NUCLEIC

ACIDS
• Deoxyribonucleic Acid (DNA) – the genetic
material that stores and encodes
hereditary information in the form of
genes
• Ribonucleic Acid (RNA) – involved in
protein synthesis and gene control

1
 OCTOBER 2016 BREAKING
NEWS!!!

The Republic of Vanuatu is an

island nation in the South
Pacific Ocean, northeast of
New Caledonia, east of
Australia and west of Fiji.

https://www.theguardian.com/world/2016/oct/04/dna-shows-first-inhabitants-of-
vanuatu-came-from-philippines-and-taiwan 5
https://www.future-science.com/pb- assets/BTN/
PDF/BioTechniques_Sequencing.pdf
3
 A QUICK TOUR OF DNA AND GENETICS
• Cells, DNA, Genes, and
Chromosomes
• Central Dogma
• Mutation
• The Human Genome Project
• Precision Medicine

4
 A LITTLE
HISTORY
• 1866: Czech monk, Gregor Mendel:
“inheritance” of characteristics in pea plants
• 1868: Swiss physician, Friedrich
Miescher: isolated a compound he named
as “nuclein”
• Uncertainties in the scientific community
about the molecule of heredity
• 1944: American scientist, Oswald
Avery, observed that bacterial diseases
can be transferred from one strain to
another
• Growing studies on DNA structure: x-ray
5
diffraction pictures
 A LITTLE HISTORY
“THE FAMOUS PHOTOGRAPH 51”:
FUZZY X
Original X-ray Diffraction Picture of DNA

Crystallographic studies
done by MAURICE
WILKINS and
ROSALIND FRANKLIN.

The fuzzy X in the middle

revealed a pattern indicating a
helical structure. 14
 A LITTLE HISTORY
ORIGINAL DNA MODEL BY WATSON
AND CRICK

7
 A LITTLE HISTORY
THE NOBEL PRIZE IN PHYSIOLOGY OR
MEDICINE, 1962
Awarded jointly to:
• Francis Harry Compton
Crick,
• James Dewey Watson,
and
• Maurice Hugh
Frederick Wilkins
"for their discoveries on the
molecular structure of
nucleic acids and its
significance for information
transfer in living material."
8
 A LITTLE HISTORY
TOO LATE TO BE RECOGNIZED

Franklin died without

being recognized for her
contributions.

“Rosalind Franklin: The

Dark Lady of DNA” –
Brenda Maddox, author,
2002
https://www.biography.com/scientist/ros
alind-franklin
9
BACTERIAL
PLASMID

10
https://www.sciencemag.org/custom-
publishing/webinars/high-resolution-look-

human-cell-introducing-human-cell-atlas 11
20
 AMNIOCENTE
SIS

https://www.mayoclinic.org/tests-procedures/amniocentesis/about/pac-2039291214
 SEM OF HUMAN
CHROMOSOMES

KARYOGRAM
Set of human
chromosomes,
coloured scanning
electron micrograph
(SEM).

http://www.psmicrographs.co.uk/full-set-of-male-chromosomes-sem/science-
22
image/maleset
 SEM OF HUMAN
CHROMOSOMES

Coloured scanning electron

micrograph (SEM) of
human chromosomes. The
SEM is overlaid on a DNA
autoradiogram background.

Magnification: x5350 at
6x7cm size.

http://www.psmicrographs.co.uk/human-chromosomes-with--dna-
23
DOWN SYNDROME
(TRISOMY 21)

16
 AVERAGE LENGTH OF DNA IN A
CELL???
• The most common estimate is that if you unfolded all of the DNA
in a single human cell, it would stretch about 2 meters.
• Humans contain roughly 100 trillion cells. So if you unfolded all
of the DNA in all of your cells and laid it end to end, it would
stretch from here to the moon and back, more than a quarter
million times 

17
PACKAGING OF DNA INTO
CHROMOSOMES

Mitosis is a process where

a single cell divides into two
identical daughter cells.
Chromosomes are
condensed and visible
during mitosis.

18
 BIOMOLECULE: NUCLEIC
ACID
C, H, O, N, P
Types:
• Deoxyribonucleic
Acid (DNA) – the
genetic material that
stores and encodes
hereditary
information in the
form of genes
• Ribonucleic Acid
(RNA) – involved in
protein synthesis and http://www.nature.com/scitable/topicpage
gene control /d iscovery-of-dna-structure-and-function-
watson-397 29
DNA
STRUCTURE
Sub-unit: nucleotide

Parts of the Nucleotide:

(1) carbohydrate molecule
(2) phosphate group
(3)nitrogenous base
(adenine, cytosine,
guanine, thymine)

30
 NUCLEIC ACID
STRUCTURE
Two types of nitrogenous bases in nucleotides:
• Purines: adenine (A), guanine (G),
• Pyrimidines: cytosine (C), thymine (T), uracil (U)

DNA: A, G, C, T
RNA: A, G, C, U

Pairing: A&T, C&G, A&U (RNA)

Kilobase (kb) – stands for 1000 nitrogenous bases; 1 kb

is
~ 0.34 micrometers in length and a mass of ~ 660,000
daltons (a unit used in expressing the molecular
weight of proteins, equivalent to atomic mass unit) 31
32
EIGHT-LETTER GENETIC
LANGUAGE

https://www.nature.com/articles/d41586-019-00650-8 23
EIGHT-LETTER GENETIC
LANGUAGE

https://www.nature.com/articles/d41586-019-00650-8 24
40
 THE CENTRAL
DOGMA

http://fourier.eng.hmc.edu/bioinformatics/intro/node8.html 41
 THE CENTRAL DOGMA DNA – RNA - PROTEIN

• DNA carries the genetic information

of a cell and consists of thousands of
genes (portions of DNA).
• Each gene serves as a recipe on
how to build a protein molecule.
• Proteins dictate our traits.
• The information from the genes
determines the protein composition
and the functions of the cell.
• The central dogma
explains the flow of genetic
information, from DNA to RNA, to
make a functional product - protein
42
4
3
https://www.sciencedaily.com/releases/2008/02/080222155212.htm
44
• In 2005 researchers identified a gene called SLC24A5 as a
key determinant of skin color. Rebecca Ginger and
colleagues now confirm that the protein product of this
gene (NCKX5) is an ion exchanger; it exchanges sodium for
calcium across a membrane, regulated by potassium. But
unlike other NCKX proteins, they found that NCKX5 is not
present on the cell surface, but internally in a compartment
known as the trans- Golgi network. This compartment is
where new proteins and vesicles are processed, modified
and sorted.
• When the researchers knocked out NCKX5 in melanocytes
(the skin cells that manufacture the melanin pigment),
melanin production decreased dramatically. They also
demonstrated that changing the ancestral amino acid
(alanine) at position 111 to the European form associated
with lighter skintone (threonine) reduced NCKX5's
https://www.sciencedaily.com/releases/2008/02/080222155212.htm
exchanger activity. 45
 THE CENTRAL DOGMA DNA –
RNA - PROTEIN
• The exact DNA Why are Proteins Important???
sequence of an • Most of the genes associated with
individual is its eye color are related to the
production, transport, and
genotype . storage of the pigment protein,
• The collection of all melanin.
observable and • Eye color: amount and quality
measurable traits of of melanin in the front layers of
that individual the iris.
is phenotype . • People with brown eyes have a
large amount of melanin in the
iris, while people with blue
eyes have much less of this
pigment.
31
32
DNA Replication
DNA – RNA - PROTEIN
• The DNA is duplicated before
cell division.
• Inside the nucleus is a
complex machinery, like a
xerox machine, which copies
the cell’s DNA before it
divides.
• Each “daughter” cell receives
an exact copy of the
dividing cell's DNA.
• Replication is
semiconservative (one
strand is copied). 50
DNA – RNA - PROTEIN
REMEMBER the GOAL!!!
• To translate the language of the genetic code
(nucleotides in the RNA – which was
transcribed from DNA) into the language of
the proteins (amino acids).

34
Types of RNA:
• mRNA - Messenger RNA:
The mRNA carries the
genetic code for protein
synthesis to the cytoplasm.
• rRNA - Ribosomal RNA:
The rRNA serves as the
site for protein synthesis.
• tRNA - Transfer RNA:
The tRNA reads the code
(mRNA) and carries the
amino acid to be
incorporated into the
developing protein.

35
36
 DNA – RNA - PROTEIN

https://www.philpoteducation.com/mod/book/view.php?id=782&chapterid=1129#54/
Protein Synthesis
• When proteins are
needed, the
corresponding genes are
transcribed into RNA
(transcription).
• In most cells, the RNA is
first processed so that
non-coding parts are
removed (processing)
and is then transported
out of the nucleus
(transport).
• Outside the nucleus,
the proteins are built
based on the code in
the RNA (translation).
• Note: proteins consist of
sub- units, amino acids.
55
https://courses.lumenlearning.com/boundless-biology/chapter/ribosomes-
and-protein-synthesis/
39
40
41
42
 DNA – RNA - PROTEIN
• The nucleotide sequence of mRNA is composed of
four different nucleotides (A, C, G, U) while a
protein is synthesized from 20 amino acids.
• How then will translation and protein synthesis occur?
• To solve the conflict above, the mRNA message is
interpreted as codons or groups of three nucleotides.

43
 DNA – RNA - PROTEIN
Translation
The codons on the mRNA
have corresponding
anticodons in the transfer
RNA (tRNA).
• Each anticodon, on the
other hand, is linked to
one specific amino
acid.
• Therefore, each codon
specifies one amino
acid. This is referred to
as the genetic code. 62
63
 (credit: modification of work by NIH)

https://courses.lumenlearning.com/wm-nmbiology1/chapter/reading-codons/64
 DNA – RNA - PROTEIN

https://www.philpoteducation.com/mod/book/view.php?id=782&chapterid=1129#65/
DNA – RNA – PROTEIN
(SUMMARY)

biochemreview.weebly.com 66
PROTEIN
FOLDING

49
 A QUICK TOUR OF DNA AND GENETICS

• Cells, DNA, Genes, and Chromosomes

• Central Dogma
• Mutation
• The Human Genome Project
• Precision Medicine

50
 MUTATION
A mutation is a change in a A mutation in one gene
cell’s DNA sequence. causes a fly to develop legs
where its antenna should be.

a: ©Andrew Syred/SPL/Science Source b: ©Eye of Science/Science Source

Copyright © 2016 McGraw-Hill Education. Permission required for reproduction or display.
 MUTATIONS

1 Wild type = original

nucleotide sequence
2 Substitution =
changed
nucleotide(s)
3 Insertion =
a codon added
4 Deletion =
nucleotide(s) deleted
5 Insertion resulting to
frameshift mutation

Remember that codons are sequences of three nucleotides. Each

word in the sentences above represents one codon.
Copyright © 2016 McGraw-Hill Education. Permission required for reproduction or display.
 MUTATIONS
“Frameshift”
mutations affect
multiple codons.

Insertion of one
nucleotide changes
every codon after the
insertion.

Section 7.6 Copyright © 2016 McGraw-Hill Education. Permission required for reproduction or display.
https://www.123rf.com/photo_23684894_st

ructure-of-human-hemoglobin-molecule-
vector-diagram-hemoglobin-is-the-
substance-in-red-blood-cells.html

72
 MUTATIONS
Normal red blood cells

No aggregation
A single base
G G A C T C C T
T CCUGAGG of hemoglobin substitution in a
A A molecules
hemoglobin gene
SEM 6 µm causes blood cells to
Pro Glu Glu form abnormally,
leading to sickle cell
Sickled red blood cells
disease.
Abnormal
G G A C A C C T aggregation
T CCUGUGG of hemoglobin
A A molecules

Pro Val Glu

SEM 6 µm
Section 7.6 a: ©Micro Discovery/Corbis; b: © Dr. Gopal Murti/SPL/Science Source
Copyright © 2016 McGraw-Hill Education. Permission required for reproduction or display.
Figure 7.14
https://fscdr.org/2017/07/14/fda-approves-new-treatment-for-sickle-cell-disease-
endari/ 74
 MUTATION: PARKINSON’S
DISEASE
• “Mutations in the leucine-rich repeat kinase 2
gene (LRRK2) cause late-onset Parkinson's disease
(PD) with a clinical appearance indistinguishable
from idiopathic PD. Initial studies suggest that
LRRK2 mutations are the most common yet
identified determinant of PD susceptibility,
transmitted in an autosomal-dominant mode of
inheritance. Herein, we characterize the LRRK2
gene and transcript in human brain and subclone
the predominant ORF.”

• http://www.ncbi.nlm.nih.gov/pubmed/16269541

57
 MUTATION: ALZHEIMER’S
DISEASE
• “A mutation at codon 717 of the beta-amyloid
precursor protein gene has been found to cosegregate
with familial Alzheimer's disease in a single family.
This mutation has been reported in a further five out
of approximately 100 families multiply affected by
Alzheimer's disease. We have identified another
family, F19, in which we have detected linkage
between the beta-amyloid precursor protein gene and
Alzheimer's disease. Direct sequencing of exon 17 in
affected individuals from this family has revealed a
base change producing a Val----Gly substitution,
also at codon 717. The occurrence of a second allelic
variant at codon 717 linked to the Alzheimer's
phenotype supports the hypothesis that they are
pathogenic mutations.”
• http://www.ncbi.nlm.nih.gov/pubmed/16269541

58
 MUTATION: BREAST
CANCER
• “BRCA1 and BRCA2 are major genes related to
hereditary breast cancer. Women who have inherited
certain mutations in these genes have a high risk of
developing breast cancer, ovarian cancer, and several
other types of cancer during their lifetimes. Men with
BRCA1 mutations also have an increased risk of
developing breast cancer. Additionally, BRCA1
mutations are associated with an increased risk of
pancreatic cancer. Mutations in the BRCA2 gene are
associated with an increased chance of developing
male breast cancer and cancers of the prostate and
pancreas. An aggressive form of skin cancer called
melanoma is also more common among people
who have BRCA2 mutations.”

• http://www.ncbi.nlm.nih.gov/pubmed/16269541

59
 THE HUMAN GENOME
PROJECT
The Human Genome Project
(HGP)’s goal was the
complete mapping and
understanding of all the
genes (genome) of human
beings.
HGP revealed about 20,500
human genes and their
sequence and location.

https://www.genome.gov/12011238/an-overview-of-the-human-genome-projec7t9/
 THE HUMAN GENOME
PROJECT
• Nature (February 2001): published the sequence of
90% of the entire genome's three billion base pairs. The
full sequence was completed and published in April 2003.

https://www.genome.gov/12011238/an-overview-of-the-human-genome-project8/0
 DNA SEQUENCING
DNA SEQUENCING IS THE PROCESS OF

DETERMINING THE PRECISE ORDER

OF NUCLEOTIDES WITHIN
a DNA molecule.
It includes any method used to determine the order
of the four bases: adenine, guanine, cytosine, and
thymine.
Why is this relevant???

62
 “THE MEASURING
STICK”

https://www.nist.gov/news-events/news/2015/05/measuring-stick-standard-gene-
63
sequencing-now-available-nist
HUMAN GENOME’S MEASURING
STICK
• The world's first reference material to help ensure laboratories
accurately "map" DNA for genetic testing, medical diagnoses and
future customized drug therapies is now available from the
National Institute of Standards and Technology (NIST).
• The new reference material, NIST RM 8398, is a "measuring stick" for
the human genome, the coded blueprints of a person's genetic traits.
It provides a well-characterized standard that can tell a laboratory
how well its processes for determining the patterns in a person's DNA
(called DNA or gene sequencing) are working by measuring the
performance of the equipment, chemistry and data analysis involved.

https://www.nist.gov/news-events/news/2015/05/measuring-stick-standard-gene-
64
sequencing-now-available-nist
 HUMAN GENOME’S MEASURING
STICK
• DNA sequencers take long strings of a person's DNA and randomly chop them into
small pieces that can be individually analyzed to determine their sequence of letters
from the genetic code (A, C, G and T representing the four key components of DNA
that code for protein production in living organisms: adenine, cytosine, guanine
and thymine). The sequenced pieces can then be compared to a defined "reference
sequence" to identify differences in the two codes. The differences reveal where
mutations have occurred in specific genes.
• However, biases and "blind spots" for certain sequences contribute to uncertainties
or errors in the sequence analysis. These biases can lead to hundreds of thousands
of disagreements between different sequencing results for the same human
genome.
• Laboratories can now use the DNA in NIST RM 8398 (taken from a cell line—
referred to as NA12878—of an individual whose genome was acquired in a 1980s
research study) to identify these biases. Using the new NIST standard as a
benchmark, DNA sequencing laboratories can be more confident in their
reporting of true positives, false positives, true negatives and false negatives.

https://www.nist.gov/news-events/news/2015/05/measuring-stick-standard-gene-
65
sequencing-now-available-nist
 Precision Medicine

http://www.cpgr.org.za/precision-medicine-in-south-africa-a-cost-benefit-analysis-
framework/ 89
PRECISION
MEDICINE

90
 PRECISION
MEDICINE
• The US National Institutes of Health (NIH) describes
precision medicine as "an emerging approach for disease
treatment and prevention that considers individual variability
in genes, environment, and lifestyle for each person."
• This will allow doctors and researchers to predict more
accurately which treatment and prevention strategies
for a particular disease will work in which groups of
people.
• Versus: "one-size-fits-all" approach - disease treatment and
prevention strategies are developed for the “average” person,
with less consideration for differences between individuals.

https://ghr.nlm.nih.gov/primer/precisionmed
91
icine/definition
 GENOTYPE TO
PHENOTYPE
RECALL: The group of genes that is responsible for a trait is
known as a genotype, while the resulting characteristic is called a
phenotype.
• Alleles: alternate forms of a gene
• Dominant vs Recessive Allele
• A dominant allele produces a dominant phenotype in individuals who
have one copy of the dominant allele.
• For a recessive allele to produce a recessive phenotype, the
individual must have two copies of the recessive allele.

69
 GENOTYPE TO
PHENOTYPE
• dominant allele + dominant allele
= dominant phenotype
• dominant allele + recessive allele =
dominant phenotype
• recessive allele + recessive allele =
recessive phenotype

70
 GENOTYPE TO
PHENOTYPE
• A Punnett square is a graphical
representation of the possible genotypes
of an offspring resulting from a particular
genetic cross of the parents

71
 SICKLE CELL
ANEMIA
• Due to presence of recessive allele, HbS
• Results to the distortion of red blood cells
into long, thin sickles
• Effect: pain, tissue damage, and
possible cell rupture
• Carriers: heterozygous genotypes (no
manifestation of symptoms).
 PUNNETT
SQUARES
• Used to predict possible HbS HbS
offspring genotypes
• Place alleles for each
parent on each side

HbA
• Alleles: alternate
form(s)
of a gene
Mother’s genotype Father’s genotype
HbA
HbA/ HbA x HbS/ HbS
 PREDICT
INHERITANCE
• From the parents’
genotypes, the offspring’s
genotypes and phenotypes
can be predicted

• HbS/ HbS = homozygous

recessive and results in
sickle cell anemia

• Both HbA/ HbS

(heterozygous) and HbA/
HbA (homozygous
dominant) are normal.
 THE WAY IN WHICH ALLELES
SEPARATE DURING MEIOSIS IS
COMPLETELY RANDOM:
PRINCIPLE OF INDEPENDENT
ASSORTMENT
 USING PUNNETT
SQUARES TO PREDICT
THE INHERITANCE OF
HITCHHIKER
• H – dominant, straight THUMB
• h – recessive, bent

77
 MUST SEE WEBINAR FROM
SCIENCE!!!
HTTPS://WWW.SCIENCEMAG.ORG/CUSTOM- PUBL
ISHING/WEBINARS/HIGH-RESOLUTION-LOOK-HUMAN-C
ELL- INTRODUCING-HUMAN-CELL-ATLAS

78