Mutation is a change in the nucleotide sequence of DNA. Mutagens such as chemicals, radiation, and viruses can induce mutations by damaging DNA. There are several types of mutations including point mutations, insertions, deletions, and frameshift mutations. DNA repair systems help maintain the integrity of DNA and correct mutations by recognizing and removing damaged DNA and replacing it. Defects in DNA repair genes can lead to genetic disorders associated with cancer predisposition or accelerated aging.
Reverse transcription of RNA, which refers to the conversion of the RNA template into its complimentary DNA strand (cDNA) is an essential step in the analysis of gene transcripts.
cDNA can be sequenced, cloned and applied to estimate the copy number of specific genes in order to characterize and to validate gene expression.
Nucleotide Biosynthesis involves 2 processes. one is Denovo synthesis and other is Salvage pathway. An outline of both the processes has given in this presentation.
Reverse transcription of RNA, which refers to the conversion of the RNA template into its complimentary DNA strand (cDNA) is an essential step in the analysis of gene transcripts.
cDNA can be sequenced, cloned and applied to estimate the copy number of specific genes in order to characterize and to validate gene expression.
Nucleotide Biosynthesis involves 2 processes. one is Denovo synthesis and other is Salvage pathway. An outline of both the processes has given in this presentation.
Replication Introduction , DNA replicating Models , Meselson and Stahl Experiments , Circuler Model of DNA replication , Replication in Prokaryotes , Replication In Eukaryotes , Comparison Between Prokaryotes and Eukaryotes Replicaton and PCR (Polymerease Chain Reaction)
In biology, a mutation is the permanent alteration of the nucleotide sequence of the genome of an organism, virus, or extra chromosomal DNA or other genetic elements.
Mutations result from errors during DNA replication (especially during meiosis) or other types of damage to DNA (such as may be caused by exposure to radiation or carcinogens), which then may undergo error-prone repair or cause an error during other forms of repair,
Dna methylation ppt
definition of Dna methylation ppt
discovery of Dna methylation ppt
types of Dna methylation ppt
history of Dna methylation ppt
process of Dna methylation ppt
mechanism of Dna methylation ppt
methylation in cancer
cytosine methylation
genomic imprinting
Replication Introduction , DNA replicating Models , Meselson and Stahl Experiments , Circuler Model of DNA replication , Replication in Prokaryotes , Replication In Eukaryotes , Comparison Between Prokaryotes and Eukaryotes Replicaton and PCR (Polymerease Chain Reaction)
In biology, a mutation is the permanent alteration of the nucleotide sequence of the genome of an organism, virus, or extra chromosomal DNA or other genetic elements.
Mutations result from errors during DNA replication (especially during meiosis) or other types of damage to DNA (such as may be caused by exposure to radiation or carcinogens), which then may undergo error-prone repair or cause an error during other forms of repair,
Dna methylation ppt
definition of Dna methylation ppt
discovery of Dna methylation ppt
types of Dna methylation ppt
history of Dna methylation ppt
process of Dna methylation ppt
mechanism of Dna methylation ppt
methylation in cancer
cytosine methylation
genomic imprinting
DNA can be damaged by a variety of processes,
some spontaneous
Damage caused by environmental agents.
Error occurs during Replication (introduction of mismatched base pairs such as G paired with T).
The cellular response to this damage includes a wide range of enzymatic systems that catalyze some chemical transformations in DNA metabolism.
All Cells Have Multiple DNA Repair Systems
Direct repair
Mismatch repair
Excision repair
Replication fork encounters an unrepaired DNA lesion
Missense mutation and non-sense mutation (molecular biology)ShafqatHussain52
Nonsense mutation: A nucleotide substitution that creates a new stop codon is called a nonsense mutation.
Missense mutation: Nucleotide substitutions in protein-coding regions that do result in changed amino acids are called missense mutations or nonsynonymous mutations.
JMeter webinar - integration with InfluxDB and GrafanaRTTS
Watch this recorded webinar about real-time monitoring of application performance. See how to integrate Apache JMeter, the open-source leader in performance testing, with InfluxDB, the open-source time-series database, and Grafana, the open-source analytics and visualization application.
In this webinar, we will review the benefits of leveraging InfluxDB and Grafana when executing load tests and demonstrate how these tools are used to visualize performance metrics.
Length: 30 minutes
Session Overview
-------------------------------------------
During this webinar, we will cover the following topics while demonstrating the integrations of JMeter, InfluxDB and Grafana:
- What out-of-the-box solutions are available for real-time monitoring JMeter tests?
- What are the benefits of integrating InfluxDB and Grafana into the load testing stack?
- Which features are provided by Grafana?
- Demonstration of InfluxDB and Grafana using a practice web application
To view the webinar recording, go to:
https://www.rttsweb.com/jmeter-integration-webinar
Builder.ai Founder Sachin Dev Duggal's Strategic Approach to Create an Innova...Ramesh Iyer
In today's fast-changing business world, Companies that adapt and embrace new ideas often need help to keep up with the competition. However, fostering a culture of innovation takes much work. It takes vision, leadership and willingness to take risks in the right proportion. Sachin Dev Duggal, co-founder of Builder.ai, has perfected the art of this balance, creating a company culture where creativity and growth are nurtured at each stage.
DevOps and Testing slides at DASA ConnectKari Kakkonen
My and Rik Marselis slides at 30.5.2024 DASA Connect conference. We discuss about what is testing, then what is agile testing and finally what is Testing in DevOps. Finally we had lovely workshop with the participants trying to find out different ways to think about quality and testing in different parts of the DevOps infinity loop.
Key Trends Shaping the Future of Infrastructure.pdfCheryl Hung
Keynote at DIGIT West Expo, Glasgow on 29 May 2024.
Cheryl Hung, ochery.com
Sr Director, Infrastructure Ecosystem, Arm.
The key trends across hardware, cloud and open-source; exploring how these areas are likely to mature and develop over the short and long-term, and then considering how organisations can position themselves to adapt and thrive.
Neuro-symbolic is not enough, we need neuro-*semantic*Frank van Harmelen
Neuro-symbolic (NeSy) AI is on the rise. However, simply machine learning on just any symbolic structure is not sufficient to really harvest the gains of NeSy. These will only be gained when the symbolic structures have an actual semantics. I give an operational definition of semantics as “predictable inference”.
All of this illustrated with link prediction over knowledge graphs, but the argument is general.
Kubernetes & AI - Beauty and the Beast !?! @KCD Istanbul 2024Tobias Schneck
As AI technology is pushing into IT I was wondering myself, as an “infrastructure container kubernetes guy”, how get this fancy AI technology get managed from an infrastructure operational view? Is it possible to apply our lovely cloud native principals as well? What benefit’s both technologies could bring to each other?
Let me take this questions and provide you a short journey through existing deployment models and use cases for AI software. On practical examples, we discuss what cloud/on-premise strategy we may need for applying it to our own infrastructure to get it to work from an enterprise perspective. I want to give an overview about infrastructure requirements and technologies, what could be beneficial or limiting your AI use cases in an enterprise environment. An interactive Demo will give you some insides, what approaches I got already working for real.
Connector Corner: Automate dynamic content and events by pushing a buttonDianaGray10
Here is something new! In our next Connector Corner webinar, we will demonstrate how you can use a single workflow to:
Create a campaign using Mailchimp with merge tags/fields
Send an interactive Slack channel message (using buttons)
Have the message received by managers and peers along with a test email for review
But there’s more:
In a second workflow supporting the same use case, you’ll see:
Your campaign sent to target colleagues for approval
If the “Approve” button is clicked, a Jira/Zendesk ticket is created for the marketing design team
But—if the “Reject” button is pushed, colleagues will be alerted via Slack message
Join us to learn more about this new, human-in-the-loop capability, brought to you by Integration Service connectors.
And...
Speakers:
Akshay Agnihotri, Product Manager
Charlie Greenberg, Host
Elevating Tactical DDD Patterns Through Object CalisthenicsDorra BARTAGUIZ
After immersing yourself in the blue book and its red counterpart, attending DDD-focused conferences, and applying tactical patterns, you're left with a crucial question: How do I ensure my design is effective? Tactical patterns within Domain-Driven Design (DDD) serve as guiding principles for creating clear and manageable domain models. However, achieving success with these patterns requires additional guidance. Interestingly, we've observed that a set of constraints initially designed for training purposes remarkably aligns with effective pattern implementation, offering a more ‘mechanical’ approach. Let's explore together how Object Calisthenics can elevate the design of your tactical DDD patterns, offering concrete help for those venturing into DDD for the first time!
Slack (or Teams) Automation for Bonterra Impact Management (fka Social Soluti...Jeffrey Haguewood
Sidekick Solutions uses Bonterra Impact Management (fka Social Solutions Apricot) and automation solutions to integrate data for business workflows.
We believe integration and automation are essential to user experience and the promise of efficient work through technology. Automation is the critical ingredient to realizing that full vision. We develop integration products and services for Bonterra Case Management software to support the deployment of automations for a variety of use cases.
This video focuses on the notifications, alerts, and approval requests using Slack for Bonterra Impact Management. The solutions covered in this webinar can also be deployed for Microsoft Teams.
Interested in deploying notification automations for Bonterra Impact Management? Contact us at sales@sidekicksolutionsllc.com to discuss next steps.
Essentials of Automations: Optimizing FME Workflows with ParametersSafe Software
Are you looking to streamline your workflows and boost your projects’ efficiency? Do you find yourself searching for ways to add flexibility and control over your FME workflows? If so, you’re in the right place.
Join us for an insightful dive into the world of FME parameters, a critical element in optimizing workflow efficiency. This webinar marks the beginning of our three-part “Essentials of Automation” series. This first webinar is designed to equip you with the knowledge and skills to utilize parameters effectively: enhancing the flexibility, maintainability, and user control of your FME projects.
Here’s what you’ll gain:
- Essentials of FME Parameters: Understand the pivotal role of parameters, including Reader/Writer, Transformer, User, and FME Flow categories. Discover how they are the key to unlocking automation and optimization within your workflows.
- Practical Applications in FME Form: Delve into key user parameter types including choice, connections, and file URLs. Allow users to control how a workflow runs, making your workflows more reusable. Learn to import values and deliver the best user experience for your workflows while enhancing accuracy.
- Optimization Strategies in FME Flow: Explore the creation and strategic deployment of parameters in FME Flow, including the use of deployment and geometry parameters, to maximize workflow efficiency.
- Pro Tips for Success: Gain insights on parameterizing connections and leveraging new features like Conditional Visibility for clarity and simplicity.
We’ll wrap up with a glimpse into future webinars, followed by a Q&A session to address your specific questions surrounding this topic.
Don’t miss this opportunity to elevate your FME expertise and drive your projects to new heights of efficiency.
GraphRAG is All You need? LLM & Knowledge GraphGuy Korland
Guy Korland, CEO and Co-founder of FalkorDB, will review two articles on the integration of language models with knowledge graphs.
1. Unifying Large Language Models and Knowledge Graphs: A Roadmap.
https://arxiv.org/abs/2306.08302
2. Microsoft Research's GraphRAG paper and a review paper on various uses of knowledge graphs:
https://www.microsoft.com/en-us/research/blog/graphrag-unlocking-llm-discovery-on-narrative-private-data/
2. Mutation
A mutation is defined as a change in nucleotide
sequence of DNA
Mutagens are substances which can induce
mutations. These can be chemicals, radiations or
viruses
The changes that occur in DNA on mutation are
reflected in replication, transcription and
translation
Statistically, out of every 106 cell divisions, one
mutation takes place
4. Point mutation
Replacement or change in a single base
Two types
Transition : replacement of a purine by
another purine (A to G or G to A)or pyrimidine
by pyrimidine (T to C or C to T)
Transversion : replacement of a purine by
pyrimidine (A to C) or pyrimidine by Purine (T
to G)
5. Deletion
Large gene deletions e.g. alpha thalassemia
(entire gene) or homophilia (partial)
Deletion of a codon, e.g. cystic fibrosis (one
amino acid, 508th phenyl alanine is missing in
the CFTR gene
Deletion of single base, which will rise to
frame shift effect
6. Insertion
Single base additions, leading to frame-shift
effect
Trinucleotide expansions, e.g. in Huntington’s
chorea, CAG trinucleotides are repeated 30 to
300 times. This leads to a polyglutamine
repeat in the protein
Duplications. E.g.in Duchenne Muscular
Dystrophy (DMD), the gene is duplicated
7. Effect of mutation
Point mutation may lead to
– Silent Mutation
– Mis-sense Mutation
• Acceptable
• Partially acceptable
• Unacceptable
– Non-sense
Insertion or deletion of single base leads to
– Frame-shift Mutation
8. Silent Mutation
A point mutation may change the codon for
one amino acid to synonym for the same
amino acid
Mutation is silent and has no effect on the
phenotype
E.g. CUA is mutated to CUC; both code for
leucine, and so this mutation has no effect
9. Mis-sense but Acceptable Mutation
A change in amino acid may be produced in
the protein; but with no functional
consequences
Acceptable mutation
HbA-β chain 67 Val
Hb(Sidney)-β chain 67 Ala
GUU
GCU
10. Mis-sense; Partially Acceptable
Mutation
o The amino acid substitution affects the functional
properties of the protein
o HbS has abnormal electrophoretic mobility and
subnormal function, leading to sickle-cell anemia
Partially Acceptable mutation
HbA-β chain 6 Glu
HbS-β chain 6 Val
GAG
GUG
11. Mis-sense; Unacceptable Mutation
o The single amino acid substitution alters the
properties of the protein to such an extent
that it becomes nonfunctional and the
condition is incompatible with normal life
Unacceptable mutation
HbA-α chain 58 His
HbM(Boston)-α chain 58 Tyr
CAU or CAC
UAU or UAC
12. Nonsense; Terminator Codon
Mutation
The codons with the altered base may become
one of the three termination codon (UAA, UAG or
UGA) called as “nonsense codon”.
This leads to premature termination of the
protein, and so functional activity may be
destroyed. E.g. beta-thalassemia
A terminator codon is altered into a coding codon
(UAA to CAA), resulting in elongation of the
protein to produce “run on polypeptide” (Hb
Constant spring)
13. Frame-shift Mutation
This is due to addition or deletion of bases.
From that point onwards, the reading frame
shifts. A “garbled” (completely irrelevant)
protein, with altered amino acid sequence is
produced.
14.
15. Not only the sequence of amino acids distal to
the addition or deletion is garbled, there may
appear a nonsense (chain termination or run-
on-polypeptide) that are non-functional
16. Manifestations of Mutations
Lethal Mutations
The alteration is incompatible with life of the cell
or the organism
E.g. mutation producing alpha-4 Hb is lethal, and
so the embryo dies
Silent Mutations
Alteration at an insignificant region of a protein
may not have any functional effect
17. Beneficial Mutations
Beneficial spontaneous mutations are the basis of
evolution
Such beneficial mutants are artificially selected in
agriculture.
E.g. normal maize is deficient in tryptophan.
Tryptophan-rich maize varieties are now available
for cultivation
Carcinogenic Effect
The mutation may not be lethal, but may alter the
regulatory mechanism.
Such a mutation in a somatic cell may result in
uncontrolled cell division leading to cancer
18. DNA damage and DNA Repair
DNA is replicated with great fidelity (accuracy).
However, DNA can be damaged by variety of
causes resulting in several distinct types of
lesions
Various physical and chemical agents produce
base alterations; these are to be appropriately
corrected immediately
The DNA polymerase has 3’ to 5’ exonuclease
activity. Hence any mispaired nucleotide added is
immediately removed
19. • Cause of DNA damage
Misincorporation of deoxynucleotides during
replication
By spontaneous deamination of bases during normal
genetic functions
From x-radiation that cause “nicks” in the DNA
From UV irradiation that causes thymine dimer
formation
From various chemicals that interact with DNA e.g.
ozone (produced by lightning), hydrazines (present in
edible mushrooms), allylisothiocynates, aflatoxin (mold
growing on peanuts and grains), alkylating agents
(busulphan, cyclophosphamide) and free radicals
(oxidative stress)
20.
21. Types of damage to DNA
1. Single-base alteration
a. Depurination
b. Deamination of cytosine to uracil
c. Deamination of adenine to hypoxanthine
d. Alkylation of base
e. Insertion or deletion of nucleotide
f. Base-analog incorporation
22. 2. Two-base alteration
a. UV light-induced thymine-thymine (pyrimidine) dimer
b. Bifunctional alkylating agent cross-linkage
3. Chain breaks
a. Ionizing radiation
b. Radioactive disintegration of backbone element
c. Oxidative free radical formation
4. Cross-linkage
a. Between bases in same or opposite strands
b. Between DNA and protein molecules (e.g. histones)
23. Mechanism of DNA Repair
the maintenance of the integrity of DNA is
very important in order to provide correct
genetic information.
The integrity of DNA after DNA replication is
maintained by the presence of specific DNA
repair system
There are several DNA repair system
24. Mechanism of DNA Repair
Mechanism Problem Repair
Mismatch repair Copying errors (single base
or two- to five-base
unpaired loops
Methyl-directed strand
cutting, exonuclease
digestion, and replacement
Base excision-repair Spontaneous, chemical, or
radiation damage to a single
base
Base removal by N-
glycosylase, abasic sugar
removal, replacement
Nucleotide excision-repair Spontaneous, chemical, or
radiation damage to a DNA
segment
Removal of an approximately
30-nucleotide oligomer and
replacement
Double-strand break
repair
Ionizing radiation,
chemotherapy, oxidative
free radicals
Synapsis, unwinding,
alignment, ligation
25. General Mechanism
Recognition of altered base
Removal of altered base along with a few
bases around that area.
A small segment of DNA with correct base
sequence is then synthesized by DNA
polymerase beta.
Then the gap or nick is sealed by DNA ligase
26. Mismatch Repair
Mismatching of bases can occur during DNA
synthesis since proof reading is not 100%
accurate
Repair enzymes:- mismatch repair protein
complexes(MutS, MutC and MutL in Ecoli and
MSh and MLH in humans), exonucleases, DNA
polymerases and DNA ligases are involved in
mismatch repair
27. Repair process
Specific proteins scan the newly synthesized DNA, using adenine
methylation within a GATC sequence as the point of reference
The template strand is methylated, and the newly synthesized strand
is not.
This difference allows the repair enzymes to identify the strand that
contains the errant nucleotide which requires replacement.
If a mismatch or small loop is found a GATC endonuclease cuts the
strand bearing the mutation at a site corresponding to the GATC.
Exonuclease digest this strand from the GATC through the mutation,
thus removing he faulty DNA
DNA polymerase fills the gap
The last phosphodiester linkage is closed by DNA ligase
28.
29. Base Excision Repair
Involves repair of alkylated bases, repair of
deaminated bases and repair of depurination
Repair enzymes:- DNA glycosylates, AP
endonucleases, helicases, excision nuclease,
DNA polymerase and DNA ligase
30. Repair of deamination
Cytosine spontaneously deaminates to form uracil
Uracil is recognized by uracil DNA glycosidase and uracil
is excised
Creation of AP (either apurine or apyrimidine) site
consisting of only deoxyribose phosphate backbone
AP endonuclease nicks the deoxyribose phosphate
backbone
Excision nuclease removes the AP site and several
nucleotides
DNA polymerase fills the gaps
DNA ligase seals the phosphodiesterase bond
31. Repair of depurination
Depurination occurs by breaking of N-glycosyl
bond between the purine and deoxyribose
AP (apurinic site) endonucleases recognizes the
site of missing purines and nicks the deoxyribose
sugar phosphate
Phosphodiesterase excises the deoxyribose
phosphate
DNA polymerase replace the purine nucleotide
DNA ligase seals the phosphodiester bond
32. Nucleotide Excision Repair
It repairs covalent bonding between adjacent thymine bases
or adjacent thymine-cytosine bases caused by ultravoilet
light. This produces thymine dimers or thymine-cytosine
cross links. Both of these alterations produce distortions of
DNA helix
Enzymes:- excinuclease, DNA polymerase and DNA ligase. At
least 18 different proteins are involved in nucleotide
excision repair. Proteins encoded by 7 genes related to
xeroderma pigmentosum (XPA to XPG) are involved in
nucleotide excision repair. Cockayne syndrome related
genes (CSA or CSB) are involved in transcription coupled
DNA repair
33. Excinuclease detects the distortion of the
helix, nicks the damaged strand on both sides
of the lesion and removes the nucleotides
DNA polymerase fills in the gap,
using the undamaged strand as
template
DNA ligase seals the
phosphodiester bond
34. • In transcription coupled repair, RNA
polymerase is made to transverse back from
the site of lesion followed by correction of the
lesion
35. Double Strand Break Repair
It is usually caused by ionizing radiation,
oxidative stress and chemicals such as
bleomycin
It can also occur during immunoglobulin gene
arrangement
Enzymes:- Ku protein with helicase activity, DNA
dependent protein kinase, exonuclease and
ligase
36. Ku protein binds to both ends of DNA double stranded
DNA segments
Recruit DNA dependent protein kinase
DNA dependent protein kinase approximates the two
separated strands and activate Ku protein
Activated Ku protein has helicase activity and unwinds
the two ends of DNA
Approximated DNA segments form the base pairing
Extra nucleotides are removed by exonuclease
Gaps are filled by ligase
37. Clinical aspect
• Xeroderma Pigmentosum
(greek xeros – dry + derma- skin)
– Defect: nucleotide excision repair; caused by the
defect in the removal of pyrimidine dimer caused
by the defective excinuclease, mutation in XPA
gene
– Features: hypersensitivity to sunlight (UV
radiation) leading to the development of skin
lesions and skin cancer
38. • Ataxia Telangiectasia
– Defect in gene involved in DNA repair and cell
cycle
– Characterized by hypersensitivity to ionizing
radiation, cerebellar ataxia, oculocutaneous
telangiectasia and immunodeficiency. These
patients are susceptible for the development of
lymphomas
39. • Fanconi’s Anemia
– Defect in double strand break repair
– Feature: hypersensitivity to DNA cross linking
agents, bone marrow failure (aplastic anemia) and
leukemia
• Bloom’s syndrome
– Defect in double strand break repair, defective
helicase
– Feature: susceptibility to ultraviolet radiation, and
the development of leukemia
40. • Hereditary Nonpolyposis Colorectal Cancer
(HNPCC)
– Defect in mismatch repair, defective HNPCC
genes, 50-60% of HNPCC is associated with
mutation on hMSH2, hMLH1 is associated with
most of other cases
– Features: condition accounts for about 15% of
colon cancers, early development of tumors
– Identification of the genes responsible for HNPCC
permit the early detection of the condition
41. • Cockayne Syndrome
– Defect in preferential repair of he transcribed
strand, mutation in proteins CSA and CSB
– Features: neurological degeneration and growth
retardation
• Warner’s syndrome
– Inherited defect in excision repair of DNA,
defective helicase
– Characterized by accelerated aging
42. References
Harper’s Illustrated Biochemistry, 28th edition
Biochemistry by Voet and Voet, 4th edition
Medical Biochemistry, AR Aroora
Text Book of Biochemistry, DM Vasudevan
Text Book of Medical Biochemistry, MN
Chatterjea
Biochemistry, U Satyanarayana