Download BIO 10 Lecture 2

BIO 10
Lecture 11
REPRODUCTION:
HUMAN HEREDITY
I. Mutants versus Variants
• Mutation: A change in the sequence, quantity
or location of DNA within the genome that is
found in less than 1% of the population
– Mutant: An individual who expresses the phenotype
associated with a mutation
• Variation: A change in the sequence, quantity
or location of DNA within the genome that is
found in more than 1% of the population
– Variant: An individual who expresses the phenotype
associated with a variation
• Example: A person with sickle cell anemia is a
mutant; a person with red hair is a variant
II. Types of Mutations
1. Change in a DNA sequence that can lead to a
mutant phenotype
– E.g. Sickle cell anemia is caused by a single base-pair
substitution in the human beta globin gene
2. Change in the quantity of DNA in the
genome that can lead to mutant phenotype
– E.g. Down Syndrome is caused by an extra copy of
human chromosome 21
3. Change in the location of a DNA
sequence that can lead to a
mutant phenotype
– E.g. Muscular dystrophy can be
caused by the breakage and
relocation of a segment of the
human X chromosome
III. The 5 Inheritance Patterns of
Single Gene Mutations
1. Autosomal recessive
– Mutation involves a gene on an autosome (1-22)
– Both copies must be mutant for a person to be
affected (aa), where “a” is the mutant allele
– Usually no bias between males and females
– Most common type of inheritance pattern
– Is the major risk of inbreeding
– Standard pattern: No prior family history
– Includes many nasty and fatal childhood
diseases: sickle cell anemia, cystic fibrosis, Tay
Sachs
Example: Sickle-cell anemia
• Prevalent in populations in or from areas of
the world with high rates of malaria
• Red blood cells become distorted into sickle
shape, clog capillaries, and cannot efficiently
carry oxygen
• Mutation is in the gene that codes for the chain polypeptide of the protein hemoglobin.
• The mutation causes the substitution of one amino acid,
causing the polypeptide chain to coalesce into crystals that
distort the red blood cells.
• Persons with one “s” allele and one normal S allele do not
have the condition, but are called “carriers” because they can
pass the gene on to their offspring
• ~1 in 12 African Americans are carriers (Ss)
• Carriers are protected against malarial infection
• Explains high rate of heterozygosity for this mutation in
certain populations but not others
• It is thought that more humans have died of malaria over
the past 100,000 years than any other cause
Example: Cystic Fibrosis
• Prevalent in Caucasians
• 1 in 22 Caucasians in a carrier
• Lack of a chloride ion channel in the plasma
membrane of epithelial cells causes salt to become
trapped within the cells
• Water flows into the cells, drying the outside of the
cell and making mucous thicker than normal
• Biggest problem is in lining of lungs and digestive tract
• Thick mucous in lungs is a breeding ground for bacteria
• Lungs become full of scar tissue from repeated infections and
eventually fail
• Slender ducts from gall bladder and other organs delivering
digestive enzymes to the small intestine become clogged
• Malnutrition used to be a huge problem
• Now children with the disorder eat digestive enzymes in pill
form with their food
• Carriers are protected against fatal dehydration
Example: Tay Sachs
• Prevalent among Jews of Central European descent
• 1 in 30 is a carrier
• One of the cruelest of childhood diseases
• Babies are normal until about 6 months of age
• A relentless decline follows, characterized by progressive
deafness, blindness, and loss of the ability to swallow
• Most children die by the age of 5 or 6 years
• Caused by a lack of the enzyme hexosaminidase A
• Catalyzes the degradation of a class of fatty acids called
gangliosides
• Without the enzyme, gangliosides begin to accumulate in
the brain
• By about 6 months, enough accumulation for symptoms
• No cure
• Most Eastern European jews are now tested for
being carriers
• Rates of the disease have declined dramatically
2. Autosomal dominant
– Mutation involves a gene on an autosome (1-22)
– Only one copy must be mutant for a person to be affected:
(Aa), where “A” in the mutant allele
– Often worse if a person has two mutant alleles (AA)
– Usually no bias between males and females
– Often mild or late onset
• Fatal mutations are quickly lost from the population because
children with them will die and never pass the mutation on
• Only mild or late onset (post-reproductive age onset) can be
passed through a family
– Examples of mild form: Nail-patella syndrome, polydactyly
– Examples of late-onset form: Inherited breast cancer,
familial Alzheimer’s Disease, Huntington’s Disease
– Second most common inheritance pattern
– If a person has an affected parent, he/she has a 50%
chance of being affected
– Seen in every generation of the family
Example: Huntington’s Disease
• Late onset neurological disorder (45+)
• Mutants pass the mutation on to their children before they
know they are affected
• Rare; only ~8 people per 100,000
• Caused by a mutation in the Huntingtin gene
• Protein aggregates inappropriately in brain cells
• Major symptoms:
• Uncontrolled movements of the limbs
• Rapid neurological decline
• Psychosis
• No good treatment or cure
• DNA testing can identify affected individuals
presymptomatically
• Only about 3% of “at risk” individuals choose to have the
testing
• Prefer to live with some hope rather than none
Example: Inherited Alzheimer’s Disease
• AD can be inherited or sporadic
• Characterized by sticky “plaques” in brain tissue
• Inherited forms:
•
•
•
•
Much earlier onset (typically in 30’s – 40’s)
More rapid decline (death in 5 years)
No good treatments or cure
Most “at risk” choose not to be tested
• Can be caused by mutations in one of several genes
• Example: APP gene on chromosome 21
• Integral membrane protein
• If cleaved improperly, secretion of “sticky” degradation
product on surface of brain cells
• Accumulation damages brain cells
• Individuals with Down Syndrome almost always get AD by
mid-40’s
• Make 1.5 times more APP than normal
Example: Inherited Breast Cancer
• “Two-hit” hypothesis
• Breast cancer caused by loss of both copies of a tumor
supressor gene (BRCA-1) in the same breast cell
• Mutation rate ~1/100,000 per gene
• To lose both copies in a single cell is unlikely:
• (10-5) x (10-5) = 1 in 10,000,000,000
• If female comes into life with one copy already mutated
• At greater risk because only 1/100,000 chance
• Lots more than 100,000 breast cells per breast
• Symptoms:
• Often many affected female relatives
• Earlier onset than most breast cancers (pre-menopause)
• Tumors in both breasts
• BUT… Prevention possible
• DNA testing followed by prophylactic breast removal
• Or … mammograms every three months to catch tumors
early
3. X-linked recessive
– Mutation involves a gene on the X chromosome
– In females, both copies must be mutant for her to be
affected (Xa Xa)
– In males, only one copy must be mutant since males
only have one copy of all genes on the X chromosome Xa
Y)
• Therefore, many more males affected than females
• May help account for the fact that the human sex ratio at
birth is slightly in favor of males
Examples include Duchenne muscular
dystrophy, hemophilia, ALD,
red-green colorblindness
4. X-linked dominant
– Mutation involves a gene on the X chromosome
– Only one copy of the gene must be mutated for a
female to be affected (XA Xa); Males who inherit the
allele are always affected and may even die (XA Y)
– More common in females than in males
• Females can get it from Mom or Dad, males only from
Mom
• In some cases, males do not survive embryogenesis
Example: Hypertrichosis
• Excessive hairiness
• If mother is affected, half her sons and half her daughters
are affected
• If father is affected, ALL his daughters (but none of his
sons) will be affected
5.
Y-linked
– Mutation involves one of the few genes located on the Y
chromosome
– Always dominant since can never be observed in the
recessive state
– Is always passed from father to son, never from mother to
son
– Never seen in females
– Rare, since there are so few genes of the Y chromosome
– Examples include: Male infertility, hairy ears, faulty tooth
enamel
IV. Pedigree Analysis
Two Sample Pedigree Problems:
• Gabby and Ted already
have two children with
CF
• What is the probability
that their next child will
have CF?
• Andy has a brother with
CF but does not know if he
is a carrier
• Andy’ wife, Ann, knows
she is a carrier for CF
• What is the probability that
Andy and Ann’s first child
will have CF?
V. Chromosome Mutations
1. Polyploidy
– Aberrations in the number of chromosome
sets (1 set, 2 sets, 3 sets, etc.)
– Animals and many plants are diploid (have
two of each chromosome).
– Sometimes organisms are formed with more
than this diploid set and are called polyploid.
– Although lethal for humans, polyploid plants
may be more robust (many crop species are
polyploid, like wheat)
• Most common cause of human polyploidy is
dispermic fertilization
• Triploid fetuses have 69 chromosomes (3 sets of 23)
• Aneuploidy
– Incorrect chromosome number.
– Usually involves one missing or extra
chromosome (e.g. 3 copies of 21)
– Members of the same species almost always
have the same number of chromosomes.
– Exceptions with fewer or more than the normal
number commonly occur (5 percent of human
pregnancies), but are usually lethal
– Aneuploidy is caused by non-disjunction—failure
of homologous chromosomes or sister chromatids
to separate during meiosis, creating sperm or
eggs with more or less than the normal 23
chromosomes
Non-Disjunction
Example: Down syndrome, Trisomy 21
• Most common form of aneuploidy in human
births (0.1 percent of all live births).
• Ninety-five percent are caused by trisomy
21.
• Phenotype—small, oval head; lower-thannormal IQ; short stature; reduced life span;
and infertility in males.
• Most trisomy 21 is result of non-disjunction
during egg formation; only 10 percent
during sperm formation. Detected by
karyotype analysis.
• Frequency of non-disjunction (and Down
syndrome) increases with age of the
mother.
– Example: Edwards Syndrome (Trisomy 18)
VERY, VERY sick babies!
Most do not make it to term
Average life span 4 months
– Example: Patau Syndrome (Trisomy 13)
Also, VERY, VERY sick babies!
Most do not make it to term
Average life span also ~4
months
• Sex Chromosome Aneuploidies
– Examples.
• Turner Syndrome
– Sterile females with XO
– Shield chest
– Short
– Neck webbing
• Klinefelter Syndrome
– Sterile males with XXY
Why are Sex Chromosome Aneuploides
more Viable than those of the Autosomes?
• Female mammals inactivate one of their X
chromosomes in each cell
– Occurs at day 16 of embryogenesis in humans
– Each cell makes its choice independently
– Once the cell has made its choice, all its mitotic daughter
cells maintain that same X inactivated
– Is a way of equalizing gene dosage between males and
females
• XXY males also inactivate one of the X
chromosomes
• XO females and normal males (XY) do not inactivate
their X since they have only one
• Tortoise Shell Cats
– Are almost always female
– Have a coat color gene located on the
X chromosome
• O = orange, o = black
– During early embryogenesis, each cell
inactivates one of these and then
mitotically divides to produce a cell
lineage with the same X inactivated
– In the adult cat, leads to a splotchy
phenotype of orange and black patches
Each cat has a
unique splotchy
pattern because the
developmental
decisions by each
cell will be different
in each embryo
Rare tortoise
shell male =
XXY
Klinefelter
kitty!!
Short Review of Lecture 11
• What is the difference between a mutant and a
variant?
• What are the different types of mutations?
• What are the 5 different possible inheritance
patterns for diseases under the control of a
single gene?
• What is the difference between polyploidy and
aneuploidy? Which is more viable in humans?
• What are some examples of human aneuploidies
involving numbered chromosomes? Sex
chromosomes?
• Why are aneuploides of sex chromosomes better
tolerated in mammals than those of autosomes?