Prediction of Genetic Disorders based on Trinucleotide Repeats

1. INDIAN INSTITUTE OF TECHNOLOGY ROORKEE
PREDICTION OF GENETIC DISORDERS BASED ON
TRINUCLEOTIDE REPEATS
Submitted by :
Surabhi Sinha (18610026)
Sourik Dey (18610023)
Tapas Ranjan Behera (18610029)
M.Sc Biotechnology, 1st Year, 2018-2019
Computer Applications (BTN-511)
Submitted to:
Dr. Deepak Sharma

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Trinucleotide Repeat Disorders
• Set of genetic disorders caused by trinucleotide repeat expansion
– Mutation where trinucleotide repeats in certain genes or introns
exceed the normal, stable threshold, which differs per gene.
• Subset of unstable microsatellite repeats that occur throughout
all genomic sequences.
• If the repeat is present in a healthy gene, a dynamic mutation may
increase the repeat count and result in a defective gene.
• If the repeat is present in an intron it can cause toxic effects by
forming spherical clusters called RNA foci in cell nuclei.

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Overview of TNRE Disorders
• Different Categories of TNRE Disorders are as follows:-
• Category I includes Huntington's disease (HD) and the spinocerebellar
ataxias that are caused by a CAG repeat expansion in protein-coding
portions of specific genes.
• Category II expansions tend to be more phenotypically diverse with
heterogeneous expansions that are generally small in magnitude, but also
found in the exons of genes.
• Category III includes fragile X syndrome, myotonic dystrophy, two of the
spinocerebellar ataxias, juvenile myoclonic epilepsy, and Friedreich's ataxia.
These diseases are characterized by typically much larger repeat expansions
than the first two groups, and the repeats are located outside of the protein-
coding regions of the genes.

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MOTIVATION OF OUR PROJECT
• Our motivation for building this project is to predict whether the
patient is a victim of these TNRE disorders at a very early stage of
diagnosis.
• Although such kinds of diseases are very difficult to treat but with
early diagnosis and prediction of the disease and recent advances
in biomedical research someday an effective cure might arise.
• For that to occur effective bioinformatic analysis of defective
genes is a must, which has been the driving force of our project.

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DISORDERS CONSIDERED
• We will discuss about two disorders in our project which are as
follows:-
• HUNTINGTON’S DISEASE
• FRAGILE X MENTAL SYNDROME

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HUNTINGTON’S DISEASE
• HD is one of several trinucleotide repeat disorders which are
caused by the length of a repeated section of a gene exceeding
a normal range.
• The HTT gene is located on the short arm of chromosome 4 at
4p16.3. HTT contains a sequence of three DNA bases—cytosine-
adenine-guanine (CAG)—repeated multiple times (i.e. ...
CAGCAGCAG ...), known as a trinucleotide repeat.
• CAG is the 3-letter genetic code (codon) for the amino
acid glutamine, so a series of them results in the production of a
chain of glutamine known as a polyglutamine tract (or polyQ
tract), and the repeated part of the gene, the PolyQ region.

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Classification of the trinucleotide repeat, and resulting disease status, depends on the
number of CAG repeats.
Repeat count Classification Disease status Risk to offspring
<26 Normal Will not be affected None
27–35 Intermediate Will not be affected Elevated but <50%
36–39 Reduced Penetrance
May or may not be
affected
50%
40+ Full Penetrance Will be affected 50%
CLASSIFICATION (HTT)

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FRAGILE X SYNDROME
• Fragile X syndrome is inherited in an X-linked dominant pattern.
• It is typically due to an expansion of the CGG triplet repeat within
the Fragile X mental retardation 1 (FMR1) gene on the X chromosome.
• This results in not enough fragile X mental retardation protein (FMRP),
which is required for the normal development of connections between
neurons.
• Normal is between 5 and 40 repeats, fragile X syndrome occurs with
more than 200, and a premutation is said to be present when a middle
number of repeats occurs. Testing for premutation carriers may allow
for genetic counselling.

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Classification of the trinucleotide repeat, and resulting disease status, depends on the
number of CGG repeats.
Repeat count Classification Disease status Risk to offspring
5-40 Normal Will not be affected None
40-200 Intermediate Will not be affected Elevated but <50%
>200 Full Penetrance Will be affected 50%
CLASSIFICATION (FMR)

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CODING OF THE PROJECT

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OUTPUTS

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HTT- 27 repeats (Normal)

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HTT-38 Repeats (Reduced Penetrance)

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HTT- 52 Repeats (Full penetrance)

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FMR- 33 Repeats (Normal)

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FMR- 129 Repeats (Intermediate)

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FMR – 228 Repeats (Full Penetrance)

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Thank You