Genetics

1. Genetics Dr.S.Chakravarty, MBBS,MD

3. Mom’s eyes Dad’s eyes What will I get?

4. Learning objectives • Explain the Mendelian laws and its application in various clinical conditions • Describe the Dominant and Recessive genes in Autosomal and x-linked inheritance patterns in various single gene disorders • List the special features of Autosomal dominant inheritance • Analyze the pattern of mitochondrial inheritance and compare it autosomal and x-linked inheritence • Describe the Punnet squares and calculate the risk in various generations

7. Human Genome Most human cells contain 46 chromosomes: • 2 sex chromosomes (X,Y): XY – in males. XX – in females. • 22 pairs of chromosomes named autosomes.

8. Locus1 Possible Alleles: A1,A2 Locus2 Possible Alleles: B1,B2,B3 Chromosome Logical Structure • Locus – location of a gene/marker on the chromosome. • Allele – one variant form of a gene/marker at a particular locus.

9. Genotypes & Phenotypes • At each locus (except for sex chromosomes) there are 2 genes. These constitute the individual’s genotype at the locus. • The expression of a genotype is termed a phenotype. For example, hair color, weight, or the presence or absence of a disease.

10. Population Frequency and RFLP Allelle 1 Allelle 2 Phenotype 2 Phenotype 3 Phenotype 1 Homozygous for allele 1 Heterozygous Homozygous for allele 2

11. Dominant vs. recessive A dominant allele is expressed even if it is paired with a recessive allele. A recessive allele is only expressed when paired with another recessive allele.

12. Dominant allele – UPPERCASE eg A • Recessive allele – lower case eg a

13. Gregor Johann Mendel

14. Heredity • What genetic principles account for the transmission of traits from parents to offspring? • One possible explanation of heredity is a “blending” hypothesis - The idea that genetic material contributed by two parents mixes in a manner analogous to the way blue and yellow paints blend to make green • An alternative to the blending model is the “particulate” hypothesis of inheritance: the gene idea - Parents pass on discrete heritable units, genes

15. Gregor Mendel • Documented a particulate mechanism of inheritance through his experiments with garden peas Gregor Mendel’s monastery garden. Fig. 2.2

16. Mendelian Genetics • Gregor Johann Mendel (1822-1884) • Augustinian monk • Czech Republic • Foundation of modern genetics • Studied segregation of traits in the garden pea (Pisumsativum) beginning in 1854 • Published his theory of inheritance in 1865. “Experiments in Plant Hybridization” • Mendel was “rediscovered” in 1902 • Ideas of inheritance in Mendel’s time were vague. One general idea was that traits from parents came together and blended in offspring. Thus, inherited information was predicted to change in the offspring, an idea that Mendel showed was wrong. “Characters,” or what we now call alleles, were inherited unchanged. This observation and the pattern of inheritance of these characters gave us the first definition of a gene

17. Mendel’s Experimental, Quantitative Approach • Mendel used the scientific approach to identify two laws of inheritance • Mendel discovered the basic principles of heredity by breeding garden peas in carefully planned experiments • Mendel chose to work with the garden pea (Pisumsativum) • Because they are available in many varieties, easy to grow, easy to get large numbers • Because he could strictly control which plants mated with which

18. Removed stamens from purple flower 1 Transferred sperm- bearing pollen from stamens of white flower to egg- bearing carpel of purple flower 2 Parental generation (P) Stamens (male) Carpel (female) Pollinated carpel matured into pod 3 Planted seeds from pod 4 Examined offspring: all purple flowers 5 First generation offspring (F1) Crossing Pea Plants

19. Mendel’s experimental design • Statistical analyses: • Worked with large numbers of plants • counted all offspring • made predictions and tested them • Excellent experimentalist • controlled growth conditions • focused on traits that were easy to score • chose to track only those characters that varied in an “either-or” manner

20. X X X X X X Mendel’s experimental design • Mendel also made sure that he started his experiments with varieties that were “true-breeding”

21. Mendel’s Studied Discrete Traits

22. Mendel’s first law • Law of segregation: The two coexisting alleles of an individual for each trait segregate (separate) during gamete formation so that each gamete gets only one of the two alleles. Alleles again unite at random fertilization of gametes. Spermatogonia Oogonia Meiosis I

23. Consequences • Each of the parents transmits only half of its hereditary factors to offspring. • The possible combinations of gametes depends on the number of paternal alleles. • E.g. if a parent has two pairs of alleles (dominant – A,B and recessive – a,b), there are four combinations transfer to children (AB,Ab,aB,ab). • An offspring receives always just one member of allelic pairs (A or a, B or b).

24. Mendel’s second law • Law of independent assortment: alleles of different genes assort independently of one another during gamete formation

25. Coat color B (brown, dominant) or b (white), • Tail length S (short, dominant) or s (long). • Parents are homozygous for each trait (SSbb and ssBB)

26. Application of Mendelian genetics in humans • Disorders caused by a defect in a single gene follow the patterns of inheritance described by Mendel and the term Mendelian inheritance has been used to denote unifactorial inheritance

27. Pedigree symbols

28. Autosomal dominant inheritance • Both males and females equally affected ( as mostly located on AUTOSOMES) • NO SKIPPED GENERATIONS - Every generation of the family is affected • Homozygotes – Genetically lethal

29. Autosomal dominant inheritance • NO SKIPS IN GENERATIONS • BOTH MALES AND FEMALES EQUALLY AFFECTED

30. Punnet square in AUTOSOMAL DOMINANT DISORDER • Affected heterozygous mother and normal homozygous father: • Affected heterozygous mother and affected heterozygous father • Affected homozygous mother and normal homozygous father

31. Special features of AD inheritance • Late onset – present very late in life • Variable expressivity – intensity of the disease varies from person to person or family members with the same disease. • Reduced Penetrance – absence of the disease even though the person is affected with the disease • New mutations – sudden development of disease in a family. • Pleiotropy - refers to a situation when a disorder has multiple effects on the body (multiple phenotypic presentations)

32. Autosomal dominant NEED TO REMEMBER THIS !!

33. Autosomal co-dominant inheritence • Two different versions (alleles) of a gene can be expressed, and each version makes a slightly different protein • Both alleles influence the genetic trait or determine the characteristics of the genetic condition. • E.g. ABO locus

34. Structure of blood group antigens

35. Autosomal Recessive Inheritance • Clinically expressed only in their homozygous states (egaa) • Disease generally seen only in one generation of a pedigree • Located on autosomes – males and females affected in roughly equal frequencies

36. Autosomal recessive inheritence • Both males and females are equally affected (homozygous) • Usually have Unaffected parents • Skipped generations • Increased incidence with consanguineous marriages and inbreeding • Enzyme deficiencies disorders are most common ( manifests very early in life).

37. Autosomal recessive pattern

38. Punnet square • Normal heterozygous mother and normal heterozygous father • Affected homozygous mother and normal homozygous father • Affected homozygous mother and normal heterozygous father

39. Autosomal recessive disease NEED TO REMEMBER THIS !!

40. X-linked dominant • Twice the number of females than males(F>M) • Father-to-son transmission does not occur • Sometimes the Males die ( genetic lethal). • Heterozygous females are mildly to overtly affected depending on the skew of the X chromosome inactivation. • Homozygous females (double dose) are overtly affected.

41. X chromosome inactivation • Males carry a X chromosome from mother and Y chromosome from father. Females get one X chr from each parent • Y CHR – 30 protein coding genes • X chr – hundreds of protein coding genes •   X INACTIVATION IS A PROCESS TO EQUALIZE • BLASTOCYST stage (100 cells ) • INACTIVATED X CHR FORMS A BARR BODY • RANDOM • INCOMPLETE • ALL X CHROMOSOMES ARE INACTIVATED EXCEPT ONE • Eg. If there are three X chromosomes in a cell = 2 Barr bodys

42. X-linked dominant inheritance

43. X-linked dominant inheritance

44. Examples of X- liked dominant inheritance • Fragile X syndrome • Hypophosphatemic rickets

45. X-linked recessive • The disorder is observed only in males. Females? • The characteristic family pedigree shows skipped generations • Father-to-son transmission does not occur • Males are usually sterile. • Heterozygous females are clinically normal but may be mildly affected depending on the skew of the X chromosome inactivation.

47. A female will not manifest the disorder the way a boy would, because she has 2 X chromosomes, and the dominant X will compensate for the defect on the recessive X. Only if a female has 2 parents with the defect on their X chromosomes will she get a milder form of the disorder. • Males have no ‘back-up’ working copy and so will generally be affected by the condition http://www.geneticseducation.nhs.uk/mededu/modes-of-inheritance/single-gene-conditions/x-linked-conditions

48. X-linked recessive Sons always affected

49. X linked recessive

50. Y-linked inheritance • Only males affected • Transmission from father to all his sons • Hairy ears – hypertrichosis • Webbed toes. • Because the Y-chromosome is small and does not contain many genes, few traits are Y-linked, and Y-linked diseases are rare