Genomics Bioinformatics

GENOMICS
Genomics is the study of whole genomes of organisms, and incorporates elements from
genetics. Genomics uses a combination of recombinant DNA, DNA sequencing methods, and
bioinformatics to sequence, assemble, and analyze the structure and function of genomes.
Genetics and Genomics:
It differs from 'classical genetics' in that it
considers an organism’s full complement of hereditary
material rather than one gene or one gene product at a
time. Moreover, genomics focuses on interactions
between loci and alleles within the genome and other
interactions such as epistasis, pleiotropy and heterosis
(Figure 1.1).
History
Genomics harnesses the availability of
complete DNA sequences for entire organisms and was
made possible by both the pioneering work of Fred
Sanger and the more recent next-generation sequencing
technology.
Fred Sanger's group established techniques of sequencing, genome mapping, data storage, and
bioinformatic analyses in the 1970s and 1980s. This work paved the way for the human genome
project in the 1990s, an enormous feat of global collaboration that culminated in the publication
of the complete human genome sequence in 2003.
A major part of genomics is determining the sequence of molecules that make up the genomic
deoxyribonucleic acid (DNA) content of an organism. The chromosomes can be further
described as containing the fundamental units of heredity, the genes. Genes are transcriptional
units, those regions of chromosomes that under appropriate circumstances are capable of
producing a ribonucleic acid (RNA) transcript that can be translated into molecules of protein.
Every organism contains a basic set of chromosomes, unique in number and size for every
species that includes the complete set of genes plus any DNA between them. While the
term genome was not brought into use until 1920, the existence of genomes has been known
since the late 19th century, when chromosomes were first observed as stained bodies visible
under the microscope. The discipline of genomics arose when the technology became available
to deduce the complete nucleotide sequence of genomes, sequences generally in the range of
billions of nucleotide pairs.
Goals
The main aim of genomics is to;
1. Sequence the entire genome by cutting it into small, manageable pieces.
2. Assemble the entire genome from the pieces.
3. Understand the how the gene is expression takes place.

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Sequencing And Bioinformatic Analysis Of Genomes

Genomic sequences are usually determined
using automatic sequencing machines. In a
typical experiment to determine a genomic
sequence, genomic DNA first is extracted
from a sample of cells of an organism and then
is broken into many random fragments. These
fragments are cloned in a DNA vector (carrier)
that is capable of carrying large DNA inserts.
Because the total amount of DNA that is
required for sequencing and additional
experimental analysis is several times the total
amount of DNA in an organism’s genome,
each of the cloned fragments is amplified
individually by replication inside a living
bacterial cell, which reproduces rapidly and in
great quantity to generate many bacterial
clones. The cloned DNA is then extracted
from the bacterial clones and is fed into the
sequencing machine. The resulting sequence
data are stored in a computer. When a large
enough number of sequences from many
different clones is obtained, the computer ties them together using sequence overlaps. The
result is the genomic sequence, which is then deposited in a publicly accessible database.
Complete genomes:
The advent of sequencing technologies resulted in a rapid intensification in the scope and speed
of completion of genome sequencing projects. The first complete genome sequence of
a eukaryotic organelle, the human mitochondrion (16,568 bp, about 16.6 kb), was reported in
1981, and the first chloroplast genomes followed in 1986. In 1992, the first eukaryotic
chromosome, chromosome III of brewer's yeast Saccharomyces cerevisiae (315 kb) was
sequenced. The first free-living organism to be sequenced was that of Haemophilus
influenzae (1.8 Mb [megabase]) in 1995. The following year a consortium of researchers from
laboratories across North America, Europe, and Japan announced the completion of the first
complete genome sequence of a eukaryote, S. cerevisiae (12.1 Mb), and since then genomes
have continued being sequenced at an exponentially growing pace.

Genomics Applications
1. Functional genomics
Analysis of genes at the functional level is one of the main uses of genomics, an area
known generally as functional genomics. Determining the function of individual genes can
be done in several ways.
i. Classical or forward genetic methodology starts with a randomly obtained mutant of
interesting phenotype and uses this to find the normal gene sequence and its function.

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ii. Reverse genetics starts with the normal gene sequence (as obtained by genomics),
induces a targeted mutation into the gene then, by observing how the mutation changes
phenotype, deduces the normal function of the gene.
The two approaches, forward and reverse, are complementary. Often a gene identified
by forward genetics has been mapped to one specific chromosomal region, and the full
genomic sequence reveals a gene in this position with an already annotated function.
iii. Gene identification by microarray genomic analysis
Genomics has greatly simplified the process of finding the complete subset of genes
that is relevant to some specific temporal or developmental event of an organism. For
example, microarray technology allows a sample of the DNA of a clone of each gene in a
whole genome to be laid out in order on the surface of a special chip, which is basically a
small thin piece of glass that is treated in such a way that DNA molecules firmly stick to
the surface. For any specific developmental stage of interest (e.g., the growth of root hairs
in a plant or the production of a limb bud in an animal), the total RNA is extracted from
cells of the organism, labeled with a fluorescent dye, and used to bathe the surfaces of the
microarrays. As a result of specific base pairing, the RNAs present bind to the genes from
which they were originally transcribed and produce fluorescent spots on the chip’s surface.
Hence, the total set of genes that were transcribed during the biological function of interest
can be determined.
Note that forward genetics can aim at a similar goal of assembling the subset of genes
that pertain to some specific biological process. The forward genetic approach is to first
induce a large set of mutations with phenotypes that appear to change the process in
question, followed by attempts to define the genes that normally guide the process.
However, the technique can only identify genes for which mutations produce an easily
recognizable mutant phenotype, and so genes with subtle effects are often missed.
2. Comparative genomics
A further application of genomics is in the study of evolutionary relationships. Using
classical genetics, evolutionary relationships can be studied by comparing
the chromosome size, number, and banding patterns between populations, species, and
genera. Comparative genomics allows the DNAs of organisms to be compared directly and
on a small scale. Overall, comparative genomics has shown high levels of similarity
between closely related animals, such as humans and chimpanzees, and, more surprisingly,
similarity between seemingly distantly related animals, such as humans and insects.
Comparative genomics applied to distinct populations of humans has shown that the human
species is a genetic continuum, and the differences between populations are restricted to a
very small subset of genes that affect superficial appearance such as skin colour.
Furthermore, because DNA sequence can be measured mathematically, genomic analysis
can be quantified in a very precise way to measure specific degrees of relatedness.
Genomics has detected small-scale changes, such as the existence of surprisingly high
levels of gene duplication and mobile elements within genomes.
3. Structural genomics
Structural genomics seeks to describe the 3- dimensional structure of every protein encoded
by a given genome. This genome-based approach allows for a high throughput method of
structure determination by a combination of experimental and modeling approaches.
4. Epigenomics

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Epigenomics is the study of the complete set of epigenetic modifications on the genetic
material of a cell that affect gene expression without altering the DNA sequence, known as
the epigenomics. Two of the most characterized epigenetic modifications are DNA
methylation and Histone modification. Epigenetic modifications play an important role in
gene expression and regulation, and are involved in numerous cellular processes such as
in differentiation/development and tumorigenesis.
5. Metagenomics
Metagenomics is the study of metagenomes, genetic material recovered directly
from environmental samples. The broad field may also be referred to as environmental
genomics, ecogenomics or community genomics. Because of its ability to reveal the
previously hidden diversity of microscopic life, metagenomics offers a powerful lens for
viewing the microbial world that has the potential to revolutionize understanding of the
entire living world. The term metagenome referenced the idea that a collection of genes
sequenced from the environment could be analyzed in a way analogous to the study of a
single genome.
6. Pharmacogenomics
It is a study of how variation in the human population correlates with drug response
patterns. The analysis of genomic data and its comparison with drug response data allows
patients to be clustered into drug response groups, so that appropriate drugs and dose
regimens can be administered. Variation is catalogued by analyzing data on mutation
(particularly SNPs) and gene expression profiles.
7. Genomic Information in Medicine
 Novel Diagnostics
 Understanding Metabolism
 Understanding Disease
o Inherited Diseases – OMIM
o Infectious Diseases
o Pathogenic Bacteria
o Viruses
 Novel Therapeutics
o Drug Target Discovery
o Rational Drug Design
o Molecular Docking
o Gene Therapy
o Stem Cell Therapy
Future of pharmainformatics
Drug companies collect the genetic know-how to make medicines tailored to specific
genes an effort called pharmacogenomics.
In the years to come, pharmacists may hand over one version of blood pressure drug based on
your unique genetic profile, while the person behind in line would get a different version of the
same medicine. There is going to be a day when somebody comes in with cancer, and diagnosis
can be done not on the basis of morphology of the cancer but by looking at the detailed patterns
of gene expression and protein-binding activities in that cell.

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