Linkage and Genetic Maps

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Linkage and Genetic Maps
IGP Genetics and Development Lecture 3 Monday,
October 10, 2005 David Greenstein
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Linkage and Genetic Maps
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What is a dominant mutant allele?
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Mitochondrial Linkage
Mitochondria maternally inherited
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Linkage and Genetic Maps
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Why Map Genes?

• Information is gained regarding
• Chromosome organization
• Gene function
• Evolution
• Mapping a gene is often the first step in its
  identification
• Identify gene responsible for phenotype and
  then
• Identify mutation
• Study gene product - function?

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The Law of Independent Assortment
Gene pairs on different chromosomes assort
independently at meiosis
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Independent segregation of traits specified by
loci on separate chromosomes
a is recessive to A b is recessive to B
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Linkage

• Is the term indicating that two genes are not
  transmitted independently.
• Why?
• Two genes physically near each other on a
  chromosome will not assort randomly in meiosis.
• Linked genes are not always inherited together,
  recombination can occur between them

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What would you expect to happen if loci A and B
are located on homologous chromosomes?
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Linkage
What are the different gametic genotypes from a
parent heterozygous for two genes?

• Unlinked
• 4 type of gametes
• PL, Pl, pL, pl
• 25 of each

Very tightly linked 2 types of gametes PL and pl
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MESSAGE A recombinant frequency 50 generally
means that the genes are unlinked and on separate
chromosomes. A recombinant frequency
significantly lt 50 shows that genes are
linked.
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Crossing over between homologous chromosomes in
meiosis
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Homologous Recombination in Meiosis
Homologous chromosomes
genes
chromatids
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Constructing a Linkage Map
Frequency of recombination between loci on
non-sister chromatids is directly related to the
physical separation of the loci.
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Linkage map a way to construct accurate maps
over large distances

• A linkage map is a diagram indicating the
  relative distance between genes
• Map distances are additive

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Uses of Genetic Linkage Maps
Genetic Manipulation Strategies used to
construct multiply mutant strains depend on
knowledge of linkage Positional Cloning
Knowledge of the precise location of a gene on
the genetic map can lead to the physical
isolation of the the gene for molecular analysis
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Linkage map of Human Genetic Disease loci on
chomosome 7
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Linkage map of Drosophila melanogaster
4 chromosomes (X 3 autosomes)
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Genetic Marker Any genetically determined
phenotypic difference used in genetic
experiments. Particularly useful for constructing
linkage maps
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QUESTION How can chromosome 2 contain over 100
map units if randomly segregating genetic markers
produce exactly 50 recombinant phenotypes in a
test cross?
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Multiple cross over events between distant loci
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RF as a measure of genetic distance is accurate
only for closely linked genes.
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How to deal with the problem of multiple cross
over events?

• Measure map distances between closely linked
  markers (lt 10 cM apart)

If probability of single cross over between A and
B 0.1 Then, probability of double cross over
event 0.1 x 0.1 0.01

• Construct genetic map by summing map distances
  between closely spaced markers.

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Number of Mapped Human Genes
http//www.ncbi.nlm.nih.gov/genemap/page.cgi?FMap
Progress.html
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Haplotype
A haplotype is linked block of alleles inherited
on one chromosome. Alleles in a block tend to
stay together linkage disequilibrium
Each number represents a different allele for
genes A-E.
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Mapping with haplotypes
Gene A Gene B Gene C Gene D Gene E
Segregation of a dominant trait is observed in
this family (filled symbols).
The trait segregates with the orange haplotype.
So, we can conclude - C allele of disorder gene
is linked to this haplotype
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Mapping with Haplotypes
III-3 and III-6 inherit recombinant
chromosomes. The location of the
recombination events indicate that the gene for
this trait is located between genes B and D.
Recombinant chromosomes
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DNA Markers the modern alleles in a haplotype

• Genetic variation exists between individuals
• This variation can be within genes dif. alleles
• Individuals can also harbor differences in the
  sequences between genes.
• Any such difference can be exploited as a DNA
  marker, or DNA polymorphism
• These polymorphic markers are used to follow
  differences
• between individuals (to map genes)
• between populations (to study the diversity of
  the population)

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Molecular Marker Site of heterozygosity for DNA
variation. Typically does not show a visible
phenotype
RFLP Restriction digest, Blot (Restriction
Fragment Length Polymorphism) VNTR Restriction
digest, Blot, PCR (Variable Nucleotide Tandem
Repeat) SNP DNA sequencing, DNA chips (Single
Nucleotide Polymorphism)
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Restriction Fragment Length Polymorphism (RFLP)
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Locus A is linked to P
Phenotypes A is dominant to a (visible traits)
P1 and P2 RFLPs detected on blots
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SNPs - the loci of modern haplotypes
AGCCCGCAAATTTAGC TCGGGCGTTTAAATCG
AGCCCGCGAATTTAGC TCGGGCGCTTAAATCG

• Sites in the DNA sequence where individuals
  differ at a single DNA base are called single
  nucleotide polymorphisms (SNPs). Sets of linked
  SNPs on the same chromosome are inherited in
  blocks
• Small sets of linked SNPs form haplotypes.
• Comparing the DNA of chromosome 21 from 7
  different people (northern Europeans) revealed
  2,745 blocks of linked SNPs or haplotypes.

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DNA Analysis in Criminal Forensics
Additional reading for the interested Jobling
and Gill. 2004. Encoded evidence DNA in
forensic analysis Nature Revies of Genetics 5
739-752
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Ampliconic Regions
Large inverted repeats Exchange by gene conversion
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