Genome Mapping

“Gene mapping refers to the mapping of genes to

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.