What is mutation A mutation is a change

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What is mutation? A mutation is a change in the genetic material that controls

What is mutation? A mutation is a change in the genetic material that controls heredity. What is genetic materials? relationship is the genetic material and chromosome?

Genetic material and chromosome

Genetic material and chromosome

homologous

homologous

Mutation Results from unrepaired damage to DNA Mutation = Damage - repair

Mutation Results from unrepaired damage to DNA Mutation = Damage - repair

Facts of mutation Mutation are stably inherited changes in the nucleotide sequence of the

Facts of mutation Mutation are stably inherited changes in the nucleotide sequence of the genome A change in nucleotide sequence due to, for example, damage to DNA is not a mutation unless it caused changes in DNAs that result from replication of the damage DNA.

Mutation or polymorphism DNA sequence variations are sometimes described as mutations and sometimes as

Mutation or polymorphism DNA sequence variations are sometimes described as mutations and sometimes as polymorphisms. What is the difference between these terms and how are they applied to the human genome?

Polymorphism DNA sequence variation that is common in the population NO standard sequence but

Polymorphism DNA sequence variation that is common in the population NO standard sequence but two or more equally acceptable alternatives The arbitrary cut-off point between a mutation and a polymorphism is 1 % That is, to be classed as a polymorphism, the least common allele must have a frequency is lower that this, the allele is regarded as a mutation.

ชนดของ mutation การแบงแยกตามขนาดทเกดขน ◦ Point mutation (gene mutation) ◦ Chromosome mutation แหลงกำเนด ◦ Spontaneous

ชนดของ mutation การแบงแยกตามขนาดทเกดขน ◦ Point mutation (gene mutation) ◦ Chromosome mutation แหลงกำเนด ◦ Spontaneous mutation ◦ Induced mutation ผลกระทบ ◦ Missense mutation ◦ Nonsense ◦ Frame shift mutation ◦ Lethal mutation

English peppered moths

English peppered moths

base substitution deletion / addition

base substitution deletion / addition

�������� (sickle-cell anemia)

�������� (sickle-cell anemia)

Mutations Germ-line mutation ◦ sperm and egg gamete cells ◦ precursor cell ���������� หากเกดการกลายพนธในเซลลสบพนธ

Mutations Germ-line mutation ◦ sperm and egg gamete cells ◦ precursor cell ���������� หากเกดการกลายพนธในเซลลสบพนธ เมอเกดการผสมพนธ (fertilization) �������������������������� ������� Somatic mutation ◦ early or late stages of embryonic development ◦ single embryonic cell ◦ timing of mutation ◦ genetic mosaic

Somatic mutation

Somatic mutation

Translocation, duplication and deletion

Translocation, duplication and deletion

Aneuploidy, euploidy

Aneuploidy, euploidy

Spontaneous deamination of cytosine and 5 -methylcytocine hot spots for mutation

Spontaneous deamination of cytosine and 5 -methylcytocine hot spots for mutation

Tuatomeric shifts

Tuatomeric shifts

Chemical mutagen Nitrous acid (HNO 2): ������������ (keto group) ���������� deamination deaminates base ◦

Chemical mutagen Nitrous acid (HNO 2): ������������ (keto group) ���������� deamination deaminates base ◦ การเปลยนเบส cytocine ���� uracil ◦ ������� adenine ���� hypoxanthine

Chemical mutagen (��� ) Nitrogen mustard ��� ethyl methanesulfonate (EMS): �������� alkyl ������ methyl

Chemical mutagen (��� ) Nitrogen mustard ��� ethyl methanesulfonate (EMS): �������� alkyl ������ methyl ����������������� alkylating agent Acridine dye ���� proflavin: ����� frameshift mutation intercalates within DNA helix

 Compounds ���� 5 -bromouracil (5 BU) ��� 2 -aminopurine: 5 BU ���� T

Compounds ���� 5 -bromouracil (5 BU) ��� 2 -aminopurine: 5 BU ���� T �������� A ��� G ���� 2 aminopurine ���� A �������� T ��� C ����� DNA replication ����� transition base analogue Chemical mutagen

I. DNA damage from environmental agents Modifying nucleotide bases When the DNA strands are

I. DNA damage from environmental agents Modifying nucleotide bases When the DNA strands are separated and copied. The altered base will pair with an incorrect base and cause mutation. Breaking the phosphate backbone (phosphodiester bond)

Breaking the phosphate backbone - Breaking the phosphate backbone of DNA within a gene

Breaking the phosphate backbone - Breaking the phosphate backbone of DNA within a gene crates a mutated form of the gene - It is possible that the mutated gene will produce a protein that differently - Cells with broken DNA will attempt to fix the broken ends by joining these free ends to other pieces of DNA within the cell - This creates a type of mutation called “translocation”. If a functions translocation breakpoint occurs within or near a gene that genes function may be affected

II. Mistakes created during DNA replication Mutations results when the DNA polymerase makes a

II. Mistakes created during DNA replication Mutations results when the DNA polymerase makes a mistake. Which happens about once every 100, 000 bases.

E. coli § DNA polymerase I and III involved in normal DNA replication §

E. coli § DNA polymerase I and III involved in normal DNA replication § DNA polymerase II, IV and V play a role in DNA repair and the replication of damaged DNA § DNA polymerase III contains a 3’ exonuclease site that remove mismatched bases.

Unusual features of DNA polymerase function The synthesis of DNA at the replication fork

Unusual features of DNA polymerase function The synthesis of DNA at the replication fork Okazaki fragment (100 to 200 nucleotide) § to complete the synthesis of Okazaki fragments § removal of RNA primers § synthesis of DNA in the area where the primers have been removed § the covalent attachment of adjacent fragments of DNA § DNA polymerase I has a 5’ to 3’ exonuclease activity § DNA ligase catalyzes a covalent bond

A three-dimensional view of DNA replication Primosome = helicase + primase Replisome = primosome

A three-dimensional view of DNA replication Primosome = helicase + primase Replisome = primosome + two DNA polymerase III § The term dimeric DNA polymerase is two DNA polymerase holoenzymes that move as a unit toward the replication fork. § the lagging strands is looped out.

The proofreading function of DNA polymerase § fidelity: DNA polymerase III is so high

The proofreading function of DNA polymerase § fidelity: DNA polymerase III is so high because the hydrogen bonding between G and C or A and T is much more stable than between mismatched paris. (one mistake per 10, 000 nucleotides) § proof reading function of DNA polymerase III decrease the error rate to a range of 1 in 100, 000 to 1 million. § proof reading occurs by the removal of nucleotides in the 3’ to 5’ direction at the 3’ exonuclease site (one mistake per 100 million)

The polymerase slippage model

The polymerase slippage model

Mutation and the next generation There are two places where mutation can be introduced

Mutation and the next generation There are two places where mutation can be introduced and carried into the next generation. A mutation occurs in the developing germ line cell, it may persist until that individual reaches reproductive age. A mutation being passed on from parents during meiosis.

Mutation and the next generation Mutations also provide a species with the opportunity to

Mutation and the next generation Mutations also provide a species with the opportunity to adapt to new environments, as well as to protect a species from new pathogens. ◦ “survival of the fittest”, the basic theory of evolution proposed by Charles Darwin in 1859. ◦ Viral genes have high mutation to serve the virus well by enabling adaptive traits, such as changes in the outer protein coat so that it can escape detection and thereby destruction by the host’s immune system. Viruses also produce infection for infection of a host cell. A mutation within such as enzyme may result in a new form that still allows the virus to infect its host but that is no longer blocked by an anti-viral drug. this will allow the virus to propagate freely in its environment.