specific locations on chromosomes, it is a critical step in the understanding of genetic diseases”
OR
“Gene mapping, also called genome mapping, is the
creation of a genetic map assigning DNA fragments to chromosomes"
When a genome is first investigated, this map is
nonexistent. The map improves with the scientific progress and is perfect when the genomic DNA sequencing of the species has been completed. During this process, and for the investigation of differences in strain, the fragments are identified by small tags. These may be genetic markers (PCR products) or the unique sequence-dependent pattern of DNA-cutting enzymes. The ordering is derived from genetic observations (recombinant frequency) for these markers or in the second case from a computational integration of the fingerprinting data.
There are two types of gene mapping:
1. Genetic Mapping or Genetic-linkage mapping:
Using linkage analysis to determine the relative position between two genes on a chromosome. Genetic mapping uses classical genetic techniques (e.g. pedigree analysis or breeding experiments) to determine sequence features within a genome. 2. Physical Mapping: Using all available techniques or information to determine the absolute position of a gene on a chromosome.
Using modem molecular biology techniques for the same
purpose is usually referred to as physical mapping.
The ultimate goal of gene mapping is to clone genes,
especially disease genes. Once a gene is cloned, we can determine its DNA sequence and study its protein product. For example, cystic fibrosis (CF) is the most common lethal inherited disease in the United States. As many as 1 in 2500 Americans of Northern European descent carry a gene with CF. In 1985, the gene was mapped to chromosome 7q31-q32 by linkage analysis. Four years later, it was cloned by Francis Collins and his co-workers. We now know that the disease is caused by the defect of a chloride channel - the protein product of this disease gene.
Physical mapping:
In physical mapping, the DNA is cut by a
restriction enzyme. Once cut, the DNA fragments are separated by electrophoresis. The resulting pattern of DNA migration (i.e. its genetic fingerprints) is used to identify when stretch of DNA is in the clone. By analyzing the fingerprint, contigs are assembled by automated (FPC) or manual mean (pathfinders) into overlapping DNA stretches. Now a good choice of clone can be made of efficiently sequence the clones to determine the DNA sequence of the organism under study (seed picking).
Macro-restriction is a type of physical mapping
wherein the high molecular weight DNA is digested with a restriction enzyme having a low number of restriction sites.
There are alternative ways to determine how
DNA in a group of clones overlaps without completely sequencing the clones. Once the map is determined, the clones can be used as a resource to efficiently contain large stretches of the genome. This type of mapping is more accurate than genetic maps.
Genes can be mapped prior to the complete
sequencing by independent approaches like in situ hybridization
Disease-association:
“The process to identify a genetic element that a sign
responsible for a disease is also referred to as mapping” If the locus in which the search is performed is already considerably constrained, the search is called the "fine-mapping" of a gene. This information is derived from the investigation of disease-manifestations in large families (Genetic linkage) or from populations-based genetic association studies.
The central idea of gene mapping, as first
developed by Sturtevant, is that the frequency of recombination between two genes can be used as a measure of the actual distance between them on a chromosome. 2
Linkage analysis:
The genetic mapping is based on the linkage
between “loci” (location of the gene). If two loci are usually inherited together, they are said to be “linked”. Two loci on different chromosomes are not linked, because they are usually separated by independent assortment.
A locus (singular of loci) may have different
sequence, referred to as alleles (one from mother, another from father). A1 and A2 are alleles A; B1 and B2 are two alleles of locus B. initially, A1 and B1 are located on the same chromosome. A2 and B2 are located on a different chromosome. (a) Two pairs of sister chromatids align during meiosis. A1 and B1 are located on the same chromosome. A2 and B2 are located on a different chromosome.
(b) DNA crossover leads to recombination if the chiasma
is located between the two loci.
(c) DNA crossover does not lead to recombination if the
chiasma is not located between the two loci.
The DNA crossover may cause recombination of
loci A and B. Namely, A1 and B2 (or A2 and B2) are located on the same chromosome. The recombination frequency depends on the distance between the two loci and the position of crossover (the chiasma). The closer they are, the less likely the recombination will occur, because recombination occurs only when the chiasma is located between the two loci. To apply this basic principle to map a disease gene, we need to analyze the pedigree and estimate recombination frequency.