Mutations types and causes

This presentation will help students to brush up their basic concepts and along with that it will help them to understand what are mutations and what are its causes.

1. MUTATION: TYPES AND CAUSES MANSI ARORA

2. PREREQUISITE KNOWLEDGE What is DNA and RNA and understanding of it’s structures. Amino acids, Polypeptide, Protein Structures (Primary, Secondary, Tertiary, Quaternary). Phenotype Genotype Alleles Codons Transcription, Translation, etc. Nucleotides Central Dogma All the Basics of Genetics

3. GOALS OF THIS LECTURE UNDERSTANDING OF THE FOLLOWING TOPICS What is Mutation Related Terminologies General characteristics Role of Mutation Central Dogma Types of Mutation Types of Mutagens Causes of Mutation

4. MUTATION A mutation occurs when DNA or it’s gene is damaged/ altered in a way that it results in alteration of the genetic message which is carried by a gene. Any type of alterations in nucleotide. It can simply be put as an abrupt change in the genotype of an organism that is not the result of recombination.

5. OTHER RELATED TERMS Mutagenesis: The process by which mutation is produced. Mutant: An organism exhibiting novel phenotype as a result of the presence of a mutation Mutagen: It is a substance that can bring about a permanent alteration to a physical composition of DNA or gene such that genetic message is changed. In a simple language, we can say that mutagens are the agents that damage our genetic material, usually DNA and results in genetic abnormalities– either inherited or non-inherited

6. MUTATION: GENERAL CHARACTERISTICS Generally recessive , but dominant mutations also occur Generally harmful to the organisms Random , occurs at any time and in any cell of the organism Recurrent ( The same mutation may occur again and again)

7. ROLE OF MUTATION Source of genetic variation and it provides the raw material for evolution Mutations result into the formation of alleles . Without it, all genes would exist in only one form Organism would be able to evolve and adapt to environmental changes

8. CENTRAL DOGMA Mutation in DNA- Most dangerous (Why?) Amplification That’s why there are ways to fix this or prevent cell from mutation

9. TYPES OF MUTATION

10. TYPES OF MUTATION Spontaneous Mutation Occurs without treatment of organism with an exogenous mutagen Ultimate source of natural genetic variation Induced Mutation Arises when mutagen reacts with parent DNA, causing structural change that affects the base pairing capability of the altered nucleotide

11. TYPES OF MUTATION: SOMATIC VS GERMLINE MUTATION Somatic Mutation Occurs in body cell and cannot be inherited (only tissues derived from mutated cell are affected) Germline Mutation Occurs in gametes and can be passed onto offspring (every cell in the entire organism will be affected)

12. POINT MUTATIONS A  point mutation  is a  mutation  that only affects a single nucleotide of nucleic acid. Base Substitution : Transition and Transversion

13. MISSENSE MUTATION (Ex: Hs- sickle) C A T C A T C A T HIS HIS HIS MUTATION OCCURS C A T C C T C A T HIS PRO HIS

14. NONSENSE MUTATIONS C A G C A G C A G Gln Gln Gln MUTATION OCCURS C A G T A G C A G Gln TRANSLATION STOPS Results into formation of truncated protein Gln UAG (mRNA)- Stop Codon. Stop codons are: UAG, UGA and UAA. Truncated Protein Non Functional, gets degraded / Can add with different truncated protein and starts to function in a completely different manner / Improper functions like original protein but not all functions are done (Examples, many scenarios possible)

15. SILENT MUTATIONS A change in the nucleotide bases which constitutes DNA, without a subsequent change in the amino acid or the function of the overall protein. CAA and CAT both codes for Valine (Wobble Hypothesis) CA- Conserved A,T- Variable ( Wobble position of codon) Mutation in DNA level still protein structure and function- Same T A C G G T C A A Met Pro Val MUTATION OCCURS T A C G G T C A T Met Pro Val

16. FRAMESHIFT MUTATIONS (INSERTION) Error in DNA replication , transcription etc. addition or deletion of nucleotide. ORF, tRNA, mRNA, Ribosome ORF- 1 Codon- 3 Nucleotides Eg : Insertion/ Addition

17. FRAMESHIFT MUTATIONS (DELETION)

18. CHROMOSOMAL MUTATIONS A mutation involving a long segment of DNA . These mutations can involve deletions , insertions , or inversions of sections of DNA. In some cases, deleted sections may attach to other chromosomes, disrupting both the chromosomes that loses the DNA and the one that gains it. Also referred to as a chromosomal rearrangement.

19. CHROMOSOMAL MUTATION: NUMERICAL

20. TYPES OF NUMERICAL CHROMOSOMAL MUTATION Polyploidy Case of a cell or an individual possessing entire extra sets of chromosomes . The type of polyploidy is designated by the number of haploid (N) sets that are present. Triploid (3N) individuals have three sets of chromosomes while tetraploid (4N) individuals have four. ( Autopollyploids and Allopolyploids) Aneuploidy Addition or deletions of less than a whole set. In this case organism gains or loses one or more chromosomes, but not a complete set. Cause- Nondisjunction during meiosis or mitosis (Monosomy (2n-1), Trisomy(2n+1)) Includes both autosomal as well as sex chromosomal aneuploids

21. ANEUPLOIDY OF SEX CHROMOSOMES 1. Klinefeltor Syndrome (47, XXY) Male Symptoms: Subfertile with small testes, developed breasts, feminine pitched voice, knock knees, etc. Less commonly, 2-3 extra X-chromosomes (48, XXY) or extra copies of both X and Y (48, XXYY) Turner’s Syndrome (45, X) Female with retarded sexual development Usually sterile, short stature, webbing of skin in the neck region Cardiovascular abnormalities and hearing impairment.

22. AUTOSOMAL ANEUPLOIDY-TRISOMY DOWN SYNDROME Trisomy 21 st chromosome 60% dies in uterus Symptoms: Asymmentrical skull, mild to moderate M.R. Epicanthus ( An epicanthal fold is a skin fold of the upper eyelid covering the inner corner of the eye) Brushfield Spots : Small white spots on the periphery of iris (human eyes) Hypertelorism is an abnormally increased distance between two organs or bodily parts, usually referring to an increased distance between the orbits (eyes), or orbital hypertelorism .

23. AUTOSOMAL TRISOMY PATAU’S SYNDROME Trisomy 13th chromosome 1 in 5000 cases , 95% dies in uterus Symptoms Microcephaly (head) Microphthalmia (eyes) Polydactyly (Extra finger or toe)

24. AUTOSOMAL TRISOMY EDWARD SYNDROME Trisomy 18 th chromosome 1 in 3000 cases, 90% dies in uterus Mental and Motor Retardation Congenital Disorder Characteristic hand appearance with clenched hands and overlapping fingers

25. CHROMOSOME ABERRATION There are 4 types of chromosome aberrations: Deletion Duplication Inversions Translocations

26. CHROMOSOME ABERRATION: DELETION

27. CHROMOSOME ABERRATION: DUPLICATION

28. CHROMOSOME ABERRATION: INVERSION

29. CHROMOSOME ABERRATION: TRANSLOCATION

30. ROBERTSONIAN TRANSLOCATION

31. CHROMOSOME ABERRATION: RING CHROMOSOME A ring chromosome is formed when a break occurs on each arm of a chromosome leaving two sticky ends on the central portion that reunites to form a ring

32. TYPES OF MUTAGEN AND CAUSES OF MUTATION Physical X-Rays, Gamma Rays, Alpha and Beta Particles, Fast and thermal neutrons and UV Rays Chemicals 1. Alkylating agents: EMS: Ethyl methane sulphonate MMS: Methyl methane sulphonate DES: Diethyl sulphate DMS: Dimethyl sulphate 2. Base analogues: 5-Bromouracil (T), 2-Aminopurine(A), 6-Aminopurine 3. Intercalating agents: Proflavine, Acridine orange, EtBr 4. Others: Mustard Gas, Caffeine, Azide , Phenol, Heavy Metal- Ni, Pb, Cu, Cd

33. TYPES OF MUTAGEN Biological Transposon Virus Eg : Rubella virus, Cytomegallo virus, Hepatitis B virus Some Bacterias

34. CAUSES OF MUTATIONS Errors in DNA Replication: On very rare occasions DNA polymerase will incorporate a noncomplementary base into the daughter strand. During the next round of replication the miss-incorporated base would lead to a mutation. This, however, is very rare as the exonuclease functions as a proofreading mechanism recognizing mismatched base pairs and excising them . Errors in DNA Recombination: DNA often rearranges itself by a process called recombination which proceeds via a variety of mechanisms. Occasionally DNA is lost during replication leading to a mutation. Chemical Damage to DNA: Many chemical mutagens, some exogenous , some man-made, some environmental , are capable of damaging DNA. Many chemotherapeutic drugs and intercalating agent drugs function by damaging DNA . Radiation: Gamma rays, X-rays, even UV light can interact with compounds in the cell generating free radicals which cause chemical damage to DNA.

35. CAUSES OF MUTATIONS Spontaneous Lesions: Naturally occurring damage to DNA, called spontaneous lesions can generate mutations. Two of most common: Depurination and Deamination Intercalating Agents are flat molecules that can slip between base pairs in the double helix, slightly unwinding the helix and hence increasing the distance between adjacent base pairs.