Unit-2 Human genome project and its applications

The Human Genome Project: Goals, Achievements, and Applications

Introduction
The Human Genome Project (HGP) was an international, collaborative research program
launched in 1990 and completed in 2003. Its primary objective was to map and understand all
the genes of human beings—the entire human genome by sequencing the entire human
genome of 3.3 billion base pairs. The HGP led to the growth of bioinformatics which is a vast
field of research. The successful sequencing of the human genome could solve the mystery of
many disorders in humans and gave us a way to cope up with them.
The primary goals of the Human Genome Project were:
1. Identify All Human Genes
Catalog the approximately 20,000–25,000 human genes and determine their
sequences and locations.
2. Determine the Complete Sequence of the Human Genome
Accurately map the 3 billion DNA base pairs that make up the human genome.
3. Store the Information in Databases
Develop robust, publicly accessible databases to store genomic information for
researchers worldwide.
4. Improve Tools for Data Analysis
Create tools and technologies to support sequencing and bioinformatics, making
genomic data analysis more efficient and accessible.
5. Address Ethical, Legal, and Social Implications (ELSI)
Explore and address the social impact of genomic research, particularly related to
privacy, discrimination, and ethical concerns.
6. Transfer Technologies to the Private Sector
Promote the development of commercial applications and ensure that discoveries
translate into innovations in health care and biotechnology.

Methods of the human genome project

In this project, two different and significant methods are typically used.

1.Expressed sequence tags wherein the genes were differentiated into the ones forming a
part of the genome and the others which expressed RNAs.

2.Sequence Annotation wherein the entire genome was first sequenced and the functional
tags were assigned later.

The process of the human genome project

 The complete gene set was isolated from a cell.

  It was then split into small fragments.
 This DNA structure was then amplified with the help of a vector which mostly was
BAC (Bacterial artificial chromosomes) and YAC (Yeast artificial chromosomes).
 The smaller fragments were then sequenced using DNA sequencers.
 On the basis of overlapping regions, the sequences were then arranged.
 All the information of this genome sequence was then stored in a computer-based
program.
 This way the entire genome was sequenced and stored as genome database in
computers. Genome mapping was the next goal which was achieved with the help of
microsatellites (repetitive DNA sequences).
Achievements of the Human Genome Project
The HGP achieved several monumental milestones:
1. Completion of a Reference Human Genome Sequence (2003)
The project successfully mapped and sequenced more than 99% of the human genome
with an accuracy of 99.99%, ahead of schedule and under budget.
2. Gene Identification and Annotation
Over 20,000 genes were identified, many of which were previously unknown. This
laid the groundwork for understanding gene function and regulation.
3. Advancement in Sequencing Technology
The HGP spurred the development of high-throughput sequencing technologies,
drastically reducing the cost and time required for sequencing.
4. Creation of Public Genomic Databases
Databases like GenBank and Ensembl were created to make genomic data freely
available to scientists worldwide.
5. Increased Understanding of Genetic Variation
The project led to the identification of millions of single nucleotide polymorphisms
(SNPs), which are key to understanding genetic diversity and disease susceptibility.
6. Foundation for Subsequent Genomic Projects
It inspired initiatives like the 1000 Genomes Project, the Cancer Genome Atlas, and
the Human Microbiome Project.
Applications of the Human Genome Project
The impact of the HGP has been wide-reaching across multiple fields:
1. Medicine and Healthcare
 Personalized Medicine: Genomic information allows tailored treatment plans based
on an individual's genetic makeup.
 Disease Diagnosis: Improved diagnostic tools for genetic disorders like cystic
fibrosis, sickle cell anemia, and Huntington’s disease.
 Drug Development: Understanding genetic factors behind diseases has facilitated the
development of targeted therapies.
2. Genetic Research
 Gene Function Studies: Researchers can better understand how genes are regulated
and expressed in health and disease.
 Model Organisms: The HGP supported sequencing of other organisms, aiding
comparative genomics and functional studies.
3. Forensics and Anthropology
 DNA Fingerprinting: Human genome data enhances accuracy in criminal
identification and paternity testing.
 Ancestry and Evolution: Insights into human migration patterns and evolutionary
relationships through genetic markers.
4. Agriculture and Biotechnology
 Crop and Livestock Improvement: Identification of genes related to yield, disease
resistance, and climate resilience.
 Synthetic Biology: Manipulating genomes for industrial and environmental
applications.
5. Ethical and Social Advancements
 Public Policy: The HGP influenced laws like the Genetic Information
Nondiscrimination Act (GINA).
 Bioethics Education: Raised awareness and discourse around the ethical use of
genetic information.
Comparative genomics
1. Comparative genomics is a field of biological research in which the genomic features
of different organisms are compared.
2. The genomic features may include the DNA sequence, genes, gene order, regulatory
sequences, and other genomic structural landmarks.
3. In this branch of genomics, whole or large parts of genomes resulting from genome
projects are compared to study basic biological similarities and differences as well as
evolutionary relationships between organisms.
4. The major principle of comparative genomics is that common features of two
organisms will often be encoded within the DNA that is evolutionarily conserved
between them.
5. Therefore, comparative genomic approaches start with making some form of
alignment of genome sequences and looking for orthologous sequences (sequences
that share a common ancestry) in the aligned genomes and checking to what extent
those sequences are conserved.
6. Based on these, genome and molecular evolution are inferred and this may in turn be
put in the context of, for example, phenotypic evolution or population genetics.
7. Started as soon as the whole genomes of two organisms became available (that is, the
genomes of the bacteria Haemophilus influenzae and Mycoplasma genitalium) in
 1995, comparative genomics is now a standard component of the analysis of every
new genome sequence
8. With the explosion in the number of genome projects due to the advancements in
DNA sequencing technologies, particularly the next-generation sequencing methods
in late 2000s, this field has become more sophisticated, making it possible to deal
with many genomes in a single study.
9. Comparative genomics has revealed high levels of similarity between closely related
organisms, such as humans and chimpanzees, and, more surprisingly, similarity
between seemingly distantly related organisms, such as humans and the yeast
Saccharomyces cerevisiae.
10. It has also showed the extreme diversity of the gene composition in different
evolutionary lineages.
11. Comparative genomics has a root in the comparison of virus genomes in the early
1980s.
12. For example, small RNA viruses infecting animals (picornaviruses) and those
infecting plants (cowpea mosaic virus) were compared and turned out to share
significant sequence similarity and, in part, the order of their genes
13. Saccharomyces cerevisiae, the baker's yeast, was the first eukaryote to have its
complete genome sequence published in 1996.
14. After the publication of the roundworm Caenorhabditis elegans genome in 1998 and
together with the fruit fly Drosophila melanogaster genome in 2000, Gerald M. Rubin
and his team published a paper titled "Comparative Genomics of the Eukaryotes", in
which they compared the genomes of the eukaryotes D. melanogaster, C. elegans, and
S. cerevisiae, as well as the prokaryote H. influenzae
15. When two or more of the genome sequence are compared, you can get the
evolutionary relationships of the sequences in a phylogenetic tree.
16. Similarity of related genomes is the basis of comparative genomics.
17. If two creatures have a recent common ancestor, the differences between the two
species genomes are evolved from the ancestors' genome.
18. The closer the relationship between two organisms, the higher the similarities between
their genomes.
19. If there is close relationship between them, then their genome will display a linear
behaviour (synteny), namely some or all of the genetic sequences are conserved.
20. Thus, the genome sequences can be used to identify genefunction, by analyzing their
homology (sequence similarity) to genes of known function.
21. Orthologous sequences are related sequences in different species: a gene exists in the
original species, the species divided into two species, so genes in new species are
orthologous to the sequence in the original species.
22. Paralogous sequences are separated by gene cloning (gene duplication): if a particular
gene in the genome is copied, then the copy of the two sequences is paralogous to the
original gene.
23. Comparative genomics exploits both similarities and differences in the proteins, RNA,
and regulatory regions of different organisms to infer how selection has acted upon
these elements.
 24. Those elements that are responsible for similarities between different species should
be conserved through time (stabilizing selection), while those elements responsible
for differences among species should be divergent (positive selection).
25. Finally, those elements that are unimportant to the evolutionary success of the
organism will be unconserved (selection is neutral).
Constrained sequences
Evolutionarily constrained sequences are regions of the genome that have remained highly
conserved across different species over evolutionary time. These sequences are subject to
purifying selection, meaning that mutations in these regions are often deleterious and are
removed by natural selection. Such sequences typically include:
1. Protein-coding genes: The sequences that encode proteins are often highly conserved due
to the essential functions of these proteins in cellular processes.
2. Regulatory elements: Non-coding regions like promoters, enhancers, and silencers that
control gene expression can also be highly conserved due to their critical roles in gene
regulation.
3. Non-coding RNAs: These can include rRNAs, tRNAs, and other non-coding RNAs that
have important regulatory functions.
The conservation of these sequences indicates their functional importance. Comparative
genomics can identify these regions by aligning the genomes of different species and looking
for sequences that have little variation.
Diversified Sequences
In contrast, diversified sequences are genomic regions that exhibit high variability between
species. These sequences are often under positive selection, which can drive rapid
evolutionary changes. Diversified sequences can include:
1. Immune system genes: Genes involved in immune responses, such as the major
histocompatibility complex (MHC) genes, often show high variability to adapt to different
pathogens.
2. Reproductive genes: Genes involved in reproduction can also be highly variable, reflecting
the evolutionary pressures related to mating strategies and reproductive success.
3. Adaptation-related genes: Genes that provide a selective advantage in specific
environmental conditions can diverge quickly, leading to adaptations that improve survival
and reproduction in those environments.
G-Value Paradox
The G-value paradox, also known as the "C-value enigma,” refers to the observation that
there is no simple correlation between the genome size (measured in base pairs) or the
number of genes (G-value) and the complexity of an organism. For example:
 1. Humans vs. other organisms: Humans have approximately 20,000-25,000 protein-
coding genes, similar to or even fewer than some simpler organisms like the
nematode Caenorhabditis elegans or the fruit fly Drosophila me/anogaster.
2. Genome slze variation: Some plants and amphibians have much larger genomes
than humans, despite not being more complex in terms of organismal biology.
Several factors contribute to the G-value paradox:
• Non-coding DNA: Much of the genome consists of non-coding DNA, including
introns, regulatory elements, and repetitive sequences, which do not necessarily
correlate with organismal complexity.
• Gene regulation: The complexity of an organism is more closely related to the
regulatory networks and the interactions between genes rather than the sheer
number of genes.
• Alternative splicing: A single gene can produce multiple proteins through
alternative splicing, increasing the functional complexity without increasing the
number of genes.
• Gene functions: The versatility and interaction of proteins, including post-
translational modifications and protein-protein interactions, contribute significantly
to biological complexity.
Comparative genomics helps unravel the G-value paradox by allowing researchers to identify
conserved and diversified sequences, understand gene regulation mechanisms, and study the
evolutionary processes that contribute to genomic and organismal complexity. By comparing
genomes across a wide range of species, scientists can gain insights into how genomic
architecture and gene regulation contribute to the diversity of life forms on Earth.
Microarray:
A microarray is a pattern of ssDNA probes which are immobilized on a surface (called a chip
or a slide). The probe sequences are designed and placed on an array in a regular pattern of
spots. The chip or slide is usually made of glass or nylon and is manufactured using
technologies developed for silicon computer chips. Each microarray chip is arranged as a
checkerboard of 105 or 106 spots or features, each spot containing millions of copies of a
unique DNA probe (often 25 nt long). Like Southern & northern blots, microarrays use
hybridization to detect a specific DNA or RNA in a sample. But whereas a Southern blot uses
a single probe to search a complex DNA mixture, a DNA microarray uses a million different
probes, fixed on a solid surface, to probe such a mixture. The exact sequence of the probes at
each feature/location on the chip is known. Wherever some of the sample DNA hybridizes to
the probe in a particular spot, the hybridization can be detected because the target DNA is
labeled (and unbound target is washed away). Therefore one can determine which of the
million different probe sequences are present in the target.
Additionally, the amount of signal directly depends on the quantity of labeled target DNA.
Thus microarrays can give a quantitative description of how much of a particular sequence is
present in the target DNA. This is particularly useful for studying gene expression, one
common application of microarray technology. Obviously, microarrays must be read
mechanically, using a laser and detector. Good software for interpreting the raw data is
crucial (as one can imagine a long list of sources of error in reading the individual spots,
including nonspecific hybridization and background fluorescence). To study gene expression,
mRNA is isolated from the cells of interest and converted into labeled cDNA. This cDNA is
then washed over a microarray carrying features representing all the genes that could possibly
be expressed in those cells. If hybridization occurs to a certain feature, it means the gene is
expressed. Signal intensity at that feature/spot indicates how strongly the gene is expressed
(as it is a sign of how much mRNA was present in the original sample). One can therefore
study gene expression in an entire cell (not just for one or two genes) under various
conditions, over time, or in normal vs. diseased cells.
1. Probe Design: Probes are short sequences of DNA corresponding to known genes.
These are attached to a solid surface in a grid pattern.
2. Sample Preparation: RNA is extracted from the cells or tissue of interest and
reverse transcribed into cDNA. This cDNA is often labeled with fluorescent dyes.
3. Hybridization: The labeled cDNA is then applied to the microarray chip, where it
hybridizes with complementary probes.
4. Detection: After hybridization, the chip is washed to remove unbound cDNA, and
the fluorescent signals are detected and quantified using a laser scanner.
5. Data Analysis: The intensity of the fluorescence at each probe location indicates the
abundance of the corresponding RNA transcript in the sample. Data normalization
and statistical analysis are then performed to identify differentially expressed genes.
Different types of microarrays
DNA microarrays, Protein microarrays, Peptide microarrays, Tissue microarrays
,Antibody microarrays, Carbohydrate arrays
Rna sequencing
RNA sequencing is the molecular technique used to identify the order of nucleotide bases
(adenine, uracil, guanine, and cytosine) in an RNA molecule.
RNA sequencing (RNA-Seq) is a newly developed next-generation sequencing approach to
the transcriptome (a complete set of RNA content within a cell including both coding and
non-coding ones) profiling. It has been very effective in transcriptomics, revealing molecular
constituents of cells, studying gene expression, disease study and diagnosis, pharmaceutical
developments, and ribosomal profiling.
Steps:
1. Isolate rna from sample
2. Fragment rna into short segments
3. Convert rna fragments into cdna
4. Ligate sequencing adaptars and amplify
5. Perform NGS sequencing
6. Map sequencing reads to transcriptome
Principle
Its basic is similar to gene sequencing (DNA sequencing), but the order of nucleotide
sequences of a target RNA molecule is obtained instead of a DNA molecule. Initially,
the Sanger Sequencing technique was used for RNA sequencing; however, shortly after the
introduction of the NGS technique, a high-throughput sequencing technique came into use.
Types of RNA Sequencing
On the basis of the formation of cDNA
1. Direct RNA Sequencing
In this method, isolated RNAs are sequenced directly without prior converting them into
cDNA. Since RNAs are unstable as compared to DNAs, they are difficult to handle and work
with. However, the conversion of RNAs into cDNAs introduces various biases, error points,
and disturbances that interfere with the accurate sequencing process. Additionally, cDNA
preparation is a multistep complex process and cDNAs are not even suitable for sequencing
smaller RNAs.
2. Indirect RNA Sequencing
It is also called complementary DNA sequencing. In this type, RNAs are first converted into
cDNAs and then the cDNAs are sequenced. Conversion of RNAs into cDNAs makes them
more stable and easy to sequence.
On the basis of types of RNA sequenced
1. Whole Transcriptome RNA-Sequencing (Total RNA-Seq)
Whole transcriptome sequencing (WTS) develops sequences of all types of RNAs present in
the sample. As it profiles the entire transcriptome, it provides all the required information
about gene expression and nucleotide of a cell.
2. mRNA-Sequencing
In this method, only mRNAs are sequenced. mRNAs are first isolated using poly-A
chromatography or poly-A magnetic beads and forming a poly-A library. The library is then
sequenced either directly or indirectly to get an mRNA sequence.
3. tRNA-Sequencing and rRNA-Sequencing
tRNAs are isolated and sequenced in tRNA-Seq. Similarly, rRNAs are sequenced in rRNA-
Seq. Both these types are rarely used.
4. Targeted RNA-Sequencing
It is the method of sequencing a specific transcript of interest.
5. Small RNAs Sequencing
In this sequencing type, small non-coding RNAs of a cell are sequenced. The most commonly
sequenced small RNAs are miRNA, siRNA, and piRNA.
6. Single Cell RNA Sequencing
In this method, RNAs extracted from a single cell line/type are sequenced. All the transcripts
of a single cell are captured, transcript libraries are developed, and the whole library is
sequenced.
Gene Expression Profiling
Gene expression profiling is a key aspect of transcriptomics that involves measuring the
expression levels of thousands of genes simultaneously to understand their functional roles
and regulatory mechanisms. Both microarrays and RNA-seq are used for this purpose.

Applications of Gene Expression Profiling:

• Dlsease Research: Identifying genes involved in dlseases such as cancer,

diabetes, and neurodegenerative disorders.
• Drug Development: Understanding the molecular mechanisms of drug
action and identifying potential biomarkers for drug efficacy.
• Developmental Biology: Studying gene expression changes during
development and differentiation.
• Environmental Response: Investigating how organisms respond to
environmental changes at the molecular level.

Epigenetic modifications
Epigenetics is the study of heritable changes in gene expression (active versus inactive genes)
that do not involve changes to the underlying DNA sequence — a change in phenotype
without a change in genotype — which in turn affects how cells read the genes
Dna methylation
DNA methylation is a process by which methyl groups are added to the DNA molecule.
 It is an epigenetic mechanism that occurs by the addition of a methyl (-CH3) group to
DNA, thereby often modifying the function of the genes and affecting gene
expression.
 The most widely characterized DNA methylation process is the covalent addition of
the methyl group at the 5-carbon of the cytosine ring resulting in 5-methylcytosine (5-
mC), also informally known as the “fifth base” of DNA.
 These methyl groups project into the major groove of DNA and inhibit transcription.
 In human DNA, 5-methylcytosine is found in approximately 1.5% of genomic DNA.
 It is typically removed during zygote formation and then re-established in the embryo
at approximately the time of implantation.
  It is the basis of chromatin structure and usually is found in a CpG dinucleotide
context.
 Research has shown that methylation plays a crucial role in the regulation of gene
expression and that these modifications tend to occur at specific locations within the
genomes of different species.
 It has been demonstrated as a vital contributor to a wide range of cellular processes,
and aberrant methylation patterns have been linked to several human diseases.
Histone Modification
Histone proteins are the main components of chromatin, acting as spools around
which DNA wlnds. Post-translational modifications of histones, such as methylation,
acetylation, phosphorylation. ubiquitination. and sumoylation, play a critical role in
regulating chromatin structure and gene expression.

Types of Modifications:
. Acetylation: Addition of acetyl groups (by histone acetyltransferases, HATs)
typically occurs on lysine residues of histone tails, reducing the positive charge of
histones and decreasing their interaction with negatively charged DNA. This usually
results in a more relaxed chromatin structure, promoting gene transcription. Histone
deacetylases (HDACs) remove these groups. leading to chromatin condensation and
gene repression.

. Methylation: Addition of methyl groups (by histone methyltransferases, HMTs) can

occur on lysine or arginine residues. The effect of histone methylation on gene
expression depends on the specific amino acid residue and the number of methyl
groups added (mono-, di-, ortri-methylation). For instance, trimethylation of lysine 4
on histone H3 (H3K4me3) is associated with active transcription, while trimethylation
of lysine 27 on histone H3 (H3K27me3) is linked to gene repression.

. Phosphorylation: Addition of phosphate groups (by kinases) typically occurs on

serine and threonine residues and is Involved in processes like DNA repair. chromatin
remodeling. and cell cycle progression. Phosphorylation can either promote or inhibit
transcription depending on the context.

Genomic Imprinting

Genomic imprinting is an epigenetic phenomenon where only one allele of a gene is

expressed, depending on whether it is inherited from the mother or the father. The
other allele is silenced. Unlike typical genes where both maternal and paternal alleles
are active, imprinted genes are marked so that only one allele—either from the mother
or the father—is expressed, while the other is silenced. This selective expression is
regulated through epigenetic modifications such as DNA methylation and histone
modification, which occur during the formation of eggs or sperm and are maintained
throughout development. Genomic imprinting plays a crucial role in growth,
development, and metabolism, particularly in the placenta and fetal tissues.
Disruptions in imprinting can lead to various genetic disorders. For example, Prader-
Willi syndrome arises when paternal genes on chromosome 15 are inactive or
deleted, while Angelman syndrome results from similar issues affecting the maternal
genes on the same chromosome. Another condition, Beckwith-Wiedemann
syndrome, involves improper imprinting on chromosome 11. Imprinted genes like
IGF2 (expressed only from the paternal allele) and H19 (expressed only from the
maternal allele) are classic examples demonstrating the functional importance of this
unique genetic regulation.

Proteome analysis:

Proteome analysis involves the identiflcation and quantification of the proteins in a

biological sample. This analysis can provide insights into protein expression levels,
post- translatlonal modifications, interactions, and functions.

1.protein Identification and Quantification:

Mass Spectrometry(MS): The most common tool for proteomics, It identifies protelns
by measuring the mass-to-charge ratio of their peptide fragments. Technlques like
tandem MS (MS/MS) enhance accuracy by further fragmenting selected peptides for
more detailed analysis.

Two-Dimensional Gel Electrophoresis (2-DE}: This technique separates proteins

based on isoelectric point (first dimension) and molecular weight (second dlmenslon).
Proteins are then excised from the gel and identified using MS.

2.Post-translatlonal Modifications(PTMs):

PTMs such as phosphorylation, glycosylatlon, ubiquitlnation, and methylation can be

identified uslng MS and specific enrichment strategies to capture modified peptldes.

3.Protein Interactions:

Techniques such as yeast two-hybrid screening, co-immunoprecipitation (Co- IP), and

affinity purification coupled with MS (AP-MS) are used to study protein- protein
interactions.

Proximity labeling methods like BioID and APEX can also map interaction networks
within cells.

Protein array

Protein microarrays are a high-throughput technology used to analyze the expression

levels and functional activity of thousands of proteins simultaneously.

Protein microarrays consist of a solid support (such as a glass slide or a membrane)

that has been coated with thousands of different proteins in a defined pattern or array.

Each protein spot on the array represents a different protein, and multiple replicates of
each protein are typically included on the array to ensure data reproducibility

The Probes on Chip

A variety of materials can be immobilize on the protein chip based on the specific
requirements. These include:

Antibodies ,Antigens ,Aptamers (Nucleic Acid based ligands) ,Affibodies (small,

robust proteins engineered to bind to a large number of target proteins or peptides with
high affinity, imitating monoclonal antibodies, and are therefore a member of the
family of antibody mimetics) ,Full length Proteins or their domains

Types of protein microarray:

1.Analytical microarrays

1. Analytical microarrays are typically used to profile a complex

mixture of proteins in order to measure binding affinities and protein
expression levels of the proteins in the mixture.
2. In this technique, a library of antibodies, aptamers, or affibodies is
arrayed on a glass microscope slide.
3. The array is then probed with a protein solution.
4. Antibody microarrays are the most common analytical microarray.
5. . These types of microarrays can be used to monitor differential
expression profiles and for clinical diagnostics.

2.Functional

1. Functional protein microarrays is different from analytical

arrays. Functional protein arrays are composed of arrays
 containing full-length functional proteins or protein domains.
2. These protein chips are used to study the biochemical activities of
an entire proteome in a single experiment.
3. They are used to study numerous protein interactions, such as
protein-protein, protein-DNA, and protein-RNA interactions.
4. Functional protein microarrays can be used to study a wide range
of biological processes, including signal transduction, transcriptional
regulation, and apoptosis.

3.Reverse phase

1. Reverse-phase protein microarrays: reverse phase protein

microarray (RPA). In RPA, cells are isolated from various tissues of
interest and are lysed.
2. The lysate is arrayed onto a nitrocellulose slide using a contact pin
microarrayer.
3. The slides are then probed with antibodies against the target protein
of interest, and the antibodies are typically detected with
chemiluminescent, fluorescent, or colorimetric assays.
4. Reverse-phase protein microarrays can be used for biomarker
discovery, drug target validation, and the study of protein expression
patterns in disease.

Applications of Proteomics and Protein Arrays

Disease Diagnostics and Biomarker Discovery,Drug Development,Systems

Blology,Agriculture and Food Science,Environmental Proteomics

Role of snp in drug response :

Pharmacogenomics is the study of how genes affect a person's response to drugs. This
field combines pharmacology (the science of drugs) and genomics (the study of genes
and their functions) to develop effective, safe medications and doses tailored to a
person's genetic makeup. The goal of pharmacogenomics is to optimize drug therapy,
with respect to the patients' genotype, to ensure maximum efficacy with minimal
adverse effects.

Role of SNPs in Drug Response

Single Nucleotide Polymorphisms tSNPs) are the most common type of genetic
variation among people. Each SNP represents a difference in a single nucleotide, the
building blocks of DNA. These variations can affect how individuals respond to drugs
by altering the function of enzymes that metabolize medications, receptors that drugs
target, and transporters that move drugs within the body.

Example: Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency

G6PD and Its Function:

G6PD is an enzyme that plays a crucial role in the pentose phosphate pathway, a
metabolic pathway that protects red blood cells (RBCs) from oxidative damage by
producing NADPH. NADPH is essential for maintaining the level of glutathione, a
powerful antioxidant, which helps protect RBCs from oxidative stress.

G6PD Deficiency:

G6PD deficiency is a genetic disorder that results from mutations in the G6PD gene.
This condition is X-linked and more common in males. People with G6PD deficiency
have lower levels of the G6PD enzyme, making their RBCs more susceptible to
oxidative damage.

SNPs and Drug Response in G6PD Deficiency:

SNPs in the G6PD gene can lead to varying degrees of enzyme deficiency. This
variation significantly impacts drug response, especially to drugs known to cause
oxidative stress, such as certain antimalarials (e.g., primaquine), sulfonamides, and
some antibiotics.