Point mutations ppt

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Point MutationsPoint Mutations
Mutations involving a few Mutations involving a few
nucleotides, sometimes as few as a nucleotides, sometimes as few as a
single one (SNPs)single one (SNPs)

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SNPsSNPs
(Pronounce: snips) (Pronounce: snips) SSingle ingle nnucleotide ucleotide
ppolymorphismsolymorphisms
1 nucleotide variations between alleles1 nucleotide variations between alleles

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A ReminderA Reminder
2 SNPs difference between estrogen receptors 2 SNPs difference between estrogen receptors
a and b. a and b.  next page next page

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Shape and AA SequenceShape and AA Sequence
Genistein, bound to
estrogen receptor-b.
Only two amino acids
(shown) differ between
the two estrogen
receptors.
(purple: ER-a)
(yellow:yellow: ER-b)

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Point MutationsPoint Mutations
The Genome Map The Genome Map
Lists diseases caused by point mutations by Lists diseases caused by point mutations by
chromosome – with imageschromosome – with images
 The – more abstract - The – more abstract - 1998 update1998 update
 The The 2002 update2002 update

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LinksLinks
ThinkQuest Genetics Lab - MutationsThinkQuest Genetics Lab - Mutations

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Point MutationPoint Mutation
We will mutate one codon in several ways. We will mutate one codon in several ways.
Assume that that codon is, for example, the Assume that that codon is, for example, the
1515
thth
codon in a chain of 100 codons in an codon in a chain of 100 codons in an
mRNA.mRNA.

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Point Mutations: Point Mutations:
Mutating a codon – SNP Effects Mutating a codon – SNP Effects
Imagine that this is codon 15 out of 100 codons of a Imagine that this is codon 15 out of 100 codons of a
protein gene mRNA. All other codons remain protein gene mRNA. All other codons remain
unchanged:unchanged:
ATAATA
UAUUAU
tyrtyr

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Point Mutations Point Mutations
Mutating a codon – SNP Effects:Mutating a codon – SNP Effects:
ATAATA TTTATA
UAUUAU AAUAAU
tyrtyr asn asn

ATTATT
UAAUAA
stopstop
mutation 1
1 AA difference

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Point Mutations Point Mutations
Mutating a codon – SNP Effects: Mutating a codon – SNP Effects:
ATAATA TTTATA
UAUUAU AAUAAU
tyrtyr asn asn



mutation 1
Mutation types:
2.missense 1 AA difference

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Point Mutations Point Mutations
Mutating a codon – SNP Effects:Mutating a codon – SNP Effects:
ATATGG ATA ATA TTTATA
UACUAC UAUUAU AAUAAU
tyrtyr tyr tyr asnasn
mutation 1mutation 2
1 AA difference
Mutation types:
2.Missense
3.Silent Sequence unchanged

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Point Mutations: Point Mutations:
Mutating a codon – Effects of SNPsMutating a codon – Effects of SNPs
ATATGG ATA ATA TTTATA
UACUAC UAUUAU AAUAAU
tyrtyr tyr tyr asnasn
mutation 3mutation 3
ATATTT
UAAUAA
stopstop
mutation 2 mutation 1

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Point Mutations: Point Mutations:
Mutating a codonMutating a codon
ATATGG ATA ATA TTTATA
UACUAC UAUUAU AAUAAU
tyrtyr tyr tyr asnasn
3 3
ATATTT
UAAUAA
stopstop
2 1
Mutation types:
2.missense
3.silent
4.nonsense (stop) – chain is aborted

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Point Mutations Can Happen Point Mutations Can Happen
During DNA RepairDuring DNA Repair

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SNP Effects – e.g. SNP Effects – e.g.
Frame ShiftFrame Shift
A cytosine A cytosine insertioninsertion in the NOD2 in the NOD2
gene leads to gene leads to Crohn’s diseaseCrohn’s disease
(CD). (CD).
CD is a chronic inflammatory gut CD is a chronic inflammatory gut
disorder, thought to be caused by disorder, thought to be caused by
an abnormal inflammatory an abnormal inflammatory
response to enteric microbes.response to enteric microbes.
For more info click For more info click here here

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How Mutations May HappenHow Mutations May Happen
Watch this Watch this animationanimation and answer the and answer the
following questions:following questions:
What type of mutation is the result of What type of mutation is the result of
new strand and new strand and
template strand template strand
slippage?slippage?

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Point Mutation Types - OverviewPoint Mutation Types - Overview
 Panel A shows the normal sequence of Panel A shows the normal sequence of
DNA from one exon and the protein DNA from one exon and the protein
product it encodesproduct it encodes
 Panel B shows a silent mutation,Panel B shows a silent mutation,
 Panel C a conservative missense Panel C a conservative missense
mutation (serine and threonine have mutation (serine and threonine have
very similar structures)very similar structures)
 Panel D a nonconservative missense Panel D a nonconservative missense
mutation (serine and proline have very mutation (serine and proline have very
different structures), different structures),
 Panel E a nonsense mutation, and Panel E a nonsense mutation, and
 Panel F a frame-shift mutation. In Panel F a frame-shift mutation. In
Panel F, the insertion of a single G Panel F, the insertion of a single G
throws off the reading frame, so that throws off the reading frame, so that
all amino acids downstream are all amino acids downstream are
changed radically. changed radically.
G

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Silent Mutations – Not Always SilentSilent Mutations – Not Always Silent
Protein folding depends on the speed at Protein folding depends on the speed at
which the mRNA moves through the which the mRNA moves through the
ribosome, since silent translations can ribosome, since silent translations can
alter that speed, they may result in alter that speed, they may result in
different protein foldingdifferent protein folding

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Mutations in PIK3CAMutations in PIK3CA
Where is this gene mutated?Where is this gene mutated?

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Structure of phosphoinositide 3-kinase gammaStructure of phosphoinositide 3-kinase gamma

Click on a Click on a
domain in the domain in the
image in this image in this
linklink for a for a
detailed detailed
description of itdescription of it
PIK3CAs have PIK3CAs have
several several
ddoommaaiinsns with with
different different
functionsfunctions
A kinase is an enzyme that places a phosphate onto another protein. More specifically, kinases take the gamma (=
3
rd
) phosphate from ATP and place it on a serine, threonine, or tyrosine amino acid of the target substrate.

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Mutations in PIK3CAMutations in PIK3CA
““Phosphatidylinositol 3-kinases (PI3Ks) are lipid kinases that regulate signaling pathways Phosphatidylinositol 3-kinases (PI3Ks) are lipid kinases that regulate signaling pathways
important for neoplasiaimportant for neoplasia
11
, including cell proliferation, adhesion, survival, and motility (, including cell proliferation, adhesion, survival, and motility (11––33). ).
To determine if PI3Ks are genetically altered in tumorigenesis, we sequenced PI3K genes in To determine if PI3Ks are genetically altered in tumorigenesis, we sequenced PI3K genes in
human cancers and corresponding normal tissue.” human cancers and corresponding normal tissue.”
““Arrowheads indicate the location of missense mutations, boxes represent functional domains Arrowheads indicate the location of missense mutations, boxes represent functional domains
(the p85 binding domain, Ras binding domain, C2 domain, helical domain, and kinase (the p85 binding domain, Ras binding domain, C2 domain, helical domain, and kinase
domain). The percentage of mutations detected within each region is indicated below, and the domain). The percentage of mutations detected within each region is indicated below, and the
fraction of tumors with mutations is noted above. fraction of tumors with mutations is noted above.

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Why Might Anyone Want Why Might Anyone Want
to Know This?to Know This?

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PIK3CAPIK3CA
A Possible Cancer Treatment?A Possible Cancer Treatment?
In most of the tumors listed above, the kinase is over-In most of the tumors listed above, the kinase is over-
expressed. Inhibiting the kinase may inhibit expressed. Inhibiting the kinase may inhibit
tumorigenesis.tumorigenesis.

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Genes and EnvironmentGenes and Environment

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Gene Expression And The Gene Expression And The
EnvironmentEnvironment
Russian rabbits have Russian rabbits have
black noses, ears, tails, black noses, ears, tails,
and paws.and paws.
Yet, the genes for the Yet, the genes for the
black pigment are black pigment are
present in ALL their present in ALL their
cells.cells.
Develop a hypothesis to Develop a hypothesis to
explain the pattern.explain the pattern.

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Genes and EnvironmentGenes and Environment
If this Russian rabbit If this Russian rabbit
has its thigh shaved and has its thigh shaved and
is then kept in a cold is then kept in a cold
environment, what will environment, what will
the new fur growth look the new fur growth look
like?like?

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Genes & EnvironmentGenes & Environment
Cuttings from the 7 different plants
on the left, grown at different
altitudes:
Plants with the same genes may Plants with the same genes may
exhibit dramatically different growth exhibit dramatically different growth
forms, depending on their forms, depending on their
environmentenvironment

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Gene, Smoking Combo Boosts Risk of Elderly Vision LossGene, Smoking Combo Boosts Risk of Elderly Vision Loss
Specific mutation raises chances of Specific mutation raises chances of
age-related macular degenerationage-related macular degeneration
MONDAY, March 20 (HealthDay News) -- A MONDAY, March 20 (HealthDay News) -- A
combination of smoking plus a specific gene variant combination of smoking plus a specific gene variant
could account for a third of cases of age-related macular could account for a third of cases of age-related macular
degeneration (AMD), researchers say. AMD is the most degeneration (AMD), researchers say. AMD is the most
common cause of visual impairment and legal blindness common cause of visual impairment and legal blindness
in older Americans. Interaction between a specific in older Americans. Interaction between a specific
variant of the LOC387715 gene and cigarette smoking variant of the LOC387715 gene and cigarette smoking
greatly increases AMD, say researchers at Duke greatly increases AMD, say researchers at Duke
University Medical Center and Vanderbilt University University Medical Center and Vanderbilt University
Medical Center. The finding emphasizes the importance Medical Center. The finding emphasizes the importance
of genetic factors in the onset of AMD, and suggests the of genetic factors in the onset of AMD, and suggests the
potential to reduce the incidence of the disease through potential to reduce the incidence of the disease through
smoking prevention and cessation programs. "The most smoking prevention and cessation programs. "The most
exciting aspect of this research is that it is the exciting aspect of this research is that it is the
combination of the gene and smoking that really puts you combination of the gene and smoking that really puts you
at risk," study senior author Margaret Pericak-Vance, at risk," study senior author Margaret Pericak-Vance,
director of the Duke Center for Human Genetics, said in director of the Duke Center for Human Genetics, said in
a prepared statement. a prepared statement.
"We demonstrate, for the first time, that a gene variant "We demonstrate, for the first time, that a gene variant
coupled with a modifiable lifestyle factor such as coupled with a modifiable lifestyle factor such as
cigarette smoking confers a significantly higher risk of cigarette smoking confers a significantly higher risk of
AMD than either factor alone," she said. The findings AMD than either factor alone," she said. The findings
appear in the online edition of the appear in the online edition of the American Journal of American Journal of
Human GeneticsHuman Genetics, and will be published in the May print , and will be published in the May print
issue of the journal. The study included 1,001 people issue of the journal. The study included 1,001 people
with all forms of AMD and 394 healthy people in a with all forms of AMD and 394 healthy people in a
control group. Researchers analyzed 185 variations in the control group. Researchers analyzed 185 variations in the
DNA sequence of genes located in a region believed to DNA sequence of genes located in a region believed to
be associated with susceptibility to AMD. The scientists be associated with susceptibility to AMD. The scientists
found that 42 percent of the chromosomes of people with found that 42 percent of the chromosomes of people with
AMD and 26 percent of the people in the control group AMD and 26 percent of the people in the control group
had a specific variant of LOC387715 statistically had a specific variant of LOC387715 statistically
associated with the highest risk of developing AMD. In associated with the highest risk of developing AMD. In
nonsmokers, this genetic variant increased AMD risk nonsmokers, this genetic variant increased AMD risk
twofold. People who had the genetic variant and smoked twofold. People who had the genetic variant and smoked
had an eightfold increased risk of AMD, compared to had an eightfold increased risk of AMD, compared to
nonsmokers without the variant. The actual function of nonsmokers without the variant. The actual function of
the LOC387715 gene in the visual system is unknown, the LOC387715 gene in the visual system is unknown,
the researchers said.the researchers said.

-- Robert Preidt -- Robert Preidt
SOURCE: Duke University, news release, March 7, 2006 SOURCE: Duke University, news release, March 7, 2006

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Without the Presence of the Environmental Factor, These Genes Do Not Lead to DiseaseWithout the Presence of the Environmental Factor, These Genes Do Not Lead to Disease
A SAMPLING OF ENVIRONMENTAL GENESA SAMPLING OF ENVIRONMENTAL GENES
PolymorphismPolymorphism FunctionFunction Environmental exposureEnvironmental exposure Associated diseaseAssociated disease
CYP1A1CYP1A1 ActivationActivation SmokingSmoking Lung cancerLung cancer
NAT2NAT2 DetoxificationDetoxification SmokingSmoking Bladder, breast cancerBladder, breast cancer
GSTT1GSTT1 DetoxificationDetoxification Chlorinated solventsChlorinated solventsCancer, toxicityCancer, toxicity
ParaoxonaseParaoxonase DetoxificationDetoxification Nerve agents, pesticidesNerve agents, pesticidesNervous system damageNervous system damage
HLA-HHLA-H Nutritional factorsNutritional factors Iron in dietIron in diet HemochromatosisHemochromatosis
TGF-alphaTGF-alpha Growth factorGrowth factor Maternal smokingMaternal smoking Cleft lip & palateCleft lip & palate
Locus on chrom. 17 in miceLocus on chrom. 17 in miceImmune/inflammatory responseImmune/inflammatory responseOzoneOzone Lung inflammationLung inflammation
HLA-DP bet1 markerHLA-DP bet1 marker Immune responseImmune response BerylliumBeryllium Chronic beryllium disease (lung disorder)Chronic beryllium disease (lung disorder)
ALADALAD BiosynthesisBiosynthesis LeadLead Lead poisoningLead poisoning
Read about: Genetics, race, ethnicity, and health

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More about diseases (heart, cancer, diabetes) and More about diseases (heart, cancer, diabetes) and
environment environment herehere (very informative!) (very informative!)

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Genes and Skin ColorGenes and Skin Color

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Genes And Skin ColorGenes And Skin Color
Findings From Golden Zebra FishFindings From Golden Zebra Fish
““Lighter variations of pigmentation in humans are associated with diminished Lighter variations of pigmentation in humans are associated with diminished
number, size, and density of melanosomes, the pigmented organelles of number, size, and density of melanosomes, the pigmented organelles of
melanocytes. Here we show that zebrafish golden mutants share these melanocytes. Here we show that zebrafish golden mutants share these
melanosomal changes and that golden encodes a putative cation exchanger melanosomal changes and that golden encodes a putative cation exchanger
slc24a5 (nckx5) that localizes to an intracellular membrane, likely the slc24a5 (nckx5) that localizes to an intracellular membrane, likely the
melanosome or its precursor.melanosome or its precursor.
The human The human orthologortholog is highly similar in sequence and functional in zebrafish. is highly similar in sequence and functional in zebrafish.
The evolutionarily conserved ancestral The evolutionarily conserved ancestral alleleallele of a human coding of a human coding polymorphismpolymorphism
predominates in African and East Asian populations. In contrast, the variant predominates in African and East Asian populations. In contrast, the variant
allele is nearly fixed in European populations, is associated with a substantial allele is nearly fixed in European populations, is associated with a substantial
reduction in regional reduction in regional heterozygosityheterozygosity, and correlates with lighter skin , and correlates with lighter skin
pigmentation in admixed populations, suggesting a key role for the SLC24A5 pigmentation in admixed populations, suggesting a key role for the SLC24A5
gene in human pigmentation. “gene in human pigmentation. “

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Two Primary Alleles for Skin Color Two Primary Alleles for Skin Color
GeneGene
Data … show … “that Data … show … “that SLC24A5SLC24A5 has two has two
primary alleles, which vary by one amino acid. primary alleles, which vary by one amino acid.
Nearly all Africans and East Asians have an Nearly all Africans and East Asians have an
allele with alanine in a key locus, whereas allele with alanine in a key locus, whereas
98% of Europeans have threonine at that 98% of Europeans have threonine at that
locus.” locus.”

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A SNP Determines Skin Color in A SNP Determines Skin Color in
Many PeopleMany People
“…“…polymorphisms within the” polymorphisms within the” SLC24A5SLC24A5 “gene. … the G “gene. … the G
and A alleles of the single nucleotide polymorphism (SNP) and A alleles of the single nucleotide polymorphism (SNP)
rs1426654 encoded alanine or threonine, respectively, at rs1426654 encoded alanine or threonine, respectively, at
amino acid 111 in the third exon of amino acid 111 in the third exon of SLC24A5SLC24A5. “. “
““The allele frequency for the The allele frequency for the ThrThr
111111
variant variant ranged from 98.7 ranged from 98.7
to 100% among several European-American population to 100% among several European-American population
samples, …samples, …
the the ancestral alanine allele (ancestral alanine allele (AlaAla
111111
)) had a frequency of 93 to had a frequency of 93 to
100% in African, Indigenous American, and East Asian 100% in African, Indigenous American, and East Asian
population samples” population samples”

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Gene SLC24A5Gene SLC24A5
… “… “the team measured the pigmentation levels of 203 African the team measured the pigmentation levels of 203 African
Americans and 105 African Caribbeans--groups that represent Americans and 105 African Caribbeans--groups that represent
an admixture of African and European ancestry--and an admixture of African and European ancestry--and
compared their compared their SLC24A5SLC24A5 genotypes. genotypes.
Subjects Subjects homozygous for the threonine allele tended to be homozygous for the threonine allele tended to be
lightest skinnedlightest skinned, ,
those those homozygous for the alanine allele were darkesthomozygous for the alanine allele were darkest, ,
and and heterozygotes were in betweenheterozygotes were in between, as shown by the degree , as shown by the degree
of reflectance of their skin. The team concludes that of reflectance of their skin. The team concludes that between between
25% and 38% of the skin-color difference between 25% and 38% of the skin-color difference between
Europeans and Africans can be attributed to Europeans and Africans can be attributed to SLC24A5SLC24A5
variantsvariants” ”

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Published by AAAS
R. L. Lamason et al., Science 310, 1782 -1786 (2005)
Fig. 6. Effect of SLC24A5 Genotype on Pigmentation in Admixed Populations

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Genes and the Genes and the
Size of a DogSize of a Dog
A SNIP in the IGF-1 Gene A SNIP in the IGF-1 Gene
Determines Dog SizeDetermines Dog Size

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Published by AAAS
N. B. Sutter et al., Science 316, 112 -115 (2007)
Relationships of skeletal size, SNP markers, IGF1 haplotype, and serum
levels of the IGF1 protein in dogs
((BB) … ) … IGF1IGF1 haplotypes and mean skeletal size. haplotypes and mean skeletal size.
Haplotypes were inferred for 20 markers Haplotypes were inferred for 20 markers
spanning the spanning the IGF1IGF1 gene (chromosome 15: gene (chromosome 15:
44,212,792 to 44,278,140, CanFam1). Out of the 44,212,792 to 44,278,140, CanFam1). Out of the
720 chromosomes with successful inference, 96% 720 chromosomes with successful inference, 96%
carry one of just two carry one of just two haplotypes, B and I, haplotypes, B and I,
identical to haplotypes inferred for small and identical to haplotypes inferred for small and
giant dogs, respectivelygiant dogs, respectively. Data are graphed as a . Data are graphed as a
histogram for each genotype: histogram for each genotype:
B/B (closed triangle, black line)B/B (closed triangle, black line)
B/I (open square, dashed line)B/I (open square, dashed line)
I/I (closed circle, gray line) I/I (closed circle, gray line)
(C) Serum levels of IGF1 protein (ng/ml) as a function of (C) Serum levels of IGF1 protein (ng/ml) as a function of
haplotype. haplotype.

39. This Rabbit Must Have The This Rabbit Must Have The
Large VersionLarge Version
04/19/1004/19/10 3939

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Last Not LeastLast Not Least
Genes and HIV ProgressionGenes and HIV Progression

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Effect of a Single Amino Acid Change in MHC Class I Effect of a Single Amino Acid Change in MHC Class I
Molecules on the Rate of Progression to AIDSMolecules on the Rate of Progression to AIDS
Conclusions: Conclusions:
This analysis shows that, in patients with HIV-1 infection, a single amino This analysis shows that, in patients with HIV-1 infection, a single amino
acid change in HLA molecules has a substantial effect on the rate of acid change in HLA molecules has a substantial effect on the rate of
progression to AIDS. progression to AIDS.
… … different consequences of HLA-B*35-PY and HLA-B*35-Px in terms different consequences of HLA-B*35-PY and HLA-B*35-Px in terms
of disease progression …of disease progression …
Human immunodeficiency virus type 1 (HIV-1)-infected individuals with Human immunodeficiency virus type 1 (HIV-1)-infected individuals with
HLA-B*35 allelic variants B*3502/3503/3504/5301 (B*35-Px) progress HLA-B*35 allelic variants B*3502/3503/3504/5301 (B*35-Px) progress
more rapidly to AIDS than do those with B*3501 (B*35-PY).more rapidly to AIDS than do those with B*3501 (B*35-PY).
'Indians vulnerable to HIV/Aids' 'Indians vulnerable to HIV/Aids'
India is home to one in seven HIV-positive people:India is home to one in seven HIV-positive people:
Indians infected with the Aids virus are more likely to contract the Indians infected with the Aids virus are more likely to contract the
disease than people in the west, a new study has found.disease than people in the west, a new study has found.

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On the Up-SideOn the Up-Side
Eternal Life?Eternal Life?

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Boosting Gene Extends Mouse Life SpanBoosting Gene Extends Mouse Life Span

Whereas lab mice can live Whereas lab mice can live
about 2 years, mice about 2 years, mice
engineered to overproduce a engineered to overproduce a
protein called Klotho protein called Klotho
[Greek goddess who spins [Greek goddess who spins
life's thread], have life's thread], have
celebrated third birthdays, celebrated third birthdays,
… …
The mutant rodents The mutant rodents
represent a rare case of a represent a rare case of a
single gene substantially single gene substantially
influencing life span in influencing life span in
mammals. mammals.
These mice, which These mice, which
overexpress the gene for overexpress the gene for
Klotho, have celebrated Klotho, have celebrated
their third birthdays.their third birthdays.

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The EndThe End