecular genetics, the order of nucleotides in a segment of DNA or RNA. 2. In clinical genetics, a recognizable pattern of dysmorphic features due to a number of different causes; to be distinguished from malformation syndrome.

Sex chromatin See Barr body.

Sex chromosomes The X and Y chromosomes.

Sex-influenced A trait that is not X-linked in its pattern of inheritance but is expressed differently, either in degree or in frequency, in males and females.

Sex-limited A trait that is expressed in only one sex, although the gene that determines the trait is not X-linked.

Sex-linked A general term referring to linkage to either of the sex chromosomes. In human and medical genetics, the term is typically not used and is replaced by X-linkage or Y-linkage.

Short tandem repeat polymorphism (STRP) A polymorphic locus consisting of a variable number of tandemly repeated dinucleotide, trinucleotide, or tetranucleotide units such as (TG)n, (CAA)n, or (GATA)n; different numbers of units constitute the different alleles. Also termed a microsatellite marker.

Sib, sibling A brother or sister.

Sibship All the sibs in a family.

Silencer A DNA sequence that acts in cis (i.e., on the same chromosome) to decrease transcription of a nearby gene. The silencer may be upstream or downstream to the gene and may be in the same or the reverse orientation (contrast with enhancer).

Single nucleotide variant (SNV) A change in DNA sequence at a single base pair in DNA. If the SNV is frequent enough to be a polymorphism, it is referred to as a single nucleotide polymorphism (SNP).

Single-copy DNA DNA whose linear order of specific nucleotides is represented only once (or at most a few times) around the entire genome. The type of DNA that makes up most of the genome.

Single-gene disorder A disorder due to one or a pair of mutant alleles at a single locus.

Slipped mispairing A mutational mechanism that occurs during DNA replication of sequences with repeats of one or more nucleotides, in which a repeat on one strand mispairs with a similar repeat on the complementary strand, generating a deletion or expansion of the number of repeats.

Small (or short) interfering RNAs (siRNAs) A class of naturally occurring or synthesized 20- to 25-nucleotide–long, double-stranded RNA molecules that regulate gene expression by inducing the degradation of complementary mRNA, by the process of RNA interference. They have substantial therapeutic potential against targets that otherwise cannot be treated by drugs.

SNP See single nucleotide variant.

SNP array A type of microarray that uses oligonucleotides corresponding to high-frequency SNPs around the genome to determine if there is a chromosomal or subchromosomal deletion or duplication. Provides an alternative approach to detecting CNVs to comparative genome hybridization.

SNV See single nucleotide variant.

Solenoid A fiber composed of compacted strings of nucleosomes, that forms the fundamental unit of chromatin organization.

Somatic cell All the cells that contribute to one's body, excluding the cells of the germline.

Somatic mutation A mutation occurring in a somatic cell rather than in the germline.

Somatic rearrangement Rearrangement of DNA sequences in the chromosomes of lymphocyte precursor cells, thus generating antibody and T-cell receptor diversity.

Southern blotting A technique, devised by the British biochemist Ed Southern, for preparation of a filter to which DNA has been transferred, following restriction enzyme digestion and gel electrophoresis to separate the DNA molecules by size. The size of specific DNA molecules can then be determined on the filter by their hybridization to labeled DNA sequences complementary to the sequences one wishes to visualize.

Specialty proteins Proteins, expressed in only one or a limited number of cell types, that have unique functions contributing to the individuality of the cells in which they are expressed. Contrast with housekeeping proteins.

Specification The first stage of commitment in which a cell will follow its developmental program if it is explanted but can still be reprogrammed to a different fate if it is transplanted to a different part of the embryo.

Specificity In diagnostic tests, the frequency with which a test result is negative when the disease is absent. Not to be confused with negative predictive value.

Spermatogonia Diploid cells derived from early germ cells in the male that both divide to replenish their population and, at puberty, undergo a series of developmental steps, including meiosis, leading to terminal differentiation into mature spermatozoa.

Spliceopathy A disorder, typified by myotonic dystrophy, in which mRNAs containing massive expansions of an untranslated unstable repeat mutation sequester splicing factors and deprive the cell of the proteins needed to carry out normal splicing of other mRNAs.

Splicing See RNA splicing.

Sporadic In medical genetics, a disease that is not the result of inheritance of a disease-causing allele from a parent. Often the result of a new germline or somatic mutation.

Standardized incidence ratio (SIR) The ratio of the incidence of cases of cancer during a given time period in relatives of a proband with a disorder such as cancer divided by the number expected from the incidence over that same time period in an age-matched group in the general population.

Stem cell A type of cell capable both of self-renewal and of proliferation and differentiation.

Stop codon See termination codon.

Stratification The situation in which a population contains a number of subgroups whose members have not freely and randomly mated with the members of other subgroups.

Structural gene A gene coding for any RNA or protein product.

Structural protein A protein that serves a structural role in the body, such as collagen.

Structural rearrangements Rearrangements of one or more chromosomes, which may be balanced if there is no change from normal genomic content, or unbalanced, if genomic content is abnormal.

Subchromosomal mutation Mutations that change only a portion of a chromosome. Can lead to partial trisomy or partial monosomy.

Submetacentric A type of chromosome with arms of different lengths.

Synapsis Close pairing of homologous chromosomes in prophase of the first meiotic division.

Synaptonemal complex The protein complex that forms at sites of meiotic recombination and mediates the recombination during synapsis in meiosis I.

Syndrome A characteristic pattern of anomalies, presumed to be causally related.

Synonymous Describes a single nucleotide variant (SNV) that does not alter a codon and therefore does not change the resulting amino acid sequence of the encoded peptide.

Synpolydactyly A birth defect of the hands and feet characterized by extra digits and the fusion of adjoining digits.

Synteny The physical presence together on the same chromosome of two or more gene loci, whether or not they are close enough together for linkage to be demonstrated (the adjective is syntenic).

Tandem repeats Two or more copies of the same (or similar) DNA sequence arranged in a direct head to tail succession along a chromosome.

TATA box A consensus sequence in the promoter region of many genes that is located approximately 25 base pairs upstream from the start site of transcription and that determines the start site.

T-cell antigen receptor (TCR) Genetically coded receptor on the surface of T lymphocytes that specifically recognizes antigen molecules.

Telocentric A type of chromosome in which the centromere is at one end of a chromosome and there is only a single arm; telocentric chromosomes do not occur in normal human karyotypes but occasionally occur in chromosomal rearrangements.

Telomerase A ribonucleoprotein reverse transcriptase that contains its own RNA molecule to use as a template for synthesizing species-specific hexamers (e.g., TTAGGG in humans) and adding them to the ends of telomeres.

Telomere The end of each chromosome arm. Human telomeres end with tandem copies of the sequence (TTAGGG)n, which is required for the proper replication of chromosome ends.

Telophase The stage of cell division that begins when the daughter chromosomes reach the poles of the dividing cell and that lasts until the two daughter cells take on the appearance of interphase cells.

Teratogen An agent that produces congenital malformations or increases their incidence.

Termination codon One of the three codons (UAG, UAA, and UGA) that terminate synthesis of a polypeptide. Also called a stop codon or chain-termination codon.

Tertiary structure Three-dimensional configuration of a molecule.

Tetraploid A cell with four (4n) copies of each chromosome, or an individual made up of such cells.

The Cancer Genome Atlas (TCGA) A vast public database of mutations, epigenomic modifications, and abnormal gene expression profiles found in a wide variety of cancers.

Trans Refers to the relationship between two sequences located across from each other on the two homologous chromosomes, or to interactions between a protein and a chromosome locus. Literally means “across from.” Contrast with cis.

Transcription The synthesis of a single-stranded RNA molecule from a DNA template in the cell nucleus, catalyzed by RNA polymerase.

Transcription factor One of a large class of proteins that regulate transcription by forming large complexes with other transcription factors and RNA polymerase; these complexes then bind to regulatory regions of genes either to promote or to inhibit transcription.

Transcriptome The collection of all RNA transcripts made in a cell.

Transfer RNA (tRNA) See RNA.

Transformation The in vivo process by which a normal cell in a tissue becomes a cancerous cell.

Translation The synthesis of a polypeptide from its mRNA template.

Translocation The transfer of a segment of one chromosome to another chromosome. If two nonhomologous chromosomes exchange pieces, the translocation is reciprocal. See also Robertsonian translocation.

Triploid A cell with three copies of each chromosome (3n), or an individual made up of such cells.

Trisomy The state of having three representatives of a given chromosome instead of the usual pair, as in trisomy 21 (Down syndrome).

tRNA Transfer RNA; see RNA.

Tumor-suppressor gene A normal gene involved in the regulation of cell proliferation. Loss-of-function mutations in both alleles can lead to tumor development, as in the retinoblastoma gene or the TP53 gene. Contrast with oncogene.

Two-hit model The hypothesis that some forms of cancer can be initiated when both alleles of a tumor-suppressor gene become inactivated in the same cell.

Ultrasonography A technique in which high-frequency sound waves are used to examine internal body structures; useful in prenatal diagnosis.

Unbalanced X inactivation The situation in which the two X chromosomes in a female are not inactivated equally, leading to a substantial deviation from the expected 50% chance for each X remaining active. Also called skewed inactivation.

Uniparental disomy The presence in the karyotype of two copies of a specific chromosome, both inherited from one parent, with no representative of that chromosome from the other parent. If both homologues of the parental pair are present, the situation is heterodisomy; if one parental homologue is present in duplicate, the situation is isodisomy. See Prader-Willi syndrome and Angelman syndrome in the text.

Unstable repeat expansion disorders See dynamic mutation.

Untranslated region (UTR) The segments of an mRNA that either precede the initiator codon (5′-UTR) or follow the stop codon (3′-UTR).

Variant An allele that differs from wild-type.

Variant of uncertain significance (VUS) A difference between an individual's sequence and that of an arbitrary reference sequence, but whose pathogenetic significance is unknown. Missense mutations are frequent VUSs in whole-exome or whole-genome sequences, although indels may also be of uncertain significance.

Vector In gene transfer therapy, a virus whose genome has been engineered to contain and express a therapeutic DNA sequence of interest. The virus is used to deliver the DNA sequence into a cell.

VNTR (variable number of tandem repeats) A type of DNA polymorphism created by a tandem arrangement of varying numbers of copies of short DNA sequences. Highly polymorphic, used in linkage studies and in DNA “fingerprinting” for paternity testing and forensic medicine.

Whole-exome sequencing (WES) Use of high-throughput sequencing methods to sequence the approximately 2% of the genome containing just the exons of protein-coding genes in an individual. See whole-genome sequencing.

Whole-genome sequencing (WGS) Use of high-throughput sequencing methods to sequence an individual's entire genome (minus the few percent that current technologies are not capable of sequencing). See whole-exome sequencing.

Wild-type A term used to indicate the normal allele (often symbolized as +) or the normal phenotype.

X;autosome translocation Reciprocal translocation between an X chromosome and an autosome.

X chromosome The larger of the two sex chromosomes, normally present in two copies in females and one copy in males.

X inactivation Inactivation of genes on one X chromosome in somatic cells of female mammals, occurring early in embryonic life, at about the time of implantation. The X inactivation center is a segment of the X chromosome that determines which X will be designated the inactive X and contains the ncRNA XIST. See Lyon's law (hypothesis).

X linkage The distinctive inheritance pattern of alleles at loci on the X chromosome that do not undergo recombination (crossing over) during male meiosis. Genes on the X chromosome, or traits determined by such genes, are X-linked.

Y chromosome The smaller of the two sex chromosomes, normally present in one copy in males only.

Y linkage Genes on the Y chromosome, or traits (e.g., the male sex) determined by such genes, are Y-linked.

Zone of polarizing activity Region in a developing limb bud that secretes morphogens like sonic hedgehog to establish a gradient that specifies the posterior side of the developing limb bud.

Zygosity The number of zygotes from which a multiple birth is derived. For example, twins may be either monozygotic (MZ) or dizygotic (DZ). To determine whether a certain pair of twins is MZ or DZ is to determine their zygosity.

Zygote A fertilized ovum.

Zygotene Stage in meiosis I when homologous chromosomes align along their entire length to permit synapsis.