Understanding DNA and Genetic Mutations: A Comprehensive Guide

1. DNA what is it • Pentose sugar (deoxyribose) • Phosphate molecule • Four nitrogenous bases • Pyrimidines: cytosine and thymine • Purines: adenine and guanine

2. Proteins • One or more polypeptides • Composed of amino acids • 20 amino acids of 64 total known are found in the structure of all plants and animals 6 we can not manufacture from scratch and are essential in diet • Directed by sequence of bases along DNA strans 3 consecutive bases = a codon

3. DNA Replication • Untwisting and unzipping of the DNA strand • Single strand acts as a template for replication and transcription to RNA • Complementary base pairing done by action of DNA polymerase • Adenine-thymine; cytosine-guanine Chargraf’s rules

4. Mutation • Any inherited alteration of genetic material • Chromosome aberrations major changes in the entire DNA strand and entire piece missing or an extra chromosome or even an extra complete set examples include Cri – du – chat mising piece of #5 or trisomy 21 Downs syndrome extra 21 chromosome • Base pair substitution • One base pair is substituted for another • Silent substitution • Substitution that does not result in an amino acid change because genetic code is redundant • RNA codons GUU, GUC, GUA, GUG all code for the amino acid valine

5. Mutation • Frameshift mutation • Insertion or deletion of one or more base pairs • Causes a change in the entire “reading frame” • Examples include sickle cell anemia

6. Mutation

7. Mutation • Spontaneous mutation • Mutation that occurs in absence of exposure to known mutagens • Mutational hotspots • Areas of the chromosomes that have high mutation rates • A cytosine base followed by a guanine are known to account for a disproportionately large percentage of disease-causing mutations

8. Mutagen • Agent known to increase the frequency of mutations • Radiation • Chemicals

9. Transcription • RNA is synthesized from the DNA template • Results in the formation of messenger RNA (mRNA) • mRNA moves out of the nucleus and into the cytoplasm

10. Transcription

11. Translation • Process by which RNA directs the synthesis of a polypeptide • Site of protein synthesis is the ribosome • tRNA contains a sequence of nucleotides (anticodon) complementary to the triad of nucleotides on the mRNA strand (codon) • The ribosome moves along the mRNA sequence to translate the amino acid sequence

12. Translation

13. Chromosomes • Somatic cells • Contain 46 chromosomes (23 pairs) • Diploid cells • Gametes • Contain 23 chromosomes • Haploid cells • One member of each chromosome pair • Meiosis • Formation of haploid cells from diploid cells

14. Chromosomes • Autosomes • The first 22 of the 23 pairs of chromosomes in males and females • The two members are virtually identical and thus said to be homologous • Sex chromosomes • Remaining pair of chromosomes • In females, it is a homologous pair (XX) • In males, it is a nonhomologous pair (XY)

15. Karyotype • Ordered display of chromosomes

16. Chromosome Aberrations • Euploid cells • Cells that have a multiple of the normal number of chromosomes • Haploid and diploid cells are euploid forms • When a euploid cell has more than the diploid number, it is called a polyploid cell • Triploidy: a zygote having three copies of each chromosome (69) • Tetraploidy: four copies of each (92 total) • Both triploid and tetraploid fetuses don’t survive

17. Chromosome Aberrations • Aneuploidy • A somatic cell that does not contain a multiple of 23 chromosomes • A cell containing three copies of one chromosome is trisomic (trisomy) • Monosomy is the presence of only one copy of any chromosome • Monosomy is often lethal, but infants can survive with trisomy of certain chromosomes • “It is better to have extra than less”

18. Chromosome Aberrations • Disjunction • Normal separation of chromosomes during cell division • Nondisjunction • Usually the cause of aneuploidy • Failure of homologous chromosomes or sister chromatids to separate normally during meiosis or mitosis

19. Nondisjunction

20. Autosomal Aneuploidy • Partial trisomy • Only an extra portion of a chromosome is present in each cell • Chromosome mosaics • Trisomies occurring only in some cells of the body

21. Autosomal Aneuploidy • Down syndrome • Best-known example of aneuploidy • Trisomy 21 • 1:800 live births • Mentally retarded, low nasal bridge, epicanthal folds, protruding tongue, poor muscle tone • Risk increases with maternal age

22. Down Syndrome

23. Sex Chromosome Aneuploidy • One of the most common is trisomy X. This is a female that has three X chromosomes. • Termed “metafemales” • Symptoms are variable: sterility, menstrual irregularity, and/or mental retardation • Symptoms worsen with each additional X

24. Sex Chromosome Aneuploidy • Turner syndrome • Females with only one X chromosome • Characteristics • Absence of ovaries (sterile) • Short stature (~ 4'7") • Webbing of the neck • Edema • Underdeveloped breasts; wide nipples • High number of aborted fetuses • X is usually inherited from mother

25. Turner Syndrome

26. Sex Chromosome Aneuploidy • Klinefelter syndrome • Individuals with at least two Xs and one Y chromosome • Characteristics • Male appearance • Develop female-like breasts • Small testes • Sparse body hair • Long limbs • Some individuals can be XXXY and XXXXY. The abnormalities will increase with each X.

27. Klinefelter Syndrome

28. Alterations in Chromosome Structure • Chromosome breakage • If a chromosome break does occur, physiological mechanisms will usually repair the break, but the breaks often heal in a way that alters the structure of the chromosome • Agents of chromosome breakage • Ionizing radiation, chemicals, and viruses

29. Alterations in Chromosome Structure • Breakage or loss of DNA • Cri du chat syndrome • “Cry of the cat” • Deletion of short arm of chromosome 5 • Low birth weight, metal retardation, and microcephaly

30. Alterations in Chromosome Structure

31. Alterations in Chromosome Structure • Duplication • Presence of a repeated gene or gene sequence • Rare occurrence • Less serious consequences because better to have more genetic material than less (deletion) • Duplication in the same region as cri du chat causes mental retardation but no physical abnormalities

32. Alterations in Chromosome Structure • Inversions • Two breaks on a chromosome • Reversal of the gene order • Usually occurs from a breakage that gets reversed during reattachment • ABCDEFG may become ABEDCFG

33. Alterations in Chromosome Structure • Translocations • The interchanging of material between nonhomologous chromosomes • Translocation occurs when two chromosomes break and the segments are rejoined in an abnormal arrangement

34. Alterations in Chromosome Structure

35. Alterations in Chromosome Structure

36. Alterations in Chromosome Structure • Fragile sites • Fragile sites are areas on chromosomes that develop distinctive breaks or gaps when cells are cultured • No apparent relationship to disease

37. Alterations in Chromosome Structure • Fragile X syndrome • Site on the long arm of the X chromosome • Associated with mental retardation; second in occurrence to Down syndrome • Higher incidence in males because they have only one X chromosome

38. Genetics • Gregor Mendel • Austrian monk • Garden pea experiments • Mendelian traits

39. Genetics • Locus • Position of a gene along a chromosome • Allele • A different form of a particular gene at a given locus • Example: Hgb A vs. Hgb S • Polymorphism • Locus that has two or more alleles that occur with appreciable frequency

40. Genetics • Homozygous • Loci on a pair of chromosomes have identical genes • Example • O blood type (OO) • Heterozygous • Loci on a pair of chromosomes have different genes • Example • AB blood type (A and B genes on pair of loci)

41. Genetics • Genotype (“what they have”) • The genetic makeup of an organism • Phenotype (“what they demonstrate”) • The observable, detectable, or outward appearance of the genetics of an organism • Example • A person with the A blood type could be AA or AO. A is the phenotype; AA or AO would be the genotype.

42. Genetics • If two alleles are found together, the allele that is observable is dominant, and the one whose effects are hidden is recessive • In genetics, the dominant allele is represented by a capital letter, and the recessive by a lowercase letter • Alleles can be co-dominant

43. Genetics • Carrier • A carrier is one that has a disease gene but is phenotypically normal • For a person to demonstrate a recessive disease, the pair of recessive genes must be inherited • Example • Ss = sickle cell anemia carrier • ss = demonstrates sickle cell disease

44. Pedigrees • Used to study specific genetic disorders within families • Begins with the proband

45. Pedigrees

46. Single-Gene Disorders • Recurrence risk • The probability that parents of a child with a genetic disease will have yet another child with the same disease • Recurrence risk of an autosomal dominant trait • When one parent is affected by an autosomal dominant disease and the other is normal, the occurrence and recurrence risks for each child are one half

47. Single-Gene Disorders • Autosomal dominant disorder • Abnormal allele is dominant, normal allele is recessive, and the genes exist on a pair of autosomes

48. Single-Gene Disorders • Autosomal dominant traits

49. Single-Gene Disorders • Autosomal dominant trait pedigree

50. Penetrance • The percentage of individuals with a specific genotype who also express the expected phenotype • Incomplete penetrance • Individual who has the gene for a disease but does not express the disease • Retinoblastoma (eye tumor in children) demonstrates incomplete penetrance (90%)