Medical Genetics
03 基因突变
Gene Mutation
Medical Genetics
Gene Mutation
Change in genes caused by
change in structure of the DNA,
Medical Genetics
1,Base(s) in DNA is (are) changed to
other(s),or a base(s) is (are)
added or removed,
2,Rearrangements of the
chromosomes occur and are also
considered,
Medical Genetics
Mutations are heritable changes
in genetic material,
Medical Genetics
1,Mutagens or Mutagenic Agents
These are substances,conditions
and forms that significantly increase
the frequency of mutations,
Medical Genetics
Mutations can occur at a
spontaneous rate,or a far greater
rate when there is exposure to
mutagenic agents,
Medical Genetics
Exposure to too high a level of
mutagens can threaten the survival
of a species; e.g.,frog species in the
states of Washington and Oregon are
facing extinction,This appears to be
caused by reduced atmospheric
ozone,and the resulting increased
level of ultraviolet radiation,
Medical Genetics
A forms of energy
Examples of a forms of energy
are ultraviolet light,x-rays,cosmic
energy,gamma radiation,alpha
particles,beta particles and neutrons,
Medical Genetics
Ultraviolet (UV) light
UV light has shorter wavelengths
than visible light,Though these
waves are invisible to the human eye,
some insects,like bumblebees,can
see them!
Medical Genetics
Scientists have divided the
ultraviolet part of the spectrum into
three regions,the near ultraviolet,
the far ultraviolet,and the extreme
ultraviolet,
Medical Genetics
The three regions are distinguished
by how energetic the ultraviolet
radiation is,and by the "wavelength"
of the ultraviolet light,which is related
to energy,
Medical Genetics
The near ultraviolet,abbreviated NUV,
is the light closest to optical or visible light,
The extreme ultraviolet,abbreviated EUV,
is the ultraviolet light closest to X-rays,
and is the most energetic of the three
types,The far ultraviolet,abbreviated FUV,
lies between the near and extreme
ultraviolet regions,It is the least explored
of the three regions,
Medical Genetics
Medical Genetics
Ultraviolet Radiation causes
pyrimidine dimers,
These can block DNA replication,
Also,dimers interfere with base
pairing between the two DNA
polymeres,
U.V,light also generates free-
radicals,which create other kinds of
genetic damage,
Medical Genetics
Medical Genetics
Medical Genetics
Gamma and X-Rays
These can act directly on DNA;
however,most damage is caused
indirectly when molecules around the
DNA such as water,are ionized,
creating free-radicals,substances
with unpaired electrons,
Medical Genetics
Most often,the result is single or
double stranded breaks in the DNA
molecules,These breaks are hard to
repair because they often leave a
phosphate tacked onto the 3' OH,
where the break occurs,
Medical Genetics
Chemical Agents
Examples of substances that are
mutagens are nitrous acid,
hydroxylamine,ethyl
methanesulfonate,5-bromouracil,
celery,benzo (a) pyrene,acridine
dyes,fungally contaminated peanuts
or peanut butter,and many,many
more,
Medical Genetics
Hydroxylating agents
(hydroxylamine,HA)
Medical Genetics
Nitrous acid is a deaminating agent,
Deaminating agents cause the loss of the
amino group,We covered spontaneous
deamination of cytosine above,Deaminating
agents would increase the frequency of
cytosine deamination,greatly,
Medical Genetics
Medical Genetics
Ethyl methanesulfonate (EMS)
Alkylating agents are
chemicals that donate alkly
groups to other molecules,
Medical Genetics
Medical Genetics
Base analogs
Base analogs are similar to the actual
correct base and so get incorporated into
the DNA as would its natural counterpart,
The problem is that,if they are more
prone to tautomeric shifts than the natural
base,the frequency for mutation goes up,
substantially,The compound 5-
bromouracil is an example of an analog to
thymine,It undergoes a tautomeric shift
to base pair with guanine instead of
adenine,causing a transition,
Medical Genetics
Medical Genetics
Intercalation agents are
compounds that can slide between
the nitrogenous bases in a DNA
molecule,This tends to cause a
greater likelihood for slippage during
replication,resulting in an increase
in frameshift mutations,
Medical Genetics
Viruses
Viruses that can integrate into
the genome are also mutagenic
agents
Medical Genetics
2,Mechanism of Mutation
? Static mutation
? Dynamic mutation
Medical Genetics
Static mutation
? Microalterations
? Macroalterations
Medical Genetics
Microalterations involve single
base pairs,
? Transitions,Purine changes to an
alternate purine; pyrimidine changes
to an alternate pyrimidine,
? Transversions,A position with a
pyrimidine changes to have a purine;
or,purine to pyrimidine
Medical Genetics
Transitions occur more
commonly than transversions even
though more theoretical
combinations of transversions are
possible,
For example,the only possible
transition for the base A is to change
to the base G,Two transversions are
possible for the base A,C and T,
Medical Genetics
Medical Genetics
The reason transitions are more
common is due to the nature of the
underlying causes of mutations and
to the size of the bases,
Medical Genetics
Medical Genetics
A purine can be altered so that it
base pairs like the other,It is
impossible for a purine to be altered
to resemble a pyrimidine,or vice
versa,
Medical Genetics
Also,remember that purines
always hydrogen bond to pyrimidines,
This leaves the same distances
between each pair in the middle of
the DNA polymer,This reduces the
likelihood that these types of
mistakes are made by DNA
polymerase during replication,
Medical Genetics
Macroalterations are large
changes,such as duplications,
deletions,inversions or
rearrangements of a large number of
bases,
Medical Genetics
Dynamic mutation
The term ‘dynamic mutation’ was introduced
to distinguish the unique properties of expanding,
unstable DNA repeat sequences from other forms
of mutation,The past decade has seen dynamic
mutations uncovered as the molecular basis for a
growing number of human genetic diseases and
for all of the characterized ‘rare’ chromosomal
fragile sites,
Medical Genetics
While the dynamic mutation
mechanism explains some unusual
genetic characteristics,unexpected
findings have raised new questions
and challenged some assumptions
about the pathways that lead from
mutation to disease,
Medical Genetics
Medical Genetics
3,Result of mutation
missense mutation
When a single base pair causes
the substitution of one amino acid for
another,it is called a missense
mutation,
Medical Genetics
Medical Genetics
Medical Genetics
Medical Genetics
nonsense mutation
When a single base pair change,
deletion or insertion result in the
generation of a premature
translation termination because of
the generation of a new stop codon,
this is called a nonsense mutation,
Medical Genetics
Medical Genetics
Medical Genetics
Frameshift mutations
Frameshift mutations are the
result of a single base,or more,
insertion or deletion,The result can
be the generation of an entirely
different protein from the point
within the coding region where it
occurs,
Medical Genetics
Medical Genetics
Medical Genetics
Medical Genetics
Because they may involve many
bases or just one,frameshifts are
sometimes macroalterations and
sometimes microalterations,
Medical Genetics
4.functional effects of the change,
Morphological Mutants have
altered shape,
Medical Genetics
Lethal Mutants die as a result
of having the mutation,can be
dominant or recessive,but most
often are recessive,This makes
sense because there are so many
enzymes an organism must have to
live; if both copies are defective,the
organism would fail to survive,
Medical Genetics
Conditional Mutants are
normal under one condition
(permissive),but abnormal under
another (restrictive),These are
extremely useful for studying
processes such as development and
DNA replication,
Medical Genetics
Biochemical Mutants cause
defects in biochemical pathways for a
substance,which is then deficient,
Medical Genetics
Loss-of-Function mutations
cause a loss of function that is found
normally in wild-type,
Medical Genetics
Gain-of-function mutations
create a new function not normally
found in the wild-type,Hairy-faced
people would be an example,
Medical Genetics
A seven-month old baby with a genetic mutation that
boosts muscle growth is seen in an undated black and
white image released by the New England Journal of
Medicine on Wednesday June 23,2004,The discovery,
reported in Thursday's New England Journal of Medicine,
represents the first documented human case of such a
mutation,The boy's mutant DNA segment was found to
block production of a protein called myostatin that limits
muscle growth,
Medical Genetics
5.Genetic Effects of mutation
Another classification of
mutations has to due with
multicellular organisms where cells
might belong to the germ-line,if
they contribute genetic information
to future generations; or,if part of
the body that will never contribute
genetic information to future
generations,the somatic cell line,
Medical Genetics
? Somatic mutation is one that will never
contribute to the germ-line of the effected
individual,
? Germinal mutation is one that occurs in
a cell that is a progenitor to a germ cell(s),
For example,if a human embryo
sustains a mutation in a cell that later
becomes a germ cell,a sperm or egg,it is
a germinal mutation,
– Otherwise,it is a somatic cell mutation,
Medical Genetics
6,Repair of Mutation
There are many different repairs
systems used by organisms,
Medical Genetics
Photolyase Repair of pyrimidine
dimers is the simplest system to
understand,and is quite interesting,
An enzyme,photolyase,sits on top
of the dimer,then using a
wavelength of light longer than U.V,
as a source of energy,it breaks the
cross-links to restore the DNA to its
original form,
Medical Genetics
Medical Genetics
Excision Repair can be
considered the second choice for
repair of pyrimidine dimers,It is
more complicated and involves
removing a whole stretch of a strand
of DNA,which leaves a section of
single-stranded DNA followed before
and after by double-stranded,
Medical Genetics
Medical Genetics
Postreplication repair involves
recombination between single-strands of
daughter double-stranded DNA near the
replication fork
Medical Genetics
Medical Genetics
Error-Prone repair will be are last
example of the sample of the many repair
systems,It is also called error prone
repair,It eliminates gaps as a last ditch
effort to preserve a chance at life,It
basically adds whatever bases,but at
least usually the right number of bases,It
is probably responsible for most of the
observed transversions,
Medical Genetics
03 基因突变
Gene Mutation
Medical Genetics
Gene Mutation
Change in genes caused by
change in structure of the DNA,
Medical Genetics
1,Base(s) in DNA is (are) changed to
other(s),or a base(s) is (are)
added or removed,
2,Rearrangements of the
chromosomes occur and are also
considered,
Medical Genetics
Mutations are heritable changes
in genetic material,
Medical Genetics
1,Mutagens or Mutagenic Agents
These are substances,conditions
and forms that significantly increase
the frequency of mutations,
Medical Genetics
Mutations can occur at a
spontaneous rate,or a far greater
rate when there is exposure to
mutagenic agents,
Medical Genetics
Exposure to too high a level of
mutagens can threaten the survival
of a species; e.g.,frog species in the
states of Washington and Oregon are
facing extinction,This appears to be
caused by reduced atmospheric
ozone,and the resulting increased
level of ultraviolet radiation,
Medical Genetics
A forms of energy
Examples of a forms of energy
are ultraviolet light,x-rays,cosmic
energy,gamma radiation,alpha
particles,beta particles and neutrons,
Medical Genetics
Ultraviolet (UV) light
UV light has shorter wavelengths
than visible light,Though these
waves are invisible to the human eye,
some insects,like bumblebees,can
see them!
Medical Genetics
Scientists have divided the
ultraviolet part of the spectrum into
three regions,the near ultraviolet,
the far ultraviolet,and the extreme
ultraviolet,
Medical Genetics
The three regions are distinguished
by how energetic the ultraviolet
radiation is,and by the "wavelength"
of the ultraviolet light,which is related
to energy,
Medical Genetics
The near ultraviolet,abbreviated NUV,
is the light closest to optical or visible light,
The extreme ultraviolet,abbreviated EUV,
is the ultraviolet light closest to X-rays,
and is the most energetic of the three
types,The far ultraviolet,abbreviated FUV,
lies between the near and extreme
ultraviolet regions,It is the least explored
of the three regions,
Medical Genetics
Medical Genetics
Ultraviolet Radiation causes
pyrimidine dimers,
These can block DNA replication,
Also,dimers interfere with base
pairing between the two DNA
polymeres,
U.V,light also generates free-
radicals,which create other kinds of
genetic damage,
Medical Genetics
Medical Genetics
Medical Genetics
Gamma and X-Rays
These can act directly on DNA;
however,most damage is caused
indirectly when molecules around the
DNA such as water,are ionized,
creating free-radicals,substances
with unpaired electrons,
Medical Genetics
Most often,the result is single or
double stranded breaks in the DNA
molecules,These breaks are hard to
repair because they often leave a
phosphate tacked onto the 3' OH,
where the break occurs,
Medical Genetics
Chemical Agents
Examples of substances that are
mutagens are nitrous acid,
hydroxylamine,ethyl
methanesulfonate,5-bromouracil,
celery,benzo (a) pyrene,acridine
dyes,fungally contaminated peanuts
or peanut butter,and many,many
more,
Medical Genetics
Hydroxylating agents
(hydroxylamine,HA)
Medical Genetics
Nitrous acid is a deaminating agent,
Deaminating agents cause the loss of the
amino group,We covered spontaneous
deamination of cytosine above,Deaminating
agents would increase the frequency of
cytosine deamination,greatly,
Medical Genetics
Medical Genetics
Ethyl methanesulfonate (EMS)
Alkylating agents are
chemicals that donate alkly
groups to other molecules,
Medical Genetics
Medical Genetics
Base analogs
Base analogs are similar to the actual
correct base and so get incorporated into
the DNA as would its natural counterpart,
The problem is that,if they are more
prone to tautomeric shifts than the natural
base,the frequency for mutation goes up,
substantially,The compound 5-
bromouracil is an example of an analog to
thymine,It undergoes a tautomeric shift
to base pair with guanine instead of
adenine,causing a transition,
Medical Genetics
Medical Genetics
Intercalation agents are
compounds that can slide between
the nitrogenous bases in a DNA
molecule,This tends to cause a
greater likelihood for slippage during
replication,resulting in an increase
in frameshift mutations,
Medical Genetics
Viruses
Viruses that can integrate into
the genome are also mutagenic
agents
Medical Genetics
2,Mechanism of Mutation
? Static mutation
? Dynamic mutation
Medical Genetics
Static mutation
? Microalterations
? Macroalterations
Medical Genetics
Microalterations involve single
base pairs,
? Transitions,Purine changes to an
alternate purine; pyrimidine changes
to an alternate pyrimidine,
? Transversions,A position with a
pyrimidine changes to have a purine;
or,purine to pyrimidine
Medical Genetics
Transitions occur more
commonly than transversions even
though more theoretical
combinations of transversions are
possible,
For example,the only possible
transition for the base A is to change
to the base G,Two transversions are
possible for the base A,C and T,
Medical Genetics
Medical Genetics
The reason transitions are more
common is due to the nature of the
underlying causes of mutations and
to the size of the bases,
Medical Genetics
Medical Genetics
A purine can be altered so that it
base pairs like the other,It is
impossible for a purine to be altered
to resemble a pyrimidine,or vice
versa,
Medical Genetics
Also,remember that purines
always hydrogen bond to pyrimidines,
This leaves the same distances
between each pair in the middle of
the DNA polymer,This reduces the
likelihood that these types of
mistakes are made by DNA
polymerase during replication,
Medical Genetics
Macroalterations are large
changes,such as duplications,
deletions,inversions or
rearrangements of a large number of
bases,
Medical Genetics
Dynamic mutation
The term ‘dynamic mutation’ was introduced
to distinguish the unique properties of expanding,
unstable DNA repeat sequences from other forms
of mutation,The past decade has seen dynamic
mutations uncovered as the molecular basis for a
growing number of human genetic diseases and
for all of the characterized ‘rare’ chromosomal
fragile sites,
Medical Genetics
While the dynamic mutation
mechanism explains some unusual
genetic characteristics,unexpected
findings have raised new questions
and challenged some assumptions
about the pathways that lead from
mutation to disease,
Medical Genetics
Medical Genetics
3,Result of mutation
missense mutation
When a single base pair causes
the substitution of one amino acid for
another,it is called a missense
mutation,
Medical Genetics
Medical Genetics
Medical Genetics
Medical Genetics
nonsense mutation
When a single base pair change,
deletion or insertion result in the
generation of a premature
translation termination because of
the generation of a new stop codon,
this is called a nonsense mutation,
Medical Genetics
Medical Genetics
Medical Genetics
Frameshift mutations
Frameshift mutations are the
result of a single base,or more,
insertion or deletion,The result can
be the generation of an entirely
different protein from the point
within the coding region where it
occurs,
Medical Genetics
Medical Genetics
Medical Genetics
Medical Genetics
Because they may involve many
bases or just one,frameshifts are
sometimes macroalterations and
sometimes microalterations,
Medical Genetics
4.functional effects of the change,
Morphological Mutants have
altered shape,
Medical Genetics
Lethal Mutants die as a result
of having the mutation,can be
dominant or recessive,but most
often are recessive,This makes
sense because there are so many
enzymes an organism must have to
live; if both copies are defective,the
organism would fail to survive,
Medical Genetics
Conditional Mutants are
normal under one condition
(permissive),but abnormal under
another (restrictive),These are
extremely useful for studying
processes such as development and
DNA replication,
Medical Genetics
Biochemical Mutants cause
defects in biochemical pathways for a
substance,which is then deficient,
Medical Genetics
Loss-of-Function mutations
cause a loss of function that is found
normally in wild-type,
Medical Genetics
Gain-of-function mutations
create a new function not normally
found in the wild-type,Hairy-faced
people would be an example,
Medical Genetics
A seven-month old baby with a genetic mutation that
boosts muscle growth is seen in an undated black and
white image released by the New England Journal of
Medicine on Wednesday June 23,2004,The discovery,
reported in Thursday's New England Journal of Medicine,
represents the first documented human case of such a
mutation,The boy's mutant DNA segment was found to
block production of a protein called myostatin that limits
muscle growth,
Medical Genetics
5.Genetic Effects of mutation
Another classification of
mutations has to due with
multicellular organisms where cells
might belong to the germ-line,if
they contribute genetic information
to future generations; or,if part of
the body that will never contribute
genetic information to future
generations,the somatic cell line,
Medical Genetics
? Somatic mutation is one that will never
contribute to the germ-line of the effected
individual,
? Germinal mutation is one that occurs in
a cell that is a progenitor to a germ cell(s),
For example,if a human embryo
sustains a mutation in a cell that later
becomes a germ cell,a sperm or egg,it is
a germinal mutation,
– Otherwise,it is a somatic cell mutation,
Medical Genetics
6,Repair of Mutation
There are many different repairs
systems used by organisms,
Medical Genetics
Photolyase Repair of pyrimidine
dimers is the simplest system to
understand,and is quite interesting,
An enzyme,photolyase,sits on top
of the dimer,then using a
wavelength of light longer than U.V,
as a source of energy,it breaks the
cross-links to restore the DNA to its
original form,
Medical Genetics
Medical Genetics
Excision Repair can be
considered the second choice for
repair of pyrimidine dimers,It is
more complicated and involves
removing a whole stretch of a strand
of DNA,which leaves a section of
single-stranded DNA followed before
and after by double-stranded,
Medical Genetics
Medical Genetics
Postreplication repair involves
recombination between single-strands of
daughter double-stranded DNA near the
replication fork
Medical Genetics
Medical Genetics
Error-Prone repair will be are last
example of the sample of the many repair
systems,It is also called error prone
repair,It eliminates gaps as a last ditch
effort to preserve a chance at life,It
basically adds whatever bases,but at
least usually the right number of bases,It
is probably responsible for most of the
observed transversions,
Medical Genetics
