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Genomics and Precision Health

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The latest science on the use of genetics, genomics, and proteomics to improve health care decisions for patients and populations.

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GLOSSARY

Allele: Alternative form of a gene or DNA sequence. Variations in clinical traits and phenotypes are allelic if they arise from the same gene sequence or locus and nonallelic if they arise from different gene sequences of different loci.
Allelism: Whether a second variant (allele) is on the same or the other chromosomal copy in a dominant or recessive condition.
Alternative splicing: Use of different exons in formation of mRNA from initially identical transcripts. This results in the generation of related proteins from 1 gene, often in a tissue or developmental stage鈥搒pecific manner.
Analytical validity: The likelihood that a test result is correct, ie, a specific variant said to be present is present or said to be absent is absent.
Aneuploidy: The occurrence of one or more extra or missing chromosomes leading to an unbalanced chromosome complement or any chromosome number that is not an exact multiple of the haploid number.
Array: See Microarray.
Attributable risk: The difference in incidence of disease in an exposed vs unexposed population; in genetics the exposure can be the presence of a specific genetic variation in the genome.
Bacteriophage: Viruses whose hosts are bacterial cells.
Base pair (bp): Two complementary nucleotides that are paired in double-stranded DNA. Adenosine (A) pairs with thymine (T), and guanine (G) pairs with cytosine (C). A bp is also used as a physical distance of length of a sequence of nucleotides, eg, 20 bp is a chain of DNA composed of 20 nucleotides.
Call rate: The rate at which assignment of a specific nucleotide base (A,G,C,T) is made at specific positions in the genome during genotyping or sequencing.
Candidate gene: A gene believed to influence expression of complex phenotypes due to known biological and/or physiological properties of its products, or to its location near a region of association or linkage.
Carrier screening: Testing of members of a population for genetic variations associated with genetic conditions (usually autosomal recessive disorders) often for the purpose of reproductive planning.
Cascade screening: A systematic process for identifying individuals with a medical condition. In genetics, the process begins with an affected family member and entails iterative rounds of testing of closely related relatives, followed by testing of close relatives of those newly discovered as affected.
cDNA (complementary DNA): A DNA copy of the messenger RNA (mRNA) transcribed from a gene. The cDNA is made from the mRNA using the enzyme reverse transcriptase.
Cell free DNA (cfDNA): Fragments of DNA circulating in the blood outside of cells.
Circulating tumor DNA (ctDNA): Fragments of DNA derived from cancer cells circulating in the blood outside of cells.
Clinical utility: The degree to which a test result guides clinical management and improves patient outcomes.
Clinical validity: The likelihood that a test result correctly predicts presence or absence of disease or risk of disease.
Coding region: Segments of the genome that contain information specifying the amino acid sequence in proteins.
Codon: Three bases in a DNA or RNA sequence that specify a single amino acid.
Copy number variants: Stretches of genomic sequence of roughly 1 kb to 3 Mb in size that are deleted or are duplicated in varying numbers.
Comparative genomic hybridization (CGH) also array CGH: Technology wherein a DNA test sample is competitively hybridized with a reference sample of DNA of known sequence to a DNA microarray, used to detect copy number changes in the test sample.
Complex trait: A trait that has a genetic component that does not follow strict mendelian inheritance. It may involve the interaction of 2 or more genes or gene-environment interactions.
Coverage: The number of times a portion of the genome is sequenced in a sequencing reaction. Often expressed as 鈥渄epth of coverage鈥� and numerically as 1X, 2X, 3X, etc.
Cytogenetics: The study of the biology of large-scale DNA structure, usually at the level of chromosomes.
Cytogenomic analysis: Technologies that assess the presence of copy number variants at locations throughout the genome, one example of which is comparative genomic hybridization.
Deletion: A type of genetic variation in which nucleotides are lost in a sequence. Deletions may range from 1 nucleotide to millions.
Denaturing high-performance liquid chromatography (DHPLC): A high-performance liquid chromatography instrument uses temperature-dependent separation of DNA containing mismatched base pairs from PCR-amplified DNA fragments for chromatographic variant analysis.
Digital polymerase chain reaction: A method for assaying or amplifying quantities of target DNA or RNA in a sample in which the reactions are partitioned to include single or small numbers of target sequences.
DNA barcoding: A method that uses a short genetic marker in an organism鈥檚 DNA to identify it as belonging to a particular species.
Environmental gene tag: Short sequences of DNA that contain bacterial genes in whole or part that can be used to aid in identification of related genetic material.
Exome: The entire portion of the genome consisting of protein-coding sequences (as opposed to introns or noncoding DNA between genes).
Exome sequencing (or whole exome sequencing, WES): A method for determining the base pair order of the protein coding regions of an organism鈥檚 DNA. Often used in diagnostic studies both because most disease-related variants occur in protein-coding regions and because it is generally less costly than whole-genome sequencing.
Exon: Any segment of a gene that is represented in the mature messenger RNA (mRNA) product.
Fetal Fraction: When referring to cell-free DNA (cfDNA), the percentage of cfDNA in maternal blood of fetal origin.
Fluorescent in situ hybridization (FISH): A cytogenetic technique in which fluorescently labeled probes capable of binding to specific DNA regions are used to detect structural variations in the genome.
Frame shift mutation: Any variation that disrupts the normal sequence of triplets causing a new sequence to be created that codes for different amino acids. Frame shift mutations are usually caused by an insertion or deletion of DNA and typically eventually produce a premature stop codon.
G-banding: A method for Giemsa staining of condensed human chromosomes from metaphase cells that allows assessment of chromosomal structure by light microscopy.
GC content: The percentage of nucleotides in a DNA sequence that are either guanine (G) or cytosine (C).
Genetic heterogeneity: A shared phenotype caused by more than 1 gene.
Genetic Information Nondiscrimination Act (GINA): US federal law passed in 2008 prohibiting the use of genetic information for decisions regarding employment or health insurance.
Genome: The sum total of the genetic material of a cell or an organism.
Genome annotation: Attachment of biological information to DNA sequence data.
Genome-wide analysis: A genetic study evaluating the potential linkage of genetic markers located throughout the genome to a specific trait. This approach has been used for mendelian (single-gene) disorders as well as complex traits (genome-wide association study [GWAS]).
Genomic inflation factor: A mathematical term from genetic epidemiology used to control for population stratification in GWAS.
Genomic medicine: A term used to describe medical advances and approaches based on human genomic information, sometimes referred to as personalized or precision medicine.
Genomics: The study of genes and their function.
Genotype: The specific set of 2 alleles inherited at a genetic locus.
Haplotype: The combination of linked marker alleles (variants) for a given region of DNA on a single chromosome.
HapMap: The International HapMap Project developed a haplotype map of the human genome, the HapMap, that describes the common patterns of human DNA sequence variation. The HapMap is a key resource for finding genes affecting health, disease, and responses to drugs and environmental factors. The first release of the HapMap was made in 2005.
Heterologous expression: A research technique that causes a protein to be produced in a cell that does not normally make (ie, express) that protein.
Heterozygous (heterozygosity): Having 2 unlike alleles at a particular locus.
Homozygous (homozygosity): Having 2 like or identical alleles at a particular locus in a diploid genome.
Human Genome Project: Collective name for several projects begun in 1986 by the US Department of Energy (DOE) and the National Institutes of Health (NIH) to create an ordered set of DNA segments from known chromosomal locations, develop new computational methods for analyzing genetic map and DNA sequence data, and develop new techniques and instruments for detecting and analyzing DNA. The joint national effort, led by DOE and the NIH, was known as the Human Genome Project. The first draft of the human genome DNA sequence, produced by the efforts of the Human Genome Project, was completed in 2001. The Human Genome Project officially ended in April 2003.
Hybridization: The bonding of single-stranded DNA or RNA into double-stranded DNA or RNA. The ability of complementary stretches of DNA or RNA to hybridize with each other is dependent on the base-pair sequence.
Identity by descent (IBD): The property of 2 or more alleles that are identical to an ancestral allele, used in gene association studies
Imputation: A statistical method for inferring genotypes that are not directly measured.
Indel (insertion/deletion): Variations in a genome including insertions and deletions of nucleotides.
Insertion: A type of genetic variation in which nucleotides are gained in a sequence. Insertions may range from 1 nucleotide to millions.
Intron: A segment of DNA that is transcribed into RNA but is ultimately removed from the transcript by splicing together the sequences on either side (exons) to produce messenger RNA (mRNA).
Karyotype: A description or visual representation of the complement of condensed chromosomes from a cell.
Kilobase (kb): One thousand base pairs of DNA or RNA.
Library: A complete set of clones that contains all the genetic material from an organism, tissue, or specific cell type at a specific stage of development.
Linkage: Two loci (genes or other designated DNA sequence) that reside close enough to each other that recombination (crossing over) rarely occurs between them. Alleles at the 2 loci do not assort independently at meiosis but are likely to be inherited together.
Linkage disequilibrium: Refers to alleles at loci close enough that they remain inherited together through many generations because their extreme proximity makes recombination (crossing over) between them highly unlikely.
Locus (plural loci): The physical site on a chromosome occupied by a particular gene or other identifiable DNA sequence characteristic.
Mendelian disorder (single-gene disorder): A trait or disease that follows the patterns of inheritance that suggest the trait or disease is determined by a gene at a single locus.
Metagenomics: Study of a collection of genetic material (genomes) from a mixed community of organisms. Metagenomics usually refers to the study of microbial communities.
Metaphase: A phase of cell division (mitosis) during which DNA is condensed into chromosomal structures that can be visualized using light microscopy.
Methylation: Covalent attachment of methyl groups to DNA, usually at cytosine bases. Methylation can reduce transcription from a gene and is a mechanism in X-chromosome inactivation and imprinting.
Microarray: A technology used to study many genes simultaneously, usually consisting of an ordered microscopic pattern of known nucleic acid sequences on a glass slide. In a common type of microarray, a sample of DNA or RNA is added to the slide and sequence-dependent binding is measured using sensitive fluorescent detection methods.
Microsatellite: A short, repetitive sequence of DNA of variable length that may serve as a marker to follow inheritance or, in tumor DNA, as an indicator of genome instability.
Minor allele: The allele of a biallelic locus that is less frequent in the study population. Minor allele frequency refers to the proportion of the less common of 2 alleles in a population (with 2 alleles carried by each person at each autosomal locus) ranging from less than 1% to less than 50%.
Missense mutation: A variation that is typically the change of a single nucleotide that results in the substitution of one amino acid for another in the final gene product.
Mutation: Any variation of a gene or genetic material from its natural state. Generally, mutations refer to changes that alter the gene in a negative sense, causing the protein product of the gene to have an altered function. (See also variant.)
Next-generation/high-throughput/massively parallel sequencing: DNA sequencing technology that permits rapid sequencing of large portions of the genome; so called because it vastly increases the throughput over classic Sanger sequencing.
Nonsense mutation: Any variation that results directly in the formation of a stop codon.
Nonsynonymous variant: A variant that results in a change in the amino acid sequence of a protein (and therefore may affect the function of the protein).
Nucleotide: The combination of a nitrogen-containing base, a 5-carbon sugar, and phosphate group forming the A, G, C, T of the sequence of DNA, for example.
Oncogene: A gene of which 1 or more forms is associated with the development of cancer. Many oncogenes are involved, directly or indirectly, in controlling the rate of cell growth.
Penetrance: The proportion of individuals of a given genotype who show any evidence of the associated phenotype.
Pharmacogenetic variant: Genetic changes that alter the way an individual metabolizes or responds to a specific medication.
Pharmacogenomics: Study of genes related to genetic controlled variation in drug responses.
Phenotype: The total observable nature of an individual, resulting from interaction of the genotype with the environment.
Plasmid: Circular extrachromosomal DNA molecules in bacteria that can independently reproduce. Plasmids can be used as vectors in recombinant DNA research, and they can contain genes important to bacterial virulence such as antibiotic resistance in nature.
Preimplantation genetic diagnosis: testing of embryos for specific genetic abnormalities for which the prospective parents are known to be at risk; performed prior to selective reintroduction of unaffected embryos to the female reproductive tract
Preimplantation genetic screening: a screening test that seeks to determine the presence of aneuploidy (either too many or too few chromosomes) in a developing embryo prior to selective reintroduction of unaffected embryos to the female reproductive tract
Polymerase chain reaction (PCR): A procedure in which segments of DNA (including DNA copies of RNA) can be amplified using flanking oligonucleotides called primers and repeated cycles of replication by DNA polymerase.
Population stratification (also population structure): A form of confounding in genetic association studies caused by genetic differences between cases and controls unrelated to disease but due to sampling them from populations of different ancestries.
Primer: a short strand of nucleotides (RNA or DNA) that helps initiate new DNA synthesis
Proband: The affected person whose disorder, or concern about a disorder, brings a family or pedigree to be genetically evaluated.
Promoter: The sequence of nucleotides located 5鈥� to the coding sequence of a gene that determines the site for binding of RNA polymerase and the initiation of transcription. More than 1 promoter may be present in a gene and may give rise to different versions of the protein. The promoter may include the DNA sequence TATAA(T)AA(T) (TATA box).
Prophage: The genome of a bacteriophage when it is integrated into the host bacterial genome or a plasmid.
Pyrosequencing: A method of determining the ordering of nucleotide bases in a DNA molecule by measuring the synthesis of the complementary DNA strand.
Quantitative PCR: A PCR-based laboratory technique that allows the accurate measurement of the amount of specific nucleic acids (usually RNA) in a sample.
Read: A discrete segment of sequence information generated by a sequencing instrument; read length refers to the number of nucleotides in the segment.
Recombination: The formation of a new set of alleles on a single chromosome that is not the same as either parent owing to a crossover during meiosis.
Restriction fragment-length polymorphism (RFLP): A type of polymorphism that results from variation in the DNA sequence recognized by restriction enzymes. RFLPs can be used in linkage and gene association studies of traits and diseases.
RNA-induced silencing complex (RISC): A cellular structure of protein and RNA that can bind in a sequence-specific manner to mRNA inhibiting protein production.
RNA interference (RNAi): Cellular processes in which small RNA molecules inhibit transcription or translation of genes.
Single-nucleotide variant (SNV; also known as a single-nucleotide polymorphism, SNP): DNA sequence variations that occur when a single nucleotide (A, T, C, or G) in the genome sequence is altered. SNVs are the most abundant variant in the human genome and are the most common source of genetic variation.
Small interfering RNA (siRNA): Naturally occurring or synthetic small, usually 20-25 bp, double-stranded RNA molecules that comprise part of the RNA-induced silencing complex (RISC). This protein鈥搉ucleic acid complex binds in a sequence-specific manner to mRNA, inhibiting translation and protein production.
Somatic mutation: A change in the DNA in non-germline cells, for example, new mutations in a tumor.
Stop codon (termination codon): The DNA triplet that causes translation to end when it is found in mRNA. The DNA stop codons are TAG, TAA, and TGA.
Structural mutation: Large-scale change in genomic DNA, for example, chromosomal inversion.
Tag SNV: A readily measured SNV that is in strong linkage disequilibrium with multiple other SNVs so that it can serve as a proxy for these SNVs on large-scale genotyping platforms.
Translocation: A chromosomal segment that has been broken off and reinserted in a different place in the genome.
Transversion: The substitution of a purine for a pyrimidine nucleotide or vice versa (eg, an A for a C or T) in a DNA sequence.
Triploidy: A rare form of aneuploidy in which there are 3 sets of each chromosome in a cell.
Uniparental disomy: The inheritance of both parental copies of a chromosome from one parent and no homologous chromosome from the other parent. The resulting offspring could be affected with a recessive disease if the parent contributing both copies is a carrier.
Variant (polymorphism): Difference in DNA sequence among individuals that may underlie differences in health. Genetic alterations occurring in more than 1% of a population would be considered useful variants for genetic linkage analysis. The vast majority of DNA variants are benign and not associated with a detectable phenotype.
Variant allele fraction: The detected percentage of a variation that is not the reference sequence in a DNA sample derived from a nonclonal sample of cells, for example, a tumor DNA sample.
Variant of unknown significance (VUS): Genetic variant that cannot be definitively determined to be associated with a specific phenotype.
Whole-genome amplification: a process by which the DNA of a organism in a sample can be chemically replicated, in its entirety, multiple times over in order to increase the amount of sample
Whole genome sequencing (WGS): A method for determining the base pair order of both protein-coding and non鈥損rotein-coding regions of an organism鈥檚 DNA. Current technology can provide a near complete human genome; some regions of the genome remain difficult to sequence.

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