HUMAN CHROMOSOMAL ABERRATIONS & ITS IMPLICATIONS

1. HUMAN CHROMOSOMAL ABERRATIONS & ITS IMPLICATIONS BY Prof. S. R. RAMESH Department of Studies in Zoology UNIVERSITY OF MYSORE Manasagangotri, MYSORE – 570 006

3. Mammalian nucleus:10 diameter (1 = 1/1000 mm)DNA : 2 mts. long (6X109bp)To fit this long molecule in to nucleus of 10  diameter, the DNA must be reduced 20,000 folds in its linear packaging!!

5. EM of Chromatin Consists of no. of ellipsoidal beads joined by thin threads

6. Basic structural unit of chromatin – Nucleosome was described by Roger Kornberg in 1974 • Partial digestion with micrococcal nucleases (from Staphylococcus aureus): • Collection of Small particles of uniform size • DNA  200bp • All Histones

9. NUCLEOSOME CORE/CORE PARTICLE • More extensive nuclease digestion: • Loss of H1 Histone • Loss of all DNA except that is complexed with Histones in bead – 147 bp that form 1¾ turns

11. Chromosomal aberrations/mutations I. Changes in number of genes in chromosomes a) Deficiency/Deletion b) Duplication II. Changes in location of genes in chromosomes a) Inversion b) Translocation III. Changes in the number of chromosomes a) Fusion b) Fission c) Aneuploidy d) Euploidy (Haploidy & Polyploidy)

13. May occur spontaneously under natural conditions ……Rare events • Could be induced by Physical agents/ Chemicals/Ionizing Radiations • May produce changes in • Phenotype • Expected genetic ratios • Linkage relationships of certain genes

14. Deletions/Deficiencies • Chromosome/Chromatin breaks • Types: • a) Size: • Small:Intragenic • Inefficient product • Truncated peptide - Nonfunctional • Inactivate gene • Large: Multigenic (Usually lethal) • b) Position: • Terminal (Single break) • Interstitial (Two breaks – followed by ‘Healing’)

17. GENETIC CONSEQUENCES OF DELETIONS • Failure of the chromosome/individual to survive as a homozygote (also occurs in lethal mutation) • Chromosomes/individuals with deletions can never revert to normal (can be detected/ realized only when a specific phenotype is associated with deletion)

18. Deletion of a region (segment) on one homologue results in the expression of recessive alleles present on the other homologue – leading to unexpected phenotype in the progeny This apparent dominance of a recessive gene is called PSEUDODOMINANCE This is one way to recognize deletions Eg. Expression of Waltzing in mice

19. Cri – du – Chat syndrome: (Haplo-insufficiency) (Cat cry syndrome) • Cat like mewing cry (in infancy) • Microcephaly • Moon like face • Physical abnormalities • Severe mental retardation • Heterozygous deletion: tip of • short arm of chromosome 5

20. Cri-du-chat chromosome 5 pair  

21. Prader-Willi/Angelman Syndrome (PWS) • Short stature • Small hands and feet • Poor muscle tone • Hypogonadism • Usually mentally retarded • Progressive obesity with compulsive eating habits

23. Wolf-Hirschhorn syndrome/Pitt-Rogers-Dank syndrome) • Low birth weight - 2 kg • Microcephaly • High forehead • Broad nose in prolongation of the eyebrows line • Ocular malformations, hare-lip / cleft palate • Long, slender, manicured fingers Malformations: heart (50%) • IQ = 20; seizures; often bedridden Karyotype: deletion of band 4p16 gives full phenotype; critical segment narrowed to 200 kb.

24. Microdeletion syndromes: • Deletion is missing a part of chromosome  delay in developmental milestones in children  mental retardation/dysmorphic physical features or both • Very very small deletions viz., ‘microdeletions’ cannot be seen by routine analysis  chromosomes appear normal • Can be the cause of specific microdeletion syndromes • Can be detected by FISH -Smith Magenis syndrome (SMS)

25. Smith Magenis syndrome (SMS)

26. Williams Syndrome Segmental aneuploid deletion of a small portion of the long arm of  Chromosome 7 (2n=46, 7q11.23-)

28. Negative Williams Syndrome FISH assay Chromosome 7: Elastin gene found on both chromosomes. The individual does not have Williams Syndrome Positive Williams Syndrome FISH assay Chromosome 7: Elastin gene found on only one chromosome. The other copy does not have elastin gene

29. Cancers associated with Deletions • Osteosarcoma • Neuroblastoma • Melanoma • Lung carcinoma • Retinoblastoma • Ovarian sarcoma

30. Large deletions: Often lethal/seriously deleterious even in heterozygotes presumably due to developmental imbalance Deletions of small chromosomal regions might not be lethal in homozygotes!! Whenever deleted genes had been previously duplicated …….. and their function could still be carried out by the remaining genes

31. GENETIC CONSEQUENCES OF DUPLICATIONS

32. Duplications may have phenotypic effects Tandem duplication of 16A in X-chromosome (7 bands in polytene) Incomplete dominance Reduction in the no. of facets in the eye

33. 15q Duplication Syndrome: Hypotonia: Appear ‘floppy' and have difficulty sucking and feeding, unusual, weak cry. Decreases with age Delay in Motor milestones: Rolling over, Sitting up, and walking are significantly delayed. Older children and adults with hypotonia often tire easily. Physical Features: Flat nasal bridge  'button' nose. Growth: Retarded in about 20 – 30% individuals. Precocious puberty in some girls

34. Seizure Disorders: 50% of people – at least one seizure, majority before age 5 • Attention Deficit Disorders:Attention Deficit Disorder or Hyperactivity • Recurrent respiratory infections in childhood, • Other menstrual irregularities • Overeating and weight gain • Middle ear effusions • Precocious puberty • Eczema

35. 22q11.2 duplication syndrome (2.09 – 3.06Mb): • Deletion in same region DiGeorge syndrome • Most frequent reported symptoms: • Mental retardation/learning disabilility (97%) • Delayed psychomotor development (67%) • Growth retardation (63%) • Muscular hypotonia (43%) • Congenital heart malformation • Visual and hearing impairment • Seizures, microcephaly, ptosis, & urogenital abnormalities

36. Cat eye syndrome: Partial tetrasomy 22, partial trisomy 22, inverted duplication 22qter – 22q11 • Iris coloboma (uni/bilateral) • Cat like eyes • Cleft palate • Cardiac defects • Skeletal problems • Mild-moderate mental impairment

37. Multiple copies of rRNA genes E.coli : 7 rRNA genes Human: 400 rRNA genes/genome (on 5 chromosomes) Xenopus: 1200 rRNA genes/genome (Single cluster)

38. Changes involving entire sets:EUPLOIDY • Haploidy • Polyploidy: • Autopolyploidy: (Homologues from same source) • Allopolyploidy: (Homologues from different sources) • PREVALENT IN PLANTS

39. B. Changes involving numbers of chromosomes in a set:ANEUPLOIDY • Monosomy: Loss of one chromosome from a set (2n-1) • Nullisomy: Loss of both chromosomes from a set (2n-2) • Polysomy: Addition of one/more chromosomes to a set • 2n+1: Trisomy • 2n+2: Tetrasomy • 2n+3: Pentasomy

40. Figure 16-12

41. Bridges - One of the first cases of Aneuploidy in Drosophila Occasionally in a cross: w/w female X +/+ male Instead of this, Bridges found White eyed females & Red eyed males

42. Bridges proposed that these unexpected results are due to failure of X-chromosomal segregation during oogenesis Morgan – cytological confirmation Failure of segregation to opposite poles during meiosis – Non disjunction  ANEUPLOIDY

43. Non disjunction in chromosome 4 of Drosophila: • Triplo IV: 3 copies of chromosome 4 • Phenotype similar to wild type • Haplo IV: Only 1 copy of chromosome 4 (Incomplete Genome) • Not robust as wild type • Shortened bristles • Roughened eyes

45. In man, a small percentage of fetuses trisomic for 8, 9, 13, 18, 21 & 22 survive • All other trisomies – spontaneously aborted • A rare monosomy in man is viable: Mentally severely retarded and suffer from too many abnormalities • All other autosomalmonosomics are spontaneously aborted

46. Patau Syndrome (Trisomy 13)

47. 1 in 5000 live births Moderate microcephaly Wide spaced eyes Beaked nose Polydactyly Trigger thumb (thumb and index fingers overlap the third finger) Cleft lip and/or palate  difficult to feed Simian crease in hands Congenital heart disease Kidney disorders Malformed genitalia Short life span

49. Edward’s syndrome (Trisomy 18)

50. 1 in 4000 live births • More frequent in females • Odd shaped head • Short thumb • Low set ears • Small mouth • Clefts of lip and/or palate – difficult to feed • Heart defects – common • Usually dies before 1 year of birth