Lecture 17: Mutation

(version 24 September 1999)

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Forward versus Back mutation

Wild type alleles are generally denoted by ⁺

A⁺ --> A forward mutation

A --> A⁺ back mutation ( reversion)

Somatic versus germline mutation

Only mutations that appear in germline cells are passed on

Somatic mutations

The somatic descents of a particular cell are called a clone

A Mutant section (or sector) is the clone descending form a mutant cell.




The flower on the left shows multiple mutant sections (mutants are white)

The plant on the right has mutant section that give rise to white flowers and hence appears in the germline in these flowers.



Mutant Types

Conditional mutations

restrictive vs. permissive conditions

ts, or temperature-sensitive mutants

The Himalayan coat phenotype in mammals arises because of a ts mutation. Normal body temperatures inactivate the pigment, while it is deposited at slightly cooler temperatures.

prototrophic (grow on minimal medium)

auxotrophic (need other stuff)

Behavior of mutants

Estimating mutation rates

How does one estimate u, the per-cell, per-generation mutation rate (the probability that a cell undergoes a mutation).

Problem: Just can't count total number of mutants

Hard to count

The four cultures above show a total of 2+0+4+1 = 7 mutant cells, but only 3 mutational events occurred.

Solution: Use the zero class of the Poisson

Suppose n total cells, u = rate per cell

Suppose N different cultures examined, k of which showed no mutations

Mutation rate u estimated by solving k/N = Exp[-nu]

u = - ln(k/N)/n

Early debate on cause of mutations

Two alternative models proposed:

Physiological change model

Exposing cells to some agent created mutations resistant to that agent

Random mutation model

mutations are pre-existing

The Lederbergs' replica-plating experiment

Showed mutations are pre-existing

Provided strong support for random mutation model

Mutation and cancer

proto-oncogenes and oncogenes

Proto-oncogenes are genes with normal (and often important) cellular functions.

They can mutate to give oncogenes, gene causing cancer

Mitosis review

Retinoblastoma

Recessive mutant.

Exists as both sporatic cases (generally, in one eye only) and hereditary cases (usually both eyes)

Rr individuals are highly prone to retinoblastoma due to mutations in the active R copy (R --> r) or Mitotic crossing-over

30% of all cases are due to second mutation

70% due to mitotic crossingover

Much more details on Retinoblastoma from the Online Mendelian Inheritance in Man website


p53

Science magazine designated p53 the 'Molecule of the Year' for 1993

The p53 tumor suppressor is found to be mutated and abundant in a wide variety of tumors. In fact p53 is the most frequently disrupted gene in cancer

After DNA damage, many cells appear to enter a sustained arrest (in the G2 phase of the cell cycle). This arrest is sustained only when p53 was present in the cell. This arrest is a critical checkpoint to prevent cells from becoming cancerous. When p53 is defective, this checkpoint it lost.

References for those interested in finding out more on p53

1. Introduction to the p53 pathway
2. More than you every wanted to know about p53 from Online Mendelian Inheritance in Man website