Mutagenesis and Mutations Overview of Genetic Disease

1. Mutagenesis and MutationsOverview of Genetic Disease DrMaha Al-Sulaimani Department of Biochemistry

2. Mutagenesis • Is a process by which the genetic information of an organism is changed, resulting in a mutation. • It may occur spontaneously, or as a result of exposure to mutagens.

3. Mutagens • Mutagens are chemical or physical agents that increase the frequency of mutations. • Essentially, all mutagens show some specificity for the type of mutations produced. • The following table indicates the type of mutations typically produced by some mutagens.

4. Mutagens and Mutations

5. Mutagenesis • It can also be achieved experimentally using laboratory procedures. • Mutagenesis can lead to cancer and various heritable diseases, but it is also the driving force of evolution.

6. Mutagenesis as a science • Mutagenesis as a science, was developed based on work done by Hermann Muller, Charlotte Auerbach and J. M. Robson, in the first half of the 20th century.

7. Mutation • Mutation is a permanent change in the nucleotide sequence of the genetic material (DNA). • Can be on chromosomal or DNA levels. • DNA levels account for 92% of mutations.

8. Mutations • Mutation could be in somatic or germ-line cells. • A mutation arising in a somatic cell cannot be transmitted to offspring, whereas if it occurs in gonadal tissue or a gamete it can be transmitted to future generations.

9. Mutations • Mutations can occur either in non-coding or coding sequences. • Mutation in the coding sequence is recognized as an inherited disorder or disease.

10. Single gene disorders • Single gene disorders are genetic conditions caused by the alteration or mutation of a specific gene in the affected person’s DNA. • Single gene disorders are heritable and often run in families. • Individuals with a family history of a single gene disorder may be at risk for passing the condition on to their children.

11. Chromosomal Disorders • A chromosome anomaly, abnormality or aberration reflects an atypical number of chromosomes or a structural abnormality in one or more chromosomes. • A Karyotype refers to a full set of chromosomes from an individual which can be compared to a "normal" Karyotype for the species via genetic testing.

12. Chromosomal Disorders • A chromosome anomaly may be detected or confirmed in this manner. • Chromosome anomalies usually occur when there is an error in cell division following meiosis or mitosis. • There are many types of chromosome anomalies. They can be organized into two basic groups, numerical and structural anomalies.

13. Chromosomal Disorders • Some anomalies, however, can happen after conception, resulting in Mosaicism(where some cells have the anomaly and some do not).

14. Chromosomal Disorders • Chromosome anomalies can be inherited from a parent or be "de novo". • This is why chromosome studies are often performed on parents when a child is found to have an anomaly. • If the parents do not possess the abnormality it was not initially inherited; however it may be transmitted to subsequent generations.

15. Mutation at the chromosomal level • Numerical abnormalities: *Aneuploidy • Monosomy (45) • Trisomy (47) • Tetrasomy (48) *Polyploidy • Triploidy (2 + 1) • Tetraploidy (2 + 2)

16. Numerical Disorders • Occur when an individual is missing either a chromosome from a pair (monosomy) or has more than two chromosomes of a pair (Trisomy, Tetrasomy, etc.). • In humans an example of a condition caused by a numerical anomaly is Down Syndrome, also known as Trisomy 21 (an individual with Down Syndrome has three copies of chromosome 21, rather than two). • Turner Syndrome is an example of a monoploidywhere the individual is born with only one sex chromosome, an X.

17. Mutation at the chromosomal level 2. Structural abnormalities: • Deletions. • Duplications. • Translocations. • Insertion. • Inversions. • Rings. • Isochromosomes.

18. Structural Disorders • This can take several forms: • Deletions: A portion of the chromosome is missing or deleted. Known disorders in humans include Wolf-Hirschhorn syndrome, which is caused by partial deletion of the short arm of chromosome 4; and Jacobsen syndrome, also called the terminal 11q deletion disorder.

19. Wolf-Hirschhorn and Jacobsen Syndromes • Wolf-Hirschhorn syndrome: facial abnormalities, growth and mental retardation, muscle hypotonia, seizures, and congenital heart defects. • Jacobsen syndrome: Most affected individuals have delayed development, including the development of motor skills (such as sitting, standing, and walking) and speech. Most also have cognitive impairment and learning difficulties.

20. Structural Disorders • Duplications: A portion of the chromosome is duplicated, resulting in extra genetic material. Known human disorders include Charcot-Marie-Tooth disease type 1A which may be caused by the duplication of the gene encoding peripheral myelin protein 22 (PMP22) on chromosome 17.

21. Translocations • Is a chromosome abnormality caused by rearrangement of parts between non-homologous chromosomes. • A gene fusion may be created when the translocation joins two otherwise separated genes, the occurrence of which is common in cancer. • It is detected on cytogenetics or a karyotype of affected cells.

22. Translocations

23. Structural Disorders • There are two main types of translocations: • In a reciprocal translocation, segments from two different chromosomes have been exchanged. • In a Robertsonian translocation, an entire chromosome has attached to another at the Centromere - in humans these only occur with chromosomes 13, 14, 15, 21 and 22.

24. Inversions • Is a chromosome rearrangement in which a segment of a chromosome is reversed end to end. • An inversion occurs when a single chromosome undergoes breakage and rearrangement within itself.

25. Inversions

26. Structural Disorders • Rings: A portion of a chromosome has broken off and formed a circle or ring. This can happen with or without loss of genetic material. • Isochromosomes: are formed by loosingone of its arms and it being replaced with an exact copy of the other arm.This is sometimes seen in some females with Turner syndrome or in tumor cells.

27. Isochromosomes

28. Chromosomal Disorders • Chromosome instability syndromes are a group of disorders characterized by chromosomal instability and breakage. • They often lead to an increased tendency to develop certain types of malignancies. • Examples are Fanconi anemia and Bloom syndrome.

29. Chromosomal Disorders • Bloom syndrome: is a rare autosomal recessive disorder characterized by short stature and predisposition to the development of cancer. • Cells from a person with Bloom syndrome exhibit a striking genomic instability.

30. Chromosomal Disorders • Fanconianemia (FA): is a genetic disease with an incidence of 1 per 350,000 births, with a higher frequency in Afrikaners in South Africa. • FA is the result of a genetic defect in a cluster of proteins responsible for DNA repair.

31. Chromosomal Disorders • As a result, the majority of FA patients develop cancer, most often acute myeloid leukemia, and 90% develop bone marrow failure by the age of 40. About 60-75% of FA patients have congenital defects, commonly short stature, abnormalities of the skin, arms, head, eyes, kidneys, and ears, and developmental disabilities. Around 75% of FA patients have some form of endocrine problem, with varying degrees of severity. • Median age of death was 30 years in 2000.

32. Prevalence and diagnosis of chromosomal instability syndromes • Chromosomal breakage syndromes are relatively rare; most practicing physicians may never see a patient with a chromosomal breakage syndrome. • Some of the specific syndromes occur at relatively high rates in certain ethnic groups. • Diagnosis is complicated because the symptoms may be varied and complex. • These disorders are often lethal.

33. Chromosomal breakage studies • The diagnosis of chromosome breakage disorders such as Fragile-X, Fanconi anemia, and Blooms syndrome involves addition of chromosome breakage inducing agents specific for each disorder, to the blood culture. The test is run simultaneously with blood of a matched control.

34. Chromosomal Disorders • Multiple cultures of the patient and control samples are set up. A positive sample will show a higher frequency of breaks, fragile sites, radial figures or sister chromatid exchanges, compared to the control (karyotype/cytogenetics).

35. Chromosomal breakage studies

36. Multi-factorial Disorders • Genetic disorders may be complex, multifactorial, or polygenic, meaning that they are likely associated with the effects of multiple genes in combination with lifestyle and environmental factors. • Multifactorial disorders include heart disease and diabetes. • Although complex disorders often cluster in families, they do not have a clear-cut pattern of inheritance(do not follow Mendelian Inheritance).

37. Multi-factorial Disorders • This makes it difficult to determine a person’s risk of inheriting or passing on these disorders. • Complex disorders are also difficult to study and treat because the specific factors that cause most of these disorders have not yet been identified.

38. Mitochondrial Disorders • Mitochondrial diseases are often caused by genetics or mutations to the mitochondrial DNAthat affect mitochondria function. • Mitochondrial diseases take on unique characteristics both because of the way the diseases are often inherited and because mitochondria are so critical to cell function.

39. Disorders of Somatic cells • Also called “aquired mutations”. • Is a mutationacquired by a somatic cell after conception. • Acquired mutations occur in somatic cells, not germ cells, and so cannot be transmitted to the children.

40. Disorders of Somatic cells • However, acquired mutations are transmitted to all cells descended from the mutant cell, giving rise to a clone (colony) of cells marked by the mutation. • Some acquired mutations are involved in the development of cancer.

41. Mutations • Mutations at the DNA level

42. Types of Mutations • Mutations can be considered in two main classes according to how they are transmitted from one generation to another: • Fixed/Stable mutations: mutation which is transmitted unchanged (unaltered).

43. Types of Mutations • Dynamic Or Unstable Mutations: this is a new class of mutation which undergo alteration as they are transmitted in families.

44. Fixed/Stable mutation • Fixed/stable point mutations can be classified according to the specific molecular changes at the DNA level. • These include single base pair: • Substitutions, • Insertions, • Deletions.

45. Fixed/Stable mutation: Substitution • Definition: a substitution is the replacement of a single nucleotide by another. • There are two types of substitution: • Transition: If the substitution involves replacement by the same type of nucleotide: a pyrimidine for a pyrimidine (C for T or vice versa) or a purine for a purine (A for G or vice versa)

46. Fixed/Stable mutation: Substitution • Transversion: Substitution of a pyrimidine by a purine or (vice versa). • Deletion involves the loss of one or more nucleotides.

47. Transitions and Transversions

48. Substitutions and Deletions

49. Fixed/Stable mutation\Insertion • An insertion involves the addition of one or more nucleotides into a gene.

50. Dynamic/Unstable mutation • Unstable or dynamic mutations consist of triplet repeat sequences which, in affected persons, occur in increased copy number when compared to the general population. • Triplet amplification or expansion has been identified as the mutational basis for a number of different single gene disorders.