Common disease–common variant hypothesis: A theory that many common diseases are caused by common alleles that individually have little effect but in concert confer a high risk.
Complex disease: A disorder in which the cause is considered to be a combination of genetic effects and environmental influences.
Deep resequencing: A technique for sequencing a gene in several thousand subjects, typically with the use of high-throughput sequencing.
Epigenetics: The study of heritable changes to DNA structure that do not alter the underlying sequence; well-known examples are DNA methylation and histone modification.
Exome: All the expressed messenger RNA sequences in any tissue.
Fine mapping: The precise mapping of a locus after it has been identified by genetic linkage or association. The initial localization is determined within megabases of DNA in genetic linkage studies and within tens of kilobases in genetic association studies. In genetic association studies, fine mapping implies finding all the variants at the locus and trying to determine which changes may be related to pathogenesis with the use of statistical, functional, or bioinformatic methods.
Genes, Environment, and Health Initiative (GEI): A project funded by the National Institutes of Health to determine the relationships between genetic factors and disease. A proportion of the funding supports research of systematic ways to quantify environmental exposures.
Genetic association: A relationship that is defined by the nonrandom occurrence of a genetic marker with a trait, which suggests an association between the genetic marker (or a marker close to it) and disease pathogenesis.
Genetic linkage: A relationship that is defined by the coinheritance of a genetic marker with disease in a family with multiple disease-affected members.
Genomewide association study: A test of the association between markers, called single-nucleotide polymorphisms (SNPs), across the genome and disease, usually involving 300,000 or more markers that are reasonably polymorphic and are spread across the genome fairly evenly. This approach is hypothesis free (i.e., there is no existing hypothesis about a particular gene or locus but the null hypothesis that no detectable association exists).
Genotype-Tissue Expression (GTEx): A project funded by the National Institutes of Health that aims to study and map the relationship between human gene expression and genetic variation. The project, which is in a pilot phase, will analyze dense genotyping and expression data collected from multiple human tissues and will correlate genetic variation and gene expression, thus producing a list of genetic regions associated with expression of specific transcripts.
Haplotype: A series of polymorphisms that are close together in the genome. The distribution of alleles at each polymorphic site is nonrandom: the base at one position predicts with some accuracy the base at the adjacent position. Persons sharing a haplotype are related, often very distantly. Haplotypes in Europeans are generally of the order of tens of kilobases long; older populations, such as those of West Africa, tend to have shorter haplotypes, since a longer period of evolutionary time means more meiotic events and a greater chance of population admixture, both of which result in shorter haplotypes.
Haplotypic structure: The general underlying segmentation of the genome. As a result of recombination events occurring throughout the history of a population, contiguous segments of DNA are shared by persons within a population. Chromosomes can thus be broken down into contiguous segments, containing haplotypes common to members of particular populations.
HapMap: A catalogue of common genetic variation in humans compiled by an international partnership of scientists and funding agencies. Its goal was to determine the identity and length of haplotypes across the genome in different human populations. Stage 1 of the process, which was completed in 2005, yielded haplotype maps from SNPs present in at least 5% of chromosomes of each of three groups defined by ancestry: Yoruban, Northern and Western European, and Asian (Chinese and Japanese). Stage 2 involves determining haplotypes made up of SNPs with a lower prevalence (at least 1% of chromosomes) in these three groups and also in the Luhya and Maasai from Kenya, Toscani from Italy, Gujarati Indians, persons of Mexican ancestry, and persons of mixed African ancestry.
High-throughput sequencing: Several new techniques that since 2005 have increased the speed and decreased the cost of DNA sequencing by two orders of magnitude.
Human Genome Project: A coordinated international effort that led to the consensus sequence of the human genome.
Linkage disequilibrium: The nonrandom association of genetic markers; a set of markers in a haplotype are said to be in linkage disequilibrium.
Monogenic disease: A disorder caused by a mutation in a single gene (also called a mendelian disease).
Positional cloning: An approach for determining the position of a gene that, when mutated, causes monogenic disease. In families with disease, genetic markers from every chromosome are typed in both affected and unaffected members. Markers that are coinherited with disease indicate the chromosomal position of the genetic defect, and then genes at that position are sequenced to find the pathogenic mutation, which in turn indicates the causative gene.
Sequence motif: DNA sequences whose functions can be inferred because they are similar to sequences whose function has been biologically determined.
Structural genomic variation: Variation within the genome that results from deletion or duplication (both referred to as copy-number variation) or from inversion of genomic segments. Although common large variants (of more than one kilobase) exist, the majority of such variants are rare.
Transcriptome: A description of all DNA that is transcribed into RNA (messenger RNA, transfer RNA, microRNA, and other RNA species). The prevalence of a specific RNA sequence in a particular tissue may be proportionate to the relevance of that RNA species in the tissue.
1000 Genomes Project: A whole-genome resequencing of 1000 subjects from the original and extended HapMap populations, which was started in 2008, with funding from an international research consortium.