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Fundamentals I
September 25, 2008 Pittler
11:00-12:00
Slide 1 and 2: Introduction
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Covers office number and cell number. Contact him if you need help. The book for this
class is not required but is recommended and is called: Human Genetics, by Ricky Lewis.
Slide 3: Inheritance
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We are going to start with classical genetics today
Inheritance:
o Parents and offspring often share observable traits. We know that.
o Grandparents and grandchildren may share traits not seen in the parents, it might
skip generations.
o Why do traits disappear in one generation and reappear in another? How does
that work?
Slide 4: Gregor Mendel: the father of modern genetics
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The first person to really take a serious look at this was Gregor Mendel, the father of
modern genetics. He combined plant breeding, statistics, and careful recordkeeping and
he described the hypothesis of transmission of traits.
Remember, this was more than one hundred years ago, and he did this without knowing
about genes or chromosomes, all he saw was the observable trait- the phenotype of
plants- what he did was describe the hypothesis of transmission of traits and we now call
this the laws of inheritance.
Slide 5: Mendel studied pea traits with two distinct forms
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So how did he do this? He looked at pea plants (studied pea traits).
What you see on the top part of this figure are dominant traits, and the bottom part is
recessive traits. Mendel looked at how those traits segregated.
For instance, what happened when two pea plants were crossed (one tall, for example,
with one that was short)? Why do we sometimes take a tall and cross it to another tall
and ultimately in successive generations we get short plants? Why is that?
Slide 6: True breeding plants
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If you take two short plants, you are going to get all short offspring. If you take two tall
plants, you will get all tall offspring (in some cases) in the next generation. These are
what we call “true breeding”.
They are plants which consistently have offspring with the same trait.
Slide 7: Monohybrid cross
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What happens when true breeding plants with two distinct forms of a trait are crossed?
So it is no longer true breeding- they have two different traits, tall and short for example.
So, in the figure, the parents are tall with all tall offspring. The progeny only show one
form of the trait. (he says next “so if they are true breeding.” Before he said this was not
true breeding…). The observed trait is called dominant.
We know that one of these plants has the potential to generate a short plant, yet they are
all tall because of the dominant tall trait. The masked trait (the one we don’t see in the
phenotype) is the short.
Slide 8: Test cross
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We can do a test cross to see if the plant showing the dominant trait is true-breeding or
not.
How do we do that? You test cross by crossing it with a plant showing the recessive trait.
Here we take a short plant (recessive) and we cross it with a tall plant and we get all tall
offspring. All tall offspring indicate that the parent is true-breeding.
In the figure on the right, we take a tall plant and a short plant and we get some tall, some
short offspring. There we have unmasked the recessive trait. Mixed offspring indicate
that the parent is hybrid (has the recessive trait as well as the dominant trait).
Slide 9: Crossing hybrids to each other
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The hybrid parents show the dominant trait (tall) and the offspring dominant trait (tall)
and true breeding will be ¼ of the total. (We’ll see how this works in a moment. The
dominant trait (tall) and NOT true-breeding is ½ of the total. The recessive trait (short)
and always true breeding is ¼ of the total. Why is that?
Mendel concluded that among the hybrid parents the short trait (recessive) was hidden
but not absent.
Slide 10: Menel’s data So here is his actual data:
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He crossed true-breeding plants differing at one of seven traits. (He didn’t just do 1 or 2
crosses, he actually looked at thousands of them)
He crossed hybrid offspring to each other, and those all showed the dominant trait.
Then he counted the offspring of hybrid crosses.
Here is what he got (see table on slide)
o Notice in each case, he looked at different traits and what he got for the
percentage with the dominant trait verses the percentage with the recessive trait
always came up in a 3:1 ratio. (So, exactly what you would predict if these traits
were segregating independently).
Slide 11: facts
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If you know the genotype of the parents, it is possible to determine the gametes (the
gametes are what will be passed on to generate the offspring- one gamete from each
parent) and use a Punnet square to determine the phenotypic ratio among the offspring.
When a monohybrid reproduces with a monohybrid, the results are 3:1. (you will always
have 3 dominant and 1 recessive)
This ratio is used to state the chances of a particular phenotype.
A 3:1 ratio means that there is a 75% chance that the dominant phenotype will occur and
a 25% chance that the recessive phenotype will occur.
Of course when you do this (when you actually cross the plants) it doesn’t come out
exactly as you see in the slide (3:1), but if you do a sufficient number of them, you will
get that ratio.
Slide 12: Punnett Squares
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Here is a Punnett square. The genes from one parent go in one of the top boxes and the
genes from the other parent go in the side boxes.
Slide 13: Punnett Squares
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TT is our tall plant, tt (small t’s) is our little plant.
In this case you have a parent that is homozygous for the tall (TT) and the other plant is
homozygous for the short (tt). Cross those together and you get all heterozygous (Tt) in
the F1 or first familial generation.
Slide 14: Gamete formation (sperm and eggs)
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Because homologous pairs separate during meiosis (we will go over meiosis in a minute),
a gamete has only one allele from each pair of alleles. So each gamete is only going to
present one allele, not both alleles like you would have in a normal cell; so the germ
cells, in other words, are not diploid.
If the allelic pair is Tt (big T little t), a gamete would contain either a big T or a little t,
but not both. Big T little t (Tt) represents the genotype of an individual. So what’s the
actual gene that can go down into the gene sequence of that individual. Gametes are
represented by either T or t.
Slide 15: One-Trait Crosses and Probability
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So how do we look at the probability? When you are looking at human disease, you can
look at the probability of the trait showing up in an individual (we can determine what the
risk for each individual is).
Laws of probability alone can be used to determine results of a cross.
The laws are:
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o the probability that two or more independent events will occur together is the
product of their chances occurring separately (so it’s additive. We’ll see that in a
moment).
o the chance that an event that can occur in two or more independent ways is the
sum of the individual chances
o so one is the product (multiplication) and one is additive.
Slide 16: facts *note: if your slide says Tw on it, it should be corrected to say Tt.
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In a heterozygous cross (two Tt’s), what is the chance of obtaining either a big T or a
little t from a parent?
The chance of a big T is ½, the chance of little t is ½: there is a 50/50 chance (it will
pass either T or t)
The probability of these genotypes is:
o The chance of TT = ½ x ½ = ¼ (product of the two)
o The chance of Tt = ½ x ½ = ¼
o The chance of tT = ½ x ½ = ¼
o The chance of tt = ½ x ½ = ¼
So the chance of each combination is ¼. So if you look at all that have a big T (tall
plants), you get a 3:1 ratio. So, you cross two heterozygotes, you end up with a 3:1 ratio
and the chance, then, of tall plants is 75%. (¼ + ¼ + ¼ = ¾ or 75%)
o We can do that for any single allele.
Slide 17: Law of segregation
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Why do traits “disappear” in one generation only to reappear in a subsequent generation?
Looking at the plants again, each plant possesses two distinct separable units (which we
will call alleles) for each trait inherited from each parent.
o So for every single trait on the 35,000 or so genes that are in the genome, each
one of those is passed, one from each parent under normal conditions.
The gametes contain one allele from each (the gamete -being the sperm or egg- will
contain half of the set.
Only one version is observed in an individual.
The unit (allele) does not disappear. It may be present but hidden, as we saw in the
plants.
Slide 18: Gene locus (locus=location)
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Let’s go to eukaryotes, let’s go to what you see in humans.
Here you have the representation of a chromosome, each allele of a chromosome. It’s
connected by the centromere. You can see representative alleles, so we can call this a
particular gene that has a dominant allele and a recessive allele (Gg, Rr, Ss, zZ), you can
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see that there are different combinations of those alleles on each one of these sister
chromatids. Under normal conditions, when you duplicate the chromosome, you
duplicate each one of the alleles.
Slide 19: Law of segregation
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Everyone should remember, you’ve had mitosis and meiosis.
If we look at the two different parents here (parent 1 and 2) going to the production of
gametes. You can see that there are segregations of each one, each one is duplicated and
then segregated into a gamete. So the chance of each one of these getting together to
make the final offspring… you can see how that segregation occurs.
The segregation of the two is independent.  that is Mendel’s second law.
Slide 20: Alleles
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Mendel’s units, or “elementen”, are what we call alleles.
o They are versions of the same gene or DNA sequence. There’s a slight
difference, it might be a single nucleotide difference that makes them different
alleles.
o They differ in DNA sequence at one or more sites.
Slide 21: Genotype and Phenotype: some definitions
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Genotype indicates the combination of alleles present. Basically, it is the actual sequence
of the gene.
o Homozygous alleles by definition are the same.
o Heterozygous alleles differ by at least one nucleotide, they might have huge
differences.
Phenotype indicates the trait observed. How the particular sequence of the genotype
outwardly expresses itself.
These terms distinguish the observed form and the underlying alleles present.
Slide 22: Genotype and Phenotype
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If the phenotype is a tall plant, homozygous dominant is going to be abbreviated TT (tall
associated alleles), and heterozygous is going to be abbreviated Tt, and a short plant
homozygous is going to be tt (recessive alleles)…
o If you have a gene defect, and it’s the recessive defect… say it’s Huntington’s
disease, we can use HD “big” or hd “little” to represent that. We’ll see how this
works in a few minutes.
Slide 23: Modern terms for Mendel’s crosses
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Mendel’s true breeding plants were homozygous (we now know that they are
homozygous- Mendel didn’t use that term) for the alleles of a trait.
Mendel’s hybrid plants were heterozygous for the alleles of a trait.
Slide 24: Wild type
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The most common version in the general population, we are going to call wildtype.
“If you really look at it carefully, there is no such thing as wildtype, but it can be
wildtype for any particular trait… so how do we define normal?”
In fruit flies and mice we can do that rather easily. In humans, we generally avoid
looking at such characteristics that way.
The mutant phenotype: different from the wildtype in some observable way.
The wildtype allele is the most frequent allele associated with the common phenotype.
o What you see in the population that most people have… can define what’s normal
and what’s not.
The mutant allele is the allele that is associated with the mutant phenotype.
Slide 25: Law of segregation: the monohybrid cross
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Going back to the Punnett square. Two heterozygous parents produce the gametes and
can arrange with T or t allele equally frequently.
If each one of the parents is heterozygous, this is what you will get: a 3:1 ratio.
o The genotype of the offspring is ¼ homozygous, ½ heterozygous, and ¼
homozygous recessive. Together, they are ¾ tall and ¼ short (3:1)
Slide 26: Mode of inheritance
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Mode of inheritance indicates the patterns with which the mutant phenotype is associated.
So what are the modes of inheritance, how can a particular disease gene transmit to the
offspring? The most common are: autosomal recessive, autosomal dominant, and Xlinked recessive.
o Autosomal recessive (that means it’s on one of the chromosomes 1-22)
 There are 23 pairs of chromosomes. Males have XY, females have XX
chromosomes 1-22 are called the autosomes; chromosomes XY/XX are
called the sex determining chromosomes.
 Autosomal recessive, then, is a recessive disease which occurs on the
autosomes.
o Autosomal dominant: a dominant disease- only need a single change on one allele
o X-linked recessive: need a change on both alleles on the X chromosome… this
only makes since in a female because you have two X chromosomes only in a
female. In the male, you only have one X chromosome, so you would call that a
hemizygous state.
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The male will definatley not have the disease unless he is in a hemizygous
state and only has one copy of it. The female would not have the disease
because she has both alleles.
o Then you have X-linked dominant which is very rare. Males and females could
have that. If the male or female gets a bad X chromosome, they will have the
disease.
o Y-linked (holandric). Very rare. One of the things you see is excessive hair
around the ears (an example of a Y-linked disease)
o Mitochondrial transmission is also seen. I don’t know if in dentistry there are
diseases which are mitochondrial, but in the eye there are certainly diseases which
are mitochondrial in origin, like hereditary optic neuropathy.
Slide 27: Autosomal dominant inheritance
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Heterozygotes exhibit the affected phenotype. So if it is dominant and you have the bad
gene, you are going to have the disease, end of story. Here you see an example of that.
Males and females are equally affected (if it is passed to that individual, its autosomal).
Affected phenotype does not skip generations.
Remember: all of the things we talk about are absolutes. In humans, we generally do not
have any absolutes, so you can have dominant disease with reduced penitrance… the
individual has the mutant gene, yet they do not show the phenotype.
o This is due to a number of different reasons, including the genetic background,
which can modify it
o Know that when I give you the absolutes, this accounts for 80-90% of all disease,
but there are a number of diseases that do not fit the pattern. (Not quite true
Mendellian).
Slide 28: Autosomal recessive inheritance
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Heterozygotes carry the recessive allele but exhibit the wildtype phenotype.
o So if you only have one bad copy, you have the potential to pass it on to your
offspring, but you do not get the disease.
Males and females are equally affected and may transmit the trait.
As you can see in this figure, the unaffected non carrier is 25 % when the parents are both
a carrier (they each have the allele). One out of 4 children is likely to get the disease.
You should know that this is only the probability. Sometimes you beat the odds and have
8 children of whom none have the disease. Sometimes you don’t beat the odds in a big
way and you have 8 children and 6 of them have the disease. So in small groups, you
must consider the risk very carefully. If we take 10,000 fruit flies and mate them, you
can see the expected distribution.
It may skip generations.
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Slide 29: Comparison of autosomal dominant and autosomal recessive inheritance
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Males and females are affected in autosomal dominant and autosomal recessive.
Males and females transmit the trait in both autosomal dominant and autosomal
recessive.
o They transmit the trait in the genotypic sense, not in the phenotypic sense. So if
they transmit the disease causing gene, and it’s autosomal recessive, then both
parents have to transmit to see the disease, but each individual parent has the
potential to transmit the disease causing gene.
Trait does not skip generations in autosomal dominant but does skip generations in
autosomal recessive.
At least one parent of affected child must be affected in autosomal dominant- we are
saying that if they have that bad allele, they will have the disease (how can a parent pass
on an allele if they don’t have it themselves?). But, in autosomal recessive this is not the
case.
Slide 30: Law of independent assortment
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Two genes on different chromosomes segregate their alleles independently.
o If you have two different genes that do not go together, each one segregates.
The inheritance of an allele of one gene does not influence which allele is inherited at a
second gene.
o Another way of saying that the genes segregate independently.
Slide 31: Law of independent assortment
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So we look again at meiosis. Here is your diploid reproductive cell and we are ultimately
going to go to our haploid gametes.
Here you see two possibilities that can happen in metaphase.
If you look at each one of these you can see we are just following two traits here (RR and
YY) and you can see the possibilities for how these segregate.
o In this case you have the homozygous YY and homozygous RR for the dominant,
and here you have homozygous transmission for the recessive
o The last two you have a mixture of the dominant and the recessive for the two
different alleles.
What are the possibilities then for transmission to the gametes? Each one of these will
transmit one allele to the gametes. Your possibilities here is that you are going to
transmit 2 that are homozygous for the recessive and here you are not going to have
anything that is homozygous for the recessive.
So alternative 2 in the figure is where you have a better chance of ending up with a
normal condition
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Slide 32: Independent assortment of two traits
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In a dihybrid cross, parents with two differing traits are crossed. Which allele is
dominant? Use the Punnet square again.
If we take a round yellow crossed to a wrinkled green, and all F1 plants are round yellow,
what does that tell us? It tells us that the round is dominant to the wrinkled and the
yellow is dominant to the green.
o It’s very simple and we can follow how that occurs. (see image) If these are
recessive and these are dominant, you can see that everything you get is going to
have a dominant allele, therefore it is going to be round yellow.
Slide 33: Two traits segregating independently
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You can follow it on the punnet square. Crossed a round yellow (RRYY) with a
wrinkled green (rryy)- the offspring are all F1 plants that are round yellow heterozygotes
(have the dominant alleles for R and Y) .
For the next generation when we cross the two heterozygotes for each one of these traits,
you can see that for all of the traits, you will end up with 16 possibilities (instead of 4)
and that ratio is going to occur at a 9:3:3:1.
Slide 34: Pedigrees: Now let’s consider what we see more in humans. (what a clinician or
genetic counselor will do:
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They will collect the family history and make a pedigree chart. They will follow how a
particular disease gene segregates within the family. They will do that using the symbols
listed in this chart.
o A circle or a square that is not filled in is a normal female/male. If they are
homozygous affected the shapes will be filled in. A heterozygous carrier will be
indicated by a half filled in shape.
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o If they are already dead at the time the information was taken they will put a line
through it (and if the information is available, the shape will be filled in correctlyif they know that the person was heterozygous, then it will be half filled, or if
homozygous, the shape will be filled.
o If they don’t have the information or the child was expected but not born yet, it
will be written as a diamond.
o If it is a stillbirth, SB will be written underneath
o A pregnancy will have a P inside the shape… if the sex has not been determined,
it will be a diamond with a P in it.
o If it is a spontaneous abortion, it will be written as a triangle
o A terminated pregnancy (abortion) will be written as a triangle with a line through
it.
o Each generation is going to be one line down.
o Parents are connected by a single horizontal line.
o Adoptions are shown by a dotted line. (no hereditary transmission)
o Siblings are shown this way (see figure)
o Twins are shown this way (see figure)
o If there is close relationship of the parents (brother/sister, first cousin) then it is
written as a double line.
o A former relationship, remarried or whatever it may be, it will be written “that
way” (see figure).
o The proband (the person that came to the office with the disease) is the person
that prompted the pedigree analysis.
o We will use Roman numerals for successive generations and Arabic numerals for
individuals in a generation.
Slide 35: Autosomal dominant inheritance of brachydactyly
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Here we have an example of a pedigree. Generations are listed in Roman numerals,
individuals listed in Arabic numbers. So the only information we have on the original
parents (grandparents if considering 1 as the proband) that we are following is that one is
affected and that one also has a brother and a sister… (We don’t we have any other
information on the other grandparent so it won’t contribute to the pedigree)
This produces 5 offspring, 3 of which have the disease. This is autosomal dominant
transmission (mode of transmission).
o It can’t be X-linked because if it were, then the father (who has the disease) could
only pass it to the daughters- because for the males he is going to pass on his Y
chromosome and for the females he is passing his X chromosome… so if the
fathers X chromosome is affected, then ONLY the females could have the
disease.
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o We generally don’t even consider Y linked and since he is passing it to the
females, it is obviously not Y linked.
o Mitochondrial is generally not the first thing we look at either. If it were
mitochondrial, it would be completely non-Mendelian, and that is a different
issue.
o So let’s look at how he is passing the gene. If he is recessive and she doesn’t
have it then you can’t get affected offspring
o Therefore, this must be a dominant transmission: it doesn’t skip generations and
we have ruled out X-linked transmission.
Slide 36: Autosomal recessive inheritance of albinism
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For autosomal recessive, we look at carrier states, so it is a question of whether they have
one affected allele or both.
In this case, you have two parents (in the grandparents generation) that are unfortunate
enough to pass the alleles to their children (male and female) that are heterozygous for
the recessive allele. (don’t have the disease but are carriers and can pass it along)
They were not lucky in the transmission and two of their children are homozygous for
that recessive allele.
Can it be X-linked? No because since the female has it in the first generation, both of her
offspring would have to be carriers.
To look at whether it is dominant, we see that it has skipped generations and therefore
cannot be dominant and must be recessive.
Slide 37: Genetic predictions
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Ellen’s brother Michael has sickle cell anemia (RBC’s sickle up and can’t pass through
properly), an autosomal recessive disease. What are the chances that Ellen’s child has a
sickle cell anemia allele?
We make a pedigree. From the pedigree, Ellen and Michael’s parents must be carriers.
If it’s a recessive disease and this child has it, then these two must be carriers.
Let’s say little a is sickle cell and big A is normal. If the parents are carriers, then they
must have passed it in this format: (see punnet square). Ellen here (the spot that is
crossed out) is not affected and therefore cannot be recessive (she doesn’t have the
disease so she can’t be recessive). What is the chance that Ellen is a carrier? 2 out of 3
total. What is the chance that the child inherits sickle cell allele? ½ (a 50/50 chance).
The overall chance that the child carries sickle cell allele from Ellen must be the product
of those two: 2/3 times ½ = 1/3. So there is a 1 out of 3 chance.
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