Chromosomes and Human Genetics

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Chromosomes andHuman Genetics

• Chapter 15

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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

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Philadelphia Chromosome

• First abnormal chromosome to be associated with a
  cancer
• Associated with a chronic leukemia
• Overproduction of white blood cells

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A Reciprocal Translocation
1
2

• Chromosome 9 and chromosome 22 exchanged pieces

6
13
15
19
20
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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

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Understanding Chromosomes

• 1882 - Walter Fleming
• 1887 - August Weismann
• 1900 - Rediscovery of Mendels work

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Genes

• Units of information about heritable traits
• In eukaryotes, distributed among chromosomes
• Each has a particular locus
• Location on a chromosome

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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

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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

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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

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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

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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

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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)
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Sex Determination
eggs
sperm
Female germ cell
Male germ cell
sex chromosome combinations possible in new
individual
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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

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Effect of YChromosome
appearance of structures that will give rise
to external genitalia
appearance of uncommitted duct system of
embryo at 7 weeks
7 weeks
Y present
Y absent
Y present
Y absent
testes
ovaries
10 weeks
ovary
testis
birth approaching
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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

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Discovering Linkage
One cross
homozygous dominant female
recessive male
x
Gametes
heterozygous female
heterozygous male
All F1 offspring have red eyes
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Discovering Linkage
Reciprocal cross
homozygous recessive female
dominant male
x
Gametes
X
X
X
Y
heterozygous females
recessive males
F1 offspring
Half are red-eyed females, half are white-eyed
males
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Discovering Linkage

• Morgans crosses showed relationship between sex
  and eye color
• Females can have white eyes
• Morgan concluded gene must be on the X chromosome

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Linkage Groups

• Genes on one type of chromosome
• Fruit flies
• 4 homologous chromosomes
• 4 linkage groups
• Indian corn
• 10 homologous chromosomes
• 10 linkage groups

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Full Linkage
AB
ab
x
Parents
F1 offspring
All AaBb
meiosis, gamete formation
50AB
50ab
With no crossovers, half of the gametes have one
parental genotype and half have the other
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Incomplete Linkage
AC
ac
x
Parents
F1 offspring
All AaCc
meiosis, gamete formation
Unequal ratios of four types of gametes
a
a
A
A
C
c
C
c
Most gametes have parental genotypes
A smaller number have recombinant genotypes
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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
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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

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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

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Pedigree for Polydactly
male
female
5,5 6,6

5,5 6,6
6,6 5,5
6,6 5,5
6
7
5,5 6,6
5,5 6,6
5,5 6,6
5,5 6,6
5,6 6,7
12
6,6 6,6
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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

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Genetic Disorder

• Inherited conditions that cause mild to severe
  medical problems
• Why dont they disappear?
• Mutation introduces new rare alleles
• In heterozygotes, harmful allele is masked, so it
  can still be passed on to offspring

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Autosomal Recessive Inheritance Patterns

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

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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- PHOSOPHATE
GALACTOSE-1- PHOSOPHATE
LACTOSE
GALACTOSE
glucose
intermediate in glycolysis
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Autosomal Dominant Inheritance

• Trait typically appears in every generation

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Huntington Disorder

• Autosomal dominant allele
• Causes involuntary movements, nervous system
  deterioration, death
• Symptoms dont usually show up until person is
  past age 30
• People often pass allele on before they know they
  have it

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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

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X-Linked Recessive Inheritance

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

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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

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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

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Hutchinson-Guilford 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

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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

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Duplication
normal chromosome
one segment repeated
three repeats
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Inversion

• A linear stretch of DNA is reversed
• within the chromosome

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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

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Translocation
chromosome
nonhomologous chromosome
reciprocal translocation
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Deletion

• Loss of some segment of a chromosome
• Most are lethal or cause serious disorder

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Aneuploidy

• Individuals have one extra or less chromosome
• (2n 1 or 2n - 1)
• Major cause of human reproductive failure
• Most human miscarriages are aneuploids

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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

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Nondisjunction
n 1
n 1
n - 1
n - 1
chromosome alignments at metaphase I
nondisjunction at anaphase I
alignments at metaphase II
anaphase II
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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

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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

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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

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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

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Phenotypic Treatments

• Symptoms of many genetic disorders can be
  minimized or suppressed by
• Dietary controls
• Adjustments to environmental conditions
• Surgery or hormonal treatments

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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

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Prenatal Diagnosis

• Amniocentesis
• Chorionic villus sampling
• Fetoscopy
• All methods have some risks

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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