polymorphism introduction ayman

8/12/2019 Polymorphism Introduction Ayman

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Genetic Polymorphism

yyman Elsamanoudy


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Definition of Genotype

This is the "internally coded, inheritable information" carried by all

living organisms. This stored information is used as a set of instructions for building

and maintaining a living creature.

These instructions are found within almost all cells (the "internal"

part), they are written in a coded language (the genetic code), theyare copied at the time of cell division or reproduction and are passed

from one generation to the next ("inheritable").

These instructions are intimately involved with all aspects of the life

of a cell or an organism.

They control everything from the formation of protein

macromolecules, to the regulation of metabolism and synthesis.

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Definition of phenotype

This is the "outward, physical manifestation" of the

organism.

These are the physical parts, the sum of the atoms,

molecules, macromolecules, cells, structures,

metabolism, energy utilization, tissues, organs,

reflexes and behaviors;>>>>>>anything that is partof the observable structure, function or behavior of

a living organism.

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Important definitions in genetics

Phenotypes:Interaction between:

organism's genes

(genotype)

+

environmental factors

Environment

GE

interaction

Genetics

Health

outcomeo

r

?


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A trait is a distinct variant of a phenotypic

characterof an organism that may be inherited,

environmentally determined or somewhere inbetween.

For example:

eye color: It is the character, which may beblue, brown and hazel >>>>> called traits.
http://en.wikipedia.org/wiki/Varianthttp://en.wikipedia.org/wiki/Phenotypic_characterhttp://en.wikipedia.org/wiki/Phenotypic_characterhttp://en.wikipedia.org/wiki/Eye_colorhttp://en.wikipedia.org/wiki/Eye_colorhttp://en.wikipedia.org/wiki/Phenotypic_characterhttp://en.wikipedia.org/wiki/Phenotypic_characterhttp://en.wikipedia.org/wiki/Variant


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Flow of genetic information Before a trait can be observed... biological information must be

expressed. ((levels of gene expression ))

DNA molecules store the necessary instructions for building a

protein macromolecule.

I. These instructions are copied from the DNA molecule into the

form of an RNA molecule. ((transcription ))

II. Each of these RNA copies (often called 'messenger RNA' or

'mRNA') move away from the DNA templates and enter the

cytoplasm of the cell, where they encounter the machinery that

will convert the biological information (the instructions) into the

correct linear sequence of amino acids that will become a

functioning protein.((translation))

III. Once the protein has been correctly assembled and folded it can

go to work.((folding &post-translation modification))

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Genetic code It is the stored information on one of the two strands of a DNA

molecules as a linear, non-overlapping sequence of the nitrogenous

bases Adenine (A), Guanine (G), Cytosine (C) and Thymine (T).

The genetic code consists of a sequence of three letter "words"

(sometimes called 'triplets', sometimes called 'codons'), written one

after another along the length of the DNA strand.

Each code word is a unique combination of three letters that willeventually be interpreted as a single amino acid in a polypeptide

chain.

There are 64 code words possible from an 'alphabet' of four letters.

One of these code words, the 'start signal' begins all the sequencesthat code for amino acid chains(AUG).

Three of these code words act as 'stop signals' that indicate that the

message is over(UGA ,UAG,UAA).

All the other sequences code for specific amino acids.8


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Definition of An allele : It is an alternative form of agene(one member of a pair) that is located at a specific

position on a specific chromosome.

These DNAcodings determine specific traits that canbe passed on from parents to offspring.

The process by which alleles are transmitted wasdiscovered by Gregor Mendel and formulated in what

is known as Mendel's law of segregation. Sometimes, different alleles can result in differenttraits, such as color. Or, different alleles will have thesame resultin the expression of a gene.

Most multicellular organisms have two sets ofchromosomes (Diploid).

Each chromosome has one gene and one allele).

If both alleles are the same, they are homozygotes

If the alleles are different, they are heterozygotes.
http://biology.about.com/library/glossary/bldefgenes.htmhttp://biology.about.com/od/geneticsglossary/g/chromosome.htmhttp://biology.about.com/od/geneticsglossary/g/DNA.htmhttp://biology.about.com/od/mendeliangenetics/ss/lawofsegregation.htmhttp://biology.about.com/od/mendeliangenetics/ss/lawofsegregation.htmhttp://biology.about.com/od/mendeliangenetics/ss/lawofsegregation.htmhttp://biology.about.com/od/mendeliangenetics/ss/lawofsegregation.htmhttp://biology.about.com/od/mendeliangenetics/ss/lawofsegregation.htmhttp://biology.about.com/od/mendeliangenetics/ss/lawofsegregation.htmhttp://biology.about.com/od/mendeliangenetics/ss/lawofsegregation.htmhttp://biology.about.com/od/mendeliangenetics/ss/lawofsegregation.htmhttp://biology.about.com/od/geneticsglossary/g/DNA.htmhttp://biology.about.com/od/geneticsglossary/g/chromosome.htmhttp://biology.about.com/library/glossary/bldefgenes.htm


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Mutationsare permenat changes of base sequence

of nucleotides in the genetic code of the DNA

genome .

Polymorphism: Variation in DNA sequence of

allele gene from one individual to another that is

common in population ( mostly not associated with

impaired protein structure).

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Mutation may be :

1- Germinal mutation :occur in the germ cells and

can be passed to the future generation .

2-Somatic mutation :occur in somatic cells and

cannot be transmitted to offspring.

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Mutationsare changes the DNA sequence of a cell's genome.

Effect on structure: I. Small scale:

1. Point mutationsexchange a single nucleotidefor another.

Transition that exchanges a purine for a purine (A G) or a

pyrimidine for a pyrimidine, (C T) .OR

Tranversion which exchanges a purine for a pyrimidine or a

pyrimidine for a purine (C/T A/G).

Effcts :

1. Silent mutations:which code for the sameamino acid.

2. Mis-sense mutations: which code for a different amino

acid.

3. Non-sense mutations: which code for a stop and can

truncate the protein.
http://en.wikipedia.org/wiki/Point_mutationhttp://en.wikipedia.org/wiki/Nucleotidehttp://en.wikipedia.org/wiki/Nucleotidehttp://en.wikipedia.org/wiki/Point_mutationhttp://en.wikipedia.org/wiki/Point_mutationhttp://en.wikipedia.org/wiki/Point_mutation


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2. Insertions add one or more

extra nucleotides into theDNA.

3. Deletions remove one ormore nucleotides from theDNA.

Both insertions &deletion alter thereading frame of the gene.So,both of which cansignificantly alter the gene

product.

II. Large-scale mutations inchromosomal structure,including: Deletion,translocation.
http://en.wikipedia.org/wiki/Insertion_%28genetics%29http://en.wikipedia.org/wiki/Genetic_deletionhttp://en.wikipedia.org/wiki/Chromosomehttp://en.wikipedia.org/wiki/Chromosomehttp://en.wikipedia.org/wiki/Genetic_deletionhttp://en.wikipedia.org/wiki/Insertion_%28genetics%29


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Effect on function:

1. Loss-of-function mutations

2. Gain-of-function mutations

3. Lethal mutations


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Effect on protein sequence:

1. A frame shift mutation is a mutation caused by insertionor

deletion.2. A nonsense mutation:is a point mutation in a sequence of

DNA that results in a premature stop codon, or a nonsensecodonin the transcribed mRNA, and possibly a truncated, andoften nonfunctional protein product.

3. Mis-sense mutations:are types of point mutation where asingle nucleotideis changed to cause substitution of a differentamino acid. This in turn can render the resulting proteinnonfunctional.

4. A neutral mutation:is a mutation that occurs in an amino acidcodon which results in the use of a different, but chemicallysimilar, amino acid (arginine by lysine)

5. Silent mutations: are mutations that do not result in a changeto the amino acid sequence of a protein.
http://en.wikipedia.org/wiki/Frameshift_mutationhttp://en.wikipedia.org/wiki/Nonsense_mutationhttp://en.wikipedia.org/wiki/Missense_mutationshttp://en.wikipedia.org/wiki/Neutral_mutationhttp://en.wikipedia.org/wiki/Silent_mutationshttp://en.wikipedia.org/wiki/Silent_mutationshttp://en.wikipedia.org/wiki/Silent_mutationshttp://en.wikipedia.org/wiki/Silent_mutationshttp://en.wikipedia.org/wiki/Neutral_mutationhttp://en.wikipedia.org/wiki/Neutral_mutationhttp://en.wikipedia.org/wiki/Neutral_mutationhttp://en.wikipedia.org/wiki/Missense_mutationshttp://en.wikipedia.org/wiki/Missense_mutationshttp://en.wikipedia.org/wiki/Missense_mutationshttp://en.wikipedia.org/wiki/Missense_mutationshttp://en.wikipedia.org/wiki/Missense_mutationshttp://en.wikipedia.org/wiki/Nonsense_mutationhttp://en.wikipedia.org/wiki/Nonsense_mutationhttp://en.wikipedia.org/wiki/Nonsense_mutationhttp://en.wikipedia.org/wiki/Frameshift_mutationhttp://en.wikipedia.org/wiki/Frameshift_mutationhttp://en.wikipedia.org/wiki/Frameshift_mutationhttp://en.wikipedia.org/wiki/Frameshift_mutationhttp://en.wikipedia.org/wiki/Frameshift_mutation


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An exon is a nucleic acid sequence that is represented in the

matureform of an RNA molecule.

An intron is any nucleotide sequence within a gene that is

removed by RNA splicing to generate the final mature RNA

product of a gene

An Intergenic region (IGR) is a stretch of DNA sequences

located between genes that contain few or no genes (Junk

DNA)

Important definitions in genetics


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Promoteris a region of DNA that facilitates the transcription

of a particular gene. Promoters are located near the genes they regulate, on the

same strand and typically upstream(towards the 5 region of

the sense strand).

Enhancer is a short region of DNA that can be bound withproteins (transcription factors) to enhance transcription levels

of genes (hence the name).

Start TerminationExon ExonIntronPromoterEnhancer

Gene

1 2 3 4 5

SNPs


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Start TerminationExon ExonIntron

PromoterEnhancer

Gene

1 2 3 4 5

SNPs

Transcription factoris a protein that binds to specific DNA

sequence, controlling the transcription of genetic informationfrom DNA to mRNA.


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Single Nucleotide Polymorphisms (SNPs)

Polymorphism: Variation in DNA sequence of

allele gene from one individual to anotherSNP:single base change in a DNA sequence that

occurs in a significant proportion (more than 1%) of

a large population.

Occur every 100 to 300 basesalong the 3 billion-base human genome (around 10-30 million SNPs

in the Human genome).

Make up about 90% of all human genetic variation.

????Mostly SNP have no effect on cell function but

some could affect disease risk and drug response.

SNPs close to particular gene acts as a marker for

that gene


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SNPs on the chromosome

SNP

Chromosome

Gene

Because only about 3-5% of a

DNA sequence codes for the

production of proteins. Most

SNPs are found outside of

coding sequences


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At least 1 percentof the populationMost of the population

Commonsequence

G to C

SNPsite

Variantsequence

SNPs


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SNP genotype

We inherit two copies of each chromosome (onefrom each parent)

For a given SNP the genotype defines the typeof alleles we carry

Example: for the SNP A/G ones genotype maybe: AAif both copies of the chromosome have A

GGif both copies of the chromosome have G

AG or GAif one copy has A and the other has G The first two cases are called homozygousand latter

two are heterozygous


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Do all SNPs lead to a change inphenotype?

No! Remember that only


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Types of SNPs Noncoding SNPs

5 UTR

3 UTR Introns

Intergenic Regions

Regulatory

Splicing

Transcriptional regulation (promoter & TF binding sites)

Translational regulation (initiation or termination)

Coding SNPs

Synonymous SNPs (third position variation)

Replacement SNPs (change Amino acid)

Functional SNPs (acceptable amino acid replacement)

Non-functional SNPs (traits & diseases)


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SNP1.This SNP could affect the binding of transcription factors

to the enhancer and thus the expression of the gene.!!! !!!

SNP2.This SNP lies in a non-functional region and will probably

have no effect. It could affect histone binding.!!! !!!

SNP3. This SNP could affect the binding of the transcriptional

machinery (esp. RNA polymerase II) to the promoter!!! !!!

SNP4. This SNP is in an exon and will code an amino acid.

However, it will only have an effect if the change triplet willencode a different amino acid (e.g. AGA and AGG both encode

arginine).

SNP5.This SNP will be spliced out and therefore it will not have

an effect.!!! !!!

Start TerminationExon ExonIntronPromoterEnhancer

Gene

1 2 3 4 5

SNPs


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SNPs in Coding Regions No Changes in Protein


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SNPs in Coding RegionsHarmless Changes in Protein

DNA SNP A to C

RNA CodonGAU to GAG

ProteinAspartic acid

to Glutamic acid

Slight change in shape

Aspartic acid Glutamic acid

mRNA

C T A

G A U G A G

GAU GAG

C T C


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SNPs in Coding RegionsHarmful Changes in Protein Mutations

DNA SNP T to A

RNA Codon

GAU to GUU

ProteinAspartic acid

to Valine

Change in shape

Aspartic acid Valine

mRNA

C T

G A U G U U

GAU GUU

C AA A

SNPs can alter the

function of the protein

1. Directly :alter an amino

acid sequence

2. indirectly :alter the

function of the

regulatory sequence


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Nomenclature

Nucleotide substitution(e.g. 76A>T)

The number is the position of the nucleotide from the 5' end.The first letter represents the wild type nucleotide

The second letter represents the nucleotide which replaced the wildtype.

So, the adenine at the 76th position was replaced by a thymine. If it becomes necessary to differentiate between mutations in

genomic DNA, mitochondrial DNA, and RNA, a simpleconvention is used.

g.100G>C if the mutation occurred in genomic DNA,

m.100G>C if the mutation occurred in mitochondrial,r.100g>c if the mutation occurred in RNA.

Note that for mutations in RNA, the nucleotide code is written inlower case.


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Nomenclature

Amino acid substitution(e.g. D111E)

The first letter is the one letter code of the wild type amino acid

The number is the position of the amino acid from the N terminus

The second letter is the one letter code of the amino acid present inthe mutation.

Nonsense mutations are represented with an Xfor the secondamino acid (e.g. D111X).

Amino acid deletion(e.g. F508)

The Greek letter (delta)indicates a deletion.

The letter refersto the amino acidpresent in the wild type

The number is the position from the N terminus of the amino acidwere it to be present as in the wild type.

N l t


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Nomenclature

There is no nucleotide 0

Nucleotide 1is theAof theATG-translation initiation codon

The nucleotide 5' of the ATG-translation initiationcodon is -1, the previous -2,etc.

The nucleotide 3' of the translation stopcodonis *1, the next *2, etc.

Beginning of the intron:the number of the last nucleotide of the previous exon, a

plus signand the position in the intron, like c.77+1G, c.77+2T, etc.

End of the intron;the number of the first nucleotide of the following exon, a minus

signand the position upstream in the intron, like c.78-1G.

SNP d Di P i


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SNPs and Disease ProgressionApplication of SNPs map

Occasionally, a SNP may actually cause a diseaseand, therefore, can be

used to search for and isolate the disease-causing gene.

To create a genetic test that will screen for a disease:

blood samples were collected from a group of individuals affected by

the disease and analyzing their DNA for SNP patterns.

compare these patterns to patterns obtained by analyzing the DNAfrom a group of individuals unaffected by the disease.

This type of comparison, called an "association study", can detect

differences between the SNP patterns of the two groups, indicating

which pattern is associated with the disease.

Then, it will only be a matter of time before physicians can screenindividuals for susceptibility to a disease just by analyzing their DNA

samples for specific SNP patterns.

V i ti C i L t t Ch


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Variations Causing Latent Changes

Many years laterMany years later

= Variations in DNA that cause latent effects

Disease predisposition: The Genetic differences between human

populations make one population more susceptible to particular

disease.


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SNPs and Disease Diagnosis

Serve as biological markers for pinpointing adisease on the human genome map, because

they are usually located near a gene found to

be associated with a certain disease.


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SNP profiles and specific

responses to treatment. SNPs will be useful in: understanding why

individuals differ in their

abilities to absorb or clear

certain drugs.

determining why an

individual may experience

an adverse side effect to a

particular drug (i.e AdverseDrug reaction).


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SNP profiles and specificresponses to treatment.

Currently, there is no simple way to determine how apatient will respond to a particular medication.

A treatment proven effective in one patient may beineffective in others.

Today, pharmaceutical companies are limited todeveloping agents to which the "average" patient willrespond.As a result, many drugs that might benefit asmall number of patients never make it to market.


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SNP profiles and specific

responses to treatment.

The most appropriate drug for an individual could be

determined in advance of treatment by analyzing a patient'sSNP profile.

The ability to target a drug to those individuals most likely

to benefit, referred to as "personalized medicine",wouldallow pharmaceutical companies to bring many more drugs

to market and allow doctors to prescribe individualized

therapies specific to a patient's needs.


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