AGB 121: Principles of Animal Genetics and Population Genetics (2+1)

CHEMICAL MUTAGENS

• The first chemical mutagen discovered was mustard gas (sulfur mustard).
• Chemical mutagens can be divided in to five main classes
  • Those that are mutagenic only to replicating DNA such as acridine dyes ( which bind to DNA and increase the probability of mistakes during DNA replication ) and base analogs ( which are incorporated into DNA instead of normal bases ).
  • Those that are mutagenic to both replicating and non-replicating DNA, such as alkylating agents ( that transfer alkyl groups such as CH₃-, CH₃CH₂- etc to DNA ) and deaminating agents ( nitrous acid ).

Base analogs

• The mutagenic base analogs have similar structure to normal bases and are thus metabolized and incorporated in to DNA during replication.
• Example:

5 Bromo Uracil ( 5 - BU )

• The pyrimidine 5-bromo uracil is a thymine analog.
• The base 2-aminopurine is a purine analog.
• In the more stable keto form, 5 bromo uracil mimics the pairing behavior of the thymine that it replaces, pairing with adenine.
• After a tautomeric shift to its enol form, rare ionized form of 5 bromo uracil pairs with guanine.
• It can thus cause GC to AT transition and AT to GC transition.

2 Amino-P( 2 - AP )

• Another analog widely used in research is 2-amino-purine (2-AP), which is an analog of adenine that can pair with thymine.
• But in its protonated state it can pair with cytosine

Acridine Dyes

• Dyes such as proflavin, acridine orange and a series of compounds called ICR170, ICR191 etc are powerful mutagens that induce frameshift mutations.
• The positively charged acridines intercalate or sandwich themselves between the stalked base pairs in DNA and increase the rigidity and cause slight “kinks” in the DNA double helix.
• When such DNA replicate, additions or deletions of base pairs occur causing frameshift mutations.

Alkylating agents

• They cause transfer of methyl or ethyl groups to bases changing their base pairing potential, causing transitions. They also induce transversions, frameshifts and chromosomal aberrations.
• Example nitrogen and sulfur mustards, methyl and ethyl methane sulfonate (MMS and EMS ), nitrosoguanidine (NTG) have several effects on DNA.

Deaminating agents

Nitrous acid (HNO₂)

• Causes mutation by the oxidative deamination of adenine, guanine and cytosine which contain amino groups.
• Adenine is deaminated to hypoxanthine, which base pairs with cytosine rather than thymine.
• This results in AT to GC transition.
• Deamination of guanine produces xanthine which pairs with cytosine just like guanine. So it is not directly mutagenic.
• Deamination of cytosine results in uracil which pairs with adenine and thus causes GC to AT transition.
• Therefore nitrous acid can cause both GC to AT and AT to GC transitions.

Miscellaneous

Hydroxylating agents

• Example : Hydroxylamine (NH₂OH). It induces only GC to AT transition.
• It hydroxylates amino group of cytosine to from hydroxylamine cytosine which can base pair with adenine causing GC to AT transition.