Transcript Document

LECTURE PRESENTATIONS
For CAMPBELL BIOLOGY, NINTH EDITION
Jane B. Reece, Lisa A. Urry, Michael L. Cain, Steven A. Wasserman, Peter V. Minorsky, Robert B. Jackson
Chapter 15
The Chromosomal Basis of
Inheritance
Lectures by
Erin Barley
Kathleen Fitzpatrick
© 2011 Pearson Education, Inc.
Mendelian inheritance has its physical basis in the
behavior of chromosomes
• Mendel’s “hereditary factors” were genes
• today we can show that genes are located on chromosomes
• the chromosome theory of inheritance states:
– Mendelian genes have specific loci (positions) on
chromosomes
– chromosomes undergo segregation and independent
assortment
All F1 plants produce
yellow-round seeds (YyRr).
F1 Generation
R
y
r
R
y
r
Y
Y
LAW OF INDEPENDENT
ASSORTMENT Alleles of genes on
nonhomologous chromosomes assort
independently during gamete
formation.
Meiosis
LAW OF SEGREGATION
The two alleles for each gene
separate during gamete formation.
r
R
r
R
Y
y
Metaphase I
y
Y
1
1
R
r
r
R
Y
y
Anaphase I
Y
y
r
R
Metaphase
II
2
Gametes
y
Y
Y
R
R
1/
4
YR
r
1/
4
yr
Y
y
Y
Y
y
r
R
2
y
Y
r
r
r
1/
4
Yr
y
y
R
R
1/
4
yR
• the behavior of chromosomes during meiosis accounts for
Mendel’s laws of segregation and independent assortment
All F1 plants produce
yellow-round seeds (YyRr).
F1 Generation
R
r
R
r
y
Y
y
Y
LAW OF INDEPENDENT
ASSORTMENT Alleles of genes on
nonhomologous chromosomes assort
independently during gamete
formation.
Meiosis
LAW OF SEGREGATION
The two alleles for each gene
separate during gamete formation.
R
r
Y
y
r
R
Y
y
Metaphase I
1
1
R
r
Y
y
r
R
Y
y
Anaphase I
R
r
Y
y
2
Gametes
y
Y
Y
R
R
1/
4
4
Y
y
Y
r
r
1/
YR
R
Y
y
r
r
Metaphase
II
yr
4
y
y
r
1/
2
R
R
1/
Yr
4
yR
• the behavior of chromosomes during meiosis accounts for
Mendel’s laws of segregation and independent assortment
LAW OF INDEPENDENT
ASSORTMENT
LAW OF SEGREGATION
F2 Generation
3
Fertilization
recombines the
R and r alleles
at random.
An F1  F1 cross-fertilization
3
9
:3
:3
:1
Fertilization results
in the 9:3:3:1
phenotypic ratio in
the F2 generation.
Morgan’s Experimental Evidence: Scientific
Inquiry
•
•
•
•
the first solid evidence associating a specific gene with a
specific chromosome came from Thomas Hunt Morgan
- an embryologist
Morgan’s experiments with fruit flies (Drosophila
melanogaster) provided convincing evidence that
chromosomes are the location of Mendel’s heritable
factors
several characteristics make fruit flies a convenient
organism for genetic studies
– they produce many offspring
– a generation can be bred every two weeks
– they have only four pairs of chromosomes
Morgan recorded wild type (or normal) phenotypes that
were common in the fly populations
– traits alternative to the wild type are called mutant
phenotypes
Drosophila mutations
-white eyes (ABC gene
mutation)
- wingless (Wnt mutation)
- curly winged, short winged
(vestigial)
- forked bristles
- ebony color, yellow color
Correlating Behavior of a Gene’s Alleles with
Behavior of a Chromosome Pair
• in one experiment, Morgan mated male flies with white eyes
(mutant) with female flies with red eyes (wild type)
– the F1 generation all had red eyes
– the F2 generation showed the 3:1 red:white eye ratio
– but only males had white eyes
EXPERIMENT
P
Generation
•
•
Morgan determined
that the white-eyed
mutant allele must be
located on the X
chromosome
Morgan’s finding
supported the
chromosome theory of
inheritance
F1
Generation
All offspring
had red eyes.
RESULTS
F2
Generation
CONCLUSION
P
Generation
w
X
X
X
Y
w
w
Eggs
F1
Generation
Sperm
w
w
w
w
w
Eggs
F2
Generation
w
w
Sperm
w
w
w
w
w
w
w
The Chromosomal Basis of Sex
44 
XY
• in many organisms there is a
chromosomal basis of sex
determination
• XX/XY determination – humans and
most mammals and some insects
– humans – Y determines the male
– fruit flies – 2 X’s determine the
female
• XX/XO determination – some
rodents & insects
– females = XX
– males = XO (absence of a second
sex chromosome)
44 
XX
Parents
22 
X

22 
or 22
Y
X
Sperm
44 
XX
(a) The X-Y system
or
44 
XY
Zygotes (offspring)
22 
XX
(b) The X-0 system
Egg
22 
X
The Chromosomal Basis of Sex
• ZW determination – birds, some reptiles
and some insects
– ZW = female
• W chromosome possesses sex
determining genes
– ZZ = male
• UV determination – some plants and algae
– U = female gametophytes
– V = male gametophytes
• haplo-diploid system – bees and ants
– diploid = female and sterile males
– haplo = males (from unfertilized eggs)
– so the queen and control gender
76 
ZW
76 
ZZ
32
(Diploid)
16
(Haploid)
(c) The Z-W system
(d) The haplo-diploid system
The Chromosomal Basis of Sex
• in humans and other mammals
 XX/XY determination
– a larger X chromosome and a
smaller Y chromosome for
males
• one X chromosome is
inactivated in females
The Chromosomal Basis of Sex
• the Y chromosome – significantly lower numbers
of genes vs. X chromosome (1846 vs. 454)
– most of them are responsible for sex
determination and development of male
reproductive structures
– the SRY gene on the Y chromosome codes for
a protein that directs the development of
male anatomical features
• BUT the ends of the Y chromosome have regions
that are homologous with corresponding regions
of the X chromosome = pseudoautosomal regions
The Chromosomal Basis of Sex
• a gene that is located on either sex chromosome is
called a sex-linked gene
• genes on the Y chromosome are called Y-linked
genes
• genes on the X chromosome are called X-linked
genes
• X chromosomes have genes for many characters
unrelated to sex
– whereas the Y chromosome mainly encodes genes
related to sex determination
– e.g. SRY gene
X-linked Genes
• X-linked genes follow specific patterns of inheritance
• for a recessive X-linked trait to be expressed
– a female needs two copies of the allele (homozygous)
– a male needs only one copy of the allele (hemizygous)
• X-linked recessive disorders are much more common in males
than in females
XNXN
Sperm Xn
XNXn
XnY
Sperm XN
Y
XNY
XNXn
Sperm Xn
Y
XnY
Y
Eggs XN
XNXn XNY
Eggs XN
XNXN XNY
Eggs XN
XNXn XNY
XN
XNXn XNY
Xn
XNXn XnY
Xn
XnXn XnY
(a)
(b)
(c)
• Some disorders caused by recessive alleles on the X
chromosome in humans
– Color blindness (mostly X-linked)
– Duchenne muscular dystrophy
– Hemophilia A and B
X Inactivation in Female Mammals
• the coloration of a calico cat is the physical
manifestation of a phenomenon called Xinactivation
• X-inactivation or lyonization process in
mammalian females is where one of the two
X chromosomes in each cell is randomly
inactivated
– in marsupials – always the paternally
derived X
• prevents the female from having twice as
many X chromosome gene products as a
male = dosage compensation
• the inactive X condenses into a Barr body
X chromosomes
Allele for
orange fur
Early embryo:
Allele for
black fur
Cell division and
X chromosome
inactivation
Two cell
populations
in adult cat:
Active X
Inactive X
Active X
Black fur
Orange fur
X Inactivation in Female Mammals
• X inactivation begins at embryonic
development – occurs in the inner cell mass
of the blastocyst
• once a specific X chromosome is inactivated –
that one will remain inactive throughout its
lifetime
– will also be inactivated in all cellular
progeny
• inactivation is an epigenetic change
– high methylation of DNA and low
acetylation of histones
– methylation results in the packaging of
the X chromosome into heterochromatin
– DNA is now a transcriptionally inactive
structure
• reversed in female germ cells undergoing
meiosis
X chromosomes
Allele for
orange fur
Early embryo:
Allele for
black fur
Cell division and
X chromosome
inactivation
Two cell
populations
in adult cat:
Active X
Inactive X
Active X
Black fur
Orange fur
X Inactivation in Female Mammals
• active X chromosome is called Xa
• inactive one is designated Xi
• if multiple X chromosomes are present (i.e. 3 vs. 2) – only one X chromosome is
still Xa
– default state is the inactive form
• hypothesis: an autosomally-encoded “blocking factor” binds to the Xa
chromosome and prevents its inactivation
– sequence in the chromosome known as the XIC – X inactivation center
– sequence is bound to these factors - prevents inactivation??
• another hypothesis: the XIC of the the Xi chromosome produces a non-coding
RNA called Xist RNA
– coats the Xi chromosome  inactivation
X Inactivation in Female Mammals
• despite the fact that the X chromosome is inactivated –
there are genes on Xi that ESCAPE inactivation
– these genes are also found on the Y chromosome of
males
– so there is dosage compensation between the two
chromosomes
Mosaicism
• Mosaicism – two or more populations of cells with different genotypes within a
single organism
• most common forms rise from errors in the first few mitotic divisions of a
fertilized zygote
–
–
–
–
mitotic crossing over!
Source of genetic variation in asexually reproducing organisms
Can occur in sexually reproducing organisms
Takes place during interphase (G1)
• other mosaicisms – result from non-disjunction during meiosis and produce
trisomies
• true mosaicism should NOT be confused with X-inactivation!!!
– all the cells in this cat have the same genotype BUT a different X is active in
different cells
Linked genes tend to be inherited together because they
are located near each other on the same chromosome
• each chromosome has hundreds or thousands of
genes (except the Y chromosome)
• genes located on the same chromosome that tend
to be inherited together are called linked genes
How Linkage Affects Inheritance
• Morgan did other experiments with fruit flies to see how linkage
affects inheritance of two characters
• Morgan crossed flies that differed in traits of body color and wing size
• found a higher percentage of parental phenotypes in the offspring
• concluded that these genes do not assort independently
– body color and wing size are inherited together
– reasoned that they were on the same chromosome
P Generation (homozygous)
Wild type
(gray body, normal wings)
Double mutant
(black body,
vestigial wings)
b b vg vg
b b vg vg
How Linkage Affects Inheritance
•
•
Mated true-breeding wild type
flies with gray bodies and
normal wings (b+b+vg+vg+)
with mutants with black
bodies and short, vestigial
wings (bbvgvg)
all F1 offspring looked like
parents and were
heterozygotes
P Generation (homozygous)
Wild type
(gray body, normal wings)
Double mutant
(black body,
vestigial wings
b b vg vg
b b vg vg
F1 dihybrid
(wild type)
Double mutant
TESTCROSS
b b vg vg
b b vg vg
Testcross
offspring
Eggsb vg
b vg
b vg
b vg
Wild type Black- Gray- Black(gray-normal)
vestigial vestigial normal
b vg
Sperm
b b vg vg
PREDICTED RATIOS
If genes are located on different
chromosomes:
If genes are located on the same
chromosome and parental alleles
are always inherited together:
b b vg vg b b vg vg b b vg vg
1
:
1
:
1
:
1
1
:
1
:
0
:
0
RESULTS 965 :
944 :
206 :
185
How Linkage Affects Inheritance
P Generation (homozygous)
•
performed a test-cross of
female F1 with true-breeding
male mutants (bbvgvg)
– expected a 1:1:1:1 ratio of
dominant to recessive
•
•
•
most offspring looked like the
parents
only possible if the b and vg
genes are linked and did not
sort independently during
meiosis
in other words – the gametes
made by the P generation
contained a chromosome with
the b+ allele AND the vg+
allele together on the same
chromosome
Wild type
(gray body, normal wings)
Double mutant
(black body,
vestigial wings)
b b vg vg
b b vg vg
F1 dihybrid
(wild type)
Double mutant
TESTCROSS
b b vg vg
b b vg vg
Testcross
offspring
Eggsb vg
b vg
Wild type
Black(gray-normal) vestigial
b vg
b vg
Grayvestigial
Blacknormal
b vg
Sperm
PREDICTED RATIOS
b b vg vg
b b vg vg b b vg vg b b vg vg
If genes are located on different
chromosomes:
1
:
1
:
1
:
1
If genes are located on the same
chromosome and parental alleles
are always inherited together:
1
:
1
:
0
:
0
RESULTS 965 :
944 :
206 :
185
F1 dihybrid female
and homozygous
recessive male
in testcross
b+ vg+
b vg
b vg
b vg
b+ vg+
b vg
Most offspring
or
b vg
b vg
• however, nonparental phenotypes were also produced
– so body color and wing size were not always linked
genetically and were recombined as a result of crossing over
or genetic recombination
Recombination of Unlinked Genes: Independent
Assortment of Chromosomes
• offspring with a phenotype matching one of the parental phenotypes
= parental types
• offspring with nonparental phenotypes (new combinations of traits)
= recombinant types, or recombinants
• a 50% frequency of recombination is observed for any two genes on
different chromosomes
Gametes from yellow-round
dihybrid parent (YyRr)
Gametes from greenwrinkled homozygous
recessive parent (yyrr)
YR
yr
Yr
yR
YyRr
yyrr
Yyrr
yyRr
yr
Parentaltype
offspring
Recombinant
offspring
Gray body, normal wings
(F1 dihybrid)
Recombination Testcross
of
parents
Linked Genes:
Crossing Over
Black body, vestigial wings
(double mutant)
b vg
b vg
b vg
b vg
Replication
of chromosomes
•
•
MEIOSIS I: crossing over
between the homologous
chromosomes of the
female parent produces
new combinations of
alleles (b+ vg and b vg+)
at the end of MEIOSIS II:
some of the gametes will
be parental and some are
recombinants
Meiosis I
Replication
of chromosomes
b vg
b vg
b vg
b vg
b vg
b vg
b vg
b vg
b vg
Meiosis I and II
b
vg
b vg
b vg
Meiosis II
bvg
Eggs
Recombinant
chromosomes
b vg
b vg
b vg
b vg
Sperm
Recombinant
chromosomes
Eggs
Testcross
offspring
bvg
965
Wild type
(gray-normal)
b vg
b vg
b vg
944
Blackvestigial
206
Grayvestigial
185
Blacknormal
b vg
b vg
b vg
b vg
b vg
b vg
b vg
b vg
Parental-type offspring
Recombinant offspring
Recombination
391 recombinants  100  17%

frequency
2,300 total offspring
b vg
Sperm
New Combinations of Alleles: Variation for
Normal Selection
• recombinant chromosomes bring alleles together in
new combinations in gametes
• random fertilization increases even further the
number of variant combinations that can be
produced
• this abundance of genetic variation is the raw
material upon which natural selection works
Mapping the Distance Between Genes Using
Recombination Data: Scientific Inquiry
• Alfred Sturtevant, one of Morgan’s students,
constructed a genetic map, an ordered list of the
genetic loci along a particular chromosome
• Sturtevant predicted that the farther apart two
genes are, the higher the probability that a
crossover will occur between them and therefore
the higher the recombination frequency
• in other words the farther apart two genes are the
more likely they will be unlinked or “broken up” by
crossing over
Mapping the Distance Between Genes Using
Recombination Data: Scientific Inquiry
• a linkage map is a genetic map of a chromosome based on
recombination frequencies
• distances between genes can be expressed as map units; one map
unit, or centimorgan, represents a 1% recombination frequency
• map units indicate relative distance and order, not precise
locations of genes
• b-vg recombination
frequency = 17%
• b-cn recombination
frequency = 9%
RESULTS
Recombination
frequencies
9%
9.5%
Chromosome
17%
b
cn
vg
• genes that are far apart on the same chromosome can
have a recombination frequency near 50%
– such genes are physically linked by being on the same
chromosome - but genetically unlinked
– they behave as if found on different chromosomes
Mutant phenotypes
Short
aristae
0
Long aristae
(appendages
on head)
Black
body
Cinnabar Vestigial
eyes
wings
48.5 57.5
Gray
body
67.0
Red Normal
eyes wings
Brown
eyes
104.5
Red
eyes
Wild-type phenotypes
• Sturtevant used recombination frequencies to make linkage maps of
fruit fly genes
• using methods like chromosomal banding - geneticists can develop
cytogenetic maps of chromosomes
• Cytogenetic maps indicate the positions of genes with respect to
chromosomal features
Abnormal Chromosome Number
• in nondisjunction -pairs of homologous chromosomes do not
separate normally during meiosis
– as a result, one gamete receives two of the same type of
chromosome, and another gamete receives no copy
Meiosis I
Nondisjunction
Meiosis I
Nondisjunction
Meiosis II
Nondisjunction
Gametes
n1
n1
n1
n1
n1
n1
n
n
Number of chromosomes
(a) Nondisjunction of homologous chromosomes in
meiosis I
(b) Nondisjunction of sister
chromatids in meiosis II
• Aneuploidy results from the fertilization of gametes in which
nondisjunction occurred
– offspring with this condition have an abnormal number of a
particular chromosome
• a monosomic zygote has only one copy of a particular
chromosome
– e.g. XO = Turner’s syndrome
• a trisomic zygote has three copies of a particular chromosome
– e.g. 3 chromosome 21 = Down’s syndrome
• Polyploidy is a condition in which an organism has more than
two complete sets of chromosomes
– Triploidy (3n) is three sets of chromosomes
– Tetraploidy (4n) is four sets of chromosomes
• polyploidy is common in plants - but not animals
• polyploids are more normal in appearance than aneuploids
• large-scale chromosomal alterations in humans and other
mammals often lead to spontaneous abortions (miscarriages) or
cause a variety of developmental disorders
– plants tolerate such genetic changes better than animals do
Aneuploidy of Autosomal Chromosomes
Down Syndrome (Trisomy 21)
• alterations of chromosome number and
structure are associated with some
serious disorders
• some types of aneuploidy appear to
upset the genetic balance less than
others - resulting in individuals surviving
to birth and beyond
• Down syndrome is an aneuploid
condition that results from three copies
of chromosome 21
• it affects about one out of every 700
children born in the United States
• the frequency of Down syndrome
increases with the age of the mother, a
correlation that has not been explained
Aneuploidy of Sex Chromosomes
• Nondisjunction of sex chromosomes produces a variety of
aneuploid conditions
– Klinefelter syndrome is the result of an extra chromosome in a
male, producing XXY individuals – most common aneuploidy
• also known as 47,XXY
• 1:500  1:1000 live births
• non-disjunction between X and Y chromosomes during meiosis I in
spermatogenesis
• most are asymptomatic
• hypogonadism (decreased endocrine function NOT size)and sterility
• gynecomastia
• reduced muscle mass, coordination and strength as kids
• taller than average
• higher incidence (vs. normal males) of breast cancer, autoimmune diseases and
osteoporosis
Aneuploidy of Sex Chromosomes
– Monosomy X, called Turner syndrome - produces
X0 females
• also known as 45, X
• all of part of the second X chromosome is absent (e.g.
deletion of the p arm)
• 1 in 2,000 to 5,000 births
• sterile – non-working ovaries
• short stature, webbing in the neck, low hairline, low wet
• congenital heart disease, hypothyroidism, diabetes,
visual problems, many autoimmune diseases, specific
cognitive problems
• it is the only known viable monosomy in humans
Aneuploidy of Sex Chromosomes
– 48,XXYY and 48,XXXY – 1 in 18,000 to 50,000 live
births
– 49,XXXXY 1 in 85,000 to 100,000 births
Alterations of Chromosome Structure
(a) Deletion
A B C D E
• breakage of a chromosome can
lead to four types of changes in
chromosome structure
– Deletion removes a
chromosomal segment
– Duplication repeats a
segment
– Inversion reverses
orientation of a segment
within a chromosome
– Translocation moves a
segment from one
chromosome to another
F G H
A deletion removes a chromosomal segment.
A B C E
F G H
(b) Duplication
A B C D E
F G H
A duplication repeats a segment.
A B C B C D E
F G H
(c) Inversion
A B C D E
F G H
An inversion reverses a segment within a
chromosome.
A D C B E
F G H
(d) Translocation
A B C D E
F G H
M N O P Q
R
A translocation moves a segment from one
chromosome to a nonhomologous chromosome.
M N O C D E
F G H
A B P Q
R
Gene Duplications and Deletions
• both can arise from unequal crossing over during meiosis
• often results between repetitive sequences shared
between them
• duplication can also result from replication slippage
– DNA polymerase dissociates and reattaches at an
incorrect position – copies the same strand of DNA
again
• these are not necessarily bad things
• cri du chat (“cry of the cat”) - results from a specific deletion of a section of
chromosome 5 (p arm)
– a child born with this syndrome is mentally retarded and has a catlike cry
– individuals who are missing the entire chromosome 5 usually die in infancy
or early childhood
http://ghr.nlm.nih.gov/condition/cri-du-chat-syndrome
Translocation
•
•
•
•
reciprocal translocations involve the
exchange of material between nonhomologous chromosomes
crossing over between non-homologous
chromosomes
1 to 625 newborns
usually harmless because they are
localized to the somatic cell
Balanced translocation
Translocation
•
some translocations may be associated with
increased chances of cancer
– Philadelphia chromosome
– associated with Chronic Myelogenous
Leukemia
– creates two fused genes  BCR-Abl
fusion protein
– speeds up the cell cycle
but increased miscarriages can result in
affected individuals
•
Normal chromosome 9
Normal chromosome 22
Reciprocal translocation
Translocated chromosome 9
•
can occur due to errors in mitosis in
somatic cells
– limited to the affected cell type
– e.g. CML and Philadelphia chr
•
can also occur in germline cells during
meiosis
– all cellular progeny affected
Translocated chromosome 22
(Philadelphia chromosome)
Translocation
• can occur due to errors in mitosis in somatic cells
– limited to the affected cell type
• can also occur in germline cells during meiosis
– cellular progeny will be affected if the gametes are altered
Some inheritance patterns are exceptions to
standard Mendelian inheritance
• there are two normal exceptions to Mendelian
genetics
• one exception involves genes located in the nucleus
• the other exception involves genes located outside the
nucleus
• in both cases, the sex of the parent contributing an
allele is a factor in the pattern of inheritance
– Genetic Imprinting
– Organelle Genes
Genomic Imprinting
Normal Igf2 allele
is expressed.
• for a few mammalian traits, the
phenotype depends on which
parent passed along the alleles for
those traits
• such variation in phenotype is
called genomic imprinting
• genomic imprinting involves the
silencing of certain genes that are
“stamped” with an imprint during
gamete production
• not a big deal as long as the active
chromosome has a “normal” gene
allele
Paternal
chromosome
Maternal
chromosome
Normal Igf2 allele
is not expressed.
Normal-sized mouse
(wild type)
(a) Homozygote
Mutant Igf2 allele
inherited from mother
Mutant Igf2 allele
inherited from father
Normal-sized mouse (wild type)
Dwarf mouse (mutant)
Normal Igf2 allele
is expressed.
Mutant Igf2 allele
is expressed.
Mutant Igf2 allele
is not expressed.
Normal Igf2 allele
is not expressed.
(b) Heterozygotes – imprinted gene comes from mother
Genomic Imprinting
• it appears that imprinting is the result of the
methylation (addition of —CH3) of the DNA
– addition of CH3 to cysteine nucleotides
– can result in transcriptional inactivation
– the methylation pattern is passed on to progeny
through meiosis
• genomic imprinting is thought to affect only a small
fraction of mammalian genes
• most imprinted genes are critical for embryonic
development
Inheritance of Organelle Genes
• extranuclear genes (or cytoplasmic genes) are found in organelles in the
cytoplasm
• mitochondria, chloroplasts, and other plant plastids carry small circular DNA
molecules
• extranuclear genes are inherited maternally because the zygote’s cytoplasm
comes from the egg
• the first evidence of extranuclear genes came from studies on the inheritance of
yellow or white patches on leaves of an otherwise green plant
•
Some defects in mitochondrial genes prevent cells from making
enough ATP and result in diseases that affect the muscular and
nervous systems
– inheritance pattern is non-Mendelian – Maternal
–
only the egg contributes mitochondria to the embryo
– e.g. mitochondrial myopathy
• type of myopathy associated with abnormal mitochondria
• muscle tissue shows “ragged red” fibers with mild
accumulations of glycogen
• muscle weakness results
• numerous types of MMs known
– e.g. Leber’s hereditary optic neuropathy
• mitochondrial dysfunction results in the degeneration of
retinal ganglion cells (neurons in the retina)
• loss of central vision