dr.s.sethupathy,m.d.,ph.d., professor and head, dept.of biochemistry, rajah muthiah medical college,...

Dr.S.Sethupathy,M.D.,Ph.D.,Professor and Head,

Dept.of Biochemistry,Rajah Muthiah Medical College,

Annamalai University

• Surviving• Non surviving

Spectrum of surviving people1.Genetically stable without diseases even

with so called risk factors for diseases2.Genetically unstable with diseases even

without risk factors3.Genetically partially stable and may develop

diseases when exposed to risk factors

1. Help not required2.Manage them for reducing morbidity and mortality

3.Intervention for prevention of diseases

Defined as any change in a DNA sequence away from normal.

There is a normal allele that is prevalent

There is a change in this to a rare and abnormal variant.

• It is a DNA sequence variation that is common in the population.

• There are two or more equally acceptable alternatives.

• The arbitrary cut-off point between a mutation and a polymorphism is 1 per cent.

• The least common allele must have a frequency of 1per cent or more in the population.

• If the frequency is lower than this, the allele is regarded as a mutation

Sequence variants that directly and overtly cause human diseases are generally rare in the population because they reduce fitness.

Such disease alleles are classed as mutations. However, not all mutations cause diseases.

Any new sequence variant, even if neutral or beneficial in effect, will start off as a rare mutation

Many are found outside of genes and are completely neutral in effect.

Others may be found within genes, but may influence characteristics such as height and hair colour rather than characteristics of medical importance.

It can contribute to disease susceptibility and can also influence drug responses

A rare disease allele in one population can become a polymorphism in another if it confers an advantage and increases in frequency.

In Caucasian populations this is a rare sequence variant of the beta-globin gene that causes a severely debilitating blood disorder.

In certain parts of Africa, however, the same allele is polymorphic because it confers resistance to the blood-borne parasite that causes malaria.

Polymorphism[in biology occurs when two or more clearly different phenotypes exist in the same population of a species

The occurrence of more than one form or morph.

Morphs must occupy the same habitat at the same time and belong to a panmictic population (one with random mating).

• It is common in nature• It is related to biodiversity, genetic variation

and adaptation• It usually functions to retain variety of form

in a population living in a varied environment.

• The most common example is sexual dimorphism, which occurs in many organisms. Other examples are human haemoglobin and blood types

Polymorphism results from evolutionary processes, as does any aspect of a species. It is heritable, and is modified by natural selection

It may be possible to inject patients with severe genetic disorders such as MS and CF with a virus and cure the disease.

  Since injecting individuals with viruses includes great risk, it is an area of genetics that is slowly moving.

• Test embryos for characterstics such as blood and marrow type that would determine a match for transplant. 

• If having a child to save another is the correct motivation to bring children into the world.

• Variants in SNPs to be two genes on Chromosome 8 and one gene on Chromosome 9. 

• Factors that increase the risk of intracranial aneurysms such as Smoking, alcohol abuse, cocaine use, and hypertension

• The individual may change their behaviors to lower their risk.

• A mutation in the BRCA1 and MRCA2 genes places at a much higher risk

• Only 2-5% of women with breast cancer are found to have this mutation. 

• Other such mutations can be found on the chromosome 10, 16, 11, 5 and 2. 

• A combination of these variants can significantly increase overall risk of breast cancer.

Estrogen has been shown to significantly increase risk for breast cancer

People with these mutations can be given drugs that block the effect of estrogen. 

People with increased risk can increase the frequency of mammograms in order to catch any cancer at a early stage.

• Alzheimer's disease is a degenerative brain disorder in old age.

• Severe dementia - A variation in  the Apolipoprotein E (ApoE) gene called ApoE4 has been found to increase the risk of late-onset Alzheimer's. 

• Individuals with high risk can be regularly monitored for the disease

Most of any one person's DNA, about 99.5 percent, is exactly the same as any unrelated person's DNA.

Differences in the sequence of DNA among individuals are called genetic variation such as eye color and blood group.

Single gene differences in individuals account for some traits and diseases, such as the ABO blood group, cystic fibrosis and sickle cell disease.

Multiple genes and the environment are responsible for many common diseases, such as diabetes, cancer, stroke, Alzheimer's disease, Parkinson's disease, depression, alcoholism, heart disease, arthritis and asthma.

• Discovering and typing single nucleotide polymorphisms (SNPs) and other forms of genetic variation

• Developing high-resolution maps of genetic variation and haplotypes. 

• Developing methods for the large-scale experimental and statistical analysis

• Developing statistical methods to relate genetic variation to phenotype.

Most diseases that are tested for by SNP analysis are also affected by environmental factors

It should not invoke despair or helplessness on an individual

It provides them the information for leading a healthier life. 

The potential of insurance companies and employers getting a hold of genetic information and using it against them. 

For example, an employer may not hire an individual because of increased risk of Parkinson's or Huntington's.

Within the approximate 3.2 billion nucleotide human genome sequence, there are an estimated 10 million SNPs

It is small genetic variation very similar to point mutations.

SNPs differ by single nucloetides and do not induce additional errors by the DNA polymerase.

SNP analsyis provides an individual with personalized information concerning health and disease.

Companies can look for genes that encode for diseases such as Alzheimer's, Macular degeneration, cancer, obesity, Parkinson's, Muscular dystrophy, Huntington's, and Cystic Fibrosis etc.

• Most SNPs are found in non-coding sequences. • SNPs in coding sequence can change amino acid

sequence and alter the biological properties.   

• SNPs for Disease Diagnosis

   Most SNPs are not responsible for a disease, they can be biological markers for detecting probability of disease.

• Usually close to a certain disease gene location. • Occasionally responsible for a disease directly.

• SNPs may be associated with sensibility of therapeutic molecules.

• It's clear that SNPs can have different effect among them.

• In the future, person could be serviced with"personalized medicine" 

• Treatment is given by analyzing a patient's SNP profile.

• The software can analyze and find differences in intensity-levels between groups of array

• To identify segments of SNPs(genes, clones) where the intensity-levels differ significantly between the groups.    

• It is a set of single nucleotide polymorphisms (SNPs) on a single chromatid that are statistically associated.

• It can unambiguously identify all other polymorphic sites in its region. Such information is very valuable for investigating the genetics behind common diseases and is collected by the International HapMap Project.

For a single-nucleotide variation to be officially considered a SNP, it must occur in at least 1% of the general population

• Most SNPs are found outside of "coding sequences”.

• SNPs found within a coding sequence affect function of a protein.

• Many of these SNPs may be responsible for our differences in physical appearance, susceptibility and resistance to disease, response to medications, and other human traits.

• Multifactorial conditions are caused by a combination of genetic, environmental and lifestyle factors.

• Regarding the genetic risk factors , it is difficult to establish because multiple genes likely interact to cause susceptibility or resistance to disease as well as affect the severity or progression of disease symptoms.

• Multiple genes interact to affect the metabolism of medications used to treat complex diseases.

To be able to use a person's total genetic information to better predict, prevent, and treat disease

• In April 1999, ten large pharmaceutical companies and the U.K. Wellcome Trust philanthropy announced the establishment of a consortium lead by Arthur L. Holden to find and map 300,000 common SNPs.

• The goal was to generate a widely accepted, high-quality, extensive, publicly available map using SNPs as markers evenly distributed throughout the human genome.

So far SNPs (1.8 million total) were discovered.

Now emphasis has shifted to studying SNPs in populations.

The goal of the TSC allele frequency/genotype project is to determine the frequency of certain SNPs in three major world populations

• The map will be a powerful research tool to enhance the understanding of disease processes and facilitate the discovery and development of safer and more effective medications.

• The SNP consortium used DNA resources from a pool of samples obtained from 24 people representing several racial groups.

• The anonymous, voluntary DNA contributions were made with informed consent specifically for this use.

Besides the TSC website, SNP data are also available from the following resources:

dbSNP database - From the National Center for Biotechnology Information (NCBI).

HGVbase (Human Genome Variation Database) - A human gene-based polymorphism database.

Association of polymorphisms in 9p21 region with CAD in North Indian population: replication of SNPs identified through GWAS

Six SNPs • rs10116277• rs10757274• rs1333040• rs2383206• rs2383207 • Rs1994016• rs10116277, rs1333040 and rs2383206 -

present at the locus 9p21 were significantly associated with CAD in the Caucasian populations and also in North Indian population

• These studies normally compare the DNA of two groups of participants: people with the disease (cases) and similar people without (controls).

• Each person gives a sample of cells, such as swabs of cells from the inside of the cheek.

• DNA is extracted from these cells, and spread on gene chips, which can read millions of DNA sequences.

• These chips are analyzed by computers using bioinformatic techniques. - DNA variations (haplotypes) are analyzed.

Gene of interest with respect to disease SNP reported Patients selection Primer designing PCR Detection of SNPS ANALYSIS

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