1. M.B.Ch.B, MSC, DCH (UK), MRCPCH
Genetics
Lec.2
Dr. Mohammed Hussein
M.B.Ch.B, MSC, DCH (UK), MRCPCH

2. Mendelian Inheritance
Autosomal Dominant Inheritance
Autosomal Recessive Inheritance
Sex - linked Dominant Inheritance
Sex - linked Recessive Inheritance

3. Autosomal Co-Dominant Inheritance
In codominant inheritance, two different versions (alleles) of a gene are expressed, and each version makes a slightly different protein.
Both alleles influence the genetic trait or determine the characteristics of the genetic condition.

5. BLOOD GRUOPS 2 Dominant Alleles : A & B 1 Recessive Allele : O
AA & AO give rise to blood group A (the RBCs have A antigen on their surface)
BB & BO give rise to blood group B (the RBCs have B antigen on their surface)
AB will give rise to different blood group called AB (the RBCs have both A & B antigens on their surface) (this is called codominance)
OO will give rise to a blood group O (the RBCs have no antigen on their surface)

6. AO BO A O B A B B O O A O O O 25% Blood group A 25% Blood group B
25% Blood group O

8. AO AO A O A A A A O O A O O O 75% Blood group A 25% Blood group O

9. AB AB A B A A A A B B A B B B 25% Blood group A 25% Blood group B
0% Blood group O

10. OO OO O O O O O O O O O O O 100% Blood group O Blood group OO O O O
Blood group O
100% Blood group O

11. Sex Linked Inheritance
X- Linked Recessive Inheritance
X- Linked Dominant Inheritance
Y- Linked Inheritance

12. X-linked Recessive Inheritance
X-linked = gene transmitted by the X chromosome
Recessive = required two copies of the gene to express the disease (Homozygous)
If the gene present with a normal gene then a carrier (Hetrozygous)

13. X-linked Recessive Inheritance
Because males have only one copy of the X chromosome, they are said to be hemizygous for the X chromosome.
As recessive disease required two copies of gene to be expressed, so X-linked recessive diseases are seen much more commonly in males than in females.
As male pass only the Y chromosome to his son, so male-to-male transmission is not seen in X-linked inheritance.

14. 100 % of female are carriers
x Y
Affected (Diseased) Male x Y X X x X Y
X X X X x X Y
Normal
Female
100 % of female are carriers
100 % of males are normal

15. 50 % of female are carriers
X Y
Normal Male X Y X X X X Y
X x
Female
carrier x X x x Y
50 % of female are carriers
50 % of males are diseased

17. Hemophilia A and B
Duchenne muscular dystrophy
Lesch-Nyhan syndrome
G6PD

18. Duchenne Muscular Dystrophy

19. Hemophilia A

20. X inactivation (the Lyon hypothesis )
Because the Y chromosome carries only about 50 protein-coding genes and the X chromosome carries hundreds of protein-coding genes, a mechanism must exist to equalize the amount of protein encoded by X chromosomes in males and females.
This mechanism, termed X inactivation, occurs in the blastocyst (~100 cells) during the development of female embryos.

23. Manifesting (female) heterozygotes
Heterozygous female will occasionally express an X-linked recessive mutation because, by random chance, most of the X chromosomes carrying the normal allele have been inactivated (extreme Lyonisation).
Such females are termed manifesting heterozygotes.

24. Manifesting (female) heterozygotes
Because they usually have at least a small population of active X chromosomes carrying the normal allele, their disease expression is typically milder than that of hemizygous males.

25. X-Linked Dominant Inheritance
Male–male transmission of the disease is not seen.
As the disease is dominant (one copy of the abnormal gene cause the disease), so Heterozygous females are affected.
Because females have two X chromosomes (and thus two chances to inherit an X-linked gene) and males have only one, X-linked dominant diseases are seen about twice as often in females as in males

26. 100 % of female are diseased
X Y
Affected Male X Y X X X X Y
X X X X X X Y
Normal
Female
100 % of female are diseased
100 % of males are normal

27. 50 % of offspring are diseased 50 % of offspring are normal
X Y
Normal Male X Y
50 % of offspring are diseased X X X X Y
X X
50 % of offspring are normal X X X X Y
Affected
Female

29. Hypophosphatemic rickets
Fragile X syndrome
Incontinentia pigmenti

30. Fragile X syndrome

31. Y- Linked inheritance Y-linked traits are extremely rare.
Y-linked inheritance would result in only males being affected, with transmition from an affected father to all his sons.
Y-linked genes determine sexual differentiation and spermatogenesis, and mutations are associated with infertility and so are rarely transmitted.

32. Summary Ask yourself the following questions
Dose an affected individual have an affected parent? Or (Multiple generations affected?)
Yes: Dominant disease
No: Recessive disease
If it is dominant, then ask: Is there male-male transmission?
Yes: autosomal dominant disease
No: may be an X-linked dominant
Are all daughters of an affected male also affected?
Yes: X-linked dominant
No: autosomal dominant disease
If it is recessive, then ask: Dose all (or almost all) affected are males?
Yes: X-linked recessive disease
No: Autosomal recessive disease

34. Autosomal Dominant

35. Autosomal Recessive

36. X-linked Recessive

37. X-linked Dominant

38. Mitochondrial Inheritance

39. Mitochondria

40. Mitochondria
Are cytoplasmic organelles involved in cellular respiration
Have their own chromosomes, each of which contains 16,569 DNA base pairs arranged in a circular molecule.
This DNA encodes 13 proteins that are subunits of complexes in the electron transport and oxidative phosphorylation processes.
In addition, mitochondrial DNA encodes 22 tRNAs and 2 rRNAs.

41. Because a sperm cell contributes no mitochondria to the egg cell during fertilization, mitochondrial DNA is inherited exclusively through females.

42. Pedigrees for mitochondrial diseases thus display a distinct mode of inheritance:
Transmission of the disease is only from a female.
All offspring of an affected female are affected.
None of the offspring of an affected male is affected.

44. Heteroplasmy

45. A typical cell contains hundreds of mitochondria in its cytoplasm.
When a specific mutation occurs in some of the mitochondria, this mutation can be unevenly distributed into daughter cells during cell division:
Some cells may inherit more mitochondria in which the normal DNA sequence predominates, while others inherit mostly mitochondria with the mutated, disease-causing gene.
This condition is known as heteroplasmy.
Variations in heteroplasmy account for substantial variation in the severity of expression of mitochondrial diseases.

46. Heteroplasmy

47. Leber hereditary optic neuropathy (LHON)
Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke (MELAS)

48. Leber hereditary optic neuropathy (LHON)

49. Important principles that can characterize single-gene diseases
Variable expression
Incomplete penetrance
Pleiotropy
Locus heterogeneity
New mutations
Delayed age of onset
Anticipation
Imprinting
Uniparental disomy

50. Variable Expression
Most genetic diseases vary in the degree of phenotypic expression: Some individuals may be severely affected, whereas others are more mildly affected.
This can be the result of several factors:
Environmental Influences: exp xeroderma pigmentosum
Allelic Heterogeneity: exp, missense mutations in the factor VIII gene tend to produce less severe hemophilia than do nonsense mutations.
Heteroplasmy in mitochondrial pedigrees.
Modifier Loci. Disease expression may be affected by the action of other loci, termed modifier loci. Often these may not be identified.

51. Incomplete Penetrance
A disease-causing mutation is said to have incomplete penetrance when some individuals who have the disease genotype do not display the disease phenotype.

53. Pleiotropy
Pleiotropy exists when a single disease-causing mutation affects multiple organ systems.
Pleiotropy is a common feature of genetic diseases.
Marfan syndrome provides a good example of the principle of pleiotropy

54. Marfan syndrome
Yao Ming

55. Locus Heterogeneity
Locus heterogeneity exists when the same disease phenotype can be caused by mutations in different loci.
For example, retinitis pigmentosa has autosomal dominant, autosomal recessive, and X-linked origins.

56. New Mutations
In many genetic diseases, a large proportion of cases are caused by a new mutation transmitted from an unaffected parent to an affected offspring.
There is thus no family history of the disease

57. Delayed Age of Onset
Many individuals who carry a disease-causing mutation do not manifest the phenotype until later in life.
This can complicate the interpretation of a pedigree because it may be difficult to distinguish genetically normal individuals from those who have inherited the mutation but have not yet displayed the phenotype.
Example: Familial breast cancer

58. Genetic Anticipation
Anticipation refers to a pattern of inheritance in which individuals in the most recent generations of a pedigree develop a disease at an earlier age or with greater severity than do those in earlier generations.
For a number of genetic diseases, this phenomenon can be attributed to the gradual expansion of trinucleotide repeat polymorphisms within or near a coding gene.

60. Imprinting
Imprinting refers to the fact that a small number of genes are transcriptionally active only when transmitted by one of the two sexes.
The homologous locus in the other parent is rendered transcriptionally inactive.
Thus, for imprinted loci, it is normal to have only the maternal (for some loci) active, or only the paternal (for other loci) active.

62. On rare occasion, the transcriptionally active gene may be deleted from the chromosome during gametogenesis.
This leaves the offspring with no active gene at that locus.
The gene from one parent is inactivated due to normal imprinting, and the gene from the other parent deleted by a mutation.
This situation may result in a genetic disease.

63. Prader-Willi Syndrome and Angelman Syndrome

66. Prader-Willi Syndrome

67. Angelman Syndrome

68. Uniparental Disomy
Uniparental disomy is a rare condition in which both copies of a particular chromosome are contributed by one parent.