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Genomic Glossary

biological atlas: Maps describing different aspects of protein function should be compiled into a "biological atlas" By integrating the information contained in the atlas, increasingly meaningful biological hypotheses could be formulated.

cDNA maps: Shows the locations of expressed DNA regions (exons) on the chromosomal map. Because they represent expressed genomic regions, cDNAs are thought to identify the parts of the genome with the most biological and medical significance. A cDNA map can provide the chromosomal location for genes whose functions are currently unknown. For disease- gene hunters, the map can also suggest a set of candidate genes to test when the approximate location of a disease gene has been mapped by genetic linkage techniques.

cell mapping: The determination of the subcellular location of proteins and of protein- protein interactions by the purification of organelles or protein complexes followed by mass- spectrometric identification of the components. Most proteins are thought to exist in the cell not as free entities but as part of ?cellular machines' which perform cellular functions cooperatively. Systematic identification of protein complexes would permit these machines to be defined and allow ?physical maps' to be created for a variety of cell types and states. Such information is of great value for the assignment of protein function.

cell maps: A cell map specifies the proteins that constitute a given organelle within a given cell type. Cell maps for normal and diseased cells can be constructed which give insight into the role proteins have in disease and can guide the drug development process.

chromosomal maps: Genes or other identifiable DNA fragments are assigned to their respective chromosomes, with distances measured in base pairs. These markers can be physically associated with particular bands (identified by cytogenetic staining) primarily by in situ hybridization, a technique that involves tagging the DNA marker with an observable label (e.g., one that fluoresces or is radioactive). The location of the labeled probe can be detected after it binds to its complementary DNA [cDNA] strand in an intact chromosome.

chromosome mapping: Any method used for determining the location of and relative distances between genes on a chromosome.

clone-based maps: The physical map of the human genome published by Nature is a clone- based physical map of 3.2 gigabases (25 times larger than any previously mapped genome). This approach involved generating an overlapping series of clones for the whole genome. With a fingerprinted BAC map clones could be selected for sequencing ensuring comprehensive coverage of the genome.

comparative genome mapping: Comparative genome mapping in the sequence-based era: early experience with human chromosome 7

contig mapping : Overlapping of cloned or sequenced DNA to construct a continuous region of a gene, chromosome or genome.

contig maps : Contig maps are important because they provide the ability to study a complete, and often large segment of the genome by examining a series of overlapping clones which then provide an unbroken succession of information about that region.

The bottom- up approach involves cutting the chromosome into small pieces, each of which is cloned and ordered. The ordered fragments form contiguous DNA blocks (contigs). Currently, the resulting library of clones varies in size from 10,000 bp to 1 Mb. An advantage of this approach is the accessibility of these stable clones to other researchers Contig construction can be verified by FISH [fluorescence in situ hybridization], which localizes cosmids to specific regions within chromosomal bands. Consist of a linked library of small overlapping clones representing a complete chromosomal segment. While useful for finding genes localized to a small area (under 2 Mb), contig maps are difficult to extend over large stretches of a chromosome because all regions are not clonable. DNA probe techniques can be used to fill in the gaps, but they are time consuming.

cosmid maps: "Constructing chromosome- and region-specific cosmid maps of the human genome"

cytogenetic maps: The visual appearance of a chromosome when stained and examined under a microscope. Particularly important are visually distinct regions, called light and dark bands, which give each of the chromosomes a unique appearance. This feature allows a person's chromosomes to be studied in a clinical test known as a karyotype, which allows scientists to look for chromosomal alterations.

epitope mapping : Methods used for studying the interactions of antibodies with specific regions of protein antigens. Important applications of epitope mapping are found within the area of immunochemistry.

evolutionary genetics: Evolutionary study of genes has been purely theoretical, but it can provide useful information for guiding gene mapping. People are now finding, for example, that a lot of things are not true associations; instead, they are an artifact of association. You can make such mistakes when you are looking at two individuals who share a common ancestry. Understanding the phylogeny helps us, for example, understand horizontal gene transfer between microorganisms. For humans or other sexually reproducing organisms, the use of phylogenetic information improves resolution for making associations by helping to avoid type I errors - that is, finding an association that is actually merely due to sharing a recent common ancestor, or, in other words, being closely related.

expression imbalance map EIM : A new visualization method, for detecting mRNA expression imbalance regions, reflecting genomic losses and gains at a much higher resolution than conventional technologies such as comparative genomic hybridization (CGH). Simple spatial mapping of the microarray expression profiles on chromosomal location provides little information about genomic structure, because mRNA expression levels do not completely reflect genomic copy number and some microarray probes would be of low quality. The EIM, which does not employ arbitrary selection of thresholds in conjunction with hypergeometric distribution- based algorithm, has a high tolerance of these complex factors.

expression mapping: The creation of quantitative maps of protein expression from cell or tissue extracts, akin to the EST maps commercially available. This approach relies on 2D gel maps and image analysis, and opens up the possibility of studying cellular pathways and their perturbation by disease, drug action or other biological stimuli at the whole- proteome level ? Expression mapping is a valuable tool in the discovery of disease markers and its use in gaining information in toxicological and drug- action studies seems assured. It is unclear at present how successful this approach will be in elucidating cellular pathways and their importance in disease processes, and how much the precise measurement of protein levels matters when compared with the rough guide provided by the measurement of mRNA levels ? the ability to measure protein- level changes directly would seem to carry inherent advantages and it seems likely that expression proteomics will be a useful tool in drug target discovery and in studying the effects of various biological stimuli on the cell.

functional maps: In addition to the raw data, it will be important to design the proper visualization tools to graphically represent the functional relationships contained in different maps ... Finally, it will be important to consider the possibility that functional maps need to be related back to particular tissues or even cell types.

gene mapping: Determination of the relative positions of genes on a DNA molecule (chromosome or plasmid) and of the distance, in linkage units or physical units, between them. [DOE]

genetic linkage map: Shows the relative locations of specific DNA markers along the chromosome. Any inherited physical or molecular characteristic that differs among individuals and is easily detectable in the laboratory is a potential genetic marker. [Primer on Molecular Genetics, Oak Ridge National Lab, US] Related term linkage maps.

genetic maps: Also known as a linkage map. A chromosome map of a species that shows the position of its known genes and/ or markers relative to each other, rather than as specific physical points on each chromosome.

The value of the genetic map is that an inherited disease can be located on the map by following the inheritance of a DNA marker present in affected individuals (but absent in unaffected individuals), even though the molecular basis of the disease may not yet be understood nor the responsible gene identified. Genetic maps have been used to find the exact chromosomal location of several important disease genes, including cystic fibrosis, sickle cell disease, Tay- Sachs disease, fragile X syndrome, and myotonic dystrophy. [Primer on Molecular Genetics, Oak Ridge National Lab, US]

genome control maps: Would identify all the components of the transcriptional machinery that have roles at any particular promoter and the contribution that specific components make to coordinate regulation of genes. The map will facilitate modeling of the molecular mechanisms that regulate gene expression and implicate components of the transcription apparatus in functional interactions with gene-specific regulators.

genome fingerprint map: The collection of all fingerprint clone contigs placed in a genome- wide map.

genome map: A reconstruction of the entire set of chromosomes for a given organism, showing the relative position of every gene.

genome scale metabolic maps: Annotated genomic data, along with legacy data on the cell's biochemistry and physiology, can be used to construct genome- scale metabolic maps. The challenge now is to formulate reliable mathematical descriptions of the integrated function of these maps. It has proven difficult, if not impossible, to formulate detailed theory-based models of these genome-scale maps. An alternative approach that is data driven and constraints based will be described. It is an iterative model-building process.

genomic cartography: [Fry's] research focuses on methods of visualizing large amounts of data from dynamic information sources. The work uses ideas from distributed and adaptive systems to form organic representations that react and respond to the input data. This work is currently directed towards Genomic Cartography which is a study into new methods to represent the data found in the human genome.

genomic mapping: While a few technologies for functional analysis on a genomic basis are being developed at present, additional approaches and technologies for genomic interpretation that can be applied efficiently and economically at the level of an entire genome will be required for comprehensive analyses. Informatics will continue to play an important role in achieving all of these goals, as well as in ensuring the maintenance and accessibility of the forthcoming data. The development and application of new technologies for acquisition, management, analysis, and dissemination of genomic data are still required.

haplotype map: Francis Collins, director of the NHGRI, speaking at BIO 2001 (San Diego CA, US, June 2001) announced plans for a public- private effort to create a human haplotype map. Creators hope this so- called haplotype map will be a tool for pinning down the genes that contribute to the development of complex diseases such as cancer, diabetes, and mental illness.

haplotype mapping: Is often carried out as part of a genome scan. In a population isolate, the appearance of a rare Mendelian disease is almost always attributable to a single founder gene or mutation. The disease allele can be identified by searching for a common haplotype signature shared among patients. As the ancestral haplotype signature is passed from generation to generation, it is disrupted by recombination. Partial conservation of the haplotype signature in a patient strongly suggests that the disease locus resides in the conserved region of the haplotype.

high-resolution genetic maps: 2-5 cM [centiMorgans]. Genetic mapping resolution has been increased through the application of recombinant DNA technology, including in vitro radiation- induced chromosome fragmentation and cell fusions (joining human cells with those of other species to form hybrid cells) to create panels of cells with specific and varied human chromosomal components.

high- resolution physical mapping: The two current approaches are termed top- down (producing a macrorestriction map) and bottom- up (resulting in a contig map). With either strategy the maps represent ordered sets of DNA fragments that are generated by cutting genomic DNA with restriction enzymes. The fragments are then amplified by cloning or by polymerase chain reaction (PCR) methods. Electrophoretic techniques are used to separate the fragments according to size into different bands, which can be visualized by direct DNA staining or by hybridization with DNA probes of interest. The use of purified chromosomes separated either by flow sorting from human cell lines or in hybrid cell lines allows a single chromosome to be mapped.

homology map: The Davis Human/ Mouse Homology Map, a table comparing genes in homologous segments of DNA from human and mouse sources, sorted by position in each genome. A total of 1793 loci are presented, most of which are genes. The authors did not include pseudogenes, members of multigene families where specific homology relationships could not be determined, nor any other genes for which homology was in doubt. In addition, for 568 of the loci there are provisional assignments of markers that link the homology map with that of the Gene Map of the Human Genome. . These links also provide a rough approximation of the position of markers in the Genethon linkage map. In constructing this table, the authors first ordered genes so as to best maintain order according to both human cytogenetic position and mouse genetic map position. Within these homologous regions, genes were ordered according to the mouse genetic mapping data.

International SNP Map Working Group: Identifies and localizes 1.42 millions SNPs in the human genome. ["A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms" International SNP Map Working Group Nature 409: 928- 933, 15 Feb. 2001]

linkage disequilibrium: Evidence for linkage disequilibrium can be helpful in mapping disease genes since it suggests that the two [alleles] may be very close to one another

linkage maps: A map of the relative positions of genetic loci on a chromosome, determined on the basis of how often the loci are inherited together. Distance is measured in centimorgans (cM).

localizome mapping: One can imagine comprehensive mapping projects of the "localizome", with the goal of recording not only where all proteins of a proteome can be found but also when.

locus: Any genomic site, whether functional or not, that can be mapped through formal genetic analysis.

macrorestriction map: Describes the order and distance between enzyme cutting (cleavage) sites ... In top- down mapping, a single chromosome is cut (with rare- cutter restriction enzymes) into large pieces, which are ordered and subdivided; the smaller pieces are then mapped further. The resulting macro- restriction maps depict the order of and distance between sites at which rare- cutter enzymes cleave. This approach yields maps with more continuity and fewer gaps between fragments than contig maps, but map resolution is lower and may not be useful in finding particular genes; in addition, this strategy generally does not produce long stretches of mapped sites. Currently, this approach allows DNA pieces to be located in regions measuring about 100,000 bp to 1 Mb.

mapping: The determination of the relative positions of genes within the chromosomes or of restriction sites along a DNA molecule.The process of determining the position of a locus on the chromosome relative to other loci.

nucleotide mapping: Two- dimensional separation and analysis of nucleotides.

optical mapping: An enabling technology for whole genome analysis which involves the capture of individual DNA molecules, obtained directly from genomic DNA, followed by digestion in situ by selected restriction endonucleases. The resulting fragments are then visualized directly to produce detailed optical restriction maps. This methodology allows patterns of sequence variation to be detected across entire genomes, without the need for DNA amplification, and, unlike other genomewide scanning methods, provides detailed haplotype information by analyzing individual DNA molecules. OpGen will provide optical mapping services to three main markets ? i.e., genome sequencing projects, cancer diagnostics, and genetic association studies.

peptide mapping: Two- dimensional separation and analysis of peptides.The characteristic pattern of fragments formed by the separation of a mixture of peptides resulting from hydrolysis of a protein or peptide.

peptide maps: One way to research the structure of a protein is to seek to identify the specific sequence of amino acids which form the protein. Tr. at 202-3. An initial approach is to cut the protein into fragments, called peptides, using enzymes or chemicals which reliably divide the chain at predictable points. Tr. at 523. These fragments can be isolated and analyzed to create "peptide maps," which show the pattern of pieces from these breaks as a unique "fingerprint." ... A peptide map does not disclose the precise order of the amino acids in a protein, although it may point to areas of difference between similar proteins.

phenome mapping: The conceptual matrix for a comprehensive "phenome" mapping project would be as follows: one axis represents all available knockouts while the other represents a large series of standardized phenotypes that can be screened.

phenome maps: Can be thought of as lists of similar phenotypes that could be referred to as "pheno- clusters".

physical mapping: The procedure of physical mapping coarsely divides into two steps First large pieces of DNA (contigs), a library of cloned fragments are ordered according to their position in the genome. Different experimental techniques are used to do that. Roughly, these are clone- probe hybridization mapping, restriction mapping, radiation- hybrid mapping and optical mapping. ... Second the cloned fragments are cut by restriction enzymes, smaller DNA fragments are obtained which are sequenced in detail (shotgun- sequencing), and the overall sequence in detail is obtained by Sequence Assembly.

physical maps: A map of the locations of identifiable landmarks on DNA (e.g. restriction enzyme cutting sites, genes) regardless of inheritance. Distance is measured in base pairs. For the human genome, the lowest- resolution physical map is the banding patterns on the 24 different chromosomes; the highest resolution map would be the complete nucleotide sequence of the chromosomes.

A chromosome map of a species that shows the specific physical locations of its genes and/ or markers on each chromosome. Physical maps are particularly important when searching for disease genes by positional cloning strategies and for DNA sequencing.

positional cloning: Requires a genetic map with a large number of markers (especially in the region of interest), and the use of physical mapping and DNA sequencing technologies to isolate and sequence the targeted gene.

protein expression map: Since 2D Electrophoresis gel patterns reveal not only the amounts of protein, but is unrivaled in its ability to detect post- translational modifications, the 2DE protein map provides much more relevant information about cellular dynamics than the corresponding expression map at the mRNA level. By comparing the 2DE gel patterns of samples exposed to different physiological conditions or different drug treatments it is possible to identify groups of proteins with related functions or whose expression is interdependent (expression proteomics).

Protein Expression Mapping PEM: Details the distribution and abundance of protein in specific samples, under defined physiological conditions. [CHI Proteomics] Quantitative study of global changes in protein expression in tissues, cells or body fluids using 2D gels and image analysis. Currently carried out by 2D gel electrophoresis, though alternatives are under investigation.

protein interaction maps: Hybrigenics" comprehensive protein interaction maps using automated yeast- two- hybrid methodology in pathogens and in cDNA of normal and diseased tissues.

protein linkage maps: With respect to a genome- wide use of the two- hybrid assay in the case of yeast, the goal is to find which proteins in the yeast genome interact with every other protein. This process would generate protein linkage maps, delineating large networks of interacting proteins. The approximately 6,000 yeast proteins can potentially interact in 18 million pairwise combinations.

proteome map: A number of organizations have announced plans to produce a map of the proteome, including Myriad Genetics, Large Scale Biology, CuraGen and others.

QTL mapping Quantitative Trait Loci mapping: A phenotype driven approach to gene function. As such it permits the discovery of new genes and can be contrasted with gene- driven approaches such knock-out and knock-in mice which allow for the study of known genes. QTL reflect natural genetic variations as they exist in the mouse strains under study. We are limited to detecting those genes that vary among the available strains. However the natural variations among mouse strains are vast and largely untapped.

RFLP (Restriction Fragment Length Polymorphism): See Genetic variations glossary Polymorphic sequences that result in RFLPs are used as markers on both physical maps and genetic linkage maps. RFLPs are usually caused by mutation at a cutting site.

Radiation Hybrid RH maps: Chromosome maps that are calculated from RH score vectors. An RH score vector is the pattern of assay results of a particular STS (marker) on a particular panel. The vector consists of 1's (did amplify) and 0's (did not amplify). Simplistically speaking, the more similar two score vectors are, the closer the markers are on the chromosome.

radiation hybrid mapping: A method for ordering genetic loci along CHROMOSOMES. The method involves fusing irradiated donor cells with host cells from another species. Following cell fusion, fragments of DNA from the irradiated cells become integrated into the chromosomes of the host cells. Molecular probing of DNA obtained from the fused cells is used to determine if two or more genetic loci are located within the same fragment of donor cell DNA.

restriction map: A description of restriction endonuclease cleavage sites within a piece of DNA. Generating such a map is usually the first step in characterizing an unknown DNA, and a prerequisite to manipulating it for other purposes. Typically, restriction enzymes that cleave DNA infrequently (e.g. those with 6 bp recognition sites) and are relatively inexpensive are used to produce at a map.

restriction mapping: Use of restriction endonucleases to analyze and generate a physical map of genomes, genes, or other segments of DNA.

SNP maps: A collection of SNPs that can be superimposed over the existing genome map, creating greater detail and facilitating further genetic studies.

Current estimates indicate that a very dense marker map (30,000 - 1,000,000 variants) would be required to perform haplotype - based association studies. We have constructed a SNP map of the human genome with sufficient density to study human haplotype structure, enabling future study of human medical and population genetics.

telomere maps: Telomeres are the tips of the chromosomes. They are crucial in maintaining the chromosomes' stability and are important in the cell cycle and ageing. Because of the way the physical maps are constructed, many telomeres of chromosomes are left out.

transcript maps: In only a year or two, most human genes will be sequence- tagged and placed on various physical maps. Such a ?transcript map' (or ?expression map') of the genome will be an important part of the sequencing infrastructure, as well as a critical resource for the positional candidate approach to gene cloning. One of the specific goals of the US Human Genome Project is the construction of a high resolution STS map of the genome. .. One of the early problems with gene- based STSs was that there simply were not enough unique human gene sequences to bother with. But all of that changed with the advent of EST sequencing, at which time several groups began mapping ESTs albeit on a limited scale and only to the resolution of a chromosome assignment.

transcriptome maps: Consist of "expression clusters" of co-regulated genes. Challenges ahead for computational biology include the integration of clusters obtained for the transcriptome, the interactome, the phenome, and the localizome.

whole genome clone- based maps: In their paper, the International Human Genome Mapping Consortium describe how they constructed the first whole- genome physical map, how they created the templates from which the genome was sequenced and demonstrated how the map was essential for the accurate assembly of the human genome by the publicly funded effort. Four short reports accompanying the whole- genome mapping paper (Bruls; Bentley; Kucherlaparti; Page), describe alternative mapping strategies that were implemented for chromosomes 12, 14 and Y, as well as a host of other chromosomes. Information from all these papers were integrated into the whole- genome paper and demonstrate how a rich resource of mapping information can be generated by the cooperation of international independent efforts.

YAC maps: Yeast artificial chromosome maps, a type of physical map.