Homologous chromosomes the one you received from

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Homologous chromosomes (the one you received
from mother-- -- and the partner that you
received from father-- ) join.
They exchange genetic material.
The resulting chromosome passed to the offspring
contains some of the paternal and some of the
maternal chromosome.
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The further away two loci are, the more likely
the chromosomes will pair up somewhere between
the two loci and the less likely the two will
be transmitted together.
The closer together two loci are, the less
likely the chromosomes will pair up somewhere
between the two loci and the more likely the
two will be transmitted together.
The probability of a recombination is very low
for loci D and E. It is very high for loci A and
G.
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Key Idea
Cosegregation of a trait (disorder) with marker
gene(s) within families.
Common sense explanation

• Affected offspring within a family will tend to
  have the same genotype(s) on the marker.
• 2) Unaffected offspring within a family will tend
  to have the same genotype(s) on the marker.
• 3) Affected offspring will have different
  genotypes than unaffected offspring on the marker.

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Fathers chromosomes are
aa
Aa
Aa
Aa
aa
Aa
Aa
aa
aa
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(To calculate gametes under linkage, see the
handoutCalculating Gametes under Linkage on the
handouts section of the course web page.)
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Problem The gene for a dominant disorder has two
alleles, D which causes the disorder, and d which
is the normal allele. This gene is located close
to a marker gene with two alleles, A and a. Give
the probabilities for the genotypes and
phenotypes of the following mating
A fathers who is
and a mother who is
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Fathers Gametes
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Mother can only give gamete ad with probability
1.0
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Fathers Gametes
aD
Ad
AD
ad
.5(1 - ?)
.5(1 - ?)
.5?
.5?
M o t h e r s
G a m e t e
AD
ad
Ad
aD
ad
ad
ad
ad
ad
1.0
.5(1 - ?)
.5?
.5(1 - ?)
.5?
normal
normal
disorder
disorder
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Offspring Phenotypes and Probabilities
Marker Phenotype
Disorder Phenotype
Probability
Aa
.5(1 - ?)
normal
Aa
affected
.5?
aa
.5?
normal
aa
.5(1 - ?)
affected
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Summary of empirical results oflinkage analysis

• Very successful for single gene disorders.
• Successful for Mendelian forms for DCGs.
• Not very successful for risk genes for DCGs and
  behavioral phenotypes.

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Haplotypes
Haplotype Series of alleles along a very short
section of the same chromosome.
Examples
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Haplotypes
Linkage Disequilibrium Some haplotypes occur
more frequently than expected by chance.
Example
Assume two linked loci, the first with alleles A
and a and the second with alleles B and b. Assume
that the frequency of allele A is .70 and the
frequency of allele B is .40. If the two loci are
in linkage equilibrium, then the frequency of the
haplotypes can be predicted using simple
probability theory.
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Haplotypes
Haplotypes expected by chance
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Haplotypes
Test for Linkage Disequilibrium Compare
observed frequencies with those expected by
chance.
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Haplotype Map Project (HapMap) international
collaborative effort to identify regions
throughout the human genome in linkage
disequilibrium.

• Linkage disequilibrium is a rule rather than an
  exception.
• Are recombination hot spots (thus, little
  linkage disequilibrium.
• If there are, say, 5 genes in a haplotype group
  in strong linkage disequilibrium, then only test
  1 gene.

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DNA region of interest

• Instead of genotyping all 37 SNPs in the region,
  genotype one SNP from each of the 7 haplotype
  blocks.
• If there is a hit for one block, then genotype
  the SNPs within the block to get closer to the
  disease gene.

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