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Human Genetics
Linkage
Linkage
The observation that
two genes are not
transmitted
independently.
Why?
Two genes
physically near each
other on a
chromosome will not
assort randomly in
meiosis.
Linkage
Tightly linked:
- two types of gametes
- in this case - PL and pl
Unlinked:
- 4 type of gametes
- PL, Pl, pL, pl
NOTE: The alleles observed to be linked (PL and
pl or Pl and pL) depends on which alleles are on
the same chromosome in the parent!
Recombination
When chromosomes
recombine new
combinations of alleles
are created.
Parental chromosomes
have the alleles present
in the original
configuration.
Recombinant
chromosomes have new
combinations of alleles.
Recombination
The frequency of recombination between two genes
is proportional to the distance between the genes.
Linkage Map
A linkage map is a diagram indicating the
relative distance between genes.
1% recombination = 1 map unit = 1
centiMorgan (cM)
Map distances are additive.
% recombination
between genes
X and Y
10
X and Z
4
Y and Z
6
Z
X
4 cM
Y
6 cM
10 cM
Inheritance of Linked Genes
 The genes for Rh factor (R) and anemia (E) are linked, but
some recombination occurs between the two genes.
 Parent 2 (mother) produces 4% recombinant gametes, therefore
the Rh factor gene and the anemia gene are 4 map units or 4 cM
apart.
Linkage Disequilibrium
The non-random association between alleles at two
locations on a chromosome is called linkage
disequilibrium.
Two genes, A and B, exist in a population.
 If the frequency of chromosomes with AB=Ab=aB=ab then
the genes are in equilibrium.
 If the frequency of one allele of gene A is seen more
frequently with a particular allele of gene B, then the genes
are in linkage disequilibrium.
LOD score
LOD is a statistical test for Linkage
It is the logarithm of the odds ratio
It is a statistical measure of likelihood
that two genes are linked at a particular
distance.
LOD scores of 3 or greater are
considered significant and indicate the
data would be observed by chance 1 in
1000 times.
LOD Calculation
NR=number of non-recombinant offspring
R=number of recombinant offspring.
0.5 is used in the denominator because any
alleles that are completely unlinked (e.g. alleles
on separate chromosomes) have a 50%
chance of recombination, due to independent
assortment.
Haplotype
A haplotype is the set
of alleles inherited
on one chromosome.
Each number indicates the
allele present for one of 5
genes A-E.
Maternal haplotype
Paternal haplotype
Gene A
Gene B
Gene C
Gene D
Gene E
11
11
11
11
11
22
22
22
22
22
12
12
12
12
12
Mapping with
haplotypes
Gene A
Gene B
Gene C
Gene D
Gene E
11
11
11
11
11
Segregation of a dominant
trait is observed in this family
(filled symbols).
22
22
22
22
22
12
12
12
12
12
33
33
33
33
33
44
44
44
44
44
34
34
34
34
34
The trait segregates with
the red haplotype.
14
14
14
14
14
23
23
23
23
23
14
14
14
13
13
13
13
13
13
13
14
14
14
14
14
23
23
24
24
24
23
23
23
23
23
Mapping with
haplotypes
Gene A
Gene B
Gene C
Gene D
Gene E
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.
11
11
11
11
11
22
22
22
22
22
12
12
12
12
12
14
14
14
14
14
23
23
23
23
23
14
14
14
13
13
33
33
33
33
33
44
44
44
44
44
34
34
34
34
34
13
13
13
13
13
14
14
14
14
14
23
23
24
24
24
23
23
23
23
23
Origins of Haplotypes
 This diagram shows two ancestral
chromosomes being scrambled
through recombination over many
generations to yield different
descendant chromosomes.
 If a genetic variant marked by the A
on the ancestral chromosome
increases the risk of a particular
disease, the two individuals in the
current generation who inherit that
part of the ancestral chromosome
will be at increased risk.
 Adjacent to the variant marked by
the A are many SNPs that can be
used to identify the location of the
variant.
HapMap
HapMap Construction
The construction of the HapMap occurs in three
steps.
Single nucleotide polymorphisms(SNPs) are
identified in DNA samples from multiple
indivduals.
Adjacent SNPs that are inherited together are
compiled into "haplotypes."
"Tag" SNPs within haplotypes are identified that
uniquely identify those haplotypes. By
genotyping the three tag SNPs shown in this
figure, researchers can identify which of the
four haplotypes shown here are present in each
individual.
HapMap Web Page
http://www.genome.gov/page.cfm?pageI
D=10001688