CHAPTER 1: THE BIOLOGY AND
GENETICS OF CELLS AND ORGANISMS
Introduction to Cancer
Dr. Cominski
CHARLES DARWIN AND GREGOR
MENDEL
• Charles Darwin – 1859, On the Origin of Species by Means of
Natural Selection
• What is meant by natural selection?
• Darwin’s theory of evolution lacked a genetic rationale until the
work of Gregor Mendel
• Gregor Mendel – established the basic rules of genetics;
govern how genes are passed down from one complex
organisms to another
• Discovered in the 1860’s using pea plants; concepts still hold true
today
• Mendelian Genetics
•
Applies to virtually all sexual organisms including metazoan
(multicellular animals) and metaphyta (multicellular plants)
• An organism’s genome (genetic information) – organized as a
collection of discrete, separable information packets, now
called genes
• Humans have about 21,000 genes
Charles Darwin
Gregor Mendel
A PARTICULATE THEORY OF INHERITANCE
• Mendel – genetic content of an organism consists of discrete
parcels of information, each responsible for a distinct
observable trait
• i.e. the heritable material for controlling the smoothness of peas
behaved independently of the material governing plant height or
flower color
• Important Genetic Terms and Concepts
• Genotype
• Phenotype
• Haploid vs. diploid
• Allele – alternate versions of a gene
• Dominant
• Recessive
• Co-dominant – expressed phenotype is a blend of the
actions of the two alleles, i.e. pink flowers in certain plant
species as a result of a white allele and a red allele
• Incomplete penetrance – dominant allele may be present
but its phenotype is not manifested because of the actions of
other genes within the genome, i.e. certain gene mutations
cause cancer, but because of incomplete penetrance, not
everyone who has the mutation will develop cancer.
• Heterozygotes (one wild-type (normal)/one mutant
allele)
THE PHENOTYPE OF AN INDIVIDUAL
OFTEN DOES NOT INDICATE GENOTYPE
• Heterozygotes (one wild-type
(normal)/one mutant allele)
• Class of alleles that predispose cells to
develop cancer encode defective versions
of enzymes involved in DNA repair.
• Heterozygotes contain one defective copy
but the normal copy functions so the
defective copy is not evident
• What would happen if two heterozygotes
mated? What would be the chance that
the offspring would inherit two defective
alleles?
• Draw a Punnet square to illustrate this!!
MENDELIAN GENETICS HELPS EXPLAIN
DARWINIAN EVOLUTION
• Genetic information is corruptible = mutations
• Mutations = genetic diversity
• Increased diversity of the gene pool (collections of alleles present in a certain species or population)
provides benefits to the species
• Some alleles/mutations can be advantageous; carriers of these alleles will have a higher probability of leaving
many decendents compared to individuals without these beneficial alleles
• Natural selection results in continuous discarding of alleles that are not beneficial to the species and these
alleles are removed from the gene pool over time
• The beneficial alleles are “selected for” and remain in the species gene pool as a result of this the overall
fitness of the species improves over time
• The majority of DNA in our genome does not specify phenotype often is not associated with specific
genes
• Junk DNA = noncoding DNA (it is not really junk!!)
• Only about 1.5% of mammalian DNA carries sequence information that codes for proteins
MUTATIONS AND EVOLUTION
Red – represents biologically important
sequences; yellow – represents “junk” DNA
POLYMORPHISMS
• Genetic polymorphisms = inter-individual, functionally silent
differences in DNA sequence that make each human genome
unique
• Because the great majority of the human genome does not
encode biologically important information, it has evolved rapidly
and has accumulated many subtle differences in sequence
• Green dots indicate areas of the DNA where an alternate
sequence compared to the sequence that is most common in the
gene pool exist = polymorphism
• Many more mutations in non-coding DNA exist in the genome
because they do not affect phenotype and are therefore, not
removed by natural selection
• See sidebar 1.1 – Evolutionary forces dictate that certain genes
are highly conserved
CHROMOSOMES
• Two sets of
chromosomes exist in
almost all cells of
complex organisms =
diploid
• Humans = 46
chromosomes (2 sets
of 23)
• Autosomes vs sex
chromosomes
Six genes linearly
arranged; different
fluorescent probes
A) Physical structure of Drosophila chromosomes. Notice dark and
light banding and the presence of specific genetic loci
Scanning electron micrograph of X and Y Chromosomes
CHROMOSOMES ARE ALTERED IN MOST
TYPES OF C ANCER CELLS
• Euploidy – normal configuration/karyotype of chromosomes –
Panel (B) below
• Aneuploidy – Deviation from the normal/euploid karyotype – Panel
(C) below – Pancreatic cancer cell aneuploid karyotype
• In addition to extra copies
of chromosomes,
translocations can also
occur (numerous are
apparent in this pancreatic
cancer cell)
• Translocation – one
segment of a chromosome
breaks off and gets added
to another
A survey of nine different types of pediatric cancer indicates that each
cancer type has characteristic gene amplification and deletion patterns with
corresponding changes in the the expression of altered genes. Based on this
graph what changes do neuroblastomas often have?
Reciprocal translocation
GERM-LINE VS SOMATIC MUTATIONS
**Understand
the difference
between germline mutations
and somatic
mutations.
**Can you
identify which is
which from a
figure like the
one here?
GENES TO PHENOTYPE
DNA
mRNA
??
Protein
??
Phenotype
Function
• About 21,000 genes – only about 5% code for proteins; what is the rest of the DNA there
for??
• regulatory sequences, repetitive sequences, retrotransposons,
• epigenetic modifications, transcriptional activation and repression, differential
expression
• mRNA processing and Splicing (Figure 1.16 on next slide)
• About 100,000 proteins in a cell
• enzymes, synthesis, metabolism, signal transduction, receptors, cytoskeleton,
• post translational modifications occur (phosphorylation, protein cleavage by proteases etc.)
• Cancer can result from alterations at any of these steps, i.e. oncogenes, RNA alterations,
oncoproteins, etc.
• Changes in signal transduction pathways in cancer cells due to altered protein function
Actin = orange; tubulin = green
Processing of pre-mRNA
*** proteins that
specify an
alternative
splicing patterns
have been
reported to have
a high expression
during the
transformation
of a normal cell
into a cancer cell
Tissue specific alternative splicing patterns of ɑ-tropomyosin pre-mRNA
molecule; black carets = introns; blue boxes = exons
GENE
EXPRESSION
• What makes cells of the human
body phenotypically different
from one another?
• Differentiation = when a cell
takes on a specific phenotype
• Cell becomes specified to
become a certain type if tissue,
i.e. brain vs. skin
• All cells of the body have the
same set of genes
Global surveys of
gene expression
arrays: red =
higher expression;
green = lower than
average expression.
mRNAs from 142
different human
tumors were
analyzed for
expression levels of
1800 different genes
HOW IS GENE EXPRESSION REGULATED?
•
•
•
Transcription factors (TF) bind to regulatory regions of the DNA to either turn on transcription or turn off transcription.
A single TF can affect the expression of multiple downstream responder genes = pleiotropy
In cancer cells, a single malfunctioning TF may affect the expression of a large group of responder genes that together create the cancer cell phenotype.
CHROMATIN AND GENE EXPRESSION
• TFs and RNA polymerase also have to
interact with proteins in order to gain access
to the DNA and alter transcription
• DNA is packaged with proteins to form
chromatin
POST- T R ANSL AT I ONAL MODI FI C ATI ONS OF H I STONE S AFFE CT CH ROMATI N
ST RUCT UR E & T R ANSCR I P T ION
• Histone modifications regulate how condensed the chromatin is, i.e. highly condensed chromatin cannot be transcribed, which results in gene repression
• Modifications that lead to chromatin being less condensed activate transcription because the DNA is easily accessible to TFs and other regulators.
• Methylation, acetylation, phosphorylation, etc.
• These histone modifications (and others) can be passed on to daughter cells = epigenetic inheritance
• This information is not part of the DNA sequence
me3 = trimethylation
UNCONVENTIONAL RNA
MOLECULES AFFECT
GENE EXPRESSION
• microRNAs can control the
levels of certain mRNAs in the
cytoplasm and/or the efficiency
of translating these mRNAs
• Fig. 1.22 – miRNAs are
processed post transcriptionally
• Many miRNAs have been found
to regulate various steps of
tumor formation; either blocking
or favoring critical steps of this
process.
• Loss of the Dicer enzyme has
been associated with cancer
progression.