BIO 10 BIO 10 Lecture 11Lecture 11BIO 10 BIO 10 Lecture 11Lecture 11

REPRODUCTION: REPRODUCTION:

HUMAN HEREDITYHUMAN 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 Mutations1. 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 213. 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-than-

normal 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 termAverage life span 4 months

– Example: Patau Syndrome (Trisomy 13)

Also, VERY, VERY sick babies!Most do not make it to termAverage 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?