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Human Genetics: concepts and applications
6th edition
Ricki Lewis
Chapter 5
Extensions and Exceptions
to Mendel’s Laws
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Alkaptonuria (OMIM 203500)
• Back spasms, spine
degeneration, cartilage
loss, dark stained diapers,
inborn error of metabolism,
pleiotrophic, deficiency of
enzyme homogentistic acid
oxidase
• Blackened nails are just
one sign of alkaptonuria,
an inborn error of
metabolism.
• It is pleiotropic.
• Deficiency of the enzyme
homogentisic acid oxidase
leads to buildup of melanin
pigment in urine, nails, skin
and cartilage.
5-2
Ch 5
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Phenylketonuria PKU (OMIM 261600)
• Autosomal
recessive
• Unable to
breakdown
phenyalanine
• Mental
retardation
• Fair skin
• Test at birth
• Special diet
5-3
Ch 5
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Porphyria variegata (OMIM 176200)
•
•
•
•
May be accompanied by skin
Disorders
•
•
5-4
Autosomal dominant
Red urine, fever, abdominal
pain, headache, insomnia,
visual delirium, convulsions,
coma, death
Variegate porphyria (VP) is an
inherited disorder of
porphyrin-heme metabolism
arising from mutations of the
gene encoding the enzyme
protoporphyrinogen oxidase.
Manifestations of VP in any
given individual may include
cutaneous photosensitivity,
systemic symptoms arising
from neurologic dysfunction,
or both.
Pleiotropic
Inborn error of metabolism
Ch 5
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Marfan Syndrome (OMIM 154700)
•
•
•
•
•
•
•
•
5-5
Autosomal dominant
Flo Hyman was a 6’5” star on
the U.S. women’s volleyball
team that won a silver medal
in the 1984 Olympics. Two
years later, at the age of 31,
she died in a volley ball game
from a ruptured aorta caused
by Marfan Syndrome.
The gene responsible for
Marfan Syndrome is located on
chromosome 15.
The normal gene codes for
fibrilin, which is part of
connective tissue.
1 in 10,000 individuals
It has been suggested that
Abraham Lincoln had Marfan.
Long limbs, sucken chest, lens
dislocation, spindly fingers,
weakened aorta
pleiotropy
Ch 4
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Leber Optic atrophy (OMIM 535000)
• Energy related genes can
cause fatigue
• Mitochondrial disorder
• A painless loss of central
vision between 12 and 30
years of age. Both eyes are
affected at the same time.
Males will not pass the
gene to any of their
children, but females with
the mutation will pass it to
all of their children,
regardless of whether they
are sons or daughters.
5-6
Ch 5
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MELHS Mitochondrial myopathy (OMIM
540000)
Avi Wolfson
Avi's medical problems began, we think,
when he was about a year old, although
he was not diagnosed with a
mitochondrial myopathy until 1993 when
he was four. Avi is now 12 years old and
actually we never thought we would come
to realize this age. His journey through
life so far has been splattered with
hospitalizations and setbacks, some
major and some minor.
5-7
• Encephalopathy lactic
acidosis syndrome
• Neuromuscular disorders
that all result in a decrease
in energy production in the
body’s tissues.
• Short statue
• Seizures
• Stroke-like episodes with
focused neurological
deficits
• Recurrent headaches
• Cognitive regression
• Disease progression
• Ragged-red fibers
Ch 5
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Enamel hypoplasia (OMIM 600907)
• Holes and cracks
in baby teath
• Autosomal
dominant
• Incomplete
penetrance and
variable
expressivity
5-8
Ch 5
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Epidermolysis bullosa (OMIM 226500,
226650, 131750)
• Intermediate filaments are
abnormal
• Epidermolysis Bullosa (EB)
is a rare genetic disease
characterized by extremely
fragile skin and recurrent
blister formation.
• An afflicted person's skin is
so fragile, that it can tear or
blister from what is
normally routine activity or
contacts.
• Approximately 2 out of
100000 Americans are
afflicted with this disease.
• This disease in typically
inherited as autosomal
dominant.
5-9
Ch 5
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Exceptions to Mendel’s Law
Mendel chose traits in peas that showed
two distinct forms.
Not all genes exhibit such simple inheritance.
•
•
•
•
5-10
Alleles interact
Genes interact
Non-nuclear genes
Segregation of genes on same chromosome
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Lethal alleles
Some allele combinations are lethal.
• Early acting lethal alleles are responsible for
spontaneous abortions in humans.
Mexican hairless dogs result from a mutation in a
gene that shows lethality
• hh
hairy
• Hh
hairless
the wildtype trait
one mutation present
creates a visible phenotype
• HH dies
two mutation are lethal
Some combinations of alleles cause problems so severe
That the fetus ceases to develop. Such lethal allele
Combinations appear to alter Mendelian ratios because
5-11
Homozygotes do not appear as a progeny class.
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This Mexican hairless dog has inherited a dominant allele that
makes it hairless. Inheriting two such dominant alleles is
lethal during embryonic development.
5-12
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Lethal alleles
The probability that a
pregancy will
spontaneously abort
if the mother and
father both carry a
recessive lethal
allele for the same
gene is 25%
Breeders cross Mexican hairless dogs to hairy (powderpuff)
Dogs to avoid dead embryos and stillbirths that represent
The HH genotypic class
5-13
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Hairless trait in dogs is a dominant allele. Inheriting one dominant allele
results in a hairless dog. Inheriting two dominant alleles is lethal to the
embryo.
In a cross between two hairless dogs, the probability
that a puppy will be born with a dominant allele is 25%
In a cross between a hairless and a hair dog, the chace that an
Embryo will receive a dominant allele is 50%.
Hairless, hairy and lethal
represent phenotypes.
In a cross between two hairless
dogs, the probability that a hairy
puppy will be born is 1/3.
You can not create a pure
Breeding line of hairless dogs.
5-14
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Multiple Alleles
• A gene may exist in more than two
allelic forms in a population.
• Genes can mutate in many ways at any
nucleotide in their DNA sequence.
5-15
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Multiple alleles: coat color in rabbits
Grey
CC or Ccch or Cch or Cc
5-16
Himalayan
chc or chch
Chinchilla
cchcch
Light grey
cchch or cchc
Albino
cc
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Predicting phenotypes based on genotype
information can be difficult.
Cystic fibrosis phenotypes:
Same genotype ->
same degree of pancreatic
insufficiency
Same genotype ->
different lung phenotype
mild to severe
5-17
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Incomplete dominance
indicates the heterozygous phenotype is distinct
from either homozygous phenotype.
The heterozygous phenotype is
typically intermediate to the
homozygous phenotype.
If allele T (long tongue) exhibits
incomplete dominance over the
recessive allele t (short tongue)
a heterozygote for this tongue
gene would most likely have
a tongue of intermediate length.
5-18
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5-19
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• A cross of pure breeding red
snapdragons with pure breeding
white snapdragons always produces
plants with pink flowers.
• You can not produce a pure breeding
line of pink snapdragons.
5-20
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Codominant alleles are observed simultaneously
The ABO gene encodes a cell
surface protein.
• Allele A makes A protein
• Allele B makes B protein
• Allele O makes no protein
Alleles A and B can be present on
the cell surface at the same
time.
• Alleles A and B are codominant.
• Allele O is recessive to both A
and B alleles.
5-21
Different alleles that are both expressed in a heterozygote are condominant
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Codominant Alleles
The IA and IB alleles of the I gene are codominant, but they
Follow Mendel’s law of segregation. These Punnett
Squares follow the genotypes that could resuld when a
Person with type A blood produces offspring with a person
5-22
With type B blood.
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Epistasis
when one gene affects
the expression of a
second gene.
H gene is epistatic to
the ABO gene.
• H protein attaches
the A or B protein to
the cell surface.
• hh genotype = no H protein.
All ABO genotypes appear
as type O.
Can a woman with blood type A have a child with blood type O with a
Man who is AB? Yes, because of epistasis between the I and H genes.
5-23
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Variable expressivity
A phenotype that varies in intensity shows
variable expressivity.
FF or Ff
all show mild, moderate or
profound deafness
Incomplete penetrance
Occurs when the disease phenotype is not always
observed among individuals carrying the
disease-associated genotype.
5-24
DD or Dd
80% polydactyly
DD or Dd
20% no polydactyly
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• A family has an autosomal dominant
condition where the second toe is
attached by webbing to the third toe
and is longer than the big toe. Only
some family members who inherit
the mutant gene have the odd toe,
and the extent of webbing varies.
This phenotype is incompletely
penetrant and variably expressed.
5-25
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• Enamel hypoplasis is an autosomal
dominant disorder that results in holes
and cracks around the crowns of baby
teeth. Some individuals are apparently
unaffected but transmit the trait to their
offspring. Individuals with the trait also
vary in the number of teeth affected. This
trait is an example of variable expressivity
and incomplete penetrance.
5-26
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Pleiotropy
• One gene controls
or influences the
expression of
many symptoms
in a disorder.
These symptoms
may be variably
expressed.
King George III suffered from the autosomal dominant
Disorder porphyria variegata – and so did several other
Family members. Because of pleiotrophy, the family’s
Varied Illnesses and quirks appeared to be different,
unrelated Disorders. In King George, symptoms appeared
every few Years in a particular order.
5-27
A Mendelian
disorder that
has many
associated
symptoms is
pleiotropic.
Marfan
Syndrome is
An example.
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Phenocopy
A trait caused by the environment that
mimics an inherited condition.
Exposure to teratogens
• Thalidomide causes limb defects akin to rare
inherited phocomelia.
Infection
• Rubella in pregnant mothers causes deafness
mimicking inherited forms of deafness.
A trait caused by an environmental influence that appears
To be inherited is phenocopy.
5-28
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Genetic heterogeneity
Different genes can produce identical
phenotypes.
Individuals with identical phenotypes
may reflect different genetic causes.
•
Deafness
•
Albinism
•
Cleft palate
•
Poor blood clotting
Genetic disorders such as deafness, cleft palate, and
Albinism that may be caused by different genes that
Produce similar phenotypes are examples of genetic
5-29
Heterogeneity.
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• A man with a recessive deafness allele on
chromosome 17 marries a woman who
also has a recessive deafness allele, but
on chromosome 3. Based on this, the
probability that their children will be deaf
is closest to 0%.
• Of nearly 200 forms of hereditary
deafness, 132 are autosomal recessive, 64
autosomal dominant, and X-linked
recessive. Hereditary deafness is
genetically heterogeneic.
5-30
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Mitochondrion
• Organelle providing cellular
energy.
• Contains small circular DNA.
• No crossing over or DNA
repair.
• Many copies of the
mitochondrial genome per
cell.
• 37 genes, no histones, no
A mitochondrion contains
introns.
several rings of DNA.
different alleles can reside
• Maternal inheritance
on
different
copies
of
5-31
mitochondrial chromosomes
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Mitochondrial Inheritance
• Mitochondria and their genome are transmitted
from a mother to all of her offspring.
Mothers pass mitochondrial genes to all offspring.
fathers do not transmit mitochondrial genes because
sperm only very rarely contribute mitochondria to
Fertilized ova.
Mitochondrial DNA differs from nuclear DNA in that it
5-32
Lacks repair mechanisms, introns, and does not cross over.
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Heteroplasmy
• There are many
copies of the
mitochondrial DNA.
• Heteroplasmy is the
condition in which
mitochondrial DNA
sequence is not the
same in all copies.
The presence of two different alleles in mitochondria within
The same cell is called heteroplsmy.
5-33
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05_03.jpg
5-34
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5-35
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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.
5-36
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Linkage
Types of gametes from a parent
heterozygous for two genes?
Unlinked :
4 type of gametes
PL, Pl, pL, pl
5-37
Tightly linked:
2 types of gametes
PL and pl
NOTE for LINKAGE: which two types are observed
(PL and pl OR Pl and pL) depends on which alleles are
on the same chromosome in the parent!
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When genes
are not linked,
they assort
independently.
The gametes
then represent
all possible
allele combinations. The
expected
phenotypic
ratio of a
dihybrid
cross is 9:3:3:1
5-38
If genes are
linked on the
same chromosome, only
two allele
combinations
are expected
in the
gametes. The
phenotypic
ratio is 3:1
the same as
for a
monohybrid
cross.
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Parents
P
p
L
l
Genotype PpLl
Genes not linked
Self-cross
5-39
P
L
p
l
Genotype PpLl
Genes linked
Self-cross
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Parents
P
p
L
l
Genotype PpLl
Genes not linked
Self-cross
P
L
p
l
Genotype PpLl
Genes linked
Self-cross
F1
5-40
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Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Parents
P
p
L
P
L
l
Genotype PpLl
Genes not linked
Self-cross
F1
Male
gametes
Pl
pL
pl
5-41
Genotype PpLl
Genes linked
Self-cross
Female gametes
PL
pl
Female gametes
PL
Pl
pL
pl
PL
p
l
Male
gametes
PL
pl
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Parents
P
p
L
l
Genotype PpLl
Genes not linked
Self-cross
F1
Female gametes
PL
Pl
pL
pl
PL
Pl
PPLL PPLl PpLL PpLl
PPLl PPll PpLl Ppll
Male
gametes
PpLL PpLl ppLL ppLl
pL
pl
5-42
P
L
PpLl Ppll ppLl ppll
p
l
Genotype PpLl
Genes linked
Self-cross
Female gametes
PL
pl
Male PL PPLL PpLl
gametes
pl PpLl ppll
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Parents
P
p
L
l
Genotype PpLl
Genes not linked
Self-cross
F1
Female gametes
PL
Pl
pL
pl
PL
Pl
PPLL PPLl PpLL PpLl
PPLl PPll PpLl Ppll
Male
gametes
PpLL PpLl ppLL ppLl
pL
pl
5-43
PpLl Ppll ppLl ppll
Phenotypic ratio 9:
P
L
p
l
Genotype PpLl
Genes linked
Self-cross
Female gametes
PL
pl
Male PL PPLL PpLl
gametes
pl PpLl ppll
Phenotypic ratio 3:
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Parents
P
p
L
l
Genotype PpLl
Genes not linked
Self-cross
F1
Female gametes
PL
Pl
pL
pl
PL
Pl
PPLL PPLl PpLL PpLl
PPLl PPll PpLl Ppll
Male
gametes
PpLL PpLl ppLL ppLl
pL
pl
5-44
PpLl Ppll ppLl ppll
Phenotypic ratio 9:3
P
L
p
l
Genotype PpLl
Genes linked
Self-cross
Female gametes
PL
pl
Male PL PPLL PpLl
gametes
pl PpLl ppll
Phenotypic ratio 3:
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Parents
P
p
L
l
Genotype PpLl
Genes not linked
Self-cross
F1
Female gametes
PL
Pl
pL
pl
PL
Pl
PPLL PPLl PpLL PpLl
PPLl PPll PpLl Ppll
Male
gametes
PpLL PpLl ppLL ppLl
pL
pl
5-45
PpLl Ppll ppLl ppll
Phenotypic ratio 9:3:3
P
L
p
l
Genotype PpLl
Genes linked
Self-cross
Female gametes
PL
pl
Male PL PPLL PpLl
gametes
pl PpLl ppll
Phenotypic ratio 3:
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Parents
P
p
L
l
Genotype PpLl
Genes not linked
Self-cross
F1
Female gametes
PL
Pl
pL
pl
PL PPLL PPLl PpLL PpLl
Pl
PPLl PPll PpLl Ppll
Male
gametes
pL PpLL PpLl ppLL ppLl
pl
5-46
PpLl Ppll ppLl ppll
Phenotypic ratio 9:3:3:1
P
L
p
l
Genotype PpLl
Genes linked
Self-cross
Female gametes
PL
pl
Male PL PPLL PpLl
gametes
pl PpLl ppll
Phenotypic ratio 3:1
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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.
Crossing over disrupts linkage. The linkage between two
genes may be interrupted if the chromosome they are
located on crosses over with its homolog at a point
between the two genes. Crossing over packages recombinant
5-47
arrangements of the genes into gametes.
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• Geneticists construct linkage maps of
chromosomes by calculating the percent
recombination between two linked genes.
• A and B are linked genes. In a study of
100 offspring, 94 had parental genotypes
for A and B, while 6 were recombinants. A
and B are 6 map units apart.
• A,B, and C are linked genes.
Recombination between A and B is 3%;
between A and C is 6% and between B and
C is 9%. What is the order of these genes
on the chromosome? B-A-C
5-48
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Recombination
The frequency of recombination between two genes
is directly related to the physical distance between
the genes.
In a heterozygote
for two linked
genes, when both
dominant alleles
are on one
chromosome
and both
recessive alleles
are on the other,
the genes are in
coupling.
Crossing over is more likely to occur between the widely
Spaced linked genes A and B, or between A and C, then
Between the more closely spaced linked genes B and C,
5-49
Because there is more room for an exchange to occur.
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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.
5-50
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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
5-51
X
Z
4 cM
Y
6 cM
10 cM
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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.
5-52
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LOD score
• Is the logarithm of the odds ratio
• 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.
5-53
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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
5-54
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
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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 yellow haplotype.
14
14
14
14
14
5-55
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
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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.
14
14
14
14
14
5-56
11
11
11
11
11
22
22
22
22
22
12
12
12
12
12
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
Recombinant chromosomes