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Mapping - determining the location of elements within a genome, with respect to identifiable
landmarks.
Types of mapping…with tools/resources utilized
Genetic mapping – linear description of DNA markers/genes on a given chromosome
with closely placed markers being inherited together more often.
• linkage mapping
• pedigree
• polymorphic markers
Physical mapping – physical location on the chromosome, relating more
towards exact positioning of gene elements.
• cytogenetic mapping
• somatic cell mapping
• radiation hybrid mapping
• restriction mapping - PFGE, BAC contigs, sequencing
Comparative mapping
• gene sequences
• databases
• DNA chips
GENOME / GENETIC MAPS - Graphic representation of the relative positions
of genes on a DNA sequences.
CLASSICAL EXPERIMENT OF MAPPING
If two alleles are far apart on the chromosome, as it is more likely that a cross-
over will occur between them and they will be separated. Genes inherited in this
way are said to be linked, and are referred to as "linkage groups." For example, in
fruit flies the genes affecting eye color are inherited together because they
appear on the same chromosome
.
chromosome.
Sturtevant from the analyze of the fruitfly
genome found, for example, that leg length
was inherited with eye color more often than with wing
length, and that wing length was inherited with eye
color more often than with leg length. .
1. Experimental crosses
- Backcrosses
- F2 intercrosses
- Introgression lines
- Recombinant inbred (RI) lines
2. Pedigree analysis
3. Association studies (Linkage disequilibrium, LD mapping)
- With candidate genes (direct approach)
- Localized association studies (chromosomal region)
- Whole-genome association studies
CONSTRUCTING GENETIC LINKAGE MAPS
A.GENERATE MARKER DATA -
informative markers - polymorphic and a
population with known relationships
The basic idea in pedigree mapping is to follow affected individuals and markers in
related families. Markers that are co-inherited with disease status are linked to the
causative gene. Most useful pedigrees contain– nil parentage error, large population
study, subsequent follow-up progeny study.
• Two unrelated pedigrees
• Haplotypes in each pedigree
are identified by numbers
(different for each family),
and determined from five
linked markers
• Dark blue - affected
• White - unaffected
• Light blue - status uncertain
• In each case one haplotype, in
red, co-segregates with the
disease
The resolution of mapping using crosses or pedigrees depends on the amount of
recombination, which is determined mostly by the number of meioses. Since
mapping studies cannot be easily performed with very large numbers of
individuals or very many generations, their resolution is generally poor. They
provide a good way for localizing genes to genomic regions, but typically do not
provide sufficient resolution to locate the gene. They are also inefficient at
finding alleles of very weak effect or at low frequencies in populations
The goal of genetic mapping is to find the genes underlying traits of interest.
The basic idea in all mapping studies is to look for markers that are inherited
with the trait. Physical linkage will result in co-inheritance, while recombination
and independent assortment will disrupt these associations. In general, markers
that are co-inherited with a trait are more likely to be physically close to the genes
underlying the trait.
Traits can be simple (controlled by one or a few genes, with little environmental
influence; e.g. eye color in Drosophila, cystic fibrosis in humans) or complex
(controlled by many genes with many environmental influences; e.g. asthma,
heart disease).
Exploits the ability of rodent (hamster) cells to stably integrate genetic material from
other species.
Cells from the target genome are fused with hamster cells. The resulting cells are
then screened for cells (hybrids) that have retained one or more of the chromosomes
from the target genome.
Ideally, a complete set of hybrids can be constructed such that each has retained a
single chromosome from the target genome.
Using PCR and gene primers-DNA from the clones can be used to see if certain
genes are present in marked clones– leading to cytogenetic gene mapping.
DNA from cell lines used to form a panel and here no polymorphisms needed.
Finer mapping (higher resolution) can be obtained if hybrids are present in the panel
that contain partial chromosomes.
(E.g., translocations)
Somatic Cell Hybrid Mapping
Chromosome
1 2 3 4 5
Probe1 0 1 0 0 0
Probe2 0 0 1 1 0
Probe3 1 1 1 1 1
EcoRI
HindIII
PstII BamHI
HindIII BamHI PstII
Restriction Mapping
BglII BglII BamHI
BglII BamHI PstI +BamHI +PstI +PstI
5.2
4.2
3.6 3.5
3.3
2.6
1.7 1.7
1.4 1.4
1.2 1.2 1.2
1.0 0.9 1.0
0.7
0.5
0.3 0.3 0.3
One of the early goals of the Human Genome Project was to select and
map a set of STS markers such that there would be at least one STS in
each stretch of 100 kb of the genome.
Comparison of chromosomal, linkage, and physical maps on Chr 17.
The chromosomal and linkage maps extend over the entire chromosome
with lines connecting the relative positions of loci mapped in both. An
example of a long-range physical map for a 1,200 kb genomic interval is
shown along with a short-range physical map for the gene itself.
Comparative Mapping
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