Chromosomes and

Human Genetics
Chromosomes & Cancer

• Some genes on chromosomes control cell

growth and division

• If something affects chromosome structure

at or near these loci, cell division may spiral
out of control

• This can lead to cancer

Philadelphia Chromosome

• First abnormal chromosome to be

associated with a cancer

• Reciprocal translocation
• Causes chronic myelogenous
leukemia (CML)
Genes

• Units of information about heritable

traits
• In eukaryotes, distributed among
chromosomes
• Each has a particular locus
– Location on a chromosome
 Homologous
Chromosomes
• Homologous autosomes are
identical in length, size, shape, and
gene sequence
• Sex chromosomes are nonidentical
but still homologous
• Homologous chromosomes interact,
then segregate from one another
during meiosis
Alleles

• Different molecular forms of a gene

• Arise through mutation
• Diploid cell has a pair of alleles at
each locus
• Alleles on homologous chromosomes
may be same or different
Sex Chromosomes

• Discovered in late 1800s

• Mammals, fruit flies
– XX is female, XY is male

• In other groups XX is male, XY female

• Human X and Y chromosomes function
as homologues during meiosis
Karyotype Preparation -
Stopping the Cycle

• Cultured cells are arrested at

metaphase by adding colchicine

• This is when cells are most

condensed and easiest to identify
Karyotype Preparation

• Arrested cells are broken open

• Metaphase chromosomes are fixed
and stained
• Chromosomes are photographed
through microscope
• Photograph of chromosomes is cut
up and arranged to form karyotype
diagram
Karyotype Diagram

1 2 3 4 5 6 7 8 9 10 11
12

13 14 15 16 17 18 19 20 21 22 XX (or XY)

Figure 12.4
Page 197
 Sex female male
Determinatio (XX) (XY)

n
eggs sperm

X x Y

X x X

X X

X XX XX

Y XY XY
Figure 12.5
Page 198
The Y Chromosome

• Fewer than two dozen genes identified

• One is the master gene for male sex
determination
– SRY gene (sex-determining region of Y)

• SRY present, testes form

• SRY absent, ovaries form
 appearance of structures appearance of
that will give rise to “uncommitted” duct system
external genitalia of embryo at 7 weeks
Effect of Y
Chromosome
7 weeks

Y Y Y Y
present absent present absent

testes ovaries

10 weeks

ovary

birth approaching testis

Figure 12.6
Page 199
Androgen Deprivation

• The “Guevedoces” of the Dominican

Republic
• Reports from isolated villages asserted
that ”children appearing to be girls
turned into men at puberty.”
(Urological Sciences Research
Foundation)
• http://www.usrf.org/news/010308-guevedoces.html
Male Pseudohermaphrodites

• “These children appeared to be girls

at birth, but at puberty these 'girls'
sprout muscles, testes, and a penis.
For the rest of their lives they are
men in nearly all respects …. Their
underlying pathology was found to
be a deficiency of the enzyme, 5-
alpha Reductase. “
Map
From the American Journal of
Medicine (Am. L. Med. 62: 170-191, 1977)
From the American Journal of
Medicine (Am. L. Med. 62: 170-191, 1977)
From the American Journal of
Medicine (Am. L. Med. 62: 170-191, 1977)
• 6. And for the rest of their lives, the
guevedoces resemble the other Dominican
men in all respects except:
* Beard growth is scanty.
* There is no hairline recession.
* None has acne.
* The prostate remains small
The X Chromosome

• Carries more than 2,300 genes

• Most genes deal with nonsexual

traits

• Genes on X chromosome can be

expressed in both males and females
 homozygous dominant recessive male
Discovering female

Linkage Gametes: x
X X X Y
All F1
have red eyes

Gametes: x
X X X Y

1/2 1/2
1/4
1/2 1/2
F2 1/4 1/4
generation:
1/4
Figure 12.7
Page 200
Linkage Groups

• Genes on one type of

chromosome
• Fruit flies
– 4 homologous chromosomes
– 4 linkage groups
• Not all genes on chromosome
are tightly linked
 Full Linkage
A a
B x b
Parents: a
A
AB b ab
B

F1 offspring: All AaBb

meiosis, gamete formation

Equal ratios of two A a

types of gametes: B b

Figure 12.8a
50% AB 50% ab Page 201
 Independent Assortment

Metaphase I:
A Aa a
OR A Aa a

B B b b b b B B

Metaphase II:
A A a a A A a a

B B b b b b B B

B B b b b b B B
Gametes: A A a a A A a a

1/4 AB 1/4 1/4 1/4 aB

ab Ab
 Incomplete Linkage
AC ac
A a
x
Parents: C A c a
C c
F1 offspring: All AaCc

meiosis, gamete formation

A a A a
Unequal ratios of four C c c C
types of gametes:

parental recombinant Figure 12.8b

genotypes genotypes Page 201
Crossover Frequency

Proportional to the distance that

separates genes
A B C D

Crossing over will disrupt linkage

between A and B more often than C
and D In-text figure
Page 201
Linkage Mapping in Humans

• Linkage maps based on pedigree

analysis through generations

• Color blindness and hemophilia are

very closely linked on X chromosome
 Pedigree male

Symbols female

marriage/mating

offspring in order of birth,

from left to right

Individual showing trait

being studied

sex not specified

I, II, III, IV... generation

Figure 12.9a
Page 202
 Pedigree for Polydactyly

I female male

II
5,5
6,6

III *
5,5 6,6 6,6
6,6 5,5 5,5

IV 6 7
5,5 5,5 5,5 5,5 5,6
6,6 6,6 6,6 6,6 6,7

V 12
6,6
*Gene not expressed in this carrier. 6,6

Figure 12.9b
Page 202
Genetic Abnormality

• A rare, uncommon version of a trait

• Polydactyly
– Unusual number of toes or fingers
– Does not cause any health problems
– View of trait as disfiguring is subjective
New Bond Girl Proud of
Her 'Little Oddity‘ by Jonathan
Crow | October 7 , 2008

“Gemma Arterton … has proven herself to

exceptional not only for her English Rose
beauty, but also because she was born
with six fingers on each hand.”
Genetic Disorder

• Inherited conditions that cause mild to

severe medical problems
• Why don’t they disappear?
– Mutation introduces new rare alleles
– In heterozygotes, harmful allele is
masked, so it can still be passed on to
offspring
 Autosomal Recessive
Inheritance Patterns

• If parents are
both
heterozygous,
child will have a
25% chance of
being affected

Figure 12.10a
Page 204
 Galactosemia

• Caused by autosomal recessive allele

• Gene specifies a mutant enzyme in the
pathway that breaks down lactose
enzyme 1 enzyme 2 enzyme 3

galactose-1- galactose-1-
lactose galactose phosphate phosphate
+
glucose intermediate
in glycolysis

In-text figure
Page 204
One Common Ancestor
Behind Blue Eyes
• People with blue eyes have a single,
common ancestor, according to new
research.
• A team of scientists has tracked down
a genetic mutation that leads to blue
eyes. The mutation occurred between
6,000 and 10,000 years ago. Before
then, there were no blue eyes.
• http://www.livescience.com/health/080131-blue-eyes.html
Percentage Frequency of Light Eyes in and Near Europe

from Beals et al., An Introduction to Anthropology, 1965

Danish geneticist Hans
Eiberg in the journal Human
Genetics
• “Originally, Eiberg says, everyone in the
world had brown eyes. But the mutation acts
as a switch that shuts off the OCA2 gene,
which controls the eye's production of
melanin. Melanin is the pigment that gives
color to eyes and hair.”

• http://www.spiegel.de/international/world/0,1
518,532346,00.html
“Inbred Mutants”
“Brad Pitt's squinting a bit in the light of the
flashbulbs, but he has blue eyes. A new study
suggests he shares a common ancestor with all
the world's other blue-eyed denizens.”

Pitt, Diaz, and Sinatra

Heterochromia

• Heterochromia is an ocular condition

in which one iris is a different color
from the other iris (complete
heterochromia), or where the part of
one iris is a different color from the
remainder (partial heterochromia or
sectoral heterochromia).

http://en.wikipedia.org/wiki/Eye_color
Complete and Sectoral
Heterochromia
Causes of Heterochromia

• Chimeras and Waardenburg

syndrome
• Injury or medication
 Autosomal
Dominant Inheritance

Trait typically
appears in
every
generation

Figure 12.10b
Page 204
Huntington Disorder

• Autosomal dominant allele

• Causes involuntary movements, nervous
system deterioration, death
• Symptoms don’t usually show up until
person is past age 30
• People often pass allele on before they
know they have it
Achondroplasia

• Autosomal dominant allele

• In homozygous form usually leads to
stillbirth
• Heterozygotes display a type of
dwarfism
• Have short arms and legs relative to
other body parts
Achondroplasia
 X-Linked Recessive
Inheritance

• Males show
disorder more
than females
• Son cannot
inherit disorder
from his father

Figure 12.12a
Page 205
Examples of X-Linked Traits

• Color blindness
– Inability to distinguish among some of all
colors
• Hemophilia
– Blood-clotting disorder
– 1/7,000 males has allele for hemophilia A
– Was common in European royal families
Royal Hemophilia

http://www.people.virginia.edu/~rjh9u/roylhema.html
• A Pedigree of Hemophilia in the Royal Families of
Europe
•
• Selected members of the pedigree
• I-1 = King George III
• III-1 and III-2 = Prince Albert and Queen Victoria
• IV-5 and IV-6 = Alice of Hesse and Ludwig IV of Hesse
• V-13 and V-14 = Alix and Nicholas II (Tsar of Russia)
• VI-16 = Alexei
• VIII-1 = Prince Charles
Fragile X Syndrome

• An X-linked recessive disorder

• Causes mental retardation
• Mutant allele for gene that specifies
a protein required for brain
development
• Allele has repeated segments of DNA
Fragile X Syndrome

http://www.tokyo-med.ac.jp/genet/index-e.htmo
Photomicrograph Fragile X
Chromosome
Hutchinson-Gilford Progeria

• Mutation causes accelerated aging

• No evidence of it running in families
• Appears to be dominant
• Seems to arise as spontaneous
mutation
• Usually causes death in early teens
Hutchinson-Gilford Progeria
 Progeria

• “It is caused by mutations in a LMNA

(Lamin A protein) gene on
chromosome 1”
• Patients age 6 to 8 times faster, but
no unusual cancer rates or neuro-
degenerative abnormalities appear
• Associated with mal-formed nuclei
http://en.wikipedia.org/wiki/Progeria
which are also seen in the elderly.
Duplication

• Gene sequence that is repeated

several to hundreds of times
• Duplications occur in normal
chromosomes
• May have adaptive advantage
– Useful mutations may occur in copy
Duplication

normal chromosome

one segment
repeated

three repeats
 Inversion

A linear stretch of DNA is reversed

within the chromosome

segments
G, H, I
become
inverted

In-text
figure
Translocation

• A piece of one chromosome becomes

attached to another nonhomologous
chromosome
• Most are reciprocal
• Philadelphia chromosome arose from a
reciprocal translocation between
chromosomes 9 and 22
Philadelphia Chromosome

http://gslc.genetics.utah.edu/units/disorders/karyotype/reciprocal.cfm
Philadelphia Karyotype

http://gslc.genetics.utah.edu/units/disorders/karyotype/reciprocal.cfm
 Translocation
one chromosome

a nonhomologous
chromosome

nonreciprocal translocation
In-text figure
Page 206

In-text
figure
Page 206
Deletion

• Loss of some segment of a chromosome

• Most are lethal or cause serious disorder
Aneuploidy

• Individuals have one extra or

less chromosome
• (2n + 1 or 2n - 1)
• Major cause of human
reproductive failure
• Most human miscarriages are
aneuploids
Polyploidy

• Individuals have three or more of

each type of chromosome (3n, 4n)
• Common in flowering plants
• Lethal for humans
– 99% die before birth
– Newborns die soon after birth
Nondisjunction

n+1

n+1

n-1

chromosome n-1
alignments at nondisjunction alignments at
metaphase I at anaphase I metaphase II anaphase II
Figure 12.17
Page 208
Down Syndrome

• Trisomy of chromosome 21
• Mental impairment and a variety of
additional defects
• Can be detected before birth
• Risk of Down syndrome increases
dramatically in mothers over age 35
Trisomy 21
Non-disjunction
Karotype Trisomy 21
Mother’s Age

Incidence/1000births

Age = 35
Boy with Down’s Syndrome
Turner Syndrome

• Inheritance of only one X (XO)

• 98% spontaneously aborted
• Survivors are short, infertile females
– No functional ovaries
– Secondary sexual traits reduced
– May be treated with hormones, surgery
Monosomy
(Having only one X chromsome
per cell)
Turner’s Syndrome
Klinefelter Syndrome

• XXY condition
• Results mainly from nondisjunction in
mother (67%)
• Phenotype is tall males
– Sterile or nearly so
– Feminized traits (sparse facial hair,
somewhat enlarged breasts)
– Treated with testosterone injections
Klinefelter

http://www.tokyo-med.ac.jp/genet/index-e.htmo
XYY Condition

• Taller than average males

• Most otherwise phenotypically normal
• Some mentally impaired
• Once thought to be predisposed to
criminal behavior, but studies now
discredit
Phenotypic Treatments

• Symptoms of many genetic disorders

can be minimized or suppressed by
– Dietary controls
– Adjustments to environmental
conditions
– Surgery or hormonal treatments
Genetic Screening

• Large-scale screening programs

detect affected persons
• Newborns in United States
routinely tested for PKU
– Early detection allows dietary
intervention and prevents brain
impairment
Prenatal Diagnosis

• Amniocentesis

• Chorionic villus sampling

• Fetoscopy

• All methods have some risks

Amniocentesis
Pedigree Analysis
Preimplantation Diagnosis

• Used with in-vitro fertilization

• Mitotic divisions produce ball of 8 cells
• All cells have same genes
• One of the cells is removed and its genes
analyzed
• If cell has no defects, the embryo is
implanted in uterus
Preimplant Diagnosis

http://www.layyous.com/book/book%20images/Untitled-196b.jpg