Understanding Inheritance Patterns in Human Genetic Disorders

1. Inheritance Patterns Many inherited disorders in humans are controlled by a single gene. All of our somatic cells possess two copies of each gene, one inherited from your mother and one inherited from your father. 46,XY male karyotype

2. Most inherited disorders are caused by autosomal recessive alleles • Autosomes are the 22 pairs of chromosomes that are not the sex chromosomes • Alleles are all of the alternate forms of a gene (ie. B and b) • Recessive means it takes two abnormal copies to exhibit the full blown phenotype • Examples of autosomal recessive disorders are : cystic fibrosis, sickle-cell disease, PKU • A Punnet Square demonstrating inheritance of an autosomal recessive deafness is found at the right Normal Dd Normal Dd PARENTS D D Eggs Sperm DD Normal d d Dd Normal (carrier) Dd Normal (carrier) OFFSPRING dd Deaf Figure 9.9A

3. Found on Chromosome 12

4. Examples: achondroplasia, Huntington’s disease • A few inherited disorders are caused by dominant alleles. Dominant alleles hide recessive alleles, phenotypically. Figure 9.9B

5. Autosomal Dominant Inheritance

6. Table 9.9

7. Sex-linked disorders affect mostly males • Most sex-linked human disorders are due to recessive alleles • These sex linked alleles are forms of genes found on the X chromosome. A male has only one X chromosome • Examples: hemophilia, red-green color blindness • These are mostly seen in males, but can be seen in females. • A male receives a single X-linked allele from his mother, and will have the disorder, while a female has to receive the allele from both parents to be affected Figure 9.23A

8. These figures illustrate inheritance patterns for white eye color (r) in the fruit fly, an X-linked recessive trait • Their inheritance pattern reflects the fact that males have one X chromosome and females have two Female Male Female Male Female Male XRXR XrY XRXr XRY XRXr XrY XR Xr XR XR XR Xr Y XRXr XRXR XRXr Y Y Xr Xr XRY XrXR XRY XrXr XRY XrY XrY R = red-eye allele r = white-eye allele Figure 9.22B-D

9. X-Linked Recessive Inheritance

10. X-Linked Dominant Inheritance

11. Incomplete dominance results in intermediate phenotypes P GENERATION Whiterr • When an offspring’s phenotype—such as flower color— is in between the phenotypes of its parents, it exhibits incomplete dominance Red RR Gametes R r PinkRr F1 GENERATION 1/2 R 1/2 r 1/2 R 1/2 R Eggs Sperm RedRR 1/2 r 1/2 r PinkRr PinkrR F2 GENERATION Whiterr Figure 9.12A

12. Incomplete dominance in human hypercholesterolemia (high levels of cholesterol in the blood) GENOTYPES: HH Homozygousfor ability to makeLDL receptors Hh Heterozygous hh Homozygousfor inability to makeLDL receptors PHENOTYPES: LDL LDLreceptor Cell Normal Mild disease Severe disease Figure 9.12B

13. Codominance-The individual expresses both phenotypes and neither is dominant.

14. Type AB express both antigens

15. Mitochondrial Gene Inheritance

16. Mitochondrial Disorders

17. Mitochondrial Disorders • Depletion of mtDNAInfantile myopathyFatal"Later-onset"AZT treatmentSeveral types of mtDNA defectDeafnessDiabetesExternal ophthalmoplegia (PEO)SporadicMaternalDominantRecessiveLeigh'sMyopathyRhabdomyolysisSensory neuropathySystemic disorders • mtDNA Point mutationsCardiomyopathyLeber's optic neuropathyLeigh's syndromeMELASMERRFNARP/MILSSingle deletion or duplicationAtaxia, LeukodystrophyDiabetes: Maternal inheritance   Kearns-SayrePearson'sPEO: SporadicMultiple deletionsAgingMyositisInclusion bodyCOX- muscle fibersMNGIEPEOWolfram

18. Mitochondrial Inheritance Mitochondrial disease begins to become apparent once the number of affected mitochondria reaches a certain level; this phenomenon is called 'threshold expression'.

19. In class………………………. • What is the mode of inheritance of the disorder you are researching? • If you are studying a particular cell type, are there diseases associated with this cell type when it is mutated and how are those diseases inherited?