The Amerithrax investigation followed the 2001 anthrax attacks that killed 5 people. Letters containing anthrax spores were sent to media outlets and two senators. The FBI investigation into the source of the anthrax took 7 years. Mutations are changes in DNA sequences that are present in less than 1% of a population. Mutations can range from single DNA base changes to missing or extra chromosomes. They can affect protein function and transcription. Most mutations are recessive and cause loss of function, while gain-of-function mutations tend to be dominant. Sickle cell disease was the first genetic illness understood at the molecular level. It results from a single amino acid substitution in the beta globin protein that causes

1. Ikram Ullah
M.Phil MLSc

2. The Amerithrax Story
 In the weeks following the 2001 terrorist attacks in the
United States,
 Several people, including two senators and individuals
at several media outlets, received letters containing
threatening messages and a mysterious white powder.
 Of the 22 people who opened the letters and were
exposed to the contents—spores of Bacillus anthracis
—five died of inhalation anthrax.
 The Federal Bureau of Investigation (FBI) dubbed the
investigation, which took 7 years, “Amerithrax

3. Mutation
 A mutation is a change in a DNA sequence that is present
in less than 1 percent of individuals in a population.
 “mutate” refers to the process of altering a DNA sequence.
 Mutations range in size from alteration of a single DNA
base; to deletion or duplication of tens, hundreds,
thousands, or even millions of bases; to missing or extra
entire chromosomes.
 Mutation can affect any part of the genome, including
sequences that encode proteins or control transcription; in
introns; repeats; and sites critical to intron removal and
exon splicing

4.  The effects of mutation vary. Mutations may impair a
function, have no effect, or even be beneficial.
 A deleterious (harmful) mutation can stop or slow
production of a protein, overproduce it, or impair the
protein’s function—such as altering its secretion, location,
or interaction with another protein.
 Geneticists describe the effect of a mutation as a “loss of
function” when the gene’s product is reduced or absent,
 or as a “gain of function” when the gene’s action changes in
some way.
 Most mutations are recessive and cause a loss of function.
Gain-of function mutations tend to be dominant.

5.  Geneticists define a mutation as being present in less
than 1 percent of a population and a polymorphism as
being present in more than 1 percent of a population.
 The term mutation refers to genotype—that is, a
change at the DNA or chromosome level. The familiar
term mutant refers to phenotype.
 In a germline mutation, the change occurs during
the DNA replication that precedes meiosis
 A somatic mutation happens during DNA
replication before a mitotic cell division

6. The Beta Globin Gene
 The first genetic illness understood at the molecular level was
sickle cell disease
 In 1904, young medical intern Ernest Irons noted “many pear-
shaped and elongated forms
 Irons sketched this first view of sickle cell disease at the cellular
level,
 In 1949, Linus Pauling discovered that hemoglobin from healthy
people and from people with the anemia, when placed in a
solution in an electrically charged field (a technique called
electrophoresis), moved to different positions
 The difference between the two types of hemoglobin lay in beta
globin

7.  Protein chemist V. M. Ingram took a shortcut to localize
the mutation in the 146-amino-acid-long beta subunit.
 He cut normal and sickle hemoglobin with a protein-
digesting enzyme, separated the pieces, stained them, and
displayed them on filter paper.
 Ingram identified the tiny mutation responsible for sickle
cell disease:
 a substitution of the amino acid valine for the glutamic acid
that is normally the sixth amino acid in the beta globin
polypeptide chain
 At the DNA level, the change was even smaller—a CTC to a
CAC, corresponding to RNA codons GAG and GUG

8.  The valine at this position changes the surfaces of
hemoglobin molecules so that in low-oxygen
conditions they attach at many more points than they
would if the wild type glutamic acid were at the site.
 The aggregated hemoglobin molecules form ropelike
cables that bend red blood cells into rigid, fragile,
sickle-shaped structures

10. Causes of Mutation
 A mutation can occur spontaneously or be induced by
exposure to a chemical or radiation. An agent that causes
mutation is called a mutagen
 Spontaneous Mutation
 Two healthy people of normal height may have a child with
achondroplasia, an autosomal dominant form of dwarfism.
 How could this happen when no other family members are
affected?
 If the mutation is dominant, why are the parents of normal
height?

11.  This is a spontaneous mutation—that is, it is not
caused by a mutagen.
 A spontaneous mutation usually originates as an error
in DNA replication.

12. Mutational Hot Spots
 In some genes mutations are more likely to occur in regions
called hot spots, where sequences are repetitive.
 It is as if the molecules that guide and carry out replication
become “confused” by short repeated sequences
 The increased incidence of mutations in repeats has a
physical basis.
 Within a gene, when DNA strands locally unwind to
replicate in symmetrical or repeated sequences, bases
located on the same strand may pair.
 A stretch of ATATAT might pair with TATATA elsewhere on
the same strand, creating a loop that interferes with
replication and repair enzymes, increasing risk of error

14.  Induced Mutation: Geneticists use mutagens on model
organisms to infer normal gene functions, yielding many
collections and insights into human health
 Intentional Use of Mutagens: Researchers have developed
several ways to test the mutagenicity of a substance
 Researchers exposed human connective tissue cells
growing in culture to liquefied cigarette smoke.
 The chemicals from the smoke cut chromosomes through
both DNA strands.
 This is an especially damaging insult because broken
chromosomes can join with each other in different ways
that can activate cancer-causing genes

15.  Accidental Exposures to Mutagens: Some mutagen
exposure is unintentional.
 This occurs from workplace contact before the danger
is known; from industrial accidents; from medical
treatments such as chemotherapy and radiation; and
from exposure to weapons that emit radiation.

16. Natural Exposure to Mutagens