Genetika Kedokteran

1. Genetika Kedokteran dr. Arfianti, M.Biomed, M.Sc Blok 2 2011

3. Basic Concepts • Gene – basic unit of genetic information. Genes determine the inherited characters. • Genome – the collection of genetic information. • Chromosomes – storage units of genes. • DNA - is a nucleic acid that contains the genetic instructions specifying the biological development of all cellular forms of life

4. Locus1 Possible Alleles: AA,Aa, aa Locus2 Possible Alleles: BB,Bb,bb Chromosome Structure • Locus – location of a gene on the chromosome. • Allele – one variant form of a gene at a particular locus.

5. 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. KARIOTIPE

6. KARIOTIPE • gambaran lengkap kromosom yang telah disusun berdasarkan pasangan homolog dan jenisnya • Tujuan  mempermudah mempelajari kromosom • Sampel  limfosit, sumsum tulang, kulit, cairan amnion atau vili korion.

7. TELOMER • Telomer  ujung kromosom sikuen tandem repeat (pada manusia adalah GGGTTA). • Direplikasi oleh enzim telomerase • Proses penuaan aktivitas telomerase akan semakin menurun panjang dari telomer akan semakin berkurang. TELOMER

8. BARR BODY • Wanita salah satu kromatin X-nya mengalami inaktivasi  kondensasi kromatin di inti sel pada saat interfase  barr body atau kromatin X. • Apus mukosa pipi (buccal smear) • Kromatin seks  1-10% sel neutrofil wanita dalam bentuk drumstick.

10. MITOSIS DAN MEIOSIS • Mitosis  seluruh sel tubuh dan berfungsi membentuk sel dengan jumlah kromosom yang sama • Meiosis hanya terjadi pada organ kelamin dan berfungsi mereduksi jumlah kromosom menjadi separuhnya.

13. MEIOSIS • Proses gametogenesis spermatogenesis dan oogenesis sel gamet dengan jumlah kromosom separuh dari jumlah kromosom sel somatik. • 2 tahap meiosis yaitu Meiosis I dan Meiosis II. • Meiosis I diploid menjadi haploid. • Meiois II = mitosis. • Antara meiosis I dan meiosis II tidak terjadi sintesis DNA.

16. Genotypes↔Phenotypes • At each locus (except for sex chromosomes) there are 2 genes genotype at the locus. • The expression of a genotype phenotype. E.g: hair color, weight, or the presence or absence of a disease.

17. Genotypes Phenotypes • IA dan IB- dominant allele. • i- recessive allele. genotypes phenotypes

18. Dominant vs. Recessive • A dominant allele is expressed even if it is paired with a recessive allele. • A recessive allele is only visible when paired with another recessive allele.

19. Female 1 2 A | A a | a 3 4 a | a Male A | a 5 6 A | a a | a heterozygote homozygote One Locus Inheritance

20. Y / y y / y Gamete production all y Gamete production ½ y/y ½ y ½ Y/y ½ Y Mendel’s 1st Law The law of segregation: Allele pairs separate or segregate during gamete formation, and randomly unite at fertilization.

21. Mendel’s 2nd Law The law of independent assortment: during gamete formation the segregation of the alleles of one allelic pair is independent of the segregation of the alleles of another allelic pair

22. Mendel 2nd law cont…

23. Genetic Disorders 6 general patterns of inheritance are observed: • Autosomal recessive • Autosomal dominant • X-linked recessive • X-linked dominant • Codominant • Mitochondrial

24. Autosomal recessive • Manifest only in homozygous state • Both males and females affected equally • Carriers (HTZ) unaffected • Consanguinity increases risk of recessive disorder • e.g., cystic fibrosis: disease affecting the mucus lining of the lungs, leading to breathing problems and other difficulties

25. Autosomal dominant • Both males and females have equal chance to inherit gene • Both can transmit disorder to both sons and daughters • HMZ often more severely affected than HTZ • Affected males and females appear in each generation of the pedigree. • Affected mothers and fathers transmit the phenotype to both sons and daughters. • e.g., Huntington disease.

26. Huntington disease • Huntington's chorea is an inherited disorder characterized by abnormal body movements called chorea, and loss of memory. • 5 to 8 per 100,000. • the New York physician George Huntington who first described it precisely in 1872.

27. X-linked recessive • Expressed in males but not usually in females • Carrier female • 50% risk of affected sons • 50% risk of carrier daughter • Affected male • all daughters carriers • all sons unaffected • e.g., hemophilia: impair the body's ability to control bleeding

29. X-linked dominant • Males and females affected, females usually less severely affected than males • 1 in 2 risk to children of affected female • All daughters of affected male affected but no male to male transmission • e.g. fragile X syndrome: a range of developmental problems:learning disabilities and mental retardation

30. Males and females affected Vitamin D resistant rickets Fragile X syndrome Lethal in males Incontinentia pigmenti Rett syndrome XL chondrodysplasia punctata X-linked dominant inheritance

31. Codominant inheritance • 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

32. Mitochondrial inheritance • Mitochondria are exclusively maternally inherited • Genes in mitochondrial DNA • Mitochondrial disorders can appear in every generation of a family and can affect both males and females E.g. Leber's hereditary optic neuropathy (LHON)

33. Question #1 • PKU is a human hereditary disease resulting from inability of the body to process the chemical phenylalanine (contained in protein that we eat). • It is caused by a recessive allele with simple Mendelian inheritance. • Some couple wants to have children. The man has a sister with PKU and the woman has a brother with PKU. There are no other known cases in their families. • What is the probability that their first child will have PKU ?

34. P/p P/p P/p P/p P/- P/- p/p p/p Question #2-Solution Highlights P – the normal allele p – the mutant allele

35. X-linked dominant disorders

36. 1 2 3 4 5 6 7 8 9 10 Question #3 • The disease is rare. • What is the most likely mode of inheritance ?

37. Question #3-Solution Highlights • Observations: • After the disease is introduced into the family in generation #2, it appears in every generation  dominant! • Fathers do not transmit the phenotype to their sons X-linked!

38. Chromosomes • Number: • Aneuploidy • Trisomy • Monosomy • Polyploidy • triploidy (69 chromosomes) • Structure: deletion/insertion/ inversion/ring translocation

39. Trisomy • Trisomy 21 • Trisomy 18 • Trisomy 13 • No survivable autosomal monosomy • Sex chromosome aneuploidy: • 45X 47XXX 47 XXY 47XYY

40. Trisomy 21: Down’s Syndrome • 1 in 700 births - maternal age related • Learning disability • Hypotonia • Nuchal thickening, short neck • Flat face, brachycephaly • Epicanthic folds, Brushfield spots • Small mouth and ‘large’ tongue • Small ‘square’ ears • Transverse palmar creases, sandal gap

41. 45,X • Turner syndrome 1:1000 female births • Cardiac defects especially coarctatio aorta • Horseshoe kidney • Short stature • Streak gonads and infertility • Webbed neck, ptosis • IQ in normal range, some specific learning diffs

42. 47XXX • Triple X syndrome • Tall stature in childhood • Normal appearance and fertility • Not associated with structural abnormalities • Learning disability, speech delay, passive personality

43. 47,XXY • Klinefelter syndrome • Males • Tall stature, eunuchoid fat distribution • Small testes and low testosterone • Poor beard growth, gynaecomastia • IQ usually within normal range but < sibs • Some increase in behaviour problems • Increased risk diabetes, varicose veins, breast cancer

44. Chromosomal inheritance • Pedigree doesn’t conform to mendelian pattern • May be history of miscarriages • Affected children may have different patterns of physical and developmental abnormality

45. Genetic conselling • Prenatal testing • “An education process that seeks to assist affected (and/or ‘at risk’) individuals to understand the nature of the genetic disorder, the nature of its transmission and the options open to them in management and family planning.” • Tests in pregnancy- • Villi chorialis • Cairan amnion