HISTORY OF GENETICS, SCOPE AND SIGNIFICANCE OF GENETICS AND

GENOMICS

Genomics is a mix of many sciences including genetics, molecular biology,

biochemistry, statistics and computer sciences. The developmental sequence of
genetics and genomics occured in different periods.

In the last few decades, the science of genetics has pervaded all aspects of biology
so that it has assumed a central position of great significance in biology as a whole.
While on the one hand, genetics is used for a study of the mechanism of heredity and
variation, on the other hand it has provided tools for the study of the fundamental
biological processes examined and taught in areas, like plant physiology,
biochemistry, ecology, plant pathology, microbiology, etc. Genetics, in fact provided
the modern paradigm (a prototype) for whole of biology. The science of genetics also
had a tremendous impact in applied areas including medicine, agriculture, forestry,
fisheries, law and religion. In view of this, all newspapers often address questions
dealing with different aspect of genetics that may be of significance to common man.
The recent upsurge of biotechnology has added further to the significance of the
science of genetics, so that the products of genetics have also become a subject of
discussion for Trade Related Aspects of Intellectual Properties (TRIPs) under the
aegis of General Agreement on Tariffs and Trade (GATT). Patenting of life forms
which may or may not be the product of genetic manipulation is one such topic, which
is receiving considerable attention of both developed and developing countries.

Genetics can be broadly classified in the following three areas for the convenience of
a discussion on its scope and significance : (i) transmission genetics involving study
of transmission of genetic material from one generation to the other; (ii) molecular and
biochemical genetics, involving study of the structure and function of genes and (iii)
population and biometrical genetics, involving study of the behavior and effects of
genes in population, often using mathematical models. The above classification is
arbitrary, and the three areas are inter-related and even enter other areas of biology.
Significance of genetics also stems from the fact that the genetic material containing
information for hereditary traits consists of nucleic acids only, across the entire
spectrum of life on the earth.

Genomics is an interdisciplinary field of science focusing on genomes. A genome is a

complete set of DNA within a single cell of an organism, and as such genomics is a
branch of molecular biology concerned with the structure, function, evolution, and
mapping of genomes. Genomics aims at the collective characterization and
quantification of genes, which direct the production of proteins with the assistance of
enzymes and messenger molecules. Proteins in turn make up body structures like
organs and tissues as well as control chemical reactions and carry signals between
cells. If a cell's DNA is mutated, an abnormal protein may be produced, which can
disrupt the body's usual processes and in some cases lead to diseases such as
cancer. In contrast to genetics, which refers to the study of genes and their roles in
inheritance, genomics is the study of genes, their functions, and related techniques,
such as applications of recombinant DNA, DNA sequencing methods, and

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bioinformatics to sequence, assemble, and analyze the function and structure of
genomes. Advances in genomics have triggered a revolution in discovery-based
research to understand even the most complex biological systems such as the brain.
The field includes efforts to determine the entire DNA sequence of organisms and
fine-scale genetic mapping. The field also includes studies of intragenomic
phenomena such as heterosis, epistasis, pleiotropy and other interactions between
loci and alleles within the genome. Research carried out into single genes does not
generally fall into the definition of genomics unless the aim of this genetic, pathway,
and functional information analysis is to elucidate its effect on, place in, and response
to the entire genomes networks.

The various important branches of genomics are the following:

Functional genomics is a field of molecular biology that attempts to make use of the
vast wealth of data produced by genomic projects (such as genome sequencing
projects) to describe gene (and protein) functions and interactions.
Structural genomics seeks to describe the 3-dimensional structure of every protein
encoded by a given genome.
Epigenomics is the study of the complete set of epigenetic modifications on the
genetic material of a cell, known as the epigenome.
Metagenomics is the study of metagenomes, genetic material recovered directly from
environmental samples.

Applications of genomics
Genomics has provided applications in many fields, including medicine,
biotechnology, anthropology and other social sciences.
Genomic medicine
Next-generation genomic technologies allow clinicians and biomedical researchers to
drastically increase the amount of genomic data collected on large study population.
When combined with new informatics approaches that integrate many kinds of data
with genomic data in disease research, this allows researchers to better understand
the genetic bases of drug response and disease.
Synthetic biology and bioengineering
The growth of genomic knowledge has enabled increasingly sophisticated
applications of synthetic biology.
Conservation genomics
Conservationists can use the information gathered by genomic sequencing in order to
better evaluate genetic factors key to species conservation, such as the genetic
diversity of a population or whether an individual is heterozygous for a recessive
inherited genetic disorder.

HISTORY

Mid to Late 19th Century: Developments regarding Evolution, Natural Selection,

Particulate Inheritance and Nuclein

In the 1858, our understanding of the origin of species and how species
variability arose was revolutionized by the research of Darwin and Wallace. They
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described how new species arose via evolution and how natural selection uses
natural variation to evolve new forms.

A few years later, Gregor Mendel, an Austrian monk, summarized his years
of research on peas in his famous publication. In that paper, he described the unit
of heredity as a particle that does not change. This was in contrast to the then
prevailing “blending theory of inheritance.” Equally important, Mendel formalized the
importance of developing pure lines, by statistically analyzing the data. His
approach of crossing individuals with variable phenotypes and following them in
successive generations is still the only approach utilized to understand the genetic
inheritance of a trait.

Research in the 19th century was often performed in isolation, with the findings
made by one was not known to others. While Mendel was concluding that inheritance
was particulate in nature, others were trying to figure out the physical nature of the
particle. Haeckel correctly predicted that the heredity material was located in the
nucleus. Miescher showed the material in the nucleus was a nucleic acid. Others
observed the behavior of chromosomes and suggested they had a role in heredity.
Early 20th Century: Mendelian Principles are extended and the
Chromosomal Theory of Inheritance gets strengthened

Mendels important findings went unnoticed. It was not until 1900 that others,
who had performed similar experiments as that of his, arrived at the same
conclusions. Their publications cited his work, leading to a rediscovery of the
Mendelian principles. Quickly following the rediscovery, other genetic principles such
as linkage, lethal genes, and a bit later, maternal inheritance were described. In each
case, the principles provided to be simple extensions of the Mendelian laws, providing
further evidence of their importance.

At the beginning of the century, the work on chromosomes merged into the
chromosomal theory of inheritance. This theory focused research on the chromosome
as the location of genes. The field of cytogenetics was based on this discovery. The
first observations of chromosomal abnormalities (duplications, deletions,
translocations, inversions) were reported. Observations such as position effect
demonstrate that there is a direct link between chromosome structure and phenotype.
All of these discoveries justified research with the intention to discover the physical
basis of heredity.

Mid 20th Century: DNA was considered as the base of life. Also, the
importance of the Darwinian theory of evolution via natural selection
was confirmed

As early as the 1870s, the material in the nucleus was determined to be a

nucleic acid. From the 1920s through the mid- 1950s, a series of experiments
demonstrated that DNA was indeed the genetic material. The transformation
experiments of Griffith demonstrated that a factor found in a lethal strain of bacteria
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could convert a non-lethal strain of the bacteria into a lethal strain. It was the careful
experiments of Avery, MacLeod and McCarty that determined DNA, not protein or
RNA was the factor responsible for the conversion. This was further confirmed by
Hershey and Chase, although their experiments had flaws which prevented them
from being definitive. Watson and Crick determined the structure of DNA, and others
suggested that DNA contained a genetic code. By the mid 1960s that code was
deciphered. Experiments involving the process of transcription and translation led to
the development of the “central dogma of molecular biology” concept by Crick.

The experiments of the early 19th century that confirmed that Mendelian
principles could be extended to many gene systems became a major component of
what was to be called the Modern synthesis (i.e. neo-Darwinism). The experimental
demonstration that mutations could be induced was also an important component of
the concept that natural selection was a major factor in evolution. Mutations create
variation; recombination develops new forms, the variation extends through the
population, and based on environmental constraints the variation is finally acted upon
by the forces of natural selection to produce more fit individuals.

Mid-late 20th Century and the Early Days of the 21st Century: Is the Age of
Molecular Genetics; Phylogenetic Studies gains importance; The Emergence
of information technology and Genomics Science occurs

The discoveries of the mid to late 20th century defined processes that would
provide the tools for molecular biology, recombinant DNA technology, and finally the
biotechnology industry. The elucidation of the process of DNA replication described
the necessary components needed for the widely-used chain termination DNA
sequencing procedure. Understanding replication helped determine those tools
necessary for the radiolabelling of DNA. The development was necessary to support
Southern hybridizations and the early molecular mapping experiments.
Understanding replication also defined the role of the ligase enzyme that is so critical
for DNA cloning. Restriction enzymes were discovered and used to construct
recombinant DNA molecules that contained foreign DNA that could be grown in
abundance in bacterial cells. The discovery of reverse transcriptase also enabled
cDNA cloning. Cloning is essential for the discovery of gene structure and function. It
is also an essential step for all of the genome sequencing projects.

The advent of protein and DNA sequencing launched a new era of

phylogenetics. Species could now be compared at the molecular level. New
procedures for the development of phylogenies are developed. The neutral theory of
molecular evolution is proposed. This was a direct blow to the preeminence of
selection as the driving force of evolution. The theory suggests that most mutations
are neutral and are fixed by genetic drift and not selection. It is debated whether the
evolution of species is driven more by neutral effects or selection. Some feel the two
theories are compatible and exert their effects on different genes.

The information age is essential to genomics. The electronic analysis,

distribution and storage of genomic data is a hallmark of the science. Critical to this
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was the development of computers, both large and small, which put computing
power in the hands of all scientists. The free distribution of analytical software
provided scientists with the tools to study the details of their experiments. The
internet spawned the distribution of information from central databases. E-mail
connected scientists and fostered the rapid exchange of ideas. The advent of the
WWW provided a new medium for the presentation of information.

Whole genome are sequenced for the first time. For other species, the gene
content is described using ESTs. Microarray analyses provided the first glimpse of
global expression patterns. Proteomics begins to describe the protein component of
the genome. Metabolomics is established.

Massively parallel sequencing technology is introduced. This new

technology greatly increases the amount of DNA sequence that can be collected
in a short period. It will also dramatically decrease the cost of sequencing.
Importantly it launches the age of individual genome sequencing which will
support an era of individualized medicine.

Now let us see the historical progress of genetics and genomics in detail.

In 1865 Gregor Mendel introduced the concept of particulate (gene)

inheritance and also demonstrated the laws of segregation and independent
assortment. He outlined the famous “pea experiments” and published article entitled
“Experiments in Plant Hybridization”. In 1866 Ernst Haeckel proposed the idea that
the hereditary material resides in the nucleus. Friedrich Miescher (1871) coined the
term nuclein for this hereditary material. And in 1874 he discovered that nuclein
consist of nucleic acid and protein. First accurate counting of chromosomes was done
by Walther Flemming in 1879. In 1892 Eduard Strasburger and Edouard van
Beneden observed cell division. And they coined terms such as chromatin, mitosis
cytoplasm, nucleoplasm, prophase, and metaphase. August Weismann in 1887
proposed universal theory of chromosome behavior which predicted that meiosis
occurs in sex cells. In 1888 Henrich Wilhelm and Gottfried Waldeyer applied the term
chromosome to the condensed version of material found in the nucleus. In 1899
William Bateson described hybridization between two individuals as a tool of the
scientific analysis of heredity. Mendel’s work was rediscovered by Carl Correns,
Hugo de Vries and Erich von Tschermak independently in 1900. In 1900 Hugo de
Vries coined the term mutation for the spontaneous appearance of new traits in
evening primrose (Oenothera).

In 1902 C.E. McClung proposed that specific chromosomes were responsible

for sex determination in animals. Walter Sutton and Theodor Boveri (1902) showed
that chromosomes occur in pairs, one parent contributes each member of the pair,
and the pairs separate during meiosis. Sutton suggested that unit of heredity reside
on chromosomes and it is known as the chromosomal theory of inheritance.

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Archibald Garrod (1902) described the first human disease that exhibits mendelian
inheritance was alkaptonuria. The terms genetics, homozygote, heterozygote,
epistasis, F1, F2, and allelomorph (shortened later to allele) were introduced by
William Bateson (1902). In 1903 Wilhelm Johannsen explained the important
concepts of phenotype, genotype, and selection.

William Bateson and R. C. Punnett (1905) performed experiments on sweet pea

and demonstrated the concept of linkage. In the same year Lethal genes were
discovered in the classic experiment involving a cross between two yellow mice. In
1907 Friedrick Laibach suggested Arabidopsis as a model organism. G. H. Hardy
and W. Weinberg formulated the Hardy-Weinberg principle of genetic equilibrium
in 1908. G. H. Shull in 1909 produced commercial seed from self-fertilized corn and it
was the direct application of the mendalian theory. The terms gene, phenotype and
genotype were introduced by Wilhelm Johannsen (1909). In the same year H.
Nilsson-Ehle explained the role of multiple gene intractions in seed coat color of
wheat and oat. This was the beginning of quantitative genetics. In 1910 Thomas
Hunt Morgan demonstrated sex linkage in Drosophila and suggested that genes
reside on chromosomes. Also the era of fruit fly as a model organism begins. The
first genetic map was developed by Alfred Sturtevant (1913) in Drosophila. Calvin
Bridges (1914) observed non-disjunction in sex chromosomes which proves the
chromosome theory of inheritance. And also Chromosome deficiencies (1917),
duplications (1919), and translocations (1923) were observed first time in
Drosophila . In 1919 Thomas Hunt Morgan proved that the number of
chromosomes equals the number of linkage groups. A. E. Boycott and C. Diver in
1923 explained Maternal inheritance based on shell coiling direction in snail. In 1925
Alfred Strutevant demonstrated Position effect based on Drosophila Bar-eye effect.
He observed inversion in Drosophila (1926). J. B. S. Haldane in 1927 observed coat
color in rodents and carnivores and proposed the concept of homologs.

In 1928 L. J. Stadler demonstrated the relationship between the number of mutations

and the x-ray dosage effect in corn. Transformation experiment in Pneumococci
was done by F. Griffith in 1928. It leads to the discovery that DNA is the genetic
material, which transform information from one generation to the next. In 1931 Harriet
Creighton and Barbara Mc Clintock reported that crossing over between two
homologous chromosomes involves the physical exchange of genetic material
between the two chromosomes. R. A. Fisher and Theodore Dobzhansky (1932-33)
formulated Modern Synthesis. This couples the laws of Mendelian inheritance and
knowledge of mutation with the Darwinian theory of evolution via natural selection. In
1941 George Beadle and E. L. Tatum proposed one gene, one enzyme hypothesis
based on biochemical studies of Neurospora. K. Mather in 1941 coined the term

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polygenes. S. E. Luria and Max Delbrück (1943) demonstrated that bacteria are
capable of undergoing spontaneous mutations. This lead to the onset of the field
bacterial genetics.
In 1944 Oswald T. Avery, Colin M. MacLeod and Maclyn McCarty extended
the experiments of the Griffith (1929) and showed that DNA is the genetic material.
Bacterial genetic recombination was demonstrated by J. Lederberg and E.L. Tatum
in 1946. It involves the movement of DNA from one bacterium to another. In 1948
Barbara McClintock proposed the concept of transposable elements. J.V. Neel in
1949 observed that Sickle-cell anemia was inherited as single recessive gene,
Mendelian trait. In 1953 James Watson and Francis Crick presented double strand
structure of DNA held together by hydrogen bond. George Gamow (1954) suggested
that DNA contains a code which is responsible for the production of proteins. In
1955 Severo Ochoa discovered RNA polymerase, which has an important role in the
mechanism of transcription. LOD score method of determining linkage distance in
humans was developed by Newton Morton (1955). In 1956 Arthur Kornberg purified
DNA polymerase I from E. coli which is a major component of DNA replication. F.
Jacob and E. L. Woolman (1956) showed that Bacterial conjugation involves the
physical exchange of DNA between two bacterial strains. In 1957 Francis Crick
proposed the central dogma of molecular biology. In the next year he predicted the
role of tRNA in translation process.

In 1958 Matthew Meselsohn and F. W. Stahl proved Semiconservative mode

of DNA replication using the technique density equilibrium centrifugation. F. Jacob
and J. Monod in 1961 published “Genetic Regulatory Mechanisms in the Synthesis of
Proteins” which explains the Lac Operon controlling network in E. coli. In the same
year Marshall Nirenberg proposed the concept that each amino acid corresponds to a
triplet code. The first identified amino acid was the phenylalanine which is coded by
AAA. Also Sydney Brenner, Francois Jacob and Matthew Meselsohn described
Ribosomes as the site of protein synthesis. It was also proven that mRNA exists and
binds to ribosome. In 1965 Margaret Dayhoff published the “Atlas of Protein
Sequence and Structure” It contains the sequence of 65 proteins and was
considered as the first publication in bioinformatics. Emile Zuckerandl and Linus
Pauling introduced molecular clock concept. According to this theory the rate of
amino acid substitutions are linear over the time. Marshall Nirenberg and H. Gobind
Khorana in 1966 completed the genetic code that correlates the triplet code for each
amino acides. In 1967 Waclaw Szybalski and W. Summers showed that only one
DNA strand act as template during the process transcription. W. M. Fitch and E.
Margoliash developed phylogentic tree in the same year. It involves the comparison
of the amino acid sequence of cytochrome C from twenty species that ranged from
fungi to mammals.

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Werner Arber and Hamilton Smith in 1970 isolated first restriction enzyme, HindII.
David Baltimore and Howard Temin explained the importance of reverse
transcriptase in the same year. In 1975 Erwin Southern introduced the technique
Southern hybridizations which play main role in the gene mapping using RFLPs.
Frederick Sanger and Walter Gilbert (1977) developed the chain-termination and
chemical methods of DNA sequencing. Phillip Sharp and Rich Roberts showed that
mammalian viral gene was interrupted by DNA sequences which are not found in the
mature mRNA. Gilbert in 1978 named this sequence as introns and it was a
common feature of eukaryotic genes.

Sanger Group in 1980 published the first complete genome sequence of

bacteriophage X174. GenBank was established in 1982, which is the database of all
DNA sequences. In 1983 Kary Mullis explained the procedure to amplify large
amounts of DNA (PCR). The procedure was later improved by the use of a DNA
polymerase from the Thermus aquaticus bacteria. The first automated DNA
sequencer was released by Leroy Hood, Lloyd Smith, Michael Hunkapiller and Tim
Hunkapiller in 1986. This development was based on fluorescent labeling of
nucleotides and the Sanger sequencing technique. In 1987 Eric Lander and group
introduced MAPMAKER, a computer program for the development of genetic linkage
maps from molecular marker. H. D. Higgins and P. M. Sharp published the Clustal
multiple sequence alignment approach in 1988. The Caenorhabditis elegans Data
Base was developed by Jean Thierr-Mieg and Richard Durbin in 1989. It was the
first database developed for genomic information. In 1990 US Government
launched 15-year Human Genome Program. The goal was to "find all the genes
on every chromosome in the body and to determine their biochemical nature."
In 1990 Altshul and coworkers introduced BLAST, a computational approach
for aligning two DNA sequences. The first EST (expressed sequence tagged)
sequences was published by Craig Venter (1991). Genthon(1993-4) published
the first high density linkage map of the human genome.

The entire Haemophilus influenzae genome sequence (1.8 Mbp) was analyzed by
shotgun genome sequencing approach by Celera Corp and Craig Venter in 1995.
In the same year Pat Brown and Ron Davis described microarray system and in 1997
deRisi et al., used this technology to study the regulatory pathways. The entire
Saccharomyces cerevisiae (yeast) genome sequence (12.1 Mbp) was published
in 1996 by Yeast Genome Consortium. E. coli genome project was launched in 1997
for sequencing its genome. Cluster analysis approaches were described by Eisen
and group, in 1998. The oligonucleotide microarray system was also developed in
the same year. Arabidopsis thaliana genome (125 Mbp) and Drosophila genome
(123 Mbp) was sequenced in 2000 and Steven Tanksley did the first cloning in the
same period.
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Human genome project was considered as the turning point in molecular
biology and human welfare. The huge data produced by International Human
Genome Sequencing Consortium lead to the invention of Ensembl Genome
Browser in 2001. Mouse genome sequencing (2500 Mbp) and rice genome
sequencing (470 Mbp) were completed in 2002. Puffer-fish ( Fugu rubripes) genome
(365 Mbp), malaria-parasite-carrying mosquito genome, Plasmodium falciparum
geneome and SARS-associated coronavirus genome sequencing completed in
following years. Next generation sequencing was introduced by Solexa in 2004.
Pyrosequencing technology was automated by Roche in next year. Applied
Biosystems, a leading groups in molecular data analysis developed oligonucleotide
ligation and detection in 2005. Pacific Biosciences released Single molecule DNA
sequencer in 2010.

2011 onwards sequencing of many organisms are in progress. Microbial world

have an outbreak in the sequencing and the sequencing of almost 2688 viruses were
completed. 1710 microbial genomic DNA sequencing were completed and almost
6085 microbial genome is in screening. 208 fungal genomic DNA was sequenced and
205 fungal genomic DNA sequencing is in process. Kingdom plants and animals have
complex genomes so, comparatively less no of organisms in these groups are
completely sequenced. 182 members of animals and 47 members of plants got
sequenced and sequencing is proceeding for 256 and 107 members of animals and
plants respectively.

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