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[Instructor] Hello and
welcome to Module 5.

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So, we'll go

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through three different
lectures in this module.

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In the first one we're going to start

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with really thinking about
how to piece together

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some of what we've learned in
the first couple of modules

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to expanding that to
patterns of inheritance

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and the actual traits that you see.

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So we're gonna start this with a lecture

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called "Genotype to phenotype."

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And as you remember, a
genotype is the sequence

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of a particular gene.

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So if someone has, say, a disease mutation

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that causes a disease,

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it's the actual mutation and the sequence

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of the gene itself, that's the genotype.

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The phenotype is the trait.

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That's actually what you see in a person,

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and that might be the disease, a disease.

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It might be something else,

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like eye color, hair color, height.

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These are all traits.

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These are all phenotypes that are affected

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in some cases directly caused by,

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and in some cases just affected

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by a particular gene
sequence or the genotype.

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So genotype determines phenotype.

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So that we're going to actually take this

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and look into it in a
little bit more depth

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and better understand
how can we transition

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from what we've learned

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about gene sequences and gene expression

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and transition that to the
actual traits that we see

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and take that into the
next couple of lectures

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where we start to think
about patterns of inheritance

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that you might record, say,

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in a pedigree from a family history

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that a patient might give you.

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Let's do a quick review.

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DNA sequence is copied into
mRNA during transcription.

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mRNA sequence is read as codons

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or triplets of bases in a specific order.

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And this will become really
important when we start talking

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about different kinds of mutations

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and the impact that
can have on the protein

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that's made from the
instructions from this gene.

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During translation, each codon
encodes for one amino acid

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or instructs the ribosome
to stop translation.

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So you remember that there
are 20 different amino acids

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and each one of those has a
couple of different codons

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that can encode for it.

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And a codon, as you recall, is just a set

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of three bases together,
but in a specific order.

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So if you remember, there
was that codon table

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and you can double
check that if you'd like

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to refresh your memory of
what that actually was,

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but that was where you
have, it's that table

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and you have basically the first base

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on the left hand column,

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the second base going horizontally across,

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and then the third base going
down on the right hand column.

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And you can look on the
table for any combination

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of three bases and see
which amino acid it encodes

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or if it encodes for a
stop signal, for example.

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Proteins are made up of a chain

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of amino acids strung
together in a specific order

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to give the protein its
specific shape and function.

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Proteins do virtually
everything in a cell,

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so getting the amino acid
sequence exactly correct

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is really important.

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And in some proteins
and some specific parts

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of certain proteins, if there
are changes in amino acids,

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it may not actually affect
the protein's function,

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but certainly for others there are regions

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of the protein where
getting the exact amino acid

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in the exact right order
is absolutely critical

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and can completely change

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or even eliminate the normal
function of the protein.

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Here are a few important terms

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and definitions that we'll talk about

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in this particular lecture.

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So first of all, genotype.

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This is the nucleotide sequence of a gene.

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So genotype is the sequence
of a particular gene.

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The phenotype, this is the
trait or characteristics

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seen in a person.

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So an example would be
the presence of a disease.

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Another example of a phenotype
would be eye color or height

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or whether or not a person
develops type 1 diabetes.

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These are all called phenotypes.

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So it's basically what you would see

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or experience in a person.

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The genotype is the DNA sequence
for the particular genes

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that would affect the phenotype.

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And allele, this is an
important definition

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and one I'd I'd like you
to try to pick up on,

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because we're going to
start using this term a lot

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and it's important that you
understand what it means

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because otherwise it can
get kind of confusing.

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But an allele is one of the
alternate versions of a gene.

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And what I mean by that is, let's take

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for example the eye color gene.

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We actually have a
couple of different genes

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that affect eye color,
but let's make it simple

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and just say there's one, one
gene that affects eye color.

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So you would have in,
say, 10 different people,

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you might have three or
four different eye colors.

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You could have green, brown, blue,

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even like a grayish color.

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And you know, there are many other colors.

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But basically what we're
talking about when we're talking

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about an allele, if we think

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about that eye color gene, let's say,

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so it's a gene which encodes a protein

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which impacts directly the
eye color of an individual.

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And a person who has brown
eyes, they would have an allele

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for a brown eye color for that
particular eye color gene.

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And another person, they might
have a blue eye color allele.

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So the allele is just
basically a different version,

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a different slight, slight
modification in the sequence

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of a gene which impacts the phenotype.

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So it would give you
a different phenotype,

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or some slightly different outcome

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for that particular trait.

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So alleles, you can have
many different alleles

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sort of in the general
population for a particular gene.

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You know, you might have hundreds

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or more different versions,

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slight variations on a particular gene.

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Each individual person,

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each person will only have two alleles

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because you have two copies of each gene.

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So you might have two alleles
that are exactly the same.

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Let's go back to the eye color example.

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Maybe both of your parents had blue eyes,

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and let's say they both donated

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to you the blue eye allele.

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So you would have, say you'd
have blue eyes in that case,

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and both of your alleles,
both of your copies

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of the eye color gene, would
be for the blue eye color.

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You can also have two different alleles.

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So alleles that two
slightly different versions

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of the same gene, and
then the question becomes,

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what would your phenotype be

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if you have two different alleles?

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Well, we'll talk about
that in a lot of detail

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in the next lecture, so
hold on to those questions.

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A SNP, or single nucleotide polymorphism,

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is a single base change in
a DNA sequence which may

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or may not be associated with a phenotype.

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And what I mean by that is
there could be a slight change.

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It's basically changing
one base to another base,

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so an A towards to a T or a C to an A

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or something like that.

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And that may result in
a different amino acid

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being coded for if this is
occurring within a gene.

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And that may or may not
impact the protein's function,

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which may or may not impact
the phenotype for a gene.

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Or it may or may not impact the phenotype

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for that particular allele.

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All right, wild type is what we would call

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the most common allele of a gene.

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So we would refer to sort
of what you might consider

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the normal copy,

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especially if we're
talking about a disease.

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Now this isn't really going to be the case

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for something like eye color or hair color

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or things like that,

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but more when we're
talking about a disease

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versus non-disease, versus, you know,

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sort of a normal functioning copy.

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The wild type is going to really be

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the normal functioning version of a gene,

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but it's considered wild type,

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and it was given that name
by earlier geneticists

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who were studying genetics
in animal species,

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different species of animals.

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And they would go out into the wild

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and they would, you know,
catch their particular animals

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that they're studying, and
many of them it was, you know,

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fruit flies that they would catch.

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And so they would say the most common,

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the most common phenotypes or
traits that they would see,

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they would consider those
to be the wild ones.

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So what you would see out in the wild.

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So that's why it actually
has the name, wild type.

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Wild type really just
means the normal version,

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the very common version

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that's mostly seen in the population.

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Mutant would be the allele
with the change in the sequence

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compared to the wild type sequence.

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And this mutant most likely is related

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to a phenotype change.

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And in the case of diseases,

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most mutant alleles
are actually associated

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with a person having a disease

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or having a greater
susceptibility for a disease.

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De novo would be what we would refer to

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as a new mutation which
occurs spontaneously

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in an individual.

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So it was not inherited
from his or her parents.

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Monogenic is a disease which
is caused by a single gene,

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so one gene, for example,
in case of a disease,

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and mutation in one
gene would be sufficient

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to cause an individual to have a disease.

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Multifactorial diseases, these
are diseases which are caused

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by multiple genes and/or
environmental influences.

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And this is actually,
most diseases would fall

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into the category of being multifactorial.

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So they're influenced
not just by one gene.

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Maybe you have a slight
influence from 10, 15,

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100 different genes,

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and also could be influenced
by the environment.

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And that could mean any
combination of things in a person,

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say for example, their diet,
their level of exercise,

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any other comorbidities they may have.

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All of these may start to impact

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and influence a multifactorial
disease as opposed

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to a monogenic disease, which
is really directly caused

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by a mutation in a single gene.

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We'll talk more about monogenic diseases

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in the next lecture as well.

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Multifactorial diseases,
we'll go into those

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in more detail in the
next module, so next week.

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All right, so I sort of gave
you an overview with that,

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but let's go back one more time

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'cause it is pretty important to get some

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of these terms correct.

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So as you recall there, you
have two copies of each gene,

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one from each parent, and the genotype

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will be the sequence of the gene.

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And so for each of us, if
we're talking about a gene,

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which say is on an autosome, right,

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we each have two copies
of all of those genes,

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so our genotype, we
would have the genotype

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for both the maternal and our
paternal copies of each gene.

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The phenotype is the
trait or characteristic

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seen in the patient, and
that would be in the case

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of what we'll be discussing more sensibly.

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That would be, say, having a disease

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or not having a disease.

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And these copies or alleles
may have slight differences,

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and we talked about this a moment ago

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with eye color gene in
the population one allele

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or sequence variant codes
for brown eyes, one for blue,

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one for green, but they
are all the same genes.

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When we're talking
about different alleles,

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these are different
alleles of the same gene.

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A protein dysfunction related

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to a disease results
from the patient having

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at least one copy of the
gene with the disease

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or disrupted sequence
or the disease allele

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or what could be called the mutant allele.

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So I just wanna take one more quick moment

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to get the concept of alleles down,

256
00:12:19,320 --> 00:12:21,510
and I apologize if this
is really being redundant,

257
00:12:21,510 --> 00:12:23,610
but I'd rather be a
little bit redundant here

258
00:12:23,610 --> 00:12:26,370
than to just lose you a little bit

259
00:12:26,370 --> 00:12:28,080
when we start throwing around terms

260
00:12:28,080 --> 00:12:30,150
like allele wild type, you know,

261
00:12:30,150 --> 00:12:32,913
when we move on in this material.

262
00:12:33,870 --> 00:12:36,690
So here's an analogy that might be useful,

263
00:12:36,690 --> 00:12:38,370
I hope it's useful to you.

264
00:12:38,370 --> 00:12:40,764
If you think of alleles,

265
00:12:40,764 --> 00:12:45,764
let's take example of
a deck of cards, okay?

266
00:12:45,990 --> 00:12:49,320
A deck of cards, so like a
regular deck of playing cards.

267
00:12:49,320 --> 00:12:53,103
So there are 52 different cards
in a typical playing deck.

268
00:12:55,560 --> 00:12:58,590
So if we're using an analogy here,

269
00:12:58,590 --> 00:13:02,010
you can think of this
as basically like saying

270
00:13:02,010 --> 00:13:05,130
there's the card gene, right?

271
00:13:05,130 --> 00:13:09,060
So all of the cards in the deck,

272
00:13:09,060 --> 00:13:11,580
even though there are 52
different cards in the deck,

273
00:13:11,580 --> 00:13:12,960
they're all cards, right?

274
00:13:12,960 --> 00:13:15,090
So let's say they're
all different versions

275
00:13:15,090 --> 00:13:16,380
of the card gene.

276
00:13:16,380 --> 00:13:18,243
We can call that the card gene.

277
00:13:19,410 --> 00:13:20,970
And there are 52 different versions of it.

278
00:13:20,970 --> 00:13:21,910
That would be like saying

279
00:13:21,910 --> 00:13:23,940
there are 52 different possible alleles.

280
00:13:23,940 --> 00:13:25,830
You could have the two of
clubs, you could have the five

281
00:13:25,830 --> 00:13:27,420
of spades, you could have
the queen of diamonds,

282
00:13:27,420 --> 00:13:29,610
you could have whatever,
let's say those are all,

283
00:13:29,610 --> 00:13:31,580
there are 52 different alleles

284
00:13:31,580 --> 00:13:33,990
or slightly different versions of cards,

285
00:13:33,990 --> 00:13:36,990
but they're all cards, so
that they're all alleles

286
00:13:36,990 --> 00:13:38,580
of the same gene.

287
00:13:38,580 --> 00:13:41,370
It's just that they have slight changes.

288
00:13:41,370 --> 00:13:45,439
So, you know, a small
percentage of the bases

289
00:13:45,439 --> 00:13:49,170
are different between
the different copies,

290
00:13:49,170 --> 00:13:51,030
and the same, you know, could be true

291
00:13:51,030 --> 00:13:53,550
if we go back to that
analogy of the cards.

292
00:13:53,550 --> 00:13:55,803
So there are 52 different
alleles, let's say,

293
00:13:56,670 --> 00:13:59,943
in our population in the card gene.

294
00:14:01,260 --> 00:14:03,990
So for each person you get to have two,

295
00:14:03,990 --> 00:14:05,130
you get to have two alleles,

296
00:14:05,130 --> 00:14:07,770
assuming this gene is
on an autosome, right?

297
00:14:07,770 --> 00:14:08,970
Not on an X chromosome,

298
00:14:08,970 --> 00:14:11,070
but on an autosome you
get to have two copies.

299
00:14:11,070 --> 00:14:14,430
So it's like taking
two cards from the deck

300
00:14:14,430 --> 00:14:18,540
and you get whatever you get
from that and those two cards,

301
00:14:18,540 --> 00:14:21,090
and, you know, let's say we have more

302
00:14:21,090 --> 00:14:23,700
than one deck of card there.

303
00:14:23,700 --> 00:14:26,040
Let's say we have five
decks of cards, okay?

304
00:14:26,040 --> 00:14:28,290
So there are 52 different
cards in the deck,

305
00:14:28,290 --> 00:14:30,968
but each of them is present, you know,

306
00:14:30,968 --> 00:14:32,940
in five different cards.

307
00:14:32,940 --> 00:14:34,980
So when you pull two cards,

308
00:14:34,980 --> 00:14:36,870
you might pull two different cards.

309
00:14:36,870 --> 00:14:41,403
You might pull a two of
clubs and a seven of spades,

310
00:14:42,390 --> 00:14:45,483
or you might pull two two of clubs.

311
00:14:47,184 --> 00:14:49,680
And what we'll talk
about in the next lecture

312
00:14:49,680 --> 00:14:53,370
would be how our phenotype can be affected

313
00:14:53,370 --> 00:14:55,470
by the different alleles

314
00:14:55,470 --> 00:14:57,270
that the two different
alleles that we have.

315
00:14:57,270 --> 00:14:59,460
So let's go back for a
second to that analogy again.

316
00:14:59,460 --> 00:15:02,070
I apologize if this isn't
coming out as clearly

317
00:15:02,070 --> 00:15:07,070
as it is in my head, but
it's basically like saying

318
00:15:07,230 --> 00:15:11,910
alleles are slightly different
versions of the same gene,

319
00:15:11,910 --> 00:15:13,920
but they're all the same gene.

320
00:15:13,920 --> 00:15:16,530
So they're all cards in our analogy.

321
00:15:16,530 --> 00:15:18,650
And you can have many different alleles

322
00:15:18,650 --> 00:15:20,400
or slightly different versions

323
00:15:20,400 --> 00:15:25,170
of a particular gene in the
population as a whole, right?

324
00:15:25,170 --> 00:15:30,170
But each individual person
only possesses two alleles.

325
00:15:30,510 --> 00:15:32,730
And those two alleles might
be different from one another

326
00:15:32,730 --> 00:15:35,310
and they might be the same as one another.

327
00:15:35,310 --> 00:15:38,490
Okay, I hope that kind of starting

328
00:15:38,490 --> 00:15:39,873
to make sense a little bit.

329
00:15:41,250 --> 00:15:43,800
So let's take a quick peek
at what this might mean

330
00:15:43,800 --> 00:15:46,380
and what are these changes
that we're talking about.

331
00:15:46,380 --> 00:15:49,980
So small changes in the
sequence are called mutations.

332
00:15:49,980 --> 00:15:54,980
So we would consider that
the most common sequence

333
00:15:55,110 --> 00:15:58,200
for a particular gene,
again, is called the what?

334
00:15:58,200 --> 00:16:00,960
Is called the wild type allele.

335
00:16:00,960 --> 00:16:03,390
And any derivation from that in terms

336
00:16:03,390 --> 00:16:06,960
of the sequence would be
considered a mutation.

337
00:16:06,960 --> 00:16:11,580
The mutation may be harmful
in the end to the person,

338
00:16:11,580 --> 00:16:13,470
it may be completely neutral,

339
00:16:13,470 --> 00:16:16,890
actually, most mutations are neutral

340
00:16:16,890 --> 00:16:19,470
or it actually may be slightly beneficial,

341
00:16:19,470 --> 00:16:23,280
and that would be what drives evolution

342
00:16:23,280 --> 00:16:26,550
and progression of a
species and adaptation.

343
00:16:26,550 --> 00:16:28,230
We're not gonna really get into that.

344
00:16:28,230 --> 00:16:29,940
We're gonna really more so focus

345
00:16:29,940 --> 00:16:33,540
on the detrimental side of mutations.

346
00:16:33,540 --> 00:16:35,490
But just keep in mind
that actually mutations

347
00:16:35,490 --> 00:16:40,110
are not entirely a bad thing,
certainly not for a species,

348
00:16:40,110 --> 00:16:43,650
because it can provide genetic diversity,

349
00:16:43,650 --> 00:16:45,110
which can be quite beneficial

350
00:16:45,110 --> 00:16:49,800
in that if we're responding
to changes in our environment,

351
00:16:49,800 --> 00:16:52,590
those individuals who have an ability

352
00:16:52,590 --> 00:16:56,430
to say survive a specific
set of conditions

353
00:16:56,430 --> 00:16:59,070
could survive and our
species could propagate.

354
00:16:59,070 --> 00:17:00,300
Anyway, we're not gonna really talk

355
00:17:00,300 --> 00:17:01,680
about beneficial mutations.

356
00:17:01,680 --> 00:17:02,850
We're really going to focus

357
00:17:02,850 --> 00:17:06,900
on those mutations which are detrimental.

358
00:17:06,900 --> 00:17:09,300
So a mutation is just a slight change.

359
00:17:09,300 --> 00:17:11,010
And let's see, in this particular example,

360
00:17:11,010 --> 00:17:14,970
it would be like taking
this sequence here,

361
00:17:14,970 --> 00:17:16,530
let's say we're just
showing the single strand

362
00:17:16,530 --> 00:17:19,997
of say a gene's sequence, okay?

363
00:17:19,997 --> 00:17:22,110
That's just one strand, and let's say

364
00:17:22,110 --> 00:17:23,730
it was actually mutated.

365
00:17:23,730 --> 00:17:26,340
So that's the wild type say on the top,

366
00:17:26,340 --> 00:17:29,520
and on the bottom, this strand here,

367
00:17:29,520 --> 00:17:33,780
so changing that adenine
base to a guanine,

368
00:17:33,780 --> 00:17:36,663
this would be a mutant, a mutant version.

369
00:17:37,890 --> 00:17:39,772
So these could be two different alleles

370
00:17:39,772 --> 00:17:42,543
if they have different phenotypes.

371
00:17:44,070 --> 00:17:47,310
And this one mutation
can result in big changes

372
00:17:47,310 --> 00:17:50,790
to the protein function,
which can cause disease.

373
00:17:50,790 --> 00:17:53,310
Or again, it may actually have no impact

374
00:17:53,310 --> 00:17:55,293
or it might just have a slight impact.

375
00:17:58,950 --> 00:18:02,220
So let's just take one quick,
a couple of examples here.

376
00:18:02,220 --> 00:18:03,853
So sickle cell disease,

377
00:18:03,853 --> 00:18:07,650
a mutation in the hemoglobin-beta
gene results in a change

378
00:18:07,650 --> 00:18:09,240
in the hemoglobin protein

379
00:18:09,240 --> 00:18:11,340
which affects its shape and function,

380
00:18:11,340 --> 00:18:14,040
the shape and function of hemoglobin.

381
00:18:14,040 --> 00:18:17,220
Mutated hemoglobin forms
long, inflexible chains

382
00:18:17,220 --> 00:18:19,530
in red blood cells, making
them stiff and angular

383
00:18:19,530 --> 00:18:22,380
and likely to become stuck
in small capillaries,

384
00:18:22,380 --> 00:18:24,450
reducing oxygen delivery to organs.

385
00:18:24,450 --> 00:18:29,280
So as you can see up here,
the normal shape of hemoglobin

386
00:18:29,280 --> 00:18:32,790
is basically, you know, a
nice sort of balled up shape,

387
00:18:32,790 --> 00:18:34,410
and it needs to be that shape

388
00:18:34,410 --> 00:18:37,080
so it can properly bind to oxygen

389
00:18:37,080 --> 00:18:41,670
and can keep the red blood
cells in normal shape

390
00:18:41,670 --> 00:18:43,680
that our body has adapted to

391
00:18:43,680 --> 00:18:46,020
and they can flow freely
through capillaries

392
00:18:46,020 --> 00:18:48,990
and deliver oxygen throughout the body.

393
00:18:48,990 --> 00:18:50,850
If, however, there is a mutation,

394
00:18:50,850 --> 00:18:53,700
it's just actually a single base change,

395
00:18:53,700 --> 00:18:57,690
single base change in
the hemoglobin beta gene,

396
00:18:57,690 --> 00:19:01,830
that can result in a change
in the protein structure

397
00:19:01,830 --> 00:19:04,710
for hemoglobin beta, which can cause it

398
00:19:04,710 --> 00:19:06,870
to form these long, inflexible chains

399
00:19:06,870 --> 00:19:09,240
which can affect the shapes of the cell.

400
00:19:09,240 --> 00:19:12,510
And these hemoglobins, hemoglobin proteins

401
00:19:12,510 --> 00:19:15,720
no longer bind oxygen as well either.

402
00:19:15,720 --> 00:19:18,586
So you have the combined effect

403
00:19:18,586 --> 00:19:21,300
of the blood cells getting
stuck in capillaries

404
00:19:21,300 --> 00:19:22,740
and not being able to deliver oxygen,

405
00:19:22,740 --> 00:19:23,910
but also when they do get there,

406
00:19:23,910 --> 00:19:27,090
the oxygen is actually not bound as well.

407
00:19:27,090 --> 00:19:28,560
So that's like an example

408
00:19:28,560 --> 00:19:32,877
of a change in a protein
affecting an outcome

409
00:19:35,250 --> 00:19:36,540
for an individual.

410
00:19:36,540 --> 00:19:38,790
So in this particular case,

411
00:19:38,790 --> 00:19:41,310
in this particular case
we could be looking

412
00:19:41,310 --> 00:19:43,920
at at least two different alleles here,

413
00:19:43,920 --> 00:19:47,190
the normal or wild type
allele, which would encode

414
00:19:47,190 --> 00:19:49,623
the normal functioning hemoglobin here,

415
00:19:51,120 --> 00:19:56,050
and also an allele that
has a single base mutation

416
00:19:57,425 --> 00:20:01,253
which would result in the
hemoglobin being disrupted

417
00:20:02,280 --> 00:20:04,860
and give the phenotype,

418
00:20:04,860 --> 00:20:07,323
the phenotype of sickle cell disease.

419
00:20:08,520 --> 00:20:10,890
All right, let's look at one more example.

420
00:20:10,890 --> 00:20:12,060
Cystic fibrosis.

421
00:20:12,060 --> 00:20:14,580
So mutations in the CFTR gene

422
00:20:14,580 --> 00:20:18,840
affect the CFTR protein's
ability to move chloride ions in

423
00:20:18,840 --> 00:20:21,390
and out of the cell, resulting
in sticky mucus building up

424
00:20:21,390 --> 00:20:23,160
on the outside of the cell.

425
00:20:23,160 --> 00:20:26,040
And in the lungs this mucus
buildup can lead to infections

426
00:20:26,040 --> 00:20:29,250
and in the pancreas the mucus
can block digestive enzymes

427
00:20:29,250 --> 00:20:32,040
from being secreted, leading
to significant health problems.

428
00:20:32,040 --> 00:20:34,890
So here what we're looking
at is on the left hand side,

429
00:20:34,890 --> 00:20:38,250
a drawing of a normal
functioning CFTR channel,

430
00:20:38,250 --> 00:20:40,860
which is the protein, the
protein's function is to act

431
00:20:40,860 --> 00:20:42,900
as basically like a channel

432
00:20:42,900 --> 00:20:46,860
through which ions can flow
in and out of the cell,

433
00:20:46,860 --> 00:20:49,230
you know, through the cell membrane.

434
00:20:49,230 --> 00:20:50,430
So that's the normal function.

435
00:20:50,430 --> 00:20:54,900
It allows chloride ions in
and out as the cell needs it

436
00:20:54,900 --> 00:20:56,550
and you don't get this buildup of mucus.

437
00:20:56,550 --> 00:21:00,420
If, however, there is a
mutation in the sequence

438
00:21:00,420 --> 00:21:04,410
for the CFTR gene, so that
would be a mutant allele,

439
00:21:04,410 --> 00:21:07,830
if a person has mutant allele for this,

440
00:21:07,830 --> 00:21:10,080
then the CFTR protein

441
00:21:10,080 --> 00:21:13,710
that's encoded would not function properly

442
00:21:13,710 --> 00:21:15,420
because it would not be built properly

443
00:21:15,420 --> 00:21:18,360
because it would be told,
the cell would be told

444
00:21:18,360 --> 00:21:22,950
to basically form a
protein, the CFTR protein

445
00:21:22,950 --> 00:21:27,030
with some changes in the amino
acids than what it should be.

446
00:21:27,030 --> 00:21:29,790
Then the protein itself
doesn't function properly

447
00:21:29,790 --> 00:21:31,620
and the chloride ions get stuck

448
00:21:31,620 --> 00:21:34,353
and it results in the buildup of mucus.

449
00:21:36,600 --> 00:21:38,400
All right, let's talk about mutations.

450
00:21:38,400 --> 00:21:41,310
So this is a change in a DNA sequence.

451
00:21:41,310 --> 00:21:42,990
New mutations occur randomly

452
00:21:42,990 --> 00:21:45,120
from uncorrected errors
in DNA replication.

453
00:21:45,120 --> 00:21:45,953
You remember that.

454
00:21:45,953 --> 00:21:47,520
We talked about that.

455
00:21:47,520 --> 00:21:50,433
I believe that was in Module 3.

456
00:21:51,285 --> 00:21:55,260
And from DNA damage by mutagens.

457
00:21:55,260 --> 00:21:56,523
So we'll talk more about mutagens

458
00:21:56,523 --> 00:21:59,640
when we go into the cancer module.

459
00:21:59,640 --> 00:22:02,490
But mutagens are basically like,

460
00:22:02,490 --> 00:22:03,600
you can kind of think of them

461
00:22:03,600 --> 00:22:06,090
as like some toxins or chemicals,

462
00:22:06,090 --> 00:22:11,090
or you know, UV radiation from sunlight.

463
00:22:11,850 --> 00:22:14,190
Those types of things can
be considered mutagens

464
00:22:14,190 --> 00:22:17,010
and they basically are
essentially chemical structures

465
00:22:17,010 --> 00:22:21,240
that enter the cell and will
damage DNA and cause mutations.

466
00:22:21,240 --> 00:22:23,790
Mutations could have been
inherited from a parent

467
00:22:23,790 --> 00:22:27,030
or could also have occurred
spontaneously in an individual.

468
00:22:27,030 --> 00:22:29,520
And these spontaneous mutations,

469
00:22:29,520 --> 00:22:32,493
which result in disease, are
called de novo mutations.

470
00:22:34,170 --> 00:22:36,750
Three basic types of changes can happen.

471
00:22:36,750 --> 00:22:39,060
And these are the three
basic types of mutations.

472
00:22:39,060 --> 00:22:42,120
So a point mutation or a change
in one base to another base,

473
00:22:42,120 --> 00:22:43,560
and this is sometimes called a SNP.

474
00:22:43,560 --> 00:22:47,040
You remember that from
the definitions page.

475
00:22:47,040 --> 00:22:49,113
A single nucleotide polymorphism.

476
00:22:50,100 --> 00:22:52,320
You can probably see why we call it SNPs.

477
00:22:52,320 --> 00:22:53,430
It's a little easier to say that

478
00:22:53,430 --> 00:22:55,380
than single nucleotide polymorphism.

479
00:22:55,380 --> 00:22:56,580
It's kind of a mouthful.

480
00:22:56,580 --> 00:23:00,570
So a point mutation is
just a single change,

481
00:23:00,570 --> 00:23:02,880
nothing added, nothing removed.

482
00:23:02,880 --> 00:23:04,710
It's just basically in this case

483
00:23:04,710 --> 00:23:07,710
what we're looking at here
instead of the cytosine

484
00:23:07,710 --> 00:23:10,320
in the third position
of the short sequence

485
00:23:10,320 --> 00:23:12,330
we're looking at, it's now an adenine.

486
00:23:12,330 --> 00:23:15,540
So it's a C to an A point mutation

487
00:23:15,540 --> 00:23:17,520
or change in the sequence.

488
00:23:17,520 --> 00:23:20,670
An insertion would be
inserting a new base or base.

489
00:23:20,670 --> 00:23:23,463
And here we're looking at
between the two cytosines,

490
00:23:23,463 --> 00:23:25,950
that third in the
fourth, we add a thymine.

491
00:23:25,950 --> 00:23:28,563
So it's now one base longer.

492
00:23:29,580 --> 00:23:33,180
And you could have an insertion
of one base of, you know,

493
00:23:33,180 --> 00:23:36,780
any number of bases, two, three,
five, 10, 20, however many.

494
00:23:36,780 --> 00:23:40,140
A deletion would be deleting
an existing base or bases.

495
00:23:40,140 --> 00:23:44,250
So here we're looking
at the TGCC sequences.

496
00:23:44,250 --> 00:23:49,250
Now we're losing one of those
cytosines, so it now is TGC.

497
00:23:49,350 --> 00:23:51,000
So one of the cytosines was lost.

498
00:23:51,000 --> 00:23:52,473
That's a deletion.

499
00:23:54,330 --> 00:23:55,500
So some possible effects

500
00:23:55,500 --> 00:23:58,860
of single nucleotide polymorphisms
on the encoded protein,

501
00:23:58,860 --> 00:24:02,070
or those point mutations, the end result.

502
00:24:02,070 --> 00:24:05,850
So what can it possibly do to the protein

503
00:24:05,850 --> 00:24:08,493
that could be encoded from this gene?

504
00:24:09,660 --> 00:24:11,880
The mutations could be silent, which means

505
00:24:11,880 --> 00:24:13,110
that while the sequence has changed,

506
00:24:13,110 --> 00:24:15,690
there is no change in the protein encoded.

507
00:24:15,690 --> 00:24:17,070
So this would be, for example,

508
00:24:17,070 --> 00:24:20,130
like a CGG being changed to a CGT.

509
00:24:20,130 --> 00:24:23,100
But both of these actually
encode for alanine,

510
00:24:23,100 --> 00:24:24,330
the amino acid alanine.

511
00:24:24,330 --> 00:24:26,910
Go look at your amino acid
chart if that's helpful

512
00:24:26,910 --> 00:24:29,670
to you, and so you can see,

513
00:24:29,670 --> 00:24:31,650
so the protein is the same either way.

514
00:24:31,650 --> 00:24:33,420
So there's no effect on phenotype.

515
00:24:33,420 --> 00:24:35,340
So this is a silent mutation

516
00:24:35,340 --> 00:24:37,020
and we actually have quite a few of these

517
00:24:37,020 --> 00:24:40,560
because there's no
selection against those.

518
00:24:40,560 --> 00:24:42,420
So individuals will survive.

519
00:24:42,420 --> 00:24:45,240
There'll be no effect whatsoever
if this particular kind

520
00:24:45,240 --> 00:24:47,880
of silent mutation occurs

521
00:24:47,880 --> 00:24:52,320
because the codon still encodes
for the same amino acid,

522
00:24:52,320 --> 00:24:54,420
'cause if you remember, there
are only 20 amino acids,

523
00:24:54,420 --> 00:24:57,990
but there are 64 different
possible DNA triplets,

524
00:24:57,990 --> 00:24:59,793
or codons, right?

525
00:25:00,870 --> 00:25:03,180
You remember that, that
occurs in translation

526
00:25:03,180 --> 00:25:06,780
where the ribosome is
reading each of the triplets,

527
00:25:06,780 --> 00:25:09,630
each of the codons, and
each of those triplets,

528
00:25:09,630 --> 00:25:12,600
it's telling it a specific
amino acid to add.

529
00:25:12,600 --> 00:25:14,640
Well, there's what's called redundancy,

530
00:25:14,640 --> 00:25:18,270
which basically means that,
as we talked about before,

531
00:25:18,270 --> 00:25:19,680
since they are only 20 amino acids

532
00:25:19,680 --> 00:25:22,710
and there's 64 different possible codons,

533
00:25:22,710 --> 00:25:23,910
that each amino acid

534
00:25:23,910 --> 00:25:26,550
actually has multiple different
codons that encode it.

535
00:25:26,550 --> 00:25:29,160
So, you could have a single base change

536
00:25:29,160 --> 00:25:31,620
and actually have no change whatsoever

537
00:25:31,620 --> 00:25:33,470
in the amino acid that it's encoding.

538
00:25:34,950 --> 00:25:36,090
All right, see, it's all starting

539
00:25:36,090 --> 00:25:37,740
to come together, hopefully.

540
00:25:37,740 --> 00:25:39,570
Hopefully you're starting to see that,

541
00:25:39,570 --> 00:25:43,350
that all the hard work you
put into learning the material

542
00:25:43,350 --> 00:25:45,120
in the first couple of modules is starting

543
00:25:45,120 --> 00:25:49,140
to come back around now and be reinforced.

544
00:25:49,140 --> 00:25:51,180
So that's the idea anyway. (laughs)

545
00:25:51,180 --> 00:25:55,390
Okay, so the next type of
possible effect of a SNP

546
00:25:56,280 --> 00:25:58,983
will be a missense mutation, a missense.

547
00:25:59,880 --> 00:26:03,000
So again, there are some
funny words in genetics.

548
00:26:03,000 --> 00:26:05,310
We talked about the antisense strand.

549
00:26:05,310 --> 00:26:08,790
This is a missense mutation,
and missense, just,

550
00:26:08,790 --> 00:26:12,660
it means it results in one amino
acid change in the protein.

551
00:26:12,660 --> 00:26:16,200
So let's take an example
of that CGG sequence.

552
00:26:16,200 --> 00:26:18,870
Instead of it being changed to CGT,

553
00:26:18,870 --> 00:26:21,000
which was coding for the same amino acid,

554
00:26:21,000 --> 00:26:23,880
let's say that the mutation was changing

555
00:26:23,880 --> 00:26:27,090
that first C to a T, so now it's a TGG.

556
00:26:27,090 --> 00:26:29,520
This would change the protein
from having an alanine

557
00:26:29,520 --> 00:26:31,372
in that location to having a threonine.

558
00:26:31,372 --> 00:26:33,630
Because if you look up on
your chart, you would see

559
00:26:33,630 --> 00:26:36,720
that a CGG codes for alanine,

560
00:26:36,720 --> 00:26:38,550
but a TGG codes for threonine,

561
00:26:38,550 --> 00:26:40,560
which is a different amino acid,

562
00:26:40,560 --> 00:26:42,060
but would only affect that one

563
00:26:42,060 --> 00:26:43,683
where the mutation is located.

564
00:26:44,940 --> 00:26:47,190
And this may have an
effect on the phenotype,

565
00:26:48,175 --> 00:26:50,340
by possibly changing the protein shape

566
00:26:50,340 --> 00:26:52,080
and therefore its function.

567
00:26:52,080 --> 00:26:53,765
And certainly there are diseases,

568
00:26:53,765 --> 00:26:56,070
as we already talked
about, sickle cell disease

569
00:26:56,070 --> 00:27:00,780
is the result of a single
amino acid being changed.

570
00:27:00,780 --> 00:27:03,840
Now, that's not the case
for most amino acids,

571
00:27:03,840 --> 00:27:05,520
I'd say, in most proteins.

572
00:27:05,520 --> 00:27:07,920
There's a little bit of flexibility

573
00:27:07,920 --> 00:27:09,180
in terms of their functions,

574
00:27:09,180 --> 00:27:11,730
so being maintained even
if there's a single change.

575
00:27:11,730 --> 00:27:15,660
But there are those very
specific amino acids

576
00:27:15,660 --> 00:27:18,750
which are really important
to have the right ones there.

577
00:27:18,750 --> 00:27:22,740
And so missense mutations
can actually cause

578
00:27:22,740 --> 00:27:24,573
or lead to certainly disease.

579
00:27:25,740 --> 00:27:28,620
A nonsense mutation results
in a truncated protein

580
00:27:28,620 --> 00:27:32,100
because of the creation of a stop codon.

581
00:27:32,100 --> 00:27:35,820
So let's take the example of
our original, our wild type,

582
00:27:35,820 --> 00:27:39,060
remember our wild type sequence, is TTT,

583
00:27:39,060 --> 00:27:41,970
and that this is now mutated to ATT,

584
00:27:41,970 --> 00:27:44,850
which would result in the
ribosomes reading a stop signal

585
00:27:44,850 --> 00:27:46,170
instead of a lysine.

586
00:27:46,170 --> 00:27:49,350
So none of the codons following
this mutation will be read

587
00:27:49,350 --> 00:27:52,350
or translated, resulting
in a shortened protein.

588
00:27:52,350 --> 00:27:55,170
So TTT codes for lysine.

589
00:27:55,170 --> 00:27:57,330
And what you would normally
have, let's say this was part

590
00:27:57,330 --> 00:27:58,743
of your mRNA sequence,

591
00:28:00,030 --> 00:28:01,110
or well, rather, let's say

592
00:28:01,110 --> 00:28:02,190
this is part of your DNA sequence,

593
00:28:02,190 --> 00:28:05,970
it gets transcribed, right, into mRNA.

594
00:28:05,970 --> 00:28:10,035
So the mRNA would read UUU,

595
00:28:10,035 --> 00:28:13,650
and that ribosome would read that

596
00:28:13,650 --> 00:28:15,300
and say, okay, that's a lysine,

597
00:28:15,300 --> 00:28:17,040
and then it would move
on to the next codon

598
00:28:17,040 --> 00:28:18,510
and move on to the next
and move on to the next

599
00:28:18,510 --> 00:28:19,830
and move on to the next.

600
00:28:19,830 --> 00:28:23,730
Well, in the case of a nonsense mutation,

601
00:28:23,730 --> 00:28:26,880
that changes the codon from a codon

602
00:28:26,880 --> 00:28:31,050
which would normally encode
for an amino acid to a stop.

603
00:28:31,050 --> 00:28:34,590
So now the ribosome gets to that sequence

604
00:28:34,590 --> 00:28:37,920
and says, oh, that means
stop, and it falls off.

605
00:28:37,920 --> 00:28:42,225
And the problem is not
only do you not translate

606
00:28:42,225 --> 00:28:46,710
or incorporate that particular,

607
00:28:46,710 --> 00:28:49,983
in this case lysine, into
the growing protein chain,

608
00:28:50,820 --> 00:28:52,500
you also don't continue on

609
00:28:52,500 --> 00:28:54,930
with reading the rest of that mRNA.

610
00:28:54,930 --> 00:28:57,600
So anything downstream or that comes

611
00:28:57,600 --> 00:29:01,280
after that new mutation

612
00:29:01,280 --> 00:29:04,380
or that nonsense mutation
doesn't get read.

613
00:29:04,380 --> 00:29:09,380
And so the protein basically
is short or truncated

614
00:29:09,390 --> 00:29:13,350
because none of the rest of
what comes after that stop,

615
00:29:13,350 --> 00:29:16,710
what is now a stop codon,
gets read by the ribosome.

616
00:29:16,710 --> 00:29:20,010
So this can be a big, big
problem, and it often is.

617
00:29:20,010 --> 00:29:22,770
So if there's a nonsense
mutation that happens,

618
00:29:22,770 --> 00:29:27,510
basically a protein will either, you know,

619
00:29:27,510 --> 00:29:30,750
have a severely reduced function to it,

620
00:29:30,750 --> 00:29:34,560
or it will actually be completely
non-functional whatsoever,

621
00:29:34,560 --> 00:29:36,480
which can be a real problem

622
00:29:36,480 --> 00:29:38,223
and can certainly lead to disease.

623
00:29:39,840 --> 00:29:42,210
Let's take a quick peek at
what I'm talking about here.

624
00:29:42,210 --> 00:29:45,960
So you can see it more visually here.

625
00:29:45,960 --> 00:29:49,050
Silent mutation, and let's
just orient ourselves

626
00:29:49,050 --> 00:29:50,160
to what we're looking at.

627
00:29:50,160 --> 00:29:53,760
On the top here is the
DNA template strand.

628
00:29:53,760 --> 00:29:56,940
So that would be, you
know, the two strands,

629
00:29:56,940 --> 00:30:00,630
and the mRNA that gets
transcribed off of that.

630
00:30:00,630 --> 00:30:03,840
And then the protein,
the amino acid sequence,

631
00:30:03,840 --> 00:30:05,370
which gets read.

632
00:30:05,370 --> 00:30:08,520
And again, you can go back
to your amino acid table

633
00:30:08,520 --> 00:30:12,060
to confirm that this is what
it basically would read.

634
00:30:12,060 --> 00:30:14,520
But let's say that this is the wild type.

635
00:30:14,520 --> 00:30:18,090
Again, remember wild type for
normal functioning sequence.

636
00:30:18,090 --> 00:30:21,480
And here you have the normal, let's say,

637
00:30:21,480 --> 00:30:23,670
I mean, this would be
extremely short for a protein.

638
00:30:23,670 --> 00:30:26,250
This is just for
demonstration purposes only.

639
00:30:26,250 --> 00:30:30,270
Normal proteins are I
think in the range of,

640
00:30:30,270 --> 00:30:34,440
I mean, at least 300,
400 amino acids usually.

641
00:30:34,440 --> 00:30:36,840
So they're much, much longer than this.

642
00:30:36,840 --> 00:30:39,420
And some of them are, you
know, even in thousands

643
00:30:39,420 --> 00:30:41,160
of amino acids long.

644
00:30:41,160 --> 00:30:43,020
But let's just look at this.

645
00:30:43,020 --> 00:30:44,790
This is just for demonstration purposes.

646
00:30:44,790 --> 00:30:49,650
You have your methionine,
lysine, phenylalanine, glycine,

647
00:30:49,650 --> 00:30:53,760
and then it reads this stop codon here.

648
00:30:53,760 --> 00:30:58,500
Well, in this case, let's
say that the guanine here

649
00:30:58,500 --> 00:31:02,610
was mutated to an adenine,
so an A instead of a G.

650
00:31:02,610 --> 00:31:06,990
So this gets read as GGU,

651
00:31:06,990 --> 00:31:09,690
but that still codes for glycine.

652
00:31:09,690 --> 00:31:12,973
GGC and the mRNA and GGU
both code for glycine.

653
00:31:12,973 --> 00:31:14,760
So this is a silent mutation.

654
00:31:14,760 --> 00:31:17,100
There's no change in the protein,

655
00:31:17,100 --> 00:31:19,020
in the amino acid sequence and stuff.

656
00:31:19,020 --> 00:31:21,300
So there's no change in
the protein whatsoever.

657
00:31:21,300 --> 00:31:23,253
So there's no detriment to this.

658
00:31:24,480 --> 00:31:27,840
Okay, a missense mutation,
a missense mutation.

659
00:31:27,840 --> 00:31:30,540
Let's look again, same type of sequence

660
00:31:30,540 --> 00:31:32,040
that we were looking at
in the previous slide.

661
00:31:32,040 --> 00:31:36,840
Here let's say instead
of the C in this location

662
00:31:36,840 --> 00:31:40,080
and the wild type strain,
wild type strand, rather,

663
00:31:40,080 --> 00:31:42,600
there's now a T, so a T instead of a C.

664
00:31:42,600 --> 00:31:43,950
And what does that change?

665
00:31:43,950 --> 00:31:48,150
Well now, instead of it
being GGC in the mRNA,

666
00:31:48,150 --> 00:31:49,590
it's now AGC,

667
00:31:49,590 --> 00:31:52,650
which is a codon which encodes for serine,

668
00:31:52,650 --> 00:31:55,638
serine as opposed to glycine.

669
00:31:55,638 --> 00:31:59,670
So there is one amino acid
difference in this protein

670
00:31:59,670 --> 00:32:01,770
as a result of a missense mutation.

671
00:32:01,770 --> 00:32:03,660
So generally missense mutations,

672
00:32:03,660 --> 00:32:06,690
so silent mutations are
really, you know, not going

673
00:32:06,690 --> 00:32:09,103
to have any effect whatsoever on a person.

674
00:32:09,103 --> 00:32:14,103
A missense mutation, very specific ones

675
00:32:14,340 --> 00:32:17,220
can have detriments to a person,

676
00:32:17,220 --> 00:32:19,860
but generally they're more tolerable

677
00:32:19,860 --> 00:32:22,110
because it's a single
amino acid be changed,

678
00:32:22,110 --> 00:32:24,570
and unless that amino acid is
in a really important location

679
00:32:24,570 --> 00:32:29,250
for the protein, then the
protein and overall the cell

680
00:32:29,250 --> 00:32:30,870
and therefore the individual might be able

681
00:32:30,870 --> 00:32:33,420
to tolerate a missense mutation.

682
00:32:33,420 --> 00:32:34,620
A nonsense mutation,

683
00:32:34,620 --> 00:32:37,020
this is the one that results
in the truncated protein

684
00:32:37,020 --> 00:32:40,800
because you're adding, you're
now creating a stop codon

685
00:32:42,720 --> 00:32:45,810
earlier on in the chain, right?

686
00:32:45,810 --> 00:32:48,570
Remember because it gets
read just like you're reading

687
00:32:48,570 --> 00:32:52,350
a sentence from left to right.

688
00:32:52,350 --> 00:32:55,950
The ribosome is also reading
the mRNA from left to right.

689
00:32:55,950 --> 00:32:58,290
So as soon as it hits what it reads

690
00:32:58,290 --> 00:33:00,330
as a stop codon, it stops.

691
00:33:00,330 --> 00:33:02,910
The ribosome falls off
and the protein is done.

692
00:33:02,910 --> 00:33:05,220
No matter what stage it's
at, it doesn't keep going

693
00:33:05,220 --> 00:33:07,380
because it reads that as a stop codon.

694
00:33:07,380 --> 00:33:11,730
So in this case, instead
of the T located here,

695
00:33:11,730 --> 00:33:13,920
this is now mutated to an A

696
00:33:13,920 --> 00:33:18,920
and this gets read as a UAG in the mRNA.

697
00:33:19,950 --> 00:33:23,880
And so basically the protein
stops being formed right here,

698
00:33:23,880 --> 00:33:25,470
and there's really nothing to it.

699
00:33:25,470 --> 00:33:28,290
It doesn't have the meat of the protein.

700
00:33:28,290 --> 00:33:31,950
So any amino acids that would be encoded

701
00:33:31,950 --> 00:33:34,170
any past this stop codon

702
00:33:34,170 --> 00:33:36,480
just will never see the light of day.

703
00:33:36,480 --> 00:33:38,370
They'll never be read by the ribosomes

704
00:33:38,370 --> 00:33:39,720
'cause the ribosomes reach that stop,

705
00:33:39,720 --> 00:33:41,400
'cause again, remember
they're moving left to right,

706
00:33:41,400 --> 00:33:44,160
they're sliding along, read
three, move up, slide along,

707
00:33:44,160 --> 00:33:46,260
read three, get up, move, read three.

708
00:33:46,260 --> 00:33:50,280
But here it reads three, it
puts methionine, it moves over

709
00:33:50,280 --> 00:33:53,430
to the next three, and it
reads, oh, stop, our job's done.

710
00:33:53,430 --> 00:33:55,227
You know, it's quitting time.

711
00:33:55,227 --> 00:33:58,310
And the ribosome drops off
and that's it for the protein.

712
00:33:58,310 --> 00:33:59,910
It basically doesn't get

713
00:33:59,910 --> 00:34:01,893
any more amino acids added onto it.

714
00:34:03,477 --> 00:34:07,110
All right, let's think about
insertions and deletions.

715
00:34:07,110 --> 00:34:09,540
So there's a couple of different
effects that can happen

716
00:34:09,540 --> 00:34:11,190
and these tend to be more severe.

717
00:34:11,190 --> 00:34:12,240
So when there's an insertion

718
00:34:12,240 --> 00:34:14,820
or a deletion, these
tend to be more severe,

719
00:34:14,820 --> 00:34:17,010
and we'll talk about why in a moment,

720
00:34:17,010 --> 00:34:20,153
more severe than a
point mutation or a SNP.

721
00:34:21,226 --> 00:34:23,250
So an in-frame insertion,
this would be one

722
00:34:23,250 --> 00:34:26,010
or more complete codons
inserted without disrupting

723
00:34:26,010 --> 00:34:28,440
any of the existing
codons resulting in one

724
00:34:28,440 --> 00:34:30,840
or more added amino acids to the protein.

725
00:34:30,840 --> 00:34:33,810
Okay, that's a lot of words,
and I'll show you visually

726
00:34:33,810 --> 00:34:34,920
what this means in a moment.

727
00:34:34,920 --> 00:34:36,150
So just hang with me for a second.

728
00:34:36,150 --> 00:34:38,910
Just wanna get a few
definitions out of the way.

729
00:34:38,910 --> 00:34:42,090
An in-frame deletion would be deleting one

730
00:34:42,090 --> 00:34:44,550
or more complete codons
without disrupting any

731
00:34:44,550 --> 00:34:46,680
of the existing codons,
which results in one

732
00:34:46,680 --> 00:34:49,023
or more amino acids
removed from the protein.

733
00:34:49,950 --> 00:34:52,080
Okay, so remember before

734
00:34:52,080 --> 00:34:55,170
when we were talking about,
say, a missense mutation,

735
00:34:55,170 --> 00:34:57,900
which would be changing one amino acid

736
00:34:57,900 --> 00:34:58,950
to a different amino acid.

737
00:34:58,950 --> 00:35:01,050
In this case with in-frame insertions

738
00:35:01,050 --> 00:35:05,280
or deletions, you're adding,
adding one more amino acid

739
00:35:05,280 --> 00:35:06,930
or taking away one amino acid.

740
00:35:06,930 --> 00:35:08,940
It's not that you're changing one.

741
00:35:08,940 --> 00:35:12,120
You're just adding one or
you're taking one away.

742
00:35:12,120 --> 00:35:14,190
A frameshift insertion or deletion,

743
00:35:14,190 --> 00:35:17,550
which is actually the most
likely kind of insertion

744
00:35:17,550 --> 00:35:21,270
or deletion, results in all
codons following the insertion

745
00:35:21,270 --> 00:35:23,100
or deletion of one or more bases,

746
00:35:23,100 --> 00:35:25,830
and that disrupts the codons
following the insertion

747
00:35:25,830 --> 00:35:27,690
or deletion to be incorrect.

748
00:35:27,690 --> 00:35:30,210
So all of the amino acids
in the protein coded for

749
00:35:30,210 --> 00:35:32,490
after the mutation will be incorrect.

750
00:35:32,490 --> 00:35:35,760
So that means all the triplets
are off by one or two.

751
00:35:35,760 --> 00:35:38,100
And as you can imagine,
that's a real problem.

752
00:35:38,100 --> 00:35:39,030
Let's take a look at that.

753
00:35:39,030 --> 00:35:40,200
But first, let's take a peek

754
00:35:40,200 --> 00:35:42,873
at the in-frame insertions and deletions.

755
00:35:44,550 --> 00:35:49,140
So in-frame versus frameshift,
frameshift is bad news

756
00:35:49,140 --> 00:35:50,070
for the protein.

757
00:35:50,070 --> 00:35:51,930
It really, really is.

758
00:35:51,930 --> 00:35:54,507
So let's take a look at why that might be.

759
00:35:54,507 --> 00:35:57,180
And if you think about
this, I've used the analogy

760
00:35:57,180 --> 00:35:59,160
of thinking about reading an mRNA

761
00:35:59,160 --> 00:36:02,970
as if you were reading
words in a sentence.

762
00:36:02,970 --> 00:36:04,200
The order of the letters

763
00:36:04,200 --> 00:36:08,250
that compose the sentence
are very important.

764
00:36:08,250 --> 00:36:10,740
And it's also important
where you put the spaces

765
00:36:10,740 --> 00:36:11,880
between those words.

766
00:36:11,880 --> 00:36:13,260
And that's kind of like thinking

767
00:36:13,260 --> 00:36:16,680
of the letters in the
words being like each base

768
00:36:16,680 --> 00:36:20,490
and the space between them
being like reading one codon

769
00:36:20,490 --> 00:36:22,020
versus the next versus the next.

770
00:36:22,020 --> 00:36:25,380
So if in the wild type,
let's say that the wild type

771
00:36:25,380 --> 00:36:26,820
would be like the sentence.

772
00:36:26,820 --> 00:36:29,970
So we're using sentences
made up of three-letter words

773
00:36:29,970 --> 00:36:33,570
because it's sort of like
the three base codons, right?

774
00:36:33,570 --> 00:36:36,120
So each letter is like a base

775
00:36:36,120 --> 00:36:38,637
and each word here is like a codon, okay?

776
00:36:38,637 --> 00:36:41,820
And let's say that the
sentence is like the protein.

777
00:36:41,820 --> 00:36:44,350
All right, so if we were
reading the wild type,

778
00:36:44,350 --> 00:36:49,350
let's say the wild type sentence
is the red bug bit the dog.

779
00:36:49,980 --> 00:36:52,710
For an in-frame insertion,

780
00:36:52,710 --> 00:36:55,980
we're adding in another three bases,

781
00:36:55,980 --> 00:36:59,230
say we're adding in basically
one additional codon.

782
00:36:59,230 --> 00:37:01,650
So it would be in inserting three bases,

783
00:37:01,650 --> 00:37:05,520
and it doesn't change,
it basically adjusts

784
00:37:05,520 --> 00:37:07,290
how the rest of the codons are read.

785
00:37:07,290 --> 00:37:10,470
So in this case it would be
like adding the word top.

786
00:37:10,470 --> 00:37:13,800
So now it would be the
red top bug bit the dog.

787
00:37:13,800 --> 00:37:15,300
So that's a little bit different,

788
00:37:15,300 --> 00:37:17,420
a little bit different than
the wild type sentence.

789
00:37:17,420 --> 00:37:19,890
So the red bug bit the dog.

790
00:37:19,890 --> 00:37:22,320
Now it reads, the red top bug bit the dog.

791
00:37:22,320 --> 00:37:23,670
So that might make a difference in terms

792
00:37:23,670 --> 00:37:24,920
of the protein's function.

793
00:37:24,920 --> 00:37:28,410
An in-frame deletion would be
like removing one of the words

794
00:37:28,410 --> 00:37:30,480
or one of the codons.

795
00:37:30,480 --> 00:37:33,060
So now it would read, the bug bit the dog.

796
00:37:33,060 --> 00:37:34,980
So you're missing some
information here, right?

797
00:37:34,980 --> 00:37:37,230
So before it was the red bug bit the dog,

798
00:37:37,230 --> 00:37:38,940
now it's just the bug bit the dog.

799
00:37:38,940 --> 00:37:42,000
So we lost red, but you can still kind

800
00:37:42,000 --> 00:37:43,590
of understand the sentence.

801
00:37:43,590 --> 00:37:45,480
I mean, it still makes sense.

802
00:37:45,480 --> 00:37:47,040
It's still providing you some information,

803
00:37:47,040 --> 00:37:48,360
just a little less.

804
00:37:48,360 --> 00:37:51,150
So most likely an in-frame
deletion like this,

805
00:37:51,150 --> 00:37:54,750
that's especially one that's
just deleting a single codon,

806
00:37:54,750 --> 00:37:57,990
would really probably not
have a dramatic impact

807
00:37:57,990 --> 00:38:00,060
on the protein's function.

808
00:38:00,060 --> 00:38:02,850
However, if we start messing around

809
00:38:02,850 --> 00:38:07,530
with the frame of how the codons are read,

810
00:38:07,530 --> 00:38:09,450
here you get into some trouble.

811
00:38:09,450 --> 00:38:11,040
So a frameshift insertion.

812
00:38:11,040 --> 00:38:14,190
So let's say we're adding
in a single nucleotide.

813
00:38:14,190 --> 00:38:17,610
Let's say in this case
you're adding a single base.

814
00:38:17,610 --> 00:38:19,380
So we'll use...

815
00:38:19,380 --> 00:38:22,650
And this is our analogy of
using letters instead of bases.

816
00:38:22,650 --> 00:38:25,104
So let's just like add in the letter F

817
00:38:25,104 --> 00:38:28,560
into the sentence that we had before.

818
00:38:28,560 --> 00:38:32,670
But you still have to read each
of these in groups of three.

819
00:38:32,670 --> 00:38:37,670
So now it would be the
ref... (speaks gibberish)

820
00:38:40,195 --> 00:38:42,900
Okay, that doesn't make any sense, right?

821
00:38:42,900 --> 00:38:44,730
I mean, you still get the word the.

822
00:38:44,730 --> 00:38:46,350
That kind of makes sense, that's fine.

823
00:38:46,350 --> 00:38:47,310
That's just the same.

824
00:38:47,310 --> 00:38:49,800
But anything that comes after,

825
00:38:49,800 --> 00:38:52,740
after that frameshift insertion
gets all totally screwed up.

826
00:38:52,740 --> 00:38:56,310
And now the ribosomes
are reading these codons

827
00:38:56,310 --> 00:38:59,730
which are now all off by one,
which totally screws it up

828
00:38:59,730 --> 00:39:02,220
because now when it goes
to read that, it's reading,

829
00:39:02,220 --> 00:39:04,290
it's coding for completely
different amino acids,

830
00:39:04,290 --> 00:39:06,750
which means the protein's
totally different.

831
00:39:06,750 --> 00:39:08,130
It makes no sense.

832
00:39:08,130 --> 00:39:10,290
The same thing is true for a deletion,

833
00:39:10,290 --> 00:39:13,050
let's say deleting a single nucleotide.

834
00:39:13,050 --> 00:39:15,570
And again, we're demonstrating that

835
00:39:15,570 --> 00:39:17,910
through taking out one of the letters.

836
00:39:17,910 --> 00:39:22,910
Now what it would be is the
(speaks gibberish) hed og.

837
00:39:23,880 --> 00:39:26,100
Yeah, that doesn't make any sense either.

838
00:39:26,100 --> 00:39:28,650
Same thing with in insertion.

839
00:39:28,650 --> 00:39:31,680
For a frameshift deletion,
you know, anything that comes

840
00:39:31,680 --> 00:39:33,630
after where that deletion occurred

841
00:39:33,630 --> 00:39:35,010
doesn't make any sense anymore.

842
00:39:35,010 --> 00:39:36,630
And now the protein's totally different,

843
00:39:36,630 --> 00:39:38,850
probably loses its function altogether

844
00:39:38,850 --> 00:39:42,480
or starts doing something crazy
that it shouldn't be doing.

845
00:39:42,480 --> 00:39:44,583
And this can definitely lead to disease.

846
00:39:45,690 --> 00:39:47,850
Let's take a quick peek at
what we're talking about here.

847
00:39:47,850 --> 00:39:50,940
So in-frame insertion, here you
have the wild type sequence,

848
00:39:50,940 --> 00:39:53,310
the DNA sequence on the
top in blue, followed

849
00:39:53,310 --> 00:39:55,920
by the mRNA sequence in red,
and then the protein sequence,

850
00:39:55,920 --> 00:39:58,800
and I'm writing that out as
the three-letter designation

851
00:39:58,800 --> 00:39:59,973
for each amino acid.

852
00:40:01,410 --> 00:40:03,690
So this is our wild type sequence.

853
00:40:03,690 --> 00:40:05,670
Then an in-frame insertion
means we're adding

854
00:40:05,670 --> 00:40:09,873
exactly three bases or
something divisible by,

855
00:40:09,873 --> 00:40:12,840
or a number divisible by
three number of bases.

856
00:40:12,840 --> 00:40:15,420
And you're also maintaining the frame.

857
00:40:15,420 --> 00:40:18,600
So here we're adding in a TCT, let's say,

858
00:40:18,600 --> 00:40:22,785
or an AGA, an AGA, right, in between

859
00:40:22,785 --> 00:40:25,920
codons two and four, or
two and three rather.

860
00:40:25,920 --> 00:40:29,280
So basically now our protein,

861
00:40:29,280 --> 00:40:30,690
what does our protein look like?

862
00:40:30,690 --> 00:40:33,120
So methionine, glutamine.

863
00:40:33,120 --> 00:40:34,450
Now there's an arginine

864
00:40:35,550 --> 00:40:37,290
and then it's followed
by the rest of, you know,

865
00:40:37,290 --> 00:40:39,090
the regular sequence of the protein.

866
00:40:39,090 --> 00:40:42,843
Cysteine, proline, proline,
leucine, glutamic acid.

867
00:40:44,880 --> 00:40:47,360
All right, so the protein
has one additional amino acid

868
00:40:47,360 --> 00:40:48,480
is the end result.

869
00:40:48,480 --> 00:40:51,270
Similarly for deletion, it's
basically like taking out

870
00:40:51,270 --> 00:40:54,180
exactly the three nucleotides

871
00:40:54,180 --> 00:40:56,160
which would encode for a single codon.

872
00:40:56,160 --> 00:40:57,930
So nothing gets shifted around,

873
00:40:57,930 --> 00:41:00,630
but you have one fewer amino acid there.

874
00:41:00,630 --> 00:41:03,465
So now we've lost our cysteine.

875
00:41:03,465 --> 00:41:06,210
And so it's methionine,
glutamine, proline, proline,

876
00:41:06,210 --> 00:41:10,650
leucine, glutamic acid, and
the cysteine is now gone.

877
00:41:10,650 --> 00:41:13,680
So this can have an impact
on the protein, certainly,

878
00:41:13,680 --> 00:41:15,933
but it's not totally
screwing everything up.

879
00:41:17,250 --> 00:41:19,110
Now if we wanna start screwing stuff up,

880
00:41:19,110 --> 00:41:22,920
let's take a look at what a
frameshift insertion would do.

881
00:41:22,920 --> 00:41:24,870
What would insertion do?

882
00:41:24,870 --> 00:41:27,300
Well, let's say we're just
adding one nucleotide.

883
00:41:27,300 --> 00:41:28,440
Like what can that hurt, right?

884
00:41:28,440 --> 00:41:29,520
Just putting one base in.

885
00:41:29,520 --> 00:41:32,040
Those other two examples,
you're adding three bases.

886
00:41:32,040 --> 00:41:33,960
Shouldn't that have a bigger impact?

887
00:41:33,960 --> 00:41:36,420
Well, no, because it totally changes

888
00:41:36,420 --> 00:41:37,620
and shifts the way

889
00:41:37,620 --> 00:41:41,040
the ribosomes are reading
those triplets of bases,

890
00:41:41,040 --> 00:41:43,920
which is so important, so important.

891
00:41:43,920 --> 00:41:47,490
So one little base off and
everything gets screwed up.

892
00:41:47,490 --> 00:41:49,800
Just like those words in the sentence

893
00:41:49,800 --> 00:41:51,120
that we were just talking about.

894
00:41:51,120 --> 00:41:54,180
You shift things over one to
the left or one to the right

895
00:41:54,180 --> 00:41:56,340
and it doesn't make any
sense anymore, right?

896
00:41:56,340 --> 00:41:59,360
It's gibberish, and that's
kind of what happens

897
00:41:59,360 --> 00:42:01,050
to the protein.

898
00:42:01,050 --> 00:42:02,790
So let's take this example.

899
00:42:02,790 --> 00:42:05,293
We're adding an A here.

900
00:42:05,293 --> 00:42:09,900
And so everything
basically gets shifted over

901
00:42:09,900 --> 00:42:13,440
to the right by one as
far as how the ribosome

902
00:42:13,440 --> 00:42:14,420
is going to read the sequence.

903
00:42:14,420 --> 00:42:17,490
So now the ribosome reads
AUG, yep, same as before,

904
00:42:17,490 --> 00:42:19,080
CAA, yep, same as before,

905
00:42:19,080 --> 00:42:22,206
but now it's reading
AUG, which is methionine

906
00:42:22,206 --> 00:42:23,830
as a cysteine.

907
00:42:23,830 --> 00:42:28,230
So it basically has totally
shifted over by one.

908
00:42:28,230 --> 00:42:31,290
So instead of reading it the
normal way it's supposed to,

909
00:42:31,290 --> 00:42:34,290
now everything gets shifted,

910
00:42:34,290 --> 00:42:36,060
gets basically shifted over one.

911
00:42:36,060 --> 00:42:38,820
So now instead of reading TGTC, CCG,

912
00:42:38,820 --> 00:42:42,420
it's now going to read TCC, GCC.

913
00:42:43,726 --> 00:42:44,559
See what I'm saying?

914
00:42:44,559 --> 00:42:46,107
ATT.

915
00:42:46,107 --> 00:42:48,603
And that's what you have down here.

916
00:42:50,280 --> 00:42:52,620
All right, and that results
in completely different,

917
00:42:52,620 --> 00:42:56,070
completely different
amino acids being read

918
00:42:56,070 --> 00:42:58,070
after the frameshift.

919
00:42:59,707 --> 00:43:01,230
A deletion, same thing.

920
00:43:01,230 --> 00:43:03,240
Delete, you're just taking
out one little base.

921
00:43:03,240 --> 00:43:04,350
What can that hurt?

922
00:43:04,350 --> 00:43:05,580
Well, there's a lot

923
00:43:05,580 --> 00:43:08,970
because now everything
gets screwed up after that.

924
00:43:08,970 --> 00:43:11,070
And, again, same thing.

925
00:43:11,070 --> 00:43:14,190
So let's say we're removing this T here,

926
00:43:14,190 --> 00:43:17,760
so everything moves
back over this way one,

927
00:43:17,760 --> 00:43:19,140
so instead of it...

928
00:43:19,140 --> 00:43:21,570
So everything gets moved over one again.

929
00:43:21,570 --> 00:43:24,330
And here you have the same,
you have the same problems,

930
00:43:24,330 --> 00:43:26,520
everything following, all the amino acids

931
00:43:26,520 --> 00:43:28,950
following that frameshift
are completely different.

932
00:43:28,950 --> 00:43:31,050
And then the protein
gets totally screwed up.

933
00:43:31,050 --> 00:43:33,120
So as you might be able
to start imagining,

934
00:43:33,120 --> 00:43:34,710
since everything that follows

935
00:43:34,710 --> 00:43:38,970
that mutation gets screwed up, the closer

936
00:43:38,970 --> 00:43:42,270
to the start codon that a
frameshift mutation happens,

937
00:43:42,270 --> 00:43:44,340
the more detrimental it is to the protein.

938
00:43:44,340 --> 00:43:49,050
Similarly, the closer to
the start codon, the start

939
00:43:49,050 --> 00:43:53,070
of translation that a
nonsense mutation happens,

940
00:43:53,070 --> 00:43:57,330
so inserting a, basically changing a codon

941
00:43:57,330 --> 00:44:00,510
for an amino acid to a stop codon,

942
00:44:00,510 --> 00:44:03,330
the closer that that
happens to the start codon,

943
00:44:03,330 --> 00:44:04,637
the more screwed up the
protein's going to be,

944
00:44:04,637 --> 00:44:06,990
'cause the shorter the
protein's going to be.

945
00:44:06,990 --> 00:44:09,270
Same thing here in a frameshift.

946
00:44:09,270 --> 00:44:12,420
The closer that that mutation happens

947
00:44:12,420 --> 00:44:16,292
to the start of translation,

948
00:44:16,292 --> 00:44:20,280
that means that all of the
amino acids following it

949
00:44:20,280 --> 00:44:21,113
are going to be screwed up,

950
00:44:21,113 --> 00:44:23,943
so the worst it actually
is for the protein.

951
00:44:25,440 --> 00:44:27,450
Okay, let's talk about
a little nomenclature

952
00:44:27,450 --> 00:44:30,690
for mutations which result
in changes to the protein.

953
00:44:30,690 --> 00:44:33,360
So this is definitely not all of it.

954
00:44:33,360 --> 00:44:35,400
Unfortunately, it's not
all totally standardized.

955
00:44:35,400 --> 00:44:37,020
So you might see this in different ways.

956
00:44:37,020 --> 00:44:38,850
I just want to give you at least one way

957
00:44:38,850 --> 00:44:40,470
that you might start to see some of these.

958
00:44:40,470 --> 00:44:42,797
I'm not going to go in a
lot of gory detail here

959
00:44:42,797 --> 00:44:45,630
'cause it gets to just be
like a lot of memorization

960
00:44:45,630 --> 00:44:47,340
and it's not totally necessary.

961
00:44:47,340 --> 00:44:50,820
I just want you to, when you
see something, say on a chart,

962
00:44:50,820 --> 00:44:52,740
or you know, in a test
result or something,

963
00:44:52,740 --> 00:44:54,960
I want you to be able to
recognize it at least.

964
00:44:54,960 --> 00:44:57,390
And then you can kind
of look up what it means

965
00:44:57,390 --> 00:44:59,010
specifically in that context.

966
00:44:59,010 --> 00:45:01,200
But to give you a sense

967
00:45:01,200 --> 00:45:04,530
of what you might see, the
nomenclature likely denotes

968
00:45:04,530 --> 00:45:06,480
the changes in the amino acid sequence,

969
00:45:06,480 --> 00:45:07,980
not the DNA sequence.

970
00:45:07,980 --> 00:45:09,630
And they may use a single letter

971
00:45:09,630 --> 00:45:12,390
or the three letter
amino acid designation.

972
00:45:12,390 --> 00:45:14,310
As you saw I was using

973
00:45:14,310 --> 00:45:16,800
the three letter amino acid designation,

974
00:45:16,800 --> 00:45:18,090
but there's also single letters,

975
00:45:18,090 --> 00:45:20,670
which is what I have down here.

976
00:45:20,670 --> 00:45:21,630
And you can look those up

977
00:45:21,630 --> 00:45:23,820
just so you can look up
a table of that online,

978
00:45:23,820 --> 00:45:26,610
you know, for the 20 amino
acids, what the single letter

979
00:45:26,610 --> 00:45:29,210
and three letter designations
are for each of those.

980
00:45:30,360 --> 00:45:35,360
For a nonsense mutation, it's
designated as the amino acid

981
00:45:35,760 --> 00:45:38,100
which is changed and its location

982
00:45:38,100 --> 00:45:39,930
along the chain of amino acids.

983
00:45:39,930 --> 00:45:41,880
And it's followed by the letter X,

984
00:45:41,880 --> 00:45:44,910
and that x basically
means it's a stop codon,

985
00:45:44,910 --> 00:45:47,580
so nothing else follows that.

986
00:45:47,580 --> 00:45:51,990
So in this case we have G542X.

987
00:45:51,990 --> 00:45:56,340
If you see that, then you
know that it is the glycine,

988
00:45:56,340 --> 00:46:00,210
which is the amino acid which
is designated by the letter G,

989
00:46:00,210 --> 00:46:04,950
glycine, at the 542nd amino acid

990
00:46:04,950 --> 00:46:06,420
in the chain of amino acids

991
00:46:06,420 --> 00:46:09,000
for this protein is normally a glycine.

992
00:46:09,000 --> 00:46:11,373
So the wild type is glycine.

993
00:46:12,270 --> 00:46:15,480
But now in this individual
who has nonsense mutation,

994
00:46:15,480 --> 00:46:17,340
it is now a stop codon.

995
00:46:17,340 --> 00:46:19,380
So it is designated as an X

996
00:46:19,380 --> 00:46:22,560
because no amino acids have Xs there.

997
00:46:22,560 --> 00:46:23,883
Single letter designation.

998
00:46:24,750 --> 00:46:29,700
Okay, a missense mutation is
designated by the wild type,

999
00:46:29,700 --> 00:46:31,560
or the old amino acid, you
can think of it that way,

1000
00:46:31,560 --> 00:46:33,330
its location, and then the new

1001
00:46:33,330 --> 00:46:36,270
or mutant amino acid
that's now in its place.

1002
00:46:36,270 --> 00:46:40,923
In this example it would
be glycine at location 176.

1003
00:46:41,830 --> 00:46:46,830
So the 176th amino acid in the
chain is no longer glycine.

1004
00:46:47,640 --> 00:46:52,640
It's now F, which stands
for phenylalanine, okay?

1005
00:46:52,759 --> 00:46:55,920
An in-frame deletion
is denoted by a delta,

1006
00:46:55,920 --> 00:47:00,920
or it could be denoted as
the letters DEL for deletion.

1007
00:47:02,460 --> 00:47:06,270
But you may see it as the
delta, the delta symbol,

1008
00:47:06,270 --> 00:47:10,560
then the amino acid which
is deleted and its location.

1009
00:47:10,560 --> 00:47:12,210
So this would be a deletion

1010
00:47:12,210 --> 00:47:14,830
of the phenylalanine at location 508

1011
00:47:15,900 --> 00:47:18,150
in that particular protein.

1012
00:47:18,150 --> 00:47:21,570
An in-frame insertion,
it would basically...

1013
00:47:21,570 --> 00:47:23,040
Here's where it starts
to get a little ugly.

1014
00:47:23,040 --> 00:47:24,930
With in-frame insertions and frameshifts,

1015
00:47:24,930 --> 00:47:28,710
it just gets really,
(laughs) it gets really hairy

1016
00:47:28,710 --> 00:47:31,560
with how it's designated,

1017
00:47:31,560 --> 00:47:34,350
and it's designated different
ways depending upon,

1018
00:47:34,350 --> 00:47:36,240
I don't know, what the person ate

1019
00:47:36,240 --> 00:47:37,890
for breakfast that morning. (laughs)

1020
00:47:37,890 --> 00:47:39,450
Honestly, like, there
doesn't seem to be a lot

1021
00:47:39,450 --> 00:47:40,800
of rhyme or reason to it sometimes.

1022
00:47:40,800 --> 00:47:42,360
But here's at least one way

1023
00:47:42,360 --> 00:47:45,183
in which an in-frame
insertion can be denoted.

1024
00:47:46,260 --> 00:47:49,650
It would be denoted as
the amino acid before

1025
00:47:49,650 --> 00:47:52,980
and the amino acid after.

1026
00:47:52,980 --> 00:47:55,740
And so it would be
denoted as the wild type,

1027
00:47:55,740 --> 00:47:59,280
which would normally be
leucine at location 21,

1028
00:47:59,280 --> 00:48:02,220
followed by a lysine at location 22,

1029
00:48:02,220 --> 00:48:04,410
and there's an insertion
now of a threonine.

1030
00:48:04,410 --> 00:48:07,410
So in this individual it would now read,

1031
00:48:07,410 --> 00:48:10,680
if you were reading their
amino acids in this protein,

1032
00:48:10,680 --> 00:48:13,500
it would read, starting at amino acid 21

1033
00:48:13,500 --> 00:48:18,300
would read as leucine threonine lysine,

1034
00:48:18,300 --> 00:48:20,670
and then all the rest of the amino acids

1035
00:48:20,670 --> 00:48:22,740
are in the normal order,

1036
00:48:22,740 --> 00:48:24,690
as you would expect for this protein.

1037
00:48:24,690 --> 00:48:26,520
Frameshifts, it gets more complicated.

1038
00:48:26,520 --> 00:48:29,910
But if you see the letters
fs in the designation,

1039
00:48:29,910 --> 00:48:32,490
that means there is a
frameshift at that location

1040
00:48:32,490 --> 00:48:33,780
that they are specifying.

1041
00:48:33,780 --> 00:48:38,220
But again, yeah, it gets a little weird.

1042
00:48:38,220 --> 00:48:40,290
I still haven't quite
figured out if there's...

1043
00:48:40,290 --> 00:48:42,690
It doesn't seem like there's
a standard way to do it.

1044
00:48:42,690 --> 00:48:44,610
So if you see the letters fs,

1045
00:48:44,610 --> 00:48:47,836
that likely means it's
referring to a frameshift.

1046
00:48:47,836 --> 00:48:50,250
And I apologize, I can't give
you more direction than that.

1047
00:48:50,250 --> 00:48:53,160
It's just, I've seen it
so many different ways

1048
00:48:53,160 --> 00:48:56,490
that it would really, I
think, be a waste of time

1049
00:48:56,490 --> 00:48:58,740
to try to go through all of them.

1050
00:48:58,740 --> 00:49:00,690
So, but anyway, if you see those,

1051
00:49:00,690 --> 00:49:05,640
at least you'll be familiar
with what those may indicate.

1052
00:49:05,640 --> 00:49:08,160
All right, let's move
on to some categories

1053
00:49:08,160 --> 00:49:09,870
of genetic disease.

1054
00:49:09,870 --> 00:49:10,860
Chromosomal disorders,

1055
00:49:10,860 --> 00:49:13,320
which we talked about a
lot in the last module.

1056
00:49:13,320 --> 00:49:15,180
These are polygenic,

1057
00:49:15,180 --> 00:49:18,747
and by that I mean they're
involved with multiple genes,

1058
00:49:18,747 --> 00:49:20,490
and that would be all of the genes

1059
00:49:20,490 --> 00:49:21,930
in the chromosome.

1060
00:49:21,930 --> 00:49:25,560
If it's aneuploidy,
basically the disorder itself

1061
00:49:25,560 --> 00:49:29,640
may be the phenotype of the disorder,

1062
00:49:29,640 --> 00:49:34,260
so let's say the phenotype
would be Down syndrome,

1063
00:49:34,260 --> 00:49:39,260
the genotype would be
trisomy of chromosome 21.

1064
00:49:40,290 --> 00:49:42,120
So the phenotype would
be the characteristic,

1065
00:49:42,120 --> 00:49:43,410
which would be Down syndrome,

1066
00:49:43,410 --> 00:49:45,300
all that's associated with that.

1067
00:49:45,300 --> 00:49:47,640
The genotype would be what caused it

1068
00:49:47,640 --> 00:49:48,690
from a sequence perspective,

1069
00:49:48,690 --> 00:49:51,660
and that would be a
trisomy of chromosome 21.

1070
00:49:51,660 --> 00:49:54,270
So chromosomal disorders
are polygenic, right?

1071
00:49:54,270 --> 00:49:56,220
So they involve many different genes,

1072
00:49:56,220 --> 00:49:57,270
however many different genes

1073
00:49:57,270 --> 00:50:00,390
are either on the chromosome
itself if it's an aneuploidy,

1074
00:50:00,390 --> 00:50:03,243
or in the region where there's
a chromosomal disorder.

1075
00:50:04,980 --> 00:50:07,770
And that contributes
to all of the different

1076
00:50:07,770 --> 00:50:10,770
and various symptoms
that you see associated

1077
00:50:10,770 --> 00:50:13,710
with chromosomal disorders.

1078
00:50:13,710 --> 00:50:16,650
A single gene disorder would
be considered monogenic.

1079
00:50:16,650 --> 00:50:19,590
There are over 6,000
different identified disorders

1080
00:50:19,590 --> 00:50:20,820
that fall into this category.

1081
00:50:20,820 --> 00:50:24,330
They're often called
Mendelian disorders as well.

1082
00:50:24,330 --> 00:50:25,170
You might hear that.

1083
00:50:25,170 --> 00:50:28,110
We'll talk about that a
lot in the next lecture.

1084
00:50:28,110 --> 00:50:29,820
And then there are multifactorial,

1085
00:50:29,820 --> 00:50:32,640
which is nearly all
diseases to varying degrees,

1086
00:50:32,640 --> 00:50:34,140
which could be considered multifactorial,

1087
00:50:34,140 --> 00:50:37,860
which means they are
involved with multiple genes

1088
00:50:37,860 --> 00:50:41,460
to different extents and
influence from the environment.

1089
00:50:41,460 --> 00:50:43,923
We'll talk about this in the next module.

1090
00:50:44,820 --> 00:50:46,020
Next module.

1091
00:50:46,020 --> 00:50:50,400
And those would be diseases
like cardiovascular disease.

1092
00:50:50,400 --> 00:50:51,990
Cancer, for example,

1093
00:50:51,990 --> 00:50:55,083
is also a multifactorial genetic disease.

1094
00:50:57,240 --> 00:51:00,843
You know, stroke risk, all
of these are multifactorial.

1095
00:51:03,330 --> 00:51:05,490
Chromosomal disorders, as you recall,

1096
00:51:05,490 --> 00:51:08,550
these would be either a full-on aneuploidy

1097
00:51:08,550 --> 00:51:11,940
or it could be a portion of a chromosome

1098
00:51:11,940 --> 00:51:15,453
is deleted, duplicated, inverted,

1099
00:51:17,850 --> 00:51:20,220
transferred from one
chromosome to another.

1100
00:51:20,220 --> 00:51:24,243
You remember all of those from
the last module, hopefully.

1101
00:51:25,230 --> 00:51:27,930
So this is excess or lack
of a whole chromosome

1102
00:51:27,930 --> 00:51:30,030
or segment of a chromosome.

1103
00:51:30,030 --> 00:51:31,590
So phenotype is the net effect

1104
00:51:31,590 --> 00:51:33,840
of changes in many different genes.

1105
00:51:33,840 --> 00:51:34,980
Okay?

1106
00:51:34,980 --> 00:51:36,150
Single gene disorders,

1107
00:51:36,150 --> 00:51:39,180
these would be disorders
like cystic fibrosis,

1108
00:51:39,180 --> 00:51:42,180
which occurs when both copies
of the CFTR gene are mutated.

1109
00:51:42,180 --> 00:51:45,090
And we will go into that
in the next lecture.

1110
00:51:45,090 --> 00:51:47,640
This would be a mutation or
disruption in a single gene

1111
00:51:47,640 --> 00:51:49,620
which results in the disease.

1112
00:51:49,620 --> 00:51:54,620
So for a person who has the genotype,

1113
00:51:54,900 --> 00:51:57,840
the genotype which
determines cystic fibrosis,

1114
00:51:57,840 --> 00:52:00,690
it doesn't matter what
that person does, right?

1115
00:52:00,690 --> 00:52:05,690
So they could live the healthiest
life they possibly could.

1116
00:52:05,940 --> 00:52:08,190
They're still going to
develop at least some

1117
00:52:08,190 --> 00:52:10,770
of the symptoms of cystic fibrosis.

1118
00:52:10,770 --> 00:52:12,780
They're still going to
develop cystic fibrosis

1119
00:52:12,780 --> 00:52:16,230
because getting that particular
disease, the manifestation

1120
00:52:16,230 --> 00:52:20,583
of that disease is 100%
determined by the genotype

1121
00:52:24,000 --> 00:52:25,560
for the cystic fibrosis gene.

1122
00:52:25,560 --> 00:52:28,440
So it's monogenic, single
gene influencing it,

1123
00:52:28,440 --> 00:52:30,630
and particular mutations in that gene

1124
00:52:30,630 --> 00:52:32,130
will give you the disease.

1125
00:52:32,130 --> 00:52:34,863
The disease will absolutely manifest,

1126
00:52:35,760 --> 00:52:39,810
as opposed to multifactorial disorders

1127
00:52:39,810 --> 00:52:42,510
where you can have really
a combination of effects.

1128
00:52:42,510 --> 00:52:44,940
And again, this is most of what you see

1129
00:52:44,940 --> 00:52:46,290
certainly on a day-to-day basis.

1130
00:52:46,290 --> 00:52:49,440
And this will be most
diseases are influenced

1131
00:52:49,440 --> 00:52:50,520
by many different factors.

1132
00:52:50,520 --> 00:52:54,060
So if you take hypertension
for example, well, as you know,

1133
00:52:54,060 --> 00:52:56,550
right, that's going to be
influenced dramatically

1134
00:52:56,550 --> 00:53:00,000
by a person's diet, by whether they smoke

1135
00:53:00,000 --> 00:53:04,420
or not, by their lifestyle,
so whether they're sedentary

1136
00:53:06,399 --> 00:53:09,330
or do regular amounts of exercise.

1137
00:53:09,330 --> 00:53:12,990
But it's also influenced by
a variety of different genes

1138
00:53:12,990 --> 00:53:15,480
and different mutations in those genes.

1139
00:53:15,480 --> 00:53:18,990
They all contribute a little
bit to the risk associated

1140
00:53:18,990 --> 00:53:22,413
with potentially developing
something like hypertension.

1141
00:53:24,330 --> 00:53:27,450
Okay, yes, and hypertension
involves over 15 genes

1142
00:53:27,450 --> 00:53:30,063
as well as diet, exercise,
and smoking exposure.

1143
00:53:31,140 --> 00:53:34,530
And we'll get into a little
more of that in the next module.

1144
00:53:34,530 --> 00:53:37,830
These become a lot more
difficult to nail down

1145
00:53:37,830 --> 00:53:40,950
and give precise estimates to patients

1146
00:53:40,950 --> 00:53:42,510
as far as what's their risk

1147
00:53:42,510 --> 00:53:44,910
because there are a lot
of factors contributing

1148
00:53:44,910 --> 00:53:46,560
a little bit of risk,

1149
00:53:46,560 --> 00:53:49,320
and it's really the combination of those

1150
00:53:49,320 --> 00:53:52,140
that will determine
whether or not a person

1151
00:53:52,140 --> 00:53:53,580
develops a particular disorder

1152
00:53:53,580 --> 00:53:55,180
and the extent to which they do.

1153
00:53:56,340 --> 00:53:57,810
All right, let's summarize here.

1154
00:53:57,810 --> 00:53:59,580
Genotype leads to phenotype.

1155
00:53:59,580 --> 00:54:03,000
So your genotype would be the sequence

1156
00:54:03,000 --> 00:54:04,140
of a particular gene,

1157
00:54:04,140 --> 00:54:06,960
and that's going to lead to the phenotype

1158
00:54:06,960 --> 00:54:09,903
or how the gene is basically,

1159
00:54:11,130 --> 00:54:14,460
how the genotype is seen in an individual.

1160
00:54:14,460 --> 00:54:18,810
So their traits are affected
by a particular genotype.

1161
00:54:18,810 --> 00:54:21,090
Changes to a gene sequence
can result in changes

1162
00:54:21,090 --> 00:54:23,970
to the protein it encodes,
which can affect phenotype.

1163
00:54:23,970 --> 00:54:27,780
We gave you a few examples
there of the sickle cell disease

1164
00:54:27,780 --> 00:54:28,890
and cystic fibrosis.

1165
00:54:28,890 --> 00:54:31,744
How changes in those proteins

1166
00:54:31,744 --> 00:54:36,183
can affect the individual.

1167
00:54:37,260 --> 00:54:39,240
Mutations include changing a base

1168
00:54:39,240 --> 00:54:40,950
or point mutation or inserting

1169
00:54:40,950 --> 00:54:42,900
or deleting one or more bases,

1170
00:54:42,900 --> 00:54:45,120
and these mutations can
cause one amino acid

1171
00:54:45,120 --> 00:54:47,790
to be different, which would
be a missense, the protein

1172
00:54:47,790 --> 00:54:50,040
to be truncated, which would be nonsense,

1173
00:54:50,040 --> 00:54:52,020
an amino acid to be added or removed,

1174
00:54:52,020 --> 00:54:54,300
which would be an in-frame
insertion or deletion,

1175
00:54:54,300 --> 00:54:56,400
or the protein to be
dramatically different,

1176
00:54:56,400 --> 00:54:58,920
which would be from a frameshift.

1177
00:54:58,920 --> 00:55:00,930
Genetic diseases can be monogenic,

1178
00:55:00,930 --> 00:55:03,300
polygenic, or multifactorial.

1179
00:55:03,300 --> 00:55:05,970
All right, so what's
up next in this module?

1180
00:55:05,970 --> 00:55:07,860
Well, the remaining two lectures,

1181
00:55:07,860 --> 00:55:12,060
we're going to dive into
patterns of inheritance

1182
00:55:12,060 --> 00:55:14,190
that are commonly called
Mendelian inheritance,

1183
00:55:14,190 --> 00:55:17,190
which means inheritance of conditions

1184
00:55:17,190 --> 00:55:21,120
that are caused by a single gene.

1185
00:55:21,120 --> 00:55:24,358
So looking at inheritance
of a single gene.

1186
00:55:24,358 --> 00:55:26,430
And so we're gonna have
two lectures on that.

1187
00:55:26,430 --> 00:55:29,370
The first one is on the basics
of Mendelian inheritance,

1188
00:55:29,370 --> 00:55:31,230
and that's where we get
those terms of dominant

1189
00:55:31,230 --> 00:55:33,330
and recessive I'm sure
you're familiar with.

1190
00:55:33,330 --> 00:55:34,950
And then we're going to move on

1191
00:55:34,950 --> 00:55:36,720
to some extensions to Mendel.

1192
00:55:36,720 --> 00:55:40,230
So, as we know all too well in genetics,

1193
00:55:40,230 --> 00:55:42,330
there's always exceptions,

1194
00:55:42,330 --> 00:55:45,330
and some of them are actually
pretty important to make sure

1195
00:55:45,330 --> 00:55:47,230
that you're familiar with and aware of

1196
00:55:48,330 --> 00:55:50,700
in things you might see in your practice

1197
00:55:50,700 --> 00:55:53,820
or patterns of inheritance that
might not quite fit exactly

1198
00:55:53,820 --> 00:55:56,880
what we learned about from
the Mendelian inheritance.

1199
00:55:56,880 --> 00:55:59,160
So with that, I will say goodbye,

1200
00:55:59,160 --> 00:56:01,310
and will talk with you
in the next lecture.