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Genetic Polymorphism


Ayman Elsamanoudy

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), they are 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.

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 part of the observable structure, function or behavior of a living organism.

Important definitions in genetics

Interaction between:

organism's genes (genotype)

environmental factors

G E interaction


Health outcome o r

A trait is a distinct variant of a phenotypic character of an organism that may be inherited, environmentally determined or somewhere in between. For example: eye color: It is the character, which may be blue, brown and hazel >>>>> called traits.

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))

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 will eventually 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 sequences that 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). 8 All the other sequences code for specific amino acids.

Definition of An allele : It is an alternative form of a gene (one member of a pair) that is located at a specific position on a specific chromosome. These DNA codings determine specific traits that can be passed on from parents to offspring. The process by which alleles are transmitted was discovered by Gregor Mendel and formulated in what is known as Mendel's law of segregation. Sometimes, different alleles can result in different traits, such as color. Or, different alleles will have the same result in the expression of a gene. Most multicellular organisms have two sets of chromosomes (Diploid). Each chromosome has one gene and one allele). If both alleles are the same, they are homozygotes If the 10 alleles are different, they are heterozygotes.

Mutations are 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).


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.


Mutations are changes the DNA sequence of a cell's genome. Effect on structure: I. Small scale: 1. Point mutations exchange a single nucleotide for 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 same amino 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.


Insertions add one or more extra nucleotides into the DNA. 3. Deletions remove one or more nucleotides from the DNA. Both insertions &deletion alter the reading frame of the gene. So,both of which can significantly alter the gene product. II. Large-scale mutations in chromosomal structure, including: Deletion, translocation.

Effect on function: 1. Loss-of-function mutations 2. Gain-of-function mutations 3. Lethal mutations


Effect on protein sequence: 1. A frame shift mutation is a mutation caused by insertion or deletion. 2. A nonsense mutation:is a point mutation in a sequence of DNA that results in a premature stop codon, or a nonsense codon in the transcribed mRNA, and possibly a truncated, and often nonfunctional protein product. 3. Mis-sense mutations:are types of point mutation where a single nucleotide is changed to cause substitution of a different amino acid. This in turn can render the resulting protein nonfunctional. 4. A neutral mutation :is a mutation that occurs in an amino acid codon which results in the use of a different, but chemically similar, amino acid (arginine by lysine) 5. Silent mutations : are mutations that do not result in a change to the amino acid sequence of a protein.

Important definitions in genetics

An exon is a nucleic acid sequence that is represented in the mature form 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)


Promoter is 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 with proteins (transcription factors) to enhance transcription levels of genes (hence the name).
Gene Enhancer SNPs 1

Promoter Start Exon

Intron Exon Termination

Enhancer SNPs 1 2 factor 3 4 that5 Transcription is a protein binds to specific DNA sequence, controlling the transcription of genetic information from DNA to mRNA. Promoter Start Exon Intro n Exon Termination


Single Nucleotide Polymorphisms (SNPs)

Polymorphism: Variation in DNA sequence of allele gene from one individual to another SNP: 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 bases along the 3 billionbase 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 20 that gene

SNPs on the chromosome

Because only about 3-5% of a DNA sequence codes for the production of proteins. Most SNPs are found outside of coding sequences

SNP Chromosome Gene


Most of the population At least 1 percent of the population

G to C

Common sequence

Variant sequence

SNP site

SNP genotype
We inherit two copies of each chromosome (one from each parent) For a given SNP the genotype defines the type of alleles we carry Example: for the SNP A/G ones genotype may be:
AA if both copies of the chromosome have A GG if both copies of the chromosome have G AG or GA if one copy has A and the other has G The first two cases are called homozygous and latter two are heterozygous

Do all SNPs lead to a change in phenotype?

No! Remember that only <2 % of human DNA encodes proteins and that a lot of DNA is non-coding or intergenic DNA. A SNP or deletion in a DNA-sequence with no function will probably not have a noticeable effect. ! ! ! ! ! ! ! ! Which of the following SNPs (1-5) are likely to cause a change in the expression or structure of the protein encoded by the gene? Gene
Enhancer SNPs Promoter Start Exon Intron Exon Termination


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)

Gene Enhancer SNPs 1 2 3 4 5 Promoter Start Exon Intron Exon Termination

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 will encode 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. !!! !!!

SNPs in Coding Regions No Changes in Protein


SNPs in Coding Regions Harmless Changes in Protein







RNA Codon GAU to GAG


Aspartic acid

Protein Glutamic acid Aspartic acid to Glutamic acid


Slight change in shape

SNPs in Coding Regions Harmful Changes in Protein Mutations





SNPs can alter the function of the protein 1. Directly : alter an amino acid sequence



RNA Codon GAU to GUU


2. indirectly : alter the function of the regulatory sequence

Aspartic acid

Protein Aspartic acid to Valine



Change in shape

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 wild type. 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 simple convention 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 in lower case.

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 in the mutation. Nonsense mutations are represented with an X for the second amino acid (e.g. D111X). Amino acid deletion (e.g. F508) The Greek letter (delta) indicates a deletion. The letter refers to the amino acid present in the wild type The number is the position from the N terminus of the amino acid were it to be present as in the wild type.



There is no nucleotide 0 Nucleotide 1 is the A of the ATG-translation initiation codon The nucleotide 5' of the ATG-translation initiation codon is -1, the previous 2,etc. The nucleotide 3' of the translation stop codon is *1, the next *2, etc. Beginning of the intron: the number of the last nucleotide of the previous exon, a plus sign and 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 32 sign and the position upstream in the intron, like c.78-1G.

SNPs and Disease Progression Application of SNPs map

Occasionally, a SNP may actually cause a disease and, 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 DNA from 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 screen individuals for susceptibility to a disease just by analyzing their DNA samples for specific SNP patterns.

Variations Causing Latent Changes

= Variations in DNA that cause latent effects Many years later Many years later

Disease predisposition: The Genetic differences between human populations 34 make one population more susceptible to particular disease.

SNPs and Disease Diagnosis

Serve as biological markers for pinpointing a disease on the human genome map, because they are usually located near a gene found to be associated with a certain disease.


SNPs will be useful in:

SNP profiles and specific responses to treatment.

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 Adverse Drug reaction).


SNP profiles and specific responses to treatment.

Currently, there is no simple way to determine how a patient will respond to a particular medication. A treatment proven effective in one patient may be ineffective in others. Today, pharmaceutical companies are limited to developing agents to which the "average" patient will respond. As a result, many drugs that might benefit a small number of patients never make it to market.


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's SNP profile. The ability to target a drug to those individuals most likely to benefit, referred to as "personalized medicine", would allow pharmaceutical companies to bring many more drugs to market and allow doctors to prescribe individualized therapies specific to a patient's needs.