بسم الله الرحمن الرحيم

1. بسم الله الرحمن الرحيم

2. MENDELIANINHERITANCE DR. Nasser A. Elhawary Prof. of Medical Genetics Faculty of Medicine Umm Al-Qura University

3. Some Definitions • Genetic locus: is a specific position or location on a chromosome. Locususually refers to a specific gene. • Alleles are alternative forms of a gene at a given locus. • Homozygous: A subject in which both alleles on a locus are identical. • Heterozygous: A subject in which both alleles on a locus are different. • Compound heterozygote: A subject having 2 different mutant alleles on a given locus.

5. Some Definitions… • Double heterozygote: A subject having two different mutant alleles at two different loci. • Genotype: A genetic constitution of an individual. • Phenotype: is the observed result of the interaction of the genotype with the environmental factors.

6. Pattern of Inheritance of Disorders • enable Genetic Counseling to family members. • show how disorders pass to their children? • taking a family history can help to diagnose the hereditary disease. e.g. OsteogenesisImperfecta, DMD

7. Pedigree and Terminology

8. Pedigree and Terminology

9. Mendelian Inheritance • Single genes represent >16,000 disorders (traits). • Autosomal inheritance • Sex-linked inheritance • Multifactorial inheritance usually doesn’t obey Mendel inheritance. e.g. height, weight, … etc or diabetes, hypertension

10. Autosomal Dominant Inheritance • Pathological phenotypes manifest in the heterozygote state (i.e. mutant/normal, M/N). • So, one can trace AD disorder via pedigree e.g. familial hypercholesterolemia. • Genetic risks to AD: 50% affected individuals to any family. • Pleiotropyis a single gene that may influence multiple, seemingly unrelated phenotypic traits (e.g. TB). In TB, learning difficulties, epilepsy, a facial rash. • Variable expressivity: The clinical features in AD disorders can show striking variations from person to person, even in the same family (e.g. polycystic kidney disease, PKD).

11. Autosomal Dominant Inheritance… • Reduced penetrance: Some heterozygotes of AD give rise to unclear abnormal clinical criteria. It is produced from the result of modifying effects of other genes or interaction with environmental factors. • Non-penetrance (skip a generation): A heterozygote having NO clinical features of the disease. • New mutations: may happen with AD affected person with normal parents.e.g.Achondroplasiathat may be diagnosed by the 50% chance. - New dominant mutations due to increased age of a father. - Non-paternity or non-maternity • Co-dominance: 2 allelic traits expressed in heterozygous states (e.g. AB blood grouping). • Homozygosity in AD traits: Each of the couples is a heterozygous to AD disease. So, the offspring has a severe phenotype or has an earlier age of onset (e.g. FHC, achondroplasia).

12. Autosomal Dominant Inheritance AD allele: Punnett’s square showing 50% chance of inheriting disease; A= dominant mutant, a= normal recessive alleles. AD pedigree is characterized by vertical transmission and is confirmed when father-to-son transmission occurs.

13. Achondroplasia… A short-limbed dwarfism, in which the parents usually have normal stature, representing a ‘new mutation’.

14. Autosomal Recessive Inheritance • Recessive traits manifest only when the mutant allele is present in homozygosity, M/M • Heterozygotes(carriers) show no clinical features for the disorder (i.e. healthy). • All affected individuals are in sibship (i.e. brother, sister). • Genetic risks to AR: 25%

15. Autosomal Recessive Inheritance… • Consanguinity: The rarer AR disorder, the greater the frequency of consanguinity among the parents of affected individuals (e.g. Alkaptonuria, in which ≥¼ of the parents were first cousins). - So, rare AR disorder are more likely to meet up in the offspring of cousins than offspring of unrelated parents.

16. Autosomal Recessive Inheritance AR allele: Punnett’s square showing 25% chance of inheriting disease; a= recessive mutant allele, A= normal dominant allele

17. Autosomal Recessive Inheritance… • Pseudo-dominance: happens when AR homozygote has offspring in 50% risk. • Locus heterogeneity:A disorder inherited in the same manner can be due to mutations in more than one gene (sensori-neural hearing impairment/deafness. e.g., 1ry AR microcephaly have 6 distinct loci. • Disorders with the same phenotype due to different genetic loci ‘genocopies’. • Mutational heterogeneity (compound heterozygotes).

18. X-Linked Recessive Inheritance XL recessive: Punnett’s square showing 50% chance of affected male; 50% chance of carrier female. Xh= a mutation for an X-linked gene

19. X-Linked Recessive Inheritance… • An XL recessive usually manifests only in males (is said to be hemizygous). • Transmitted by female heterozygote (healthy) to affected males. • XL-heterozygote → affected male → obligate carrier daughter • None of his son will be affected (e.g. Hemophilia, Queen Victoria was a carrier, but Edward VII was healthy). • Examples: DMD, G6PD, …

20. X-Linked Recessive Inheritance… • Variable expression in Heterozygous female e.g. XL-Ocular albinism (depigmentn. of iris and oculus fundus). - This is due to random process ofX-inactivation in which active-X carries the mutant allele. • Females affected with XLR: female heterozygote manifest clin. criteria. Explanations: - Skewed X-inactivation - Numerical X-chr abnormalities (Turner Syndrome) - X-autosome translocation

21. X-Linked Recessive Inheritance… X-Autosome Translocations

22. X-Linked Dominant Inheritance XL dominant: Punnett’s square showing 50% chance of affected male; 50% chance of carrier female.

23. X-Linked Dominant Inheritance… • XL-dominant manifests in heterozygous females (such as males). • XL-D resemble AD bcuz both the daughters and sons of the affected female have 50% chance risk. • Difference: in case of XD, the patient male transmits the disease to all daughters but not to the sons. • In XL-D, increase of risk to females. • e.g. Vitamin D-resistant rickets & Charcot-Marie-Tooth disease.

24. Y-Linked (Holandric) Inheritance • Only males are affected. • Y-linked traits to all of his sons but not to daughters. • Deletion of gene(s) involved in spermato-genesis (Y-chr) leads to infertility - e.g. Azoospermia (absence of sperm in semen), or oligospermia (little amount of sperms).

25. Y-Linked Inheritance… • Partial sex-linkage: - During meiosis, pairing occurs betn. homo-logous distal parts of the Xp and Yp chromo-somes (psuedoautosomal region). - So, transfer from X- to Y- or vice versa. • Sex influence: Autosomal traits are expressed more in one sex than in another. e.g. males affects frequently in Gout, Baldness (AD). - Hemochromatosis, AR, are much less in females than in males.

26. Multiple Alleles & Complex Traits • Multiple alleles are monogenic or polygenic. • ABO blood group has 4 alleles (A1, A2, B, O) • An individual can possess only 2 of them. • So, women has 2 alleles to transmit, but man has only 1 allele to transmit bcuz…

27. Mitochondrial Inheritance • Each cell have a thousands of copies of mitDNA • mitDNA is more found in cells that have high energy requirements (e.g. brain, muscles). • mitDNA is exclusively inherited from mother through the oocyte. • mitDNA has a higher rate of spontaneous mutation than nuclear DNA. • Accumulation of mutations in mitDNA is responsible for some somatic effects seen with ageing.

28. Mitochondrial inheritance… Only transmitted through females, so-called maternal or matrilineal inheritance