OVERVIEW:

GENETICS AND DISCOVERIES IN GENETICS

Introduction

• Genetics: science of heredity (attempts to explain the

similarities and the differences that occur among organisms).
- deals with the transfer of biological information from cell to cell,
from parents to offspring, and thus from generation to generation.

Point to ponder: Physical characteristics, behavior and

capabilities of living things are inherited. Therefore, to
understand an organism fully, we must understand its heredity.
Agree, disagree? If disagree, why?
What is genetics? Genetics come from the Latin word genesis -
means birth. So, genetics is the study of birth or more broadly,
the study of heredity.
• Gregor Johann Mendel
(1865 – science of genetics start) – discoveries of the
fundamental laws of inheritance (every cell contained
pairs of ‘factor’ and that each pair determined a specific traits). – foundation of
modern genetics and core of classical genetics.

• Genetics – grown at explosive rate since 1900.

• Science of genetics taken a prominent place among the biological sciences

with:
a) the concept of the gene
b) chromosome theory
c) the discovery that the chemical DNA is genetic material.

• Applications have developed through plant and animal breeding and the
increased understanding of the mechanism of living systems.
• Era of genomics, proteomics, transcriptomics, metabolomics – study all of
the genes (complete genome), all of the proteins (the proteome), RNA
(transcriptome) of an individual, organ, tissue or a cell and study of chemical
processes involving metabolites.

• Molecular genetics – powerful tools to study genes. 1985 (Kary Mullis) –

PCR (produce millions of copies of DNA for molecular analyses). DNA
fingerprinting (forensic – examine variation in the sequence analyses).

• Relevance of genetics to many aspects of human life and society (health,

behavior, food production, forensic etc.)
1859 Charles Darwin publishes The Origin of Species
1865 Gregor Mendel's paper, Experiments on Plant Hybridization
1869 Friedrich Miescher discovers a weak acid in the nuclei of white blood cells
that today we call DNA (Hartl and Jones).
1880-1890 Walther Flemming, Eduard Strasburger, and Edouard van Beneden
elucidate chromosome distribution during cell division
1903 Chromosomes are discovered to be hereditary units[1]
1906 The term "genetics" is first introduced publicly by the British biologist
William Bateson at the Third International Conference on Genetics in London,
England.
1910 Thomas Hunt Morgan shows that genes reside on chromosomes, and
discovered linked genes on chromosomes that do not follow Mendel's law of
independent allele segregation
1913 Alfred Sturtevant makes the first genetic map of a chromosome
1913 Gene maps show chromosomes containing linear arranged genes
1918 Ronald Fisher publishes On the correlation between relatives on the
supposition of Mendelian inheritance - the modern synthesis starts.
1927 Physical changes in genes are called mutations
1928 Frederick Griffith discovers a hereditary molecule that is transmissible
between bacteria (see Griffiths experiment)
1931 Crossing over is the cause of recombination (see Barbara McClintock and
cytogenetics)
1941 Edward Lawrie Tatum and George Wells Beadle show that genes code for
proteins; see the original central dogma of genetics
1944 Oswald Theodore Avery, Colin McLeod and Maclyn McCarty isolate DNA as
the genetic material (at that time called transforming principle)
1950 Erwin Chargaff shows that the four nucleotides are not present in nucleic acids
in stable proportions, but that some general rules appear to hold (e.g., the nucleotide
bases Adenine-Thymine and Cytosine-Guanine always remain in equal proportions).
Barbara McClintock discovers transposons in maize
1952 The Hershey-Chase experiment proves the genetic information of phages (and
all other organisms) to be DNA
1953 DNA structure is resolved to be a double helix by James D. Watson and
Francis Crick, with the help of Rosalind Franklin[2]
1956 Jo Hin Tjio and Albert Levan established the correct chromosome number in
humans to be 46
1958 The Meselson-Stahl experiment demonstrates that DNA is semiconservatively
replicated
1961 The genetic code is arranged in triplets
1964 Howard Temin showed using RNA viruses that Watson's central dogma is not
always true
1970 Restriction enzymes were discovered in studies of a bacterium, Haemophilus
influenzae, enabling scientists to cut and paste DNA
1952 The Hershey-Chase experiment proves the genetic information of phages
(and all other organisms) to be DNA
1953 DNA structure is resolved to be a double helix by James D. Watson and
Francis Crick, with the help of Rosalind Franklin[2]
1956 Jo Hin Tjio and Albert Levan established the correct chromosome number in
humans to be 46
1958 The Meselson-Stahl experiment demonstrates that DNA is
semiconservatively replicated
1961 The genetic code is arranged in triplets
1964 Howard Temin showed using RNA viruses that Watson's central dogma is
not always true
1970 Restriction enzymes were discovered in studies of a bacterium,
Haemophilus influenzae, enabling scientists to cut and paste DNA
1972, Walter Fiers and his team at the Laboratory of Molecular Biology of the
University of Ghent (Ghent, Belgium) were the first to determine the sequence of
a gene: the gene for Bacteriophage MS2 coat protein[3].
1976, Walter Fiers and his team determine the complete nucleotide-sequence of
Bacteriophage MS2-RNA[4]
1977 DNA is sequenced for the first time by Fred Sanger, Walter Gilbert, and
Allan Maxam working independently. Sanger's lab complete the entire genome of
sequence of Bacteriophage Φ-X174[5].
1983 Kary Banks Mullis discovers the polymerase chain reaction enabling the
easy amplification of DNA
1985 Alec Jeffreys discovers genetic finger printing.
1989 The first human gene is sequenced by Francis Collins and Lap-Chee Tsui. It
encodes the CFTR protein. Defects in this gene cause cystic fibrosis
1995 The genome of Haemophilus influenzae is the first genome of a free living
organism to be sequenced.
1996 Saccharomyces cerevisiae is the first eukaryote genome sequence to be
released
1998 The first genome sequence for a multicellular eukaryote, C. elegans is
released.
2001 First draft sequences of the human genome are released simultaneously by
the Human Genome Project and Celera Genomics.
2003 (14 April) Successful completion of Human Genome Project with 99% of
the genome sequenced to a 99.99% accuracy [1]
2006 Marcus Pembrey and Olov Bygren publish Sex-specific, male-line
transgenerational responses in humans, a proof of epigenetics. [2]
 WHY STUDY GENETICS?

• A prehistoric field - e.g, our ancestors’ selection of more fruitful grains to

grow and more desirable animals to breed.
• Also a modern and fascinating field of tomorrow - e.g. experimental gene
therapy (ie. in cancer research), pest-resistant plants, high-yielding crops (ie.
giant pumpkin).
• Manipulate genes and/or organisms to produce important products - e.g.
human growth hormone for dwarfism, interleukin-2 for cancer therapy and
biodegradable plastics.
• Identified the defective genes responsible for diseases - ie. Cystic fibrosis
and muscular dystrophy - testing strategies for treating these diseases by
implanting the corresponding unmutated genes.
• However, debate about benefits vs risks and even about whether it is
appropriate for us to use such awesome tools at all is ongoing. So, it is
important that the public be educated about genetics in order to make
intelligent decisions about these issues.
 Objectives

• Understand the key biological molecules that are associated

with the study of genetics.

• Understand the relationships between genes and traits and the

types of traits that are studied by geneticists.

• Understand the four principle levels of genetic study.

• Recognize the three major fields of genetics and the general

characteristics of each field.
Genetics in the news; a
sampling of some recent
headlines.
 Gregor Mendel
▪The Grandfather of Genetics
• Modern genetics had its beginnings in an abbey
garden, where a monk named Gregor Mendel
documented a particulate mechanism of inheritance.

• He discovered the basic principles of heredity by breeding garden peas in

carefully planned experiments.

• His approach to science had been influenced at the University of Vienna

by one of his professors: the physicist Doppler.

• In order to study inheritance, Mendel chose to use peas, probably as they

are available in many varieties.

• The use of plants also allowed strict control over the mating.
He chose to study only characters that varied in an ‘either-or’ rather than
a ‘more-or-less’ manner.
▪ To hybridise 2
varieties of pea
plants, Mendel used
an artist’s brush.

▪ Example: He
transferred pollen
from a true breeding
white flower to the
carpel of a true
breeding purple
flower.
• Genetics and society – Human Genome Project (1990) :
to map and sequence all the genetic information of humans
and a few important genetic organisms by year 2005
(but completed in 2003).
- Project between National Institute of Health (NIH) and the
Department of Energy (DOE).
- human genome – contains approximately 3 billion nucleotides.
- 99.99% accurate (1 in 10,000 nucleotides).
- have dramatic effects on ability to diagnose and devise effective
treatments for human diseases – very positive impact on human health,
but also raise complex moral, ethical and legal questions.
- enables scientists to:
a. determine the number of genes and living cells.
b. examine the relationship between genes and living cells.
c. study the evolution of the species.
d. understand development genetics.
e. explore the relationship between genetic mutations and diseases.
f. develop new technologies for genetic studies.
• Result of development associated with Human Genome Project:
- genetics and medicine, modern agriculture.

a. Development of new medicines,

eg. Humulin (human insulin by E. coli bacteria),
treatment of phenylketonuria (PKU) inherited
disorder cause severe mental
retardation.
b. DNA fingerprinting for forensic studies.
c. Cloning of mammals, such Dolly the
sheep (Ian Wilmut et al. (1997).
d. Production of transgenic organisms.

Dolly the cloned sheep

Some of the many varieties of beef cattle produced by hybridization
and selection.
Some of the many varieties of chickens produced by hybridization
and selection.
The Relationship Between Genes and Traits

• Genes – represent basic unit of heredity.

• Traits – represent characteristics of an organisms.

• Genes provide the blueprint for an organisms’ traits.

• Biochemicals in Living Cells:

- organic molecules – provide energy for cellular function as well as the
building blocks for larger molecules.
- biologically important organic molecules – nucleic acids, proteins,
carbohydrates, lipids.
- molecules that are made of repetitive units of smaller building blocks –
macromolecules.
- larger cellular structures such as chromosome are built from combinations
of micromolecules and macromolecules.
Chemical composition of living cells.
The formation of a peptide bond between two amino acids by the removal
of water.
 Structures of the four common
deoxyribonucleotides present in DNA.
Diagram of the double-
helix structure of DNA.
• Principles of genetics: Role of DNA (genetic material).
- genetic information – stored in nucleic acids
(DNA-contains sugar 2’deoxyribose and RNA- sugar ribose).
- in all cellular organisms, genetic material is DNA
(stores information needed for synthesis of cellular proteins).
- DNA (made of nucleotides). Each nucleotide includes
a nitrogenous base, either adenine (A), thymine (T), cytosine (C),
or guanine (G). (in RNA, uracil (U) occurs in place of T).

Two-dimensional view of DNA structure.

- Information in DNA – contains information on sequence of amino acid in a

protein (genetic code is used to relate the genetic information to the correct
amino acids).
- In cells, DNA is found in chromosomes. The information on a chromosome
is organised as genes (on average, a human chromosome = between 1,000
and 2,000 genes).
- DNA replication: transmission of genetic information.
DNA replication.
• DNA and Gene Expression (control of growth and development).
- refers to the use of genetic information to synthesis
a cellular protein.
- involves 2 steps:
1. transcription (information in the DNA is copied into RNA).
2. translation (RNA is then translated into a functional protein).
- Distinctive structure of protein determines its cellular function.

Gene expression
Transcription and translation, the initial steps in
gene expression, are illustrated by using the
synthesis of human ß-globin as an example .
The chromosomes of a female with Down syndrome.
 Schematic of human
chromosome 17
showing the location of
the breast cancer gene,
BRCA1.
Cellular Proteins:

• Cellular characteristics are determined primarily by proteins.

• General roles of proteins – cellular support, transport across the cell

membrane, biological motors, cell-to-cell recognition and cell signaling.

• Enzymes – primarily proteins that accelerate chemical reaction (catalyst).

- catabolic enzyme break down molecules and release energy.
- anabolic enzyme synthesise larger molecules.
 CHEMISTRY OF THE GENE

At its most fundamental level, life is chemistry. All living things are made
of molecules. Life is sustained by thousands of chemical reactions
occurring constantly in your body. In order to have a fundamental
understanding of life, we must know something about its chemistry.

Genes are informational molecules.

Genes are stored in the form of
deoxyribonucleic acid (DNA). Pairs
of DNA make up a chromosome.
But how did scientists discovered
that DNA are hereditary and
informational molecules? And in
what form of information do genes
code for?
 STEP BY STEP DISCOVERIES

• Frederick Griffith laid the foundation for the identification of DNA as the
genetic material in 1928 - transformation experiments in the bacterium
Streptococcus pneumoniae.
• (A) Wild-type (WT) organism - meaning original, unmutated form - spherical in
shape, surrounded by a mucous coat (capsule) - cells are large, form glistening
colonies, characterized as smooth (S) - cells are virulent - cause lethal
infections upon injection into mice.
• (B) Mutant organism - lost its ability to form capsule - cells are small, colonies
are rough (R) - cells are avirulent - does not cause lethal infection - because
does not have protective capsule - so, engulfed by the host’s white blood cells
before it can proliferate.
• (C) Heat killed S cells - by themselves are avirulent.
• (D) Heat-killed S cells + R cells - could transform avirulent R cells to virulent
S ones - the virulent trait passed from the dead cells to the live, avirulent ones
and later to their descendants as a hereditary trait.
• Hypothesis: the transforming substance in the heat-
killed bacteria was probably the gene for virulence
itself.
• The missing piece of the puzzle was the chemical
nature of the transforming substance. Whoever
discovered this would reveal the nature of genes.

DNA: The Transforming Material

• Oswald Avery, Colin MacLeod and Maclyn McCarty supplied the missing
piece in 1944.
• Used transformation test similar with Griffith - but they went the extra mile by
defining the chemical nature of the transforming substance from virulent cells.
The experiment:
S cells
Cell extract
treat with treat with treat with treat with
organic digestive ribonuclease dexyribonucle
solvents to enzymes e.g. (RNase) to ase (DNase)
remove trypsin and digest RNA to digest DNA
proteins chymotrypsin
to digest
proteins

Still transformed

Did not transform

 Further analysis:
(1) Ultracentrifugation (2) Electrophoresis (3) Ultraviolet
absorption
Placed transforming
Spun the transforming spectrophotometry
substance in an eletric
substance in an
field to see how rapidly Placed transforming
ultracentrifuge to estimate
size it moved substance in a
spectrophotometer to see
Transforming substance what kind of UV light it
Transforming substance absorbed most strongly
had a relatively high
sedimented rapidly -
suggesting high mobility also
molecular weight - characteristic of DNA
characteristic of DNA Absorbed UV light most
strongly at 200 nm, in
(4) Elementary chemical analysis contrast to protein at 280 nm
- also characteristic of DNA.
N/P ratio = 1.67 - as estimated for DNA -
which is rich in both elements - but a lot
lower than the value expected for protein
(rich in N, poor in P)
 Chargaff’s Rules
“A great old man is dead, one of the last
bridges to the age of civilisation broke. I
wish I had known him earlier and lost
him later.” – unknown author.

• Erwin Chargaff proposed 2 rules:

(1) Best known achievement - was to show that in natural DNA the number
of guanine units equals the number of cytosine (G=C) units and the
number of adenine units equals the number of thymine units (A=T). In
human DNA, for example, the four bases are present in these
percentages: A=30.9% and T=29.4%; G=19.9% and C=19.8%.

• This strongly hinted towards the base pair makeup of the DNA,
although Chargaff was not able to make this connection himself. Most
workers had previously assumed that deviations from equimolar base
ratios (G = C, A = T) were due to experimental error, but Chargaff
documented that the variation was real, with [C + G] typically being
slightly less abundant.
• Chargaff met Francis Crick and James D. Watson at Cambridge in 1952,
and explained his findings to them. Chargaff's research would later help
Watson and Crick to deduce the double helical structure of DNA.

(2) The composition of DNA varies from one species to another, in particular
in the relative amounts of A, G, T, and C bases.

• Such evidence of molecular diversity, which had been presumed absent

from DNA, made DNA a more credible candidate for the genetic material
than protein.
 One gene, One enzyme Hypothesis

• George Beadle and Edward Tatum showed that genes code for
proteins.

• Beadle and Tatum's key experiments involved exposing the bread

mold Neurospora crassa to X-rays, causing mutations. In a series of
experiments, they showed that these mutations caused changes in
specific enzymes involved in metabolic pathways. These experiments,
published in 1941, led them to propose a direct link between genes and
enzymatic reactions, known as the "one gene, one enzyme" hypothesis.
Genes are made of DNA – the genetic material

• Alfred Hershey and Martha Chase identified DNA to be the genetic

material, not protein. They proved this by using phage in their experiments.
Before this experiment was conducted, it was said that proteins were the
genetic material in viruses, not DNA.

• (Some extra info: A phage is a small virus that infects bacteria. A phage
consists of a protein coat that encloses the genetic material. When a
phage infects a bacterium, it inserts its genetic material into the bacterium,
while its coat remains outside).
• They conducted 2 experiments:

1st experiment: Labeled DNA of T2 phages with radioactive 32P -infected

bacteria – separate bacteria from phage coats by blending & centrifugation -
most radioactivity was found in the infected bacteria.

2nd experiment: Labeled protein of T2 phages with radioactive 35S -infected

bacteria - separate bacteria from phage coats by blending & centrifugation -
most radioactivity was found in the phage coat.

• DNA is the genetic material of phage and that protein does not transmit
genetic information.
• Traits:
- display characteristic of an organism.
- morphological traits - associated with the appearance of an organisms (eg.
Eye colour, height etc.).
- physiological traits – associated with the ability of the organisms to function
(eg. metabolic function).
- genetics spans 4 levels of biological organisation:
a. molecular level (process of transcription and translation).
b. cellular level (function of a protein within the cell).
c. organisms level (observed traits of an organisms).
d. population level ( occurrence of the traits in a population under given
conditions).
- forms of a gene – called alleles. Eg. Eye colour in human, the gene is for
eye pigmentation, the alleles of the gene determine the colour.
The relationship between genes and
traits at (a) molecular level, (b) cellular
level, (c) organisms level and (d)
population level.
• Genetic Variation:
- the differences in inherited traits among individuals of a population.
- Morphs – species that occupy wide geographic ranges,
these differences may be drastic enough so that scientists
may consider the organisms to be different species.
- genetic variation is due to changes in the nucleotide sequence of DNA that
may be caused by;
a. Gene mutation at the nucleotide level.
b. Major structural changes in a chromosome.
c. Variation in the total number of chromosomes in an organism.

• Traits = Genes + Environment

- external environment – may influence an organisms’s traits.
- eg. Human disease phenylketonuria (PKU), which encodes gene called
phenylalanine hydrolase (allows metabolism of phenylalanine amino acid). –
mutation causing defect in the gene; toxic level of phenylalanine accumulate
in blood, causing mental retardation (1 in 8000 individual in US).
Genetic variation
• Sexual Reproduction and the Passing of Traits
- Gregor Mendel – first established that genetic information
was passed from parent to offspring as discrete units (genes).
- sexually reproducing species – diploid (2 copies of each
chromosome, or 2n)
- copies of each chromosome – homologues.
- gamete = haploid (1 copy of each chromosome, or n)
- sexual reproduction – increase genetic variation in a population.

• Genetics and Species

- Change in genetic composition of a species over time – biological evolution.
- Charles Darwin – theory of natural selection as the mechanism for biological
evolution.
Fields of Genetics

• Modern geneticists define 3 main branches of contemporary genetics:

(1) Transmission Genetics
• Seeks to explain the pattern of transmission of traits from one
generation to the next.
• Framework – provided by Mendel (suggested that genetic
determinants, gene were discrete units that were passed from
generation to generation).
• Studies of transmission genetics – rely on genetic cross to examine
how traits are passed from parents to offspring. It relies mainly on the
same kind of experimental approach used by Gregor Mendel.
Organisms with different phenotypes are mated and the transmission
of these trains to the next generation is observed. Because this work
was pioneered by Mendel, this approach to genetics is also known as
Mendelian or classical genetics.
(2) Molecular Genetics – genetic engineering
(DNA recombinant etc.)

• The study of the activities of genes, the molecules

that carry genetic information.
• Working of the genetic material at the molecule
level.
• Use of model organisms such as Drosophila, E.
Coli, Saccharomyces cerevisiae and Arabidopsis.
• Use genetic approach to study mutant genes with Male
an abnormal function. (loss of function alleles Female
(mutation) help geneticists understand the role of
the gene in the organisms).
• Approaches genetics from its chemical
foundation: molecules. Instead of examining
phenotypic characters, molecular geneticists
examine the gene themselves. They are
concerned with the molecules that compose the Genetic sexing of White-
genes, the molecules that control genes and the bellied Sea Eagle from
molecules that are the products of genes - gave Penang Bird Park, Penang.
birth to molecular cloning in the 1970s.
( 3) Population Genetics

• The study of variation of genes between

and within population.
• Involves the use of mathematical/statistical
theories explain the prevalence of certain
genes in a population.
• Provides link between transmisson
genetics (Mendel) and natural selection
(Darwins).
• Study relationship between genetic
variation and the environment that an
organism inhabits.
• Examines the extent of genetic variation
within and among populations. Geneticists
traditionally studied this variation on the
phenotypic level, but population geneticists
now focus increasingly on molecular
variation in a population. Such studies are
aimed at understanding how the observed
genetic variation evolved.
 List of Key Investigators

• Darwin, Charles – Proposed the theory of natural selection as

the mechanism for biological evolution.
• Mendel, Gregor – Determined that genetic information was from
generation to generation in discrete units.
• Wilmut, Ian – Created Dolly, the first mammalian clone from an
adult animal.
 George Beadle at the blackboard.

Thomas Hunt Morgan –

working in his lab with fruit
flies. Discovered genes
are on chromosomes and
allelic mutations.

George Beadle and students.

 McCarty warmly greets Watson and
Crick at the 1979 Waterford
Biomedical Science Awards ceremony
at the Scripps Institute.

Rosalind Franklin –
the crystallographer
who contributed in
elucidating the
structure of DNA
Watson & Crick explaining the The stained glass window dedicated in
structure of DNA memory of Crick in Caius University
 Barbara McClintock –
Barbara McClintock Barbara McClintock discovered “jumping
receiving the Nobel Price teaching her students genes” in maize
from King Carl Gustaf

“If you know you are on the right track, if you have this inner knowledge,
then nobody can turn you off. . . no matter what they say.”
-Barbara McClintock
 Robert W. Har Gobind Marshall W.
Holley Khorana Nirenberg
The genetic code crackers –interpreted the genetic
code and its function in protein synthesis

Joshua Lederberg
Discovered genetic
recombination and the
organization of the genetic
material of bacteria
Arthur Kornberg Roger Kornberg
Discovered the mechanisms in the
Studied of the molecular basis of
biological synthesis of ribonucleic acid
eukaryotic transcription
and deoxyribonucleic acid
Learning Objectives

Students should be able to:

1. Understand the key biological molecules that are associated

with the study of genetics.

2. Understand the relationship between genes and traits and

types of traits that are studied by geneticists.

3. Understand the four principle levels of genetic study.

4. Recognise the three major fields of genetics and the general

characteristics of each field.