Welcome to Genome 351!
Human Genetics
April 1, 2013
There is still space available in this
course; if you are not registered and
wish to take this course, see me during
the break, or immediately after class
Welcome to Genome 351!
Human Genetics
March 28, 2011
There is still space available in this
course; if you are not registered and
wish to take this course, see me during
the break, or immediately after class
Course goals
-Basic understanding of the concepts of
(human) genetics
-Be able to critically read the science
section of the New York Times
-Informed citizen, voter, health consumer
Genome 351 – Human Genetics
Instructors:
Evan Eichler on 4/5
Leo Pallanck (4/1-5/3)
Evan Eichler (5/6-6/7)
Office hours (by appointment): Fridays 1:00-2:00PM
Teaching Assistants:
Adam Gordon; Office hours: Thursdays 4:00PM 5:00PM S-110
Blake Hovde; Office hours: Wednesdays 2:30PM –
3:30 PM S-110
Discussion Section (AA) Wednesday 10:30-11:20 AM S110
Discussion Section (AB) Wednesday 1:30-2:20 PM S110
NO DISCUSSION SECTION THIS WEEK
General course information
Suggested Textbook:
The Human Genome -- A User’s Guide,
Julia E. Richards & R. Scott Hawley
Elsevier Science in Society Series, 3rd ed.
2010
Course website:
http://courses.washington.edu/gen351/
Will use course website to post:
-announcements (e.g., room changes)
-suggested reading
-lectures; problem sets; answer keys
This
week:
Chapters
1&2
Course content
4/1-5/3: Basic Genetics/Molecular Biology (Leo Pallanck)
-Mendel’s Laws & Segregation
-DNA Replication
-Transcription, Splicing & Translation
-Cell Cycle, Mitosis & Meiosis
-Recombination & Aneuploidy
-Mutations
5/6-6/7: Human Genetics/Disease (Evan Eichler)
-Human Genome
-Human Molecular Evolution
-Population Genetics
-Mapping Genetic Traits
-Disease Mechanisms
-Cancer Genetics
-Stem Cells & Gene Therapy
Grading
• Midterm exam (125 points)
• Final exam (125 points) – not cumulative, but…
• Six problem sets (60 total points) – handed out
on Fridays, due the following Friday
• 2-3 Discussion section debates (40 points)
Grading on curve; mean = 2.8
To pass the course you must receive a minimum
of 175 points
No make-up Exams!
How to succeed in this course
» Attend class (lecture and discussion section)
» If you don’t understand something, don’t wait… ask
for help! Can you explain today’s lecture to your nonscientist parents/friends without referring to the
notes?
» Use the book as a resource to understand the
lectures
» Work the problem sets/make sure you understand the
answers
» Form study/discussion groups
» Make use of help time!
Today…
Genome 351, 1 April 2013, Lecture 1
»
Outline of course
»
Pedigrees (example: cystic fibrosis)
» Mendel’s experiments with pea plants
»
Proteins
»
Cells
Cystic fibrosis
-Inherited disease that affects the lungs and digestive
system
-Affects ~30,000 children and adults in the United
States (~70,000 worldwide).
-A defective gene and its corresponding protein product
cause the body to produce unusually thick, sticky mucus
that:
* clogs the lungs and leads to life-threatening lung
infections; and
* obstructs the pancreas and stops natural enzymes
from helping the body break down and absorb food.
A simple pedigree
Two unaffected individuals have three children, the
youngest of whom has cystic fibrosis (CF)
= cystic
fibrosis
= Normal
How can you tell if CF
is a genetic disorder?
A larger family
Two unaffected individuals have eight children, two
of whom have cystic fibrosis
Does this tell you
that CF is a genetic
disorder?
What else might
you want to know?
Another generation
Building pedigrees
= Unaffected male
= Affected male
= Unaffected female
= Affected female
= Deceased male
= sex unspecified
Horizontal line = mating
Vertical line = offspring
= Identical twins
Building pedigrees (cont’d)
=
Building pedigrees (cont’d)
I
II
=
III
Proband: affected
individual who first brings
attention to the trait
Some early theories on heredity
• Blending of traits
• Vital spark (paternal or maternal)
• Sperm carries preformed individual
(homunculus)
Gregor Mendel (1822–1884) introduces a
more systematic approach
Reasons why Mendel was successful:
• Choice of a good model organism—garden pea
-
relatively short generation time—one per year
lots of progeny per cross
self-pollination and out-crossing possible
true-breeding strains readily available from local
merchant
• Choice of clear character differences to track
- Yellow vs. green seed pods, round vs. wrinkled
seeds, purple vs. white flowers, etc.
• Careful mathematical analysis of the results
- allowed him to develop and test specific models
Mendel’s experiments
Establish true-breeding
strains, each of which exhibit
clear character differences
crosses within the true-breeding
population yield progeny that show
the same trait as the parent
x
x
Make crosses between
different true-breeding
strains
Identify and count the
progeny traits (phenotypes)
Make crosses between the
progeny…
x
??
…are the progeny traits (phenotypes)
like one parent or the other? How
many of each class are there?
Results of Mendel’s experiments:
Generation
I:
True-breeding
green pea pod
strain
x
True-breeding
yellow pea pod
strain
Predictions of:
Blending Hypothesis
Greenish/yellow
Vital spark Hypothesis
All Green or yellow
Homunculus Hypothesis
All Green or yellow
Actual results:
Generation II:
Reciprocal
cross gave
same result
What happened
to the yellow
seed pod trait?
Hybrid pea
plants
The yellow trait returns in generation III
True-breeding
green pea pod
strain
Generation
I:
x
True-breeding
yellow pea pod
strain
Hybrid pea
plants
Generation II:
Cross hybrid plants to one another (or self-cross)
Generation III:
in 3:1 ratio (green:yellow)
was this just
a peculiarity
of the seed
pod color
trait?
Identical findings seen with other traits…
Parental Phenotypes
Gen II
Gen III
Ratio (gen III)
1. Green X yellow pod
Green
428 Green
152 yellow
2.82 : 1
2. Yellow X green seed
Yellow
6022 yellow
2001 green
3.01 : 1
3. Purple X white petal
How
3.15 : 1
4.
Purple
705 purple
did
Mendel
224 white
interpret these
Inflated X pinched pod Inflated 882 inflated
findings? 299 pinched
2.95 : 1
5. Round X wrinkled seed
Round
6. Axial X terminal flowers Axial
7. Long X short stem
Long
5474 Round
2.96 : 1
1850 wrinkled
651 axial
207 terminal
3.14 : 1
787 long
277 short
2.84 : 1
Mendel’s interpretations
Both parents contribute a “determinant” (gene) that
influences the seed pod color trait
The “G” or
“g” gene
Truebreeding
green pea
pod strain
x
Truebreeding
yellow pea
pod strain
Each parent randomly donates only one of their two genes
for any given trait to their offspring
Mendel’s interpretations
There are two forms of a gene (alleles) for the seed pod color
trait; the trait conferred by one allele (recessive) can be
masked by the trait conferred by the other allele (dominant)
alleles:
variants
of a gene
Truebreeding
green pea
pod strain
x
Truebreeding
yellow pea
pod strain
recessive
dominant
The g allele (which confers yellow seed pods) is recessive
to the dominant G allele (which confers green seed pods).
Mendel’s interpretations
Genes are particulate (i.e., do not mix); recessive traits that
are not evident in heterozygotes can be unmasked in progeny
True-breeding
(homozygous)
green pea pod
strain
Generation
I:
Generation II:
x
True-breeding
(homozygous)
yellow pea pod
strain
Hybrid
(heterozygous)
pea plants
Cross hybrid plants to one another (or self-cross)
Generation III:
The recessive trait
reappears intact in
generation III
How did Mendel explain the 3:1 ratio?
-The Punnett Square
gametes = sperm or eggs
x
male gametes
female gametes
G
g
G
g
Explains the 3:1
ratio in the
Generation III
offspring from
Mendel’s crosses
General conclusions of Mendel’s work
1. Many traits (phenotypes) are determined by genes
2. Gene variants (alleles) can confer dominant or
recessive traits (phenotypes)
3. There are two copies of each gene
4. Each parent randomly transmits only one of their two
alleles of a given gene to their offspring
Some vocabulary
Gene: unit of information passed from one generation to
the next.
Alleles : variants of a gene (e.g., yellow vs. green)
Homozygote: both copies of the gene are the same
Heterozygote: the two copies of the gene are different
Genotype: the information specifying a trait
Phenotype: the manifestation of the trait itself
Genotypes?
GG
Gg
gg
Gg
Phenotypes? green green yellow green
Information passes from one
generation to the next!
Applying Mendel’s principles to CF
Two unaffected individuals have eight
children, two of whom have cystic fibrosis
C = common allele
c = cystic
fibrosis allele
C?
cc
Cc
C?
Cc
C?
C?
cc
C?
What are
the odds
that this
child is a
carrier?
C?
The Punnett Square
Cc
Heterozygous parents
C
C
c
CC
Cc
Cc
cc
Cc
c
Applying Mendel’s principles to CF
Two unaffected individuals have eight
children, two of whom have cystic fibrosis
C = common allele
c = cystic
fibrosis allele
C?
cc
Cc
C?
Cc
C?
C?
cc
C?
What are
the odds
that this
child is a
carrier?
C?
The cystic fibrosis gene specifies
a membrane protein
Proteins are the workhorses of the cell
• Many sizes and shapes
– Rod-like, globular
– Single subunit, multimeric
• Many distinct properties
– Water soluble, lipid loving
• Many functions
– Structure, catalysts, motors, signals, pumps
• Mutations often alter proteins
Including cystic fibrosis
Cystic fibrosis is recessive
The allele that predominates in
the population
+
Homozygous (wild-type)
Heterozygous
CFTR
CFTR+
Homozygous (mutant)
NO
CFTR+
CFTR-
A rare allele in
the population
Cystic Fibrosis
NO
CFTRCFTR-
YES
One wild-type version of the gene is sufficient
But what are proteins (chemically)?
Polymers of 20 different amino acids
(only 11 can be made by humans, others
must be obtained from the diet)
Have a repeating backbone structure
Distinguished by their
side chains (R groups)
The 20 amino acids
Proteins adopt a variety of structures
•Average protein = 300 to 400 aa’s
•Variety of linear amino acid sequences is almost infinite...
e.g., a protein of 100 amino acids made with the 20
different known amino acids can have 20100 different
linear sequences
•Frequently have globular (spherical) 3-D shapes & are
negatively charged
•E. coli (human intestinal bacteria) makes about 3,000
proteins
•humans make about 100,000 different proteins with
25,000 genes (WOW!)
Distinct proteins are different length
chains of different amino acids
Insulin -- Met-ala-leu-trp-met … glu-gln-tyr-cys-gln (110 aa)
Collagen -- Met-his-pro-gly-leu … cys-met-lys-ser-leu (1678 aa)
ß-Hemoglobin -- Met-val-his-leu … ala-his-lys-tyr-his (147 aa)
Protein
Function
Actin, myosin
Antibodies
Muscle contraction
Immunity
Hemoglobin, myoglobin
Insulin, glucagon
Collagen
Kinases
Oxygen transport
Blood glucose control
Tendons,dermis
Modulate protein activity
Dehydrogenases
Thrombin, fibrinogen
Keratin
Metabolism
Blood clotting
Hair and skin
Trypsin, proteases
Digestion
Polymerases
NaATPases
DNA, RNA synthesis
Ion pumps
Collagen
Albumin
Cells -- the basic unit of life
• Organisms can be single cells (e.g., bacteria, yeast)
or collections of many cells
• Prokaryotes (bacteria) lack a nucleus
The Basic Unit of Life
• Eukaryotes have a nucleus and other compartments
42
An animal cell
• Surrounded by the
plasma membrane
• Contains a nucleus
(where >99% of the
genes are located) and
cytoplasm with
specialized organelles
•Come in many
different shapes
The plasma membrane
The cystic fibrosis gene specifies
a membrane protein
Mitochondria
• Site of ATP
(energy) production
• Has its own
circular DNA (<1%
of the cellular
genes located here)
• Mitochondrial
genes are inherited
from the mother
Human Cells
• Hundreds of cell types
• Several categories
– Epithelial (skin, intestinal, lung,
but also pancreas, liver, kidney)
– Muscle
– Nerve
– Connective
– Blood
Levels of Organization
•
•
•
•
•
Organism
Organ systems
Organs
Tissues
Cells
Next time…
DNA is the genetic material
Structure of DNA reveals a digital code
Replication of DNA
CFTR regulates Cl- transport across membranes
Gene responsible for Cystic Fibrosis
Cystic Fibrosis
Affected persons can have unaffected parents
Disease can skip generations
Both sexes equally affected
Genetics of Cystic Fibrosis (CF)
* Autosomal recessive trait
* ~1/25 Caucasians is a carrier
* ~1/65 Africans is a carrier
* ~1/90 Asians is a carrier
* Gene lies chromosome 7q31.2
* Gene encodes a chloride channel expressed in
lung, skin and pancreas
* DNA diagnosis in utero