- usually DNA in Keto form -> can be enol/imino form - spont A becomes A -> pairs up with G -> next cycle returns to Keto --> the C would persist in daughter DNA

- base loses Purine - during DNA replication -> apurinic site cannot be used a template - thus by default A is added (serves in next cycle as template)

- Arcidine Orange - Ethidium Bromide - Acrylamide

- piece of DNA covalently bound to Cancer-Causing Chemical - initial step of carcinogenesis

-defective in Hereditory Non-Polyposis Colon Cancer - adenosines of the 5'GATC sequence methylated on template strand is methylated - -> endonuclease cleaves at palindromic sequences --> exonuclease degrades liberated strand --> Dna Pol I fills in + DNA ligase closes nick

-problem in Deamination (Cys --> Uracil) - DNA glycolyase + Endonuclease cuts out the Uracil - -> replaced by DNA pol

Lecture 4 - Genetic Variation Flashcards by Naufel Atia

Significance of Genetic Variability

-provides raw material for evolution - allowing species to adapt to the environment

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What causes Genetic Variability

1) Sexual Reproduction:
- meiosis
- crossing over
- independent assortment of Homologues chromosomes
- Fertilization

2) Mutation (new variations produced)

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Mutation

-allele of DNA sequence which yield a slightly modified mmolecule

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Polymorphism

-allele of DNA sequence which has no effect on the Phenotype and it’s frequency > 1% in a population

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Classification of Mutation

1) Cause
2) Site
3) Size
4) Function
5) Fitness

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What can the Causes be for Mutation

1) Spontaneous:
- Chem Rxns:
> Tautomerization
> Depurination
> Deamination

-Error withDNA Proccessing:
> Replication + Repair
> Recombination

2) Induced:
- physical
- chemical

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Tautomerization

usually DNA in Keto form -> can be enol/imino form

- spont A becomes A* -> pairs up with G -> next cycle returns to Keto –> the C would persist in daughter DNA

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Other causes of Tautomerization

Induced mutation:

-> by mutagenic source

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Depurination

base loses Purine
during DNA replication -> apurinic site cannot be used a template
thus by default A is added (serves in next cycle as template)

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Deamination

C -> U (repaired)

5-methyl-C –> Thymidine (not recognised)

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Causes of Induced

1) Physical (radiation):
- Heat
- Ionization
- UV

2) Chemical:
- Natural Toxic Mutagen
- Lab Chem
- Pollutants
- Biowarfare

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Definition of Mutagen

Mutagen = Environmental agent capable of causing mutation

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Natural Toxic Mutagen

Psoralen
Aflatoxin
Aspergillen

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Lab Chemical

Arcidine Orange
Ethidium Bromide
Acrylamide

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Pollutants

-Benzpyrine:

> metabolized in Liver to epoxides -> DNA Adduct

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Biwarfare

-Mustard Gas

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DNA Adduct

piece of DNA covalently bound to Cancer-Causing Chemical

- initial step of carcinogenesis

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Direct Repair vs Excision Repair

DIRECT REPAIR:
-change is reversed w/o a template
> DNA Photolysase: repair thymi dimers by photoactivation
> DNA Methyltransferase

INDIRECT REPAIR
-template needed

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Mismatch Repair

-defective in Hereditory Non-Polyposis Colon Cancer

adenosines of the 5’GATC sequence methylated on template strand is methylated
-> endonuclease cleaves at palindromic sequences –> exonuclease degrades liberated strand –> Dna Pol I fills in + DNA ligase closes nick

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Base Exision repair

-problem in Deamination (Cys –> Uracil)

DNA glycolyase + Endonuclease cuts out the Uracil
-> replaced by DNA pol

Nucleotide Exision Repair

defective in Xeroderma Pigmentosum
fixes thymidine dimers

-Endonuclease cleaves at 2 spots –> removed –> DNA Pol I fills in segment –> Ligase closes nick

Diseases caused by Nucleotide Excision Repair

-coded by 11 genes

> Xeroderma pignmentosum
> Cockanye Syndrome
> Trichothiodystrophy

Types of ds DNA repair

1) Homologous Recombination

2) Non-Homologous Recombination

Homologous Recombination

seen in Meiosis

- restricted to: S or G2 Phase

Non-Homologous Recombination

- occur throughout the cell cycle - works well against: oxidative damage + ionizing rad - does not return amended DNA to the original sequence

Where is Non-Homologous Recombination useful for

-benefit in generating AG-Rec diversity (as it does not return amended DNA to original sequence)

ATM

- Ser/Thr Protein Kinase --> serves as a sensor for DNA damage (dsdmg) - activates several proteins to initiate cell cycle arrest/DNA repair/apoptosis

Targets of ATM

- p53 - CHK2 - TSG (BRCA)

When ATM is mutated what is affect

-Neurogenerative disease

BRCA

- the effect in repair of DSB - mut -> incr probability of Chrom Repairr problem/Aneuploidy/Malformation - ovarian + breast cancer

Classification by Site (in orgnaism)

1) Somatic: - inherited by Cells in the organism 2) Generative: - inherited by the next generation

Classification by Site (in a gene)

1) Promotor -> Decr. Transcription 2) Exon -> Change in AA seq/ formation of Truncated protein 3) Intron -> error in splicing 4) Polyadenylation site -> reduced mRNA stability 5) 5'UTR -> Disturbed ribosome binding

Classification by Function

- loss of function - gain of function - back mutation (point mut reverses back to orig seq) - Lethal

Classificaion by Size

1) Genome Mut -> change in Chromo number 2) Chromo Mut -> Change in Chromo Structure 3) Gene Mut

Types of Repeats

- Interspersed repeats | - Tandem Repeats

Types of Tandem Repeats

- Satellite DNA - MiniSatellite (VNTR) - Microsatellite (STR)

Satellite Repeats

- large arrays of tandem repeats of non-coding DNA - produce different frequency of NT -> lower density than normal DNA - Satellite Band -> as it has G+C content

Where are Satellite Repeats

1) Functional Component of Centromere | 2) Structura Component of hetereochromatin

Minisatellite Repeats (VNTR)

- 10-60 BP | - Telomere = Minisatellite with thousands of repeating TTAGGG

Significance of VNTR

-amount of repeats at various locations -> varies amongst people --> banding pattern of VNTR used in DNA fingerprinting

Microsatellite Repeats (STR)

- 2-4BP - Tripet repeats are frequent - marker of Kinship

Triple Repeats Disease

Fragile X: ->non-coding CGG Spinobulbar Muscular Atrophy: -> coding repeats of CAG Huntington's Disease: -> coding repeats of CAG in Huntington gene -> yields Glu residues

Polyalanine Disorders

1) Synpolydactylia Type 2: - HOXD13 issue 2) Holoprosencepthaly: - issue with ZIC2

Types of Deletion and Insertions

1) Point Mutation: one NT changed 2) Frame-shift: - gain/loss NT -> fucks reading frame 3) In-frame mutation: - > deletion/gain of triplet doesnt fuck the reading frame

Tay Sachs

Frameshift Mutation -> addition of 4 BP in region of Hexosaminodase gene

Types of Point Mutation

1) Transition (pyr -> Pyr or Pur ->ur) 2) Transversion (pyr -> pur) 3) Silient -> mut doesnt cause chara change in AA 4) Misense 5) non-sense

Sickle Cell Anemia

- mis-sense mut | - GAG -> GTG (Glu - Val)

Duchenne

- deletion leading to -> non-sense mut | - exon 45-54 deleted

hBecker

-deletion -> in-frame transcript