THE CHROMOSOMAL BASIS OF Introduction

INHERITANCE • It was not until 1900 that biology finally caught up

with Gregor Mendel.
Intended learning outcomes (ILOs) • Independently, Karl Correns, Erich von Tschermak,
1. How does the Mendelian inheritance has its physical basis in the
and Hugo de Vries all found that Mendel had
behavior of chromosomes during sexual life cycles? explained the same results 35 years before.
2. How did Morgan trace a gene to a specific chromosome? • Still, resistance remained about Mendel’s laws of
3. How do the linked genes tend to be inherited together because they
segregation and independent assortment until
are located on the same chromosome?
evidence had mounted that they had a physical basis
4. How do the independent assortment of chromosomes and crossing
over produce genetic recombinants?
in the behavior of chromosomes.
5. How do the geneticists use recombination data to map genetic loci on • Mendel’s hereditary ‘factors’ are the genes located
chromosomes? on chromosomes.

1. Mendelian inheritance has its physical • Around 1902, Walter Sutton, Theodor Boveri, and
basis in the behavior of chromosomes others noted these parallels and a chromosome
during sexual life cycles theory of inheritance began to take form.

• Around 1900, cytologists and geneticists began to

see parallels between the behavior of chromosomes
and the behavior of Mendel’s factors.
• Chromosomes and genes are both present in pairs in
diploid cells.
• Homologous chromosomes separate and alleles segregate
during meiosis.
• Fertilization restores the paired condition for both
chromosomes and genes.

2. Morgan traced a gene to a specific • Morgan spent a year looking for variant
chromosome individuals among the flies he was breeding.

• Thomas Hunt Morgan was the first to associate a • He discovered a single male fly with white eyes instead
of the usual red.
specific gene with a specific chromosome in the
early 20th century. • The normal character phenotype is the wild type.
• Like Mendel, Morgan made an insightful choice as • Alternative
an experimental animal, Drosophila melanogaster, a traits are
fruit fly species that eats fungi on fruit. mutant
phenotypes.
• Fruit flies are prolific breeders and have a generation time
of two weeks.
• Fruit flies have three pairs of autosomes and a pair of sex
chromosomes (XX in females, XY in males).

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• When Morgan crossed his white-eyed male with a • Morgan deduced that the gene
red-eyed female, all the F1 offspring had red eyes, with the white-eyed mutation is
on the X chromosome alone, a
• The red allele appeared dominant to the white allele. sex-linked gene.
• Crosses between the F1 offspring produced the • Females (XX) may have two red-
classic 3:1 phenotypic ratio in the F2 offspring. eyed alleles and have red eyes or
may be heterozygous and have red
• Surprisingly, the white-eyed trait appeared only in eyes.

males. • Males (XY) have only a single

allele and will be red eyed if they
• All the females and half the males had red eyes. have a red-eyed allele or white-
eyed if they have a white-eyed
• Morgan concluded that a fly’s eye color was linked allele.
to its sex.

3. Linked genes tend to be inherited • Morgan observed this linkage and its deviations
together because they are located on the when he followed the inheritance of characters for
same chromosome body color and wing size.
• The wild-type body color is gray (b+) and the mutant
• Each chromosome has hundreds or thousands of black (b).
genes.
• The wild-type wing size is normal (vg+) and the mutant
• Genes located on the same chromosome, linked has vestigial wings (vg).
genes, tend to be inherited together because the • Morgan crossed F1 heterozygous females
chromosome is passed along as a unit. (b+bvg+vg) with homozygous recessive males
• Results of crosses with linked genes deviate from (bbvgvg).
those expected according to independent assortment.

• According to independent assortment, this should

produce 4 phenotypes in a 1:1:1:1 ratio.
• Surprisingly, Morgan observed a large number of
wild-type (gray-normal) and double-mutant (black-
vestigial) flies among the offspring.
• These phenotypes correspond to those of the parents.

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• Morgan reasoned that body color and wing shape
are usually inherited together because their genes • The other two phenotypes (gray-vestigial and
are on the same chromosome. black-normal) were fewer than expected from
independent assortment (and totally unexpected
from dependent assortment).

• These new phenotypic variations must be the result

of crossing over.

4. Independent assortment of chromosomes • Mendel’s dihybrid cross experiments produced some

and crossing over produce genetic offspring that had a combination of traits that did
recombinants not match either parent in the P generation.
• If the P generation consists of a yellow-round parent
• The production of offspring with new combinations (YYRR) crossed with a green-wrinkled seed parent (yyrr),
of traits inherited from two parents is genetic all F1 plants have yellow-round seeds (YyRr).
recombination. • A cross between an F1 plant and a homozygous recessive
• Genetic recombination can result from independent plant (a test-cross) produces four phenotypes.
assortment of genes located on nonhomologous • Half were of parental types, with phenotypes that match
chromosomes or from crossing over of genes located the original P parents, either with yellow-round seeds or
on homologous chromosomes. green-wrinkled seeds.
• Half are recombinants, new combination of parental
traits, with yellow-wrinkled or green-round seeds.

• A 50% frequency of recombination is observed for • In contrast, linked genes, genes located on the
any two genes located on different same chromosome, tend to move together through
(nonhomologous) chromosomes. meiosis and fertilization.
• The physical basis of recombination between • Under normal Mendelian genetic rules, we would
unlinked genes is the random orientation of not expect linked genes to recombine into
homologous chromosomes at metaphase 1. assortments of alleles not found in the parents.
• The F1 parent (YyRr) can produce gametes with four • If the seed color and seed coat genes were linked, we
different combinations of alleles. would expect the F1 offspring to produce only two types
of gametes, YR and yr when the tetrads separate.
• These include YR, Yr, yR, and yr.
• One homologous chromosome from a P generation
• The orientation of the tetrad containing the seed color
parent carries the Y and R alleles on the same
gene has no bearing on the orientation on the tetrad
chromosome and the other homologous chromosome
with the seed shape gene.
from the other P parent carries the y and r alleles.

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• The results of Morgan’s testcross for body color • Morgan proposed that some mechanism
and wing shape did not conform to either occasionally exchanged segments between
independent assortment or complete linkage. homologous chromosomes.
• Under independent assortment the testcross should • This switched alleles between homologous
produce a 1:1:1:1 phenotypic ratio. chromosomes.
• If completely linked, we should expect to see a 1:1:0:0 • The actual mechanism, crossing over during
ratio with only parental phenotypes among offspring. prophase I, results in the production of more types
• Most of the offspring had parental phenotypes, of gametes than one would predict by Mendelian
suggesting linkage between the genes. rules alone.
• However, 17% of the flies were recombinants,
suggesting incomplete linkage.

• The occasional production of recombinant gametes 5. Geneticists can use recombination data to
during prophase I accounts for the occurrence of map a chromosome’s genetic loci
recombinant phenotypes in Morgan’s testcross.
• One of Morgan’s students, Alfred Sturtevant, used
crossing over of linked genes to develop a method
for constructing a genetic map.
• This map is an ordered list of the genetic loci along a
particular chromosome.

• Sturtevant hypothesized that the frequency of • Sturtevant used the testcross design to map the
recombinant offspring reflected the distances relative position of three fruit fly genes, body color
between genes on a chromosome. (b), wing size (vg), and eye color (cn).
• The farther apart two genes are, the higher the • The recombination frequency between cn and b is 9%.
probability that a crossover will occur between • The recombination frequency between cn and vg is
them and therefore a higher recombination 9.5%.
frequency. • The recombination frequency between b and vg is 17%.
• The greater the distance between two genes, the more • The only possible
points between them where crossing over can occur. arrangement of these
three genes places
• Sturtevant used recombination frequencies from
the eye color gene
fruit fly crosses to map the relative position of between the other two.
genes along chromosomes, a linkage map.

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• Sturtevant expressed the distance between genes, • Some genes on a chromosome are so far apart that
the recombination frequency, as map units. a crossover between them is virtually certain.
• One map unit (sometimes called a centimorgan) is • In this case, the frequency of recombination
equivalent to a 1% recombination frequency. reaches its maximum value of 50% and the genes
• You may notice that the three recombination act as if found on separate chromosomes and are
frequencies in our mapping example are not quite inherited independently.
additive: 9% (b-cn) + 9.5% (cn-vg) > 17% (b-vg). • In fact, several genes studies by Mendel are located on
the same chromosome.
• This results from multiple crossing over events.
• For example, seed color and flower color are far
• A second crossing over “cancels out” the first and
enough apart that linkage is not observed.
reduces the observed number of recombinant offspring.
• Plant height and pod shape should show linkage, but
• Genes farther apart (for example, b-vg) are more likely
Mendel never reported results of this cross.
to experience multiple crossing over events.

• Genes located far apart on a chromosome are • A linkage map provides an imperfect picture of a
mapped by adding the recombination frequencies chromosome.
between the distant genes and intervening genes. • Map units indicate relative distance and order, not
• Sturtevant and his precise locations of genes.
colleagues were able • The frequency of crossing over is not actually uniform
to map the linear over the length of a chromosome.
positions of genes in
• Combined with other methods like chromosomal
Drosophila into four
banding, geneticists can develop cytological maps.
groups, one for each
chromosome. • These indicated the positions of genes with respect to
chromosomal features.
• More recent techniques show the absolute distances
between gene loci in DNA nucleotides.

1. The chromosomal basis of sex varies with

THE CHROMOSOMAL BASIS OF INHERITANCE: the organism
Sex Chromosomes • Although the anatomical and physiological
Intended learning outcomes (ILOs) differences between women and men are numerous,
the chromosomal basis of sex is rather simple.
1. How do the chromosomal basis of sex varies with the • In human and other mammals, there are two varieties
organism? of sex chromosomes, X and Y.
2. What the sex-linked genes and how do they have unique • An individual who inherits two X chromosomes usually
patterns of inheritance develops as a female.
• An individual who inherits an X and a Y chromosome
usually develops as a male.

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• This X-Y system of • In the X-Y system, Y and X chromosomes behave
mammals is not the only as homologous chromosomes during meiosis.
chromosomal mechanism • In reality, they are only partially homologous and rarely
of determining sex. undergo crossing over.
• Other options include the • In both testes (XY) and ovaries (XX), the two sex
X-0 system, the Z-W chromosomes segregate during meiosis and each
system, and the haplo- gamete receives one.
diploid system.
• Each egg receives an X chromosome.
• Half the sperm receive an X chromosome and half
receive a Y chromosome.
• Because of this, each conception has about a fifty-
fifty chance of producing a particular sex.

• In humans, the anatomical signs of sex first appear 2. Sex-linked genes have unique patterns of
when the embryo is about two months old. inheritance
• In individuals with the SRY gene (sex-determining
• In addition to their role in determining sex, the sex
region of the Y chromosome), the generic
chromosomes, especially the X chromosome, have
embryonic gonads are modified into testes.
genes for many characters unrelated to sex.
• Activity of the SRY gene triggers a series of
biochemical, physiological, and anatomical features • These sex-linked genes follow the same pattern of
because it regulates many other genes. inheritance as the white-eye locus in Drosophila.
• In addition, other genes on the Y chromosome are
necessary for the production of functional sperm.
• In individuals lacking the SRY gene, the generic
embryonic gonads develop into ovaries.

• If a sex-linked trait is due to a recessive allele, a • Several serious human disorders are sex-linked.
female will have this phenotype only if • Duchenne muscular dystrophy affects one in
homozygous. 3,500 males born
• Heterozygous females will be carriers.
• Affected individuals rarely live past their early
• Because males have only one X chromosome 20s.
(hemizygous), any male receiving the recessive
• This disorder is due to the mutation in an X-linked gene
allele from his mother will express the trait. for a key muscle protein, called dystrophin.
• The chance of a female inheriting a double dose of • The disease is characterized by a progressive weakening
the mutant allele is much less than the chance of a of the muscles and a loss of coordination.
male inheriting a single dose.
• Therefore, males are far more likely to inherit sex-
linked recessive disorders than are females.

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• Hemophilia is a sex-linked recessive trait defined • Although female mammals inherit two X
by the absence of one or more clotting factors. chromosomes, only one X chromosome is active.
• Individuals with hemophilia have prolonged • Therefore, males and females have the same
bleeding because a firm clot forms slowly. effective dose (one copy ) of genes on the X
• Bleeding in muscles and joints can be painful and lead chromosome.
to serious damage. • During female development, one X chromosome per
cell condenses into a compact object, a Barr body.
• Individuals can be treated with intravenous
injections of the missing protein. • This inactivates most of its genes.
• The condensed Barr body chromosome is
reactivated in ovarian cells that produce ova.

• Mary Lyon, a British geneticist, has demonstrated • In humans, this mosaic pattern is evident in women
that the selection of which X chromosome to form who are heterozygous for a X-linked mutation that
the Barr body occurs randomly and independently prevents the development of sweat glands.
in embryonic cells at the time of X inactivation. • A heterozygous woman will have patches of normal
• As a consequence, females consist of a mosaic of skin and skin patches lacking sweat glands.
cells, some with an active paternal X, others with
an active maternal X.
• After Barr body formation, all descendent cells have the
same inactive X.
• If a female is heterozygous for a sex-linked trait,
approximately half her cells will express one allele and
the other half will express the other allele.

• Similarly, the orange and black pattern on

tortoiseshell cats is due to patches of cells Errors and
THE CHROMOSOMAL BASIS OF INHERITANCE:
expressing an orange allele while others have a Exceptions in Chromosomal Inheritance
nonorange allele.
Intended learning outcomes (ILOs)
1. How do the alterations of chromosome number or structure
cause some genetic disorders?
2. How the phenotypic effects of some mammalian genes depend
on whether they are inherited from the mother or the father
(imprinting)?
3. How do the extranuclear genes exhibit a non-Mendelian
pattern of inheritance?

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Introduction 1. Alterations of chromosome number or
• Sex-linked traits are not the only notable deviation structure cause some genetic disorders
from the inheritance patterns observed by Mendel. • Nondisjunction occurs when problems with the
• Also, gene mutations are not the only kind of meiotic spindle cause errors in daughter cells.
changes to the genome that can affect phenotype. • This may occur if
• Major chromosomal aberrations and their tetrad chromosomes
do not separate
consequences produce exceptions to standard properly during
chromosome theory. meiosis I.
• Alternatively, sister
chromatids may fail
to separate during
meiosis II.

• As a consequence of nondisjunction, some gametes • Aneuploidy can also occur during failures of the
receive two of the same type of chromosome and mitotic spindle.
another gamete receives no copy. • If aneuploidy happens early in development, this
• Offspring results from fertilization of a normal condition will be passed along by mitosis to a large
gamete with one after nondisjunction will have an number of cells.
abnormal chromosome number or aneuploidy.
• This is likely to have a substantial effect on the
• Trisomic cells have three copies of a particular organism.
chromosome type and have 2n + 1 total chromosomes.
• Monosomic cells have only one copy of a particular
chromosome type and have 2n - 1 chromosomes.
• If the organism survives, aneuploidy typically leads
to a distinct phenotype.

• Organisms with more than two complete sets of • Polyploids are more nearly normal in phenotype
chromosomes, have undergone polypoidy. than aneuploids.
• This may occur when a normal gamete fertilizes • One extra or missing chromosome apparently
another gamete in which there has been upsets the genetic balance during development
nondisjunction of all its chromosomes. more than does an entire extra set of chromosomes.
• The resulting zygote would be triploid (3n).
• Alternatively, if a 2n zygote failed to divide after
replicating its chromosomes, a tetraploid (4n)
embryo would result from subsequent successful
cycles of mitosis.

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• Breakage of a chromosome can lead to four types • An inversion occurs when a chromosomal
of changes in chromosome structure. fragment reattaches to the original chromosome
• A deletion occurs when a chromosome fragment but in the reverse orientation.
lacking a centromere is lost during cell division. • In translocation, a chromosomal fragment joins a
• This chromosome will be missing certain genes. nonhomologous chromosome.
• Some translocations are reciprocal, others are not.
• A duplication occurs when a fragment becomes
attached as an extra segment to a sister chromatid.

• Deletions and duplications are common in meiosis. • Several serious human disorders are due to
• Homologous chromatids may break and rejoin at alterations of chromosome number and structure.
incorrect places, such that one chromatid will lose more • Although the frequency of aneuploid zygotes may
genes than it receives.
be quite high in humans, most of these alterations
• A diploid embryo that is homozygous for a large are so disastrous that the embryos are
deletion or male with a large deletion to its single X spontaneously aborted long before birth.
chromosome is usually missing many essential • These developmental problems result from an
genes and this leads to a lethal outcome. imbalance among gene products.
• Duplications and translocations are typically harmful. • Certain aneuploid conditions upset the balance
• Reciprocal translocation or inversion can alter less, leading to survival to birth and beyond.
phenotype because a gene’s expression is influenced • These individuals have a set of symptoms - a syndrome
by its location. - characteristic of the type of aneuploidy.

• One aneuploid condition, Down syndrome, is due • Most cases of Down syndrome result from
to three copies of chromosome 21. nondisjunction during gamete production in one
• It affects one in 700 children born in the United States. parent.
• Although chromosome 21 is the smallest human • The frequency of Down syndrome correlates with
chromosome, it severely alters an individual’s the age of the mother.
phenotype in specific ways. • This may be linked to some age-dependent abnormality
in the spindle checkpoint during meiosis I, leading to
nondisjunction.
• Trisomies of other chromosomes also increase in
incidence with maternal age, but it is rare for
infants with these autosomal trisomies to survive
for long.

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• Nondisjunction of sex chromosomes produces a • Klinefelter’s syndrome, an XXY male, occurs once
variety of aneuploid conditions in humans. in every 2000 live births.
• These individuals have male sex organs, but are sterile.
• Unlike autosomes, this aneuploidy upsets the
genetic balance less severely. • There may be feminine characteristics

• This may be because the Y chromosome contains • Their intelligence is normal.

relatively few genes. • Males with an extra Y chromosome (XYY) tend to
• Also, extra copies of the X chromosome become somewhat taller than average.
inactivated as Barr bodies in somatic cells. • Trisomy X (XXX), which occurs once in every
2000 live births, produces healthy females.
• Monosomy X or Turner’s syndrome (X0), which
occurs once in every 5000 births, produces
phenotypic, but immature females.

• Structural alterations of chromosomes can also • Chromosomal translocations between

cause human disorders. nonhomologous chromosomes are also associated
with human disorders.
• Deletions, even in a heterozygous state, cause
severe physical and mental problems. • Chromosomal translocations have been implicated
in certain cancers, including chronic myelogenous
• One syndrome, cri du chat, results from a specific leukemia (CML).
deletion in chromosome 5. • CML occurs when a fragment of chromosome 22
• These individuals are mentally retarded, have a small switches places with a small fragment from the tip of
chromosome 9.
head with unusual facial features, and a cry like the
mewing of a distressed cat. • Some individuals with Down syndrome have the
• This syndrome is fatal in infancy or early childhood.
normal number of chromosomes but have all or part
of a third chromosome 21 attached to another
chromosome by translocation.

2. The phenotypic effects of some • Two disorders with different phenotypic effects,
mammalian genes depend on whether they Prader-Willi syndrome and Angelman syndrome,
were inherited from the mother or the are due to the same cause, a deletion of a specific
segment of chromosome 15.
father (imprinting)
• Prader-Willi syndrome is characterized by mental
• For most genes it is a reasonable assumption that a retardation, obesity, short stature, and unusually small
specific allele will have the same effect regardless of hands and feet.
whether it was inherited from the mother or father.
• These individuals inherit the abnormal chromosome
• However, for some traits in mammals, it does depend from their father.
on which parent passed along the alleles for those
traits. • Individuals with Angelman syndrome exhibit
spontaneous laughter, jerky movements, and other motor
• The genes involved are not sex linked and may or may not and mental symptoms.
lie on the X chromosome.
• This is inherited from the mother.

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• The difference between the disorders is due to • In the new generation,
genomic imprinting. both maternal and
• In this process, a gene on one homologous paternal imprints are
chromosome is silenced, while its allele on the apparently “erased” in
homologous chromosome is expressed. gamete-producing cells.
• Then, all chromosomes
• The imprinting status of a given gene depends on
are reimprinted according
whether the gene resides in a female or a male.
to the sex of the
• The same alleles may have different effects on individual in which they
offspring, depending on whether they arrive in the
reside.
zygote via the ovum or via the sperm.

• In many cases, genomic imprinting occurs when

methyl groups are added to cytosine nucleotides on
one of the alleles.
• Heavily methylated genes are usually inactive.
• The animal uses the allele that is not imprinted.
• In other cases, the absence of methylation in the
vicinity of a gene plays a role in silencing it.
• The active allele has some methylation.
• Several hundred mammalian genes, many critical
for development, may be subject to imprinting.
• Imprinting is critical for normal development.

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