Presentation on theme: "REPRODUCTION: HUMAN HEREDITY"— Presentation transcript:
1REPRODUCTION: HUMAN HEREDITY BIO 10 Lecture 11REPRODUCTION:HUMAN HEREDITY
2I. 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 populationMutant: An individual who expresses the phenotype associated with a mutationVariation: A change in the sequence, quantity or location of DNA within the genome that is found in more than 1% of the populationVariant: An individual who expresses the phenotype associated with a variationExample: A person with sickle cell anemia is a mutant; a person with red hair is a variant
3II. Types of Mutations1. Change in a DNA sequence that can lead to a mutant phenotypeE.g. Sickle cell anemia is caused by a single base-pair substitution in the human beta globin gene2. Change in the quantity of DNA in the genome that can lead to mutant phenotypeE.g. Down Syndrome is caused by an extra copy of human chromosome 213. Change in the location of a DNAsequence that can lead to amutant phenotypeE.g. Muscular dystrophy can be caused by the breakage and relocation of a segment of the human X chromosome
4III. The 5 Inheritance Patterns of Single Gene Mutations 1. Autosomal recessiveMutation 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 alleleUsually no bias between males and femalesMost common type of inheritance patternIs the major risk of inbreedingStandard pattern: No prior family historyIncludes many nasty and fatal childhood diseases: sickle cell anemia, cystic fibrosis, Tay Sachs
5Example: Sickle-cell anemia Prevalent in populations in or from areas of the world with high rates of malariaRed blood cells become distorted into sickle shape, clog capillaries, and cannot efficiently carry oxygenMutation 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 infectionExplains high rate of heterozygosity for this mutation in certain populations but not othersIt is thought that more humans have died of malaria over the past 100,000 years than any other cause
7Example: Cystic Fibrosis Prevalent in Caucasians1 in 22 Caucasians in a carrierLack of a chloride ion channel in the plasma membrane of epithelial cells causes salt to become trapped within the cellsWater flows into the cells, drying the outside of the cell and making mucous thicker than normalBiggest problem is in lining of lungs and digestive tractThick mucous in lungs is a breeding ground for bacteriaLungs become full of scar tissue from repeated infections and eventually failSlender ducts from gall bladder and other organs delivering digestive enzymes to the small intestine become cloggedMalnutrition used to be a huge problemNow children with the disorder eat digestive enzymes in pill form with their foodCarriers are protected against fatal dehydration
8Example: Tay Sachs Prevalent among Jews of Central European descent 1 in 30 is a carrierOne of the cruelest of childhood diseasesBabies are normal until about 6 months of ageA relentless decline follows, characterized by progressive deafness, blindness, and loss of the ability to swallowMost children die by the age of 5 or 6 yearsCaused by a lack of the enzyme hexosaminidase ACatalyzes the degradation of a class of fatty acids called gangliosidesWithout the enzyme, gangliosides begin to accumulate in the brainBy about 6 months, enough accumulation for symptomsNo cureMost Eastern European jews are now tested for being carriersRates of the disease have declined dramatically
92. 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 alleleOften worse if a person has two mutant alleles (AA)Usually no bias between males and femalesOften mild or late onsetFatal mutations are quickly lost from the population because children with them will die and never pass the mutation onOnly mild or late onset (post-reproductive age onset) can be passed through a familyExamples of mild form: Nail-patella syndrome, polydactylyExamples of late-onset form: Inherited breast cancer, familial Alzheimer’s Disease, Huntington’s DiseaseSecond most common inheritance patternIf a person has an affected parent, he/she has a 50% chance of being affectedSeen in every generation of the family
10Example: Huntington’s Disease Late onset neurological disorder (45+)Mutants pass the mutation on to their children before they know they are affectedRare; only ~8 people per 100,000Caused by a mutation in the Huntingtin geneProtein aggregates inappropriately in brain cellsMajor symptoms:Uncontrolled movements of the limbsRapid neurological declinePsychosisNo good treatment or cureDNA testing can identify affected individuals presymptomaticallyOnly about 3% of “at risk” individuals choose to have the testingPrefer to live with some hope rather than none
12Example: Inherited Alzheimer’s Disease AD can be inherited or sporadicCharacterized by sticky “plaques” in brain tissueInherited forms:Much earlier onset (typically in 30’s – 40’s)More rapid decline (death in 5 years)No good treatments or cureMost “at risk” choose not to be testedCan be caused by mutations in one of several genesExample: APP gene on chromosome 21Integral membrane proteinIf cleaved improperly, secretion of “sticky” degradation product on surface of brain cellsAccumulation damages brain cellsIndividuals with Down Syndrome almost always get AD by mid-40’sMake 1.5 times more APP than normal
13Example: Inherited Breast Cancer “Two-hit” hypothesisBreast cancer caused by loss of both copies of a tumor supressor gene (BRCA-1) in the same breast cellMutation rate ~1/100,000 per geneTo lose both copies in a single cell is unlikely:(10-5) x (10-5) = 1 in 10,000,000,000If female comes into life with one copy already mutatedAt greater risk because only 1/100,000 chanceLots more than 100,000 breast cells per breastSymptoms:Often many affected female relativesEarlier onset than most breast cancers (pre-menopause)Tumors in both breastsBUT… Prevention possibleDNA testing followed by prophylactic breast removalOr … mammograms every three months to catch tumors early
143. 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 femalesMay help account for the fact that the human sex ratio at birth is slightly in favor of malesExamples include Duchenne muscular dystrophy, hemophilia, ALD,red-green colorblindness
154. 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 malesFemales can get it from Mom or Dad, males only from MomIn some cases, males do not survive embryogenesis
16Example: Hypertrichosis Excessive hairinessIf mother is affected, half her sons and half her daughters are affectedIf father is affected, ALL his daughters (but none of his sons) will be affected
175. Y-linkedMutation involves one of the few genes located on the Y chromosomeAlways dominant since can never be observed in the recessive stateIs always passed from father to son, never from mother to sonNever seen in femalesRare, since there are so few genes of the Y chromosomeExamples include: Male infertility, hairy ears, faulty tooth enamel
19Two Sample Pedigree Problems: Gabby and Ted already have two children with CFWhat is the probability that their next child will have CF?Andy has a brother with CF but does not know if he is a carrierAndy’ wife, Ann, knows she is a carrier for CFWhat is the probability that Andy and Ann’s first child will have CF?
20V. Chromosome Mutations 1. PolyploidyAberrations 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 fertilizationTriploid fetuses have 69 chromosomes (3 sets of 23)
21Aneuploidy 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 lethalAneuploidy 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
23Example: 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.
29Why are Sex Chromosome Aneuploides more Viable than those of the Autosomes? Female mammals inactivate one of their X chromosomes in each cellOccurs at day 16 of embryogenesis in humansEach cell makes its choice independentlyOnce the cell has made its choice, all its mitotic daughter cells maintain that same X inactivatedIs a way of equalizing gene dosage between males and femalesXXY males also inactivate one of the X chromosomesXO females and normal males (XY) do not inactivate their X since they have only one
30Tortoise Shell Cats Are almost always female Have a coat color gene located on the X chromosomeO = orange, o = blackDuring early embryogenesis, each cell inactivates one of these and then mitotically divides to produce a cell lineage with the same X inactivatedIn the adult cat, leads to a splotchy phenotype of orange and black patches
31Each cat has a unique splotchy pattern because the developmental decisions by each cell will be different in each embryo
32Rare tortoise shell male = XXY Klinefelter kitty!!
33Short 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?