7. Chromosomes
• Chromosomes are large molecules
contributed by the mother and father
Human adult: nearly
all cells have a
nucleus with exact
copies of the same
chromosomes
8. Where are the genes?
• “Classical molecular gene”
– Located inside cell nucleus
– Make up portions of chromosomes
– 1950s: chromosomes are made up mostly of DNA
9. DNA
• Watson & Crick identified structure of DNA
– Double-stranded, twisted helix
– Structure allows information to be passed from
parents to offspring.
10. DNA
• What does DNA do?
– Segments of DNA hold information used to
construct proteins.
– Classical molecular gene = segment of DNA that
contains information used to construct proteins.
11. Proteins
• Long sequences of elements strung together
– Proteins are arranged like beads on a string
– DNA also arranged like beads on a string
• DNA sequences correspond to sequence of elements in
proteins
• DNA sequences store information that can be used to
construct proteins with elements arranged in the right
order
12. Proteins
• Protein strings bunch up in specific ways
– The way that a protein bunches up is related to
the sequence of elements
– Ends up with a distinctive 3-dimensional shape
– Shape allows proteins to serve specific bodily
functions
13. Proteins
• Examples of bodily functions:
– Immune system activity: recognizing bacteria
– Muscle contraction (including heart)
– Mood regulation
• Neurotransmitters and receptors (e.g., serotonin and
serotonin receptors)
14. What do genes do?
• Provide information for use in construction of
proteins
– Proteins influence our characteristics
– So, genes influence our characteristics
– (as do nongenetic factors)
15. Are genes real?
• Genes are a theoretical entity
– An often useful idea that doesn’t capture reality
well
– National Human Genome Research Institute:
• No discrete entity in DNA that we can point to and say
“this gene codes for that protein”
• “the view of a gene as a discrete element in the
genome has been shaken”
16. Are genes real?
• Evelyn Fox Keller (2000):
– The gene has become many things to many
people
– It is no longer a single entity
• Alexandre Reymond:
– “we still have not truly answered the question,
‘What is a gene?’”
• Moore:
– Only a convenient way to communicate
17. Working definition
• Gene = segment/segments of DNA containing
sequence information that is used to construct
a protein or other product.
20. Gregor Mendel
• 1860s: Series of
experiments on pea plants
in his garden.
• Proposed that “heritable
factors”
– were responsible for
determining plant
characteristics
• 1900: theory became
prominent after his death
21. “Heritable factors”
• Scientists tried to identify these heritable
factors
– Had to meet certain criteria
1. Have to be transmittable from parents to offspring
2. Have to be transmittable from fertilized egg to
“daughter” cells during cell division
3. Have to be able to influence structure and
functioning of the daughter cells
22. “Heritable factors”
• Watson & Crick (1953): DNA structure
– DNA’s structure allows it to meet these three
criteria
• DNA’s structure allows it to replicate itself
– Copies of DNA are present in every sperm and egg
cell
23. DNA: the details
• Each chromosome is made of a long strand of
DNA
– A single DNA molecule is made of two long
chemical strands twisted around each other.
– Two distinct strands wrapped around each other
to form a single strand
• Some stretches of DNA do not have functions that have
been identified.
• Some stretches of DNA help cells produce proteins
24.
25. DNA: the details
• Both strands of a DNA molecule is made of a
series of nucleotide bases
– Like beads on the strand
– Four types of bases:
• A: adenine
• C: cytosine
• G: guanine
• T: thymine
26.
27. DNA: the details
• Meaningful elements in a DNA sequence are
always three letters long
– E.g., C-A-G
– Like words that are all the same length
– “Genes” can consist of a very large number of
these triplets
28. DNA: the details
• What makes these triplets meaningful?
– A particular triplet’s presence can lead to the
addition of a particular molecule on a protein
29. DNA: the details
• Proteins are also made of a long chain of
elements
– Like beads on a string
– Only one strand, not two like DNA
– Elements that make up proteins are amino acids
– Any particular triplet of DNA corresponds to a
specific amino acid
• C-A-G corresponds to glutamine
• T-A-T corresponds to tyrosine
30. DNA: the details
Order of bases
in a gene
Order of
amino acids in
a protein
Shape of the
protein
Function in
body
31. DNA: the details
• Chromosome (and DNA) are located in cell
nucleus
– Proteins are not built in the nucleus
– Instead, DNA sequence information is transported
to the cell cytoplasm by RNA
– RNA is similar to but different from DNA
• Also made of nucleotide bases
• But only one strand
32. DNA: the details
Order of bases
in a gene
Order of
amino acids in
a protein
Shape of the
protein
Function in
body
Order of bases
in RNA
(in nucleus) (in cytoplasm)
33. DNA: the details
• Transcription:
– The process by which a succession of DNA bases is
used to create a complementary succession of
RNA bases
– Produces a transcript.
– RNA transcripts transport sequence information
from DNA to protein construction sites in
cytoplasm
35. DNA: the details
• Translation:
– The process in which sequence information
transported by RNA is used to build a particular
protein.
– Cellular machinery “reads” information extracted
from a DNA strand to build a protein
36. DNA: the details
Order of bases
in a gene
Order of
amino acids in
a protein
Shape of the
protein
Function in
body
Order of bases
in RNA
(in nucleus) (in cytoplasm)
transcription translation
37. Noncoding DNA
• DNA used to build proteins = 1.2%
• DNA not used to build proteins = 98.8%
• What is noncoding DNA for?
38. Noncoding DNA
• 40 years ago, it was thought of as junk DNA
– But now strong evidence that most noncoding
DNA has some sort of function
– Sometimes noncoding sequences are present in
distantly related species
• (if retained by natural selection, they probably serve
some function, even if not currently known)
– And even noncoding DNA is transcribed in RNA at
some point (again points to some unknown
function)
39. Humans
• Some disease have found to be associated
with abnormal noncoding DNA:
– Some cancers
– Alzheimer’s disease
– Prader-Willi syndrome
– Other neurological diseases
40. RNA splicing
• Noncoding DNA is scattered throughout
coding DNA
• Imagine meaningful information stored like
this:
– Meaningful information: “Dawn needs serotonin
receptors here”
– Stored “Dawnkor ampneeds 2 dopamineserotonin
recepbi er jawlfioghjtormolecules t here”
41. RNA splicing
• RNA splicing is the process of extracting useful
sequence information from a seemingly
nonsensical segment of DNA
– Exon = DNA segment that contains sequence
information that will be expressed
– Intron = lies in between exons and will not be
expressed
– RNA splicing: introns are cut out of the sequence
42. RNA splicing
• Original sequence (including noninformation)
is transcribed into RNA
• Then, cellular machinery cuts out meaningless
introns and splices exons together to produce
a mature RNA strand.
43. RNA splicing
• RNA transcripts can be spliced in several
different ways
– Can yield different products/outcomes
– So, a particular DNA sequence has the potential to
do multiple things.
45. RNA splicing
• Wang et al. (2008):
– “Individual mammalian genes… may have related,
distinct, or even opposing functions.”
46. RNA splicing
• The context determines which alternative
splicing is used.
• There is variation in splicings across
individuals
– The exact same genes may do different things in
different people
– Moore: a gene in Humphrey Bogart might do
something different than the exact same gene in
Frank Sinatra
47. RNA splicing
• Alternative splicings can be affected by
experience
• Rats learning about a novel environment
– Brain cells use specific DNA segment to produce a
specific protein as they form memories of the
experience
– If given an electric shock in that environment and
form a memory association, the same DNA
segment is used to produce a different protein.
48. RNA splicing
• 1999: biologists thought that alternative
splicing occurs for 33% of DNA
• 2003: at least 74% of multi-exon genes
• 2008: 92%-93% of human genes undergo
alternative splicing
49. RNA splicing
• Some mature RNA is constructed by
combining 2+ RNA transcripts from different
sections on DNA strand
– Or even two different chromosomes
50. What does this mean?
• The gene does not necessarily have a
particular place on a chromosome
• DNA does not contain a code that specifies
particular outcomes
• Genes are used in context-dependent ways.
– DNA splicing depends on contexts
51. What does this mean?
• Genes are not able to determine phenotypes
independently of their environments.
56. Problem 1:
pluripotency-differentiation
• Pluripotency = the capacity of a embryonic
stem cell to develop into any type of cell in the
mature body.
• Differentiation = the process of developing
distinctive features of particular types of
mature cells (basically, the process of
specialization).
57. Problem 1:
pluripotency-differentiation
• Embryonic stem cells can develop into any of
the 200 kinds of cells
– Each stem cell must contain all the information
required to produce any kind of cell
– After these cells differentiate (develop specialized
features), they lose their pluripotency
• E.g., neuron cells don’t spontaneously become liver
cells
58. Problem 1:
pluripotency-differentiation
• But why do differentiated cells lose their
potential?
– They don’t actually lose the information required
to become other types of cells
• Frederick Steward (1958): grew a whole new plant from
a single root cell from a mature plant
– Instead, the information is there but somehow
locked away and inactive
59. Problem 1:
pluripotency-differentiation
• Some mechanism must allow embryonic stem
cells to selectively use a portion of the
information available
– in order to become one kind of specialized cell
and not a different kind of specialized cell
60. Problem 2:
multiple X chromosomes
• Women have two X chomosomes; men have
one X chromosome
– Genes/DNA are located in the chromosomes
– Specific genes correspond to specific proteins
– Why do women not have twice as much of the
proteins specified on their X chromosomes
61. Problem 2:
multiple X chromosomes
• Mary Lyon (1961) deduced that one of the
two X chromosomes in female embryos is
– shut down early in development
– kept in an inactive state
– Now we know of a process called X-inactivation
• Women inherit an X-chromosome from father and from
mothers
• but one is inactivated before the embryo implants in
the uterus
62. Problem 1:
pluripotency-differentiation
• X-inactivation also solves the pluripotency-
differentiation problem
– There is a system that activates some genes,
deactivates others
– Allows some cells to develop in a particular way
(depending on which genes are activated)
• And other cells to develop in a different way
• (without actually losing any information)
– This is the regulation of gene expression
63. Problem 1:
pluripotency-differentiation
• As we develop, different genes are turned on
and off in different ways
– Creating different patterns of gene expression
– Must understand how genes develop
65. Chromatin
• Chromatin is what makes up chromosomes
– Comprised of DNA and proteins (twice as much
protein as DNA)
– Proteins are mostly in the form of histones
66. Histones
• Histones help bundle DNA into chromosomes
in an efficient way
– look like spools that DNA is wound around
– Each spool is made of eight histones
– Located in chromosomes along with DNA
– Are not DNA itself but are in contact with DNA
• They are literally “epigenetic” because they are on our
genes
67. Epigenome
• Genome = our genetic features
• Epigenome = all of the epigenetic features
that characterize our cells
• The genome and epigenome are equally
influential
68. Histones
• (spools DNA is wrapped around)
• Histones influence what DNA does
– When DNA is tightly wrapped around histones, it
is silenced
• Because it cannot be accessed to be transcribed,
proteins that correspond to that particular gene can’t
be produced
• (Doesn’t change what DNA is there, just whether or not
it is used)
69. Other epigenetic mechanisms
• DNA methylation (affects DNA directly)
• Histone modification (affects DNA indirectly)
70. DNA methylation
• A methyl group (a molecule) gets attached to
a DNA strand
Moore: like “pepper
particles sprinkled on a
bowl of spaghetti might
stick to strands of pasta”
71. DNA methylation
• When methylation occurs (when methyl
groups get attached)
– The methylated section closes up and become
inaccessible—cannot be transcribed
– Hypermethylation = methyl groups get added to
DNA strand reduce expression of those genes
– Hypomethylation = methyl groups get stripped
from DNA strand increases likelihood that
genes will be expressed
73. Histone modification
• More complicated because its effects depend
on other factors
– Histone methylation can silence or activate
nearby genes, depending on other factors
74. Histone modification
• Histone acetylation = an acetyl group gets
attached to a histone
– Has opposite effect as DNA methylation
– Causes a section of DNA to open up, making that
section accessible
75. Epigenetic marks
• DNA methylation and histone modification
can influence specific DNA segments
– DNA methylation can mark the genome for life
– Histone modifications are more dynamic (change
more)
76. Epigenetic marks
• Patterns of epigenetic marks are highly
organized
– Specific genes are not permanently activated or
disabled—they undergo regular changes
(chromatin remodeling)
– Silencing/activating genes is not binary (on/off)—
probably more like a dimmer switch
• Even if binary for particular cells, effectively non-binary
in groups of same cells
77. Epigenetic marks
• Chromatin remodeling regulates what genes
do at any particular moment
– To know why a person is they way he/she is
• Just as important to understand his/her epigenetic
state as it would be to know about his/her genetic
make-up.
• In other words, knowing that a gene is present doesn’t
tell you what it is doing.
78. Experience
• The epigenetic states of some cells change in
response to experiences
– Epigenetics = “the study… of how gene expression
changes during [cell differentiation], and how
environmental factors can modify how genes are
expressed” (Lickliter, 2009).
– Behavioral epigenetics = the study of how epigenetics
influences psychological processes (Moore)
• E.g., emotional reactivity, memory and learning, mental
health, behavior
80. Example 1. Cloning
• Dolly the sheep = ewe cloned (1996, Scotland)
– Genome came from a mature (differentiated) cell
from another ewe’s mammary gland
• *Not an embryonic stem cell
– Scientists found a way to get a differentiated cell
to behave like a pluripotent embryonic stem cell.
82. Example 1. Cloning
• Several important take-aways:
1. Cell differentiation does not entail irreversible
change in genetic information
• The information for growing a whole animal is present
in mature cells.
• Cell differentiation is achieved through an interaction
between the nucleus and the cellular environment
– Dolly’s genome was placed into an already existing fertilized
egg—an environment that enabled her to development
83. Example 1. Cloning
• Several important take-aways:
2. Clones are not copies of each other or of
parent—they are not indistinguishable
• They merely have the same DNA—that’s all
• The phenotypes of different clones differ from one
another because they are the result of different gene-
environment interactions.
84. Example 1. Cloning
• Several important take-aways:
3. Cloning process returns mature cells to an
earlier pluripotent state
• Creation of stem cells that can become neurons,
pancreatic cells, etc.
• Potential for treating people with
– degenerative disorders (Parkinson’s),
– autoimmune disorder (type 1 diabetes),
– conditions associated with cell death (heart attack)
• Based in research on epigenetic processes involved in
cell differentiation
85. Example 2. Prader-Willi syndrome
• Prader-Willi syndrome = epigenetic disorder
– Characterized by
• mental retardation, tendency to overeat, obsessive
behavior, poor gross motor skills, aggression
– Associated with the deletion of genetic material
on the 15th chromosome inherited from the father
• Paternal and maternal chromosomes can differ in
epigenetic marks
– need both sets because they function differently
86. Example 2. Prader-Willi syndrome
• Prader-Willi patients: 15th paternal
chromosome is missing
– 15th maternal chromosome is epigenetically
silenced (this is normal) through “imprinting” and
cannot compensate
• At first, looked like a genetic disease
87. Example 2. Prader-Willi syndrome
• But sometimes Prader-Willi patients have two
15th chromosomes
– Have different abnormality: two 15th
chromosomes from mother
– Both are epigenetically silenced
88. Example 2. Prader-Willi syndrome
• Prader-Willi develops when required DNA
segment cannot be used because either
– Missing required information on 15th chromosome
or
– Have the information but cannot access it because
it is from the wrong parent and has been
epigenetically silenced through imprinting
91. Example 3. Calico cats
• Calico cats occur through X-inactivation
• X-inactivation differs from imprinting:
– X-inactivation only occurs in females (why?)
– X-inactivation occurs early in the development of
the embryo (imprinting occurs before conception)
– X-inactivation affects more genes (more than 1000
genes)
– X-inactivation proceeds regardless of whether the
X chromosome came from father or mother
(imprinting is parent-specific)
92. Example 3. Calico cats
• Which X chromosome will be inactivated is
random
– In any particular cell of a female, the inactivated X
chromosome could be from mother or father
– Female mammals = epigenetic mosaics
• X chromosomes from different cells can be in different
epigenetic states
• Calico cats: can actually see the epigenetic mosaic
93. Example 3. Calico cats
• Calico cats are virtually always female
– One gene in X chromosome is used to produce
pigment—either black, white, or orange-ish
– Male cats only have on X chromosome have a
solid color
– Some female cats get same gene (same sequence
information) from both parents have a solid
color
– Some female cats inherit different sequence
information from parents calico coat
94. Example 3. Calico cats
• New female cat embryo
– Inherits one X chromosome that says orange fur
and a second X chromosome that says black fur
– In each cell, one of these chromosomes will be
inactivated (X-inactivation), sometimes orange,
sometimes black
– When the cell divides, the daughter cells inherit
the activation pattern
– Result: groups of related cells in a given region
95. Example 3. Calico cats
Inactivated black pigment gene
Inactivated orange pigment gene
96. Example 3. Calico cats
• House pet clone: owner sought to reproduce
calico cat name Rainbow
100. X-inactivation center
• A portion of the X chromosome that has a role
in the inactivation process
– X-inactivation center is present on all X
chromosomes
• can produce an RNA transcript but only in X
chromosomes that are about to be inactivated
• RNA transcript (XIST) generated by X-inactivation center
is responsible for inactivating the chromosome that
generated it (a self-destruct switch?)
• XIST = transcript for noncoding RNA
102. X-inactivation center
• When X chromosome expresses XIST
– XIST attaches itself to that chromosome and
covers it, makes it less accessible
– XIST also attracts other molecules to the nearby
histones, makes transcription increasingly difficult
– Increased methylation makes transcription even
more difficult, maintaining inactivity of X
chromosome
– Cascade of epigenetic events
103. XIST
Moore: “In the end, an X chromosome that has expressed XIST winds up slinking off to
the side of the nucleus while becoming compacted into a small, ineffectual, nearly
silent blob of chromatin.”
