1. Patterns of single gene inheritance Mahmoud A. Alfaqih BDS PhD Jordan University of Science and Technology School of Medicine Department of Biochemistry and Physiology

2. Reading material Genetics in Medicine by Thompson and Thompson, 7 th Edition Chapter 7

3. Overview and concepts Need to understand the following terms:  Locus  Allele: Wild type Vs. Variant (mutant)  Mutation  Haplotype  Polymorphic locus

4. Genotype Vs. phenotype Genotype: set of alleles that make up his or her genetic constitution, either collectively at all loci or, more typically, at a single locus Phenotype: the observable expression of a genotype as a morphological, clinical, cellular, or biochemical trait.

5. Pleiotropic  When single abnormal gene produces diverse phenotypic effects  The connection between the gene defect and the various manifestations is neither obvious nor well understood

6. Single gene disorders A disorder that is determined primarily by the alleles at a single locus Homozygous Vs. heterozygous Compound heterozygote: a genotype in which two different mutant alleles of the same gene are present, rather than one normal and one mutant.

7. Hemizygous In the special case in which a male has an abnormal allele for a gene located on the X chromosome and there is no other copy of the gene

8. Pedigrees Single-gene disorders are characterized by their patterns of transmission in families To establish the pattern of transmission, a usual first step is:  Obtain information about the family history.  Summarize the details in the form of a pedigree  Pedigree is a graphical presentation of family tree

9. Important definitions in pedigrees Kindred Proband Sibs Sibship: family of sibs First degree relatives: sibs, offspring, parents Second degree relatives: Grandparents, grandchildren, uncles and aunts, nephews and nieces Third degree relatives: first cousins

10. Important definitions in pedigrees Consanguineous: Couples that have one or more shared ancestors Sporadic case: if the disorder is determined to be due to new mutation in the proband

14. MENDELIAN INHERITANCE

15. Autosomal and X linked inheritance Autosomal disorders, in general, affect males and females equally. Males have only a single X and are therefore hemizygous with respect to X-linked genes Females can be heterozygous or homozygous at X-linked loci. Alleles for most X-linked genes are expressed from only one of the two X chromosomes in any given cell of a female

16. Recessive Inheritance Phenotype expressed only in homozygotes (or male hemizygotes) and not in heterozygotes is recessive. Recessive disorders are due to mutations that reduce or eliminate the function of the gene product Also called loss-of-function mutations.

17. Dominant inheritance A phenotype expressed in both homozygotes and heterozygotes for a mutant allele is inherited as a dominant In a pure dominant disease, homozygotes and heterozygotes for the mutant allele are both affected equally (very rare) Dominant disorders more severe in homozygotes than in heterozygotes (incomplete dominance), more common

18. Factors affecting pedigree patterns 1.Penetrance and Expressivity 2.New mutations 3.Age of onset

19. Penetrance

20. New mutation

21. Other factors that complicate pedigree analysis 1.Allelic heterogeneity 2.Locus heterogeneity: Retinitis pigmentosa 3.Phenotypic heterogeneity

22. Autosomal Recessive Inheritance

23. Typical pedigree of autosomal recessive inheritance

24. Factors that increase carrier mating 1.Consanguinity 2.Inbreeding 3.Genetic isolates

25. Consanguinity

28. Autosomal dominant inheritance

30. Sex limited inheritance When autosomal dominant phenotypes have a sex ratio that differs significantly from 1:1 The defect is autosomally transmitted but expressed in only one sex Example: male-limited precocious puberty

32. X-linked recessive inheritance

35. X linked dominant inheritance

36. Notice the lack of male-to-male transmission

37. Mitochondrial inheritance: Mitochondrial genome  One circular chromosome  16.5 kb in size  Located inside the mitochondrial organelle  Most cells contain at least 1000 mtDNA molecules Mature oocyte has more than 100,000 copies of mtDNA

38. Mitochondrial genome  Codes for 37 genes:  13 polypeptides that are subunits of enzymes of oxidative phosphorylation  two types of ribosomal RNA  22 transfer RNAs required for translating the transcripts of the mitochondria-encoded polypeptides  More than 100 different rearrangements and 100 different point mutations have been identified in mtDNA that cause disease  Disease often involves the central nervous and musculoskeletal systems

40. Replicative segregation of mtDNA  Absence of the tightly controlled segregation seen during mitosis and meiosis of nuclear chromosomes  At cell division, copies of mtDNA in each of the mitochondria in a cell replicate and sort randomly among new mitochondria  The mitochondria, in turn, are distributed randomly between the two daughter cells

41. Homoplasmy and heteroplasmy  When a mutation arises in the mtDNA, it is at first present in only one of the mtDNA molecules in a mitochondrion  With replicative segregation, a mitochondrion containing a mutant mtDNA will acquire multiple copies of mutant DNA  With cell division, a cell containing a mixture of normal and mutant mtDNAs can distribute very different proportions of mutant and wild-type mitochondrial DNA to its daughter cells One daughter cell may receive mitochondria that contain only a pure population of normal mtDNA or a pure population of mutant mtDNA or a mixture of both

43. Maternal inheritance of mtDNA  Sperm mitochondria are generally eliminated from the embryo  mtDNA is inherited from the mother  All the children of a female who is homoplasmic for a mtDNA mutation will inherit the mutation  None of the offspring of a male carrying the same mutation will inherit the defective DNA