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Presentation on theme: "REPRODUCTION: HUMAN HEREDITY"— Presentation transcript:


2 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

3 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

4 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

5 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


7 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

8 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

9 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

10 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


12 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

13 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

14 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

15 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

16 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

17 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

18 IV. Pedigree Analysis

19 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?

20 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)

21 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

22 Non-Disjunction

23 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.


25 Example: Edwards Syndrome (Trisomy 18)
VERY, VERY sick babies! Most do not make it to term Average life span 4 months

26 Example: Patau Syndrome (Trisomy 13)
Also, VERY, VERY sick babies! Most do not make it to term Average life span also ~4 months

27 Sex Chromosome Aneuploidies
Examples. Turner Syndrome Sterile females with XO Shield chest Short Neck webbing

28 Klinefelter Syndrome Sterile males with XXY

29 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

30 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

31 Each cat has a unique splotchy pattern because the developmental decisions by each cell will be different in each embryo

32 Rare tortoise shell male = XXY
Klinefelter kitty!!

33 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?


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