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Chromosomes andHuman Genetics
Chapter 11
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
• Associated with a chronic leukemia
– Overproduction of white blood cells
A Reciprocal Translocation1 2
6
13 15
19 20
Chromosome 9
and chromosome
22 exchanged
pieces
An Altered Gene
• When the reciprocal translocation occurred, a gene at the end of chromosome 9 fused with a gene from chromosome 22
• This hybrid gene encodes an abnormal protein that stimulates uncontrolled division of white blood cells
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
Human Karyotype
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)
Sex Determination
XX
XY
XX
XY
X X
Y
X
sex chromosome combinations possible in new individual
Y
X
sperm
X
X
eggs
Female germ cell Male germ cell
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
Effect of YChromosome
10 weeks
Y present
Y absent
7 weeks
birth approaching
appearance of structuresthat will give rise toexternal genitalia
appearance of “uncommitted” duct system
of embryo at 7 weeks
Y present
Yabsent
testis
ovary
testes ovaries
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
Discovering Linkage
homozygous dominant female
recessive male
Gametes:
XX X Y
All F1 offspring have red eyes
x
heterozygous male
heterozygousfemale
One cross
Discovering Linkage
homozygous recessive female
dominantmale
Gametes:
XX X Y
F1 offspring
x
recessive males
heterozygousfemales
Half are red-eyed females, half are white-eyed males
Reciprocal cross
Discovering Linkage
• Morgan’s crosses showed relationship
between sex and eye color
• Females can have white eyes
• Morgan concluded gene must be on the
X chromosome
Full Linkage
xAB ab
50%AB
50%ab
All AaBb
meiosis, gamete formation
Parents:
F1 offspring:
With no crossovers, half of the gametes have one parental genotype and half have the other
AB
ab
AB
ab
ab
AB
Incomplete Linkage
Parents:
F1 offspring
Unequal ratios of four types of gametes:
All AaCc
x
meiosis, gamete formation
AC acA
C AC
AC
ac
ac
Ac
aC
ac
Most gametes have parental genotypes
A smaller number have recombinant genotypes
Crossover Frequency
Proportional to the distance that
separates genesA B C D
Crossing over will disrupt linkage between
A and B more often than C and D
Linkage Mapping in Humans
• Linkage maps based on pedigree analysis through generations
• Color blindness and hemophilia are very closely linked on X chromosome – Recombination frequency is 0.167%
Pedigree
• Chart that shows genetic connections
among individuals
• Standardized symbols
• Knowledge of probability and Mendelian
patterns used to suggest basis of a trait
• Conclusions most accurate when drawn
from large number of pedigrees
Fig. 11.9, p. 178
male
female
marriage/mating
Individual showing trait being studied
sex not specified
generationI,II, III, IV...
offspring in order of birth, from left to right
I
II
III
IV
V
6 7
12
5,56,6
5,56,6
5,56,6
5,56,6
5,56,6
5,56,6
6,65,5
6,65,5
5,66,7
6,66,6Gene not expressed in this carrier.
Pedigree for Polydactly
I
II
III
IV
V
6 7
12
5,5 6,6
5,5 6,6
5,5 6,6
5,5 6,6
5,5 6,6
5,5 6,6
6,6 5,5
6,6 5,5
5,6 6,7
6,6 6,6*Gene not expressed in this carrier.
*
malefemale
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
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
Galactosemia
• Caused by autosomal recessive allele
• Gene specifies a mutant enzyme in the pathway that breaks down lactose
LACTOSE GALACTOSEGALACTOSE-1-PHOSOPHATE
GALACTOSE-1-PHOSOPHATE
enzyme 1 enzyme 2 enzyme 3
+glucose intermediate
in glycolysis
Autosomal Dominant Inheritance
Trait typically appears in every generation
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
Acondroplasia
• 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
X-Linked Recessive Inheritance
• Males show disorder more than females
• Son cannot inherit disorder from his father
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
Fig. 11.12b, p. 181
I
II
III
IV
V
VI
Albert Victoria
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
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
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
Translocation
chromosome
nonhomologous chromosome
reciprocal translocation
Deletion
• Loss of some segment of a chromosome
• Most are lethal or cause serious disorder
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
n - 1chromosome alignments at metaphase I
nondisjunction at anaphase I
alignments at metaphase II anaphase II
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
Fig. 11.18, p. 185
inci
den
ce
per
1,0
00 b
irth
s
20
15
10
5
020 25 30 35 40 45
mother's age
1 2 3 4 5
6 7 8 9 10 11 12
13 14 15 16 17 18
19 20 21 22 23
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
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
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
Fig. 11.19, p. 186Karyotype analysis
Fetal cells
Centrifugation
Growth for weeks in culture medium
Removal of about 20 ml of amniotic fluid containing suspended cells that were sloughed off from the fetus
A few biochemical analyses with some of the amniotic fluid
Quick determination of fetal sex and analysis of purified DNA
Biochemical analysis for the presence of alleles that cause many different metabolic disorders