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For this module, we're going to talk about the way in which peas and

people remember and transmit information across generations.

This is the structure of the DNA molecule and

we'll be talking a little more about this in this module.

So DNA is a long, long, long, long molecule.

But in the body it's organized in the nucleus of each cell,

the center part of each cell.

Not as a long unwound piece of spaghetti, but

wound up on structures called centromeres.

And those structures then compact themselves into structures

that are actually visible under the microscope called chromosomes.

And a picture of the chromosome is shown at the top of this cartoon.

So when you look at a nucleus of a human cell, you'll see 22 pairs

of chromosomes plus one set of sex chromosomes, X and Y.

If you have two X chromosomes that defines a female, and

an X chromosome and Y chromosome define a male.

The other 22 chromosomes come in pairs and those are called autosomes.

The longest one is chromosome 1, the shortest one is chromosome 22.

It's not a very imaginative numbering system.

And that's the situation in each cell in the body

with the exception of sperm cells and egg cells.

Sperm cells and egg cells each have half of the complement of chromosomes,

randomly choosing one of each pair of the autosomes and

one sex chromosome in each sperm cell and in each egg cell.

So when a sperm cell and egg cell come together to create a fertilized ovum,

then you have a complete collection of 46 chromosomes, half from mother and

half from father.

And that's the mechanism for the heredity.

And the fact is that DNA can reproduce itself, can replicate itself,

through mechanisms that I mentioned in the earlier talk, and so

that gives us an opportunity to create offspring.

Now, here are two sets of chromosomes and they come together to generate one child.

The blue chromosomes are from the father and

the pink chromosomes are from the mother.

And it could be any color, they're obviously not colored that way.

What's interesting to notice here is that this is a male child because he has an x

chromosome and a y chromosome and the y chromosome has to come from his father.

And the father's Y chromosome had to have come from his father.

And the grandfather's Y chromosome had to have come from his grandfather, so

each male carries in him a Y chromosome that comes from his father's line,

his father's father's father's father's father's line.

And that becomes important when it comes time to figure out who we are in

ancestral terms, where our forbearers came from.

We can track that through the Y chromosome.

It turns out there's also DNA that comes exclusively from the mother, and

the DNA that comes from the mother is not in the nucleus where the chromosomes live.

But actually in structures called mitochondria.

Mitochondria are little energy factories that are not in the nucleus but

in what we call the cytoplasm, the non-nucleus part of each cell.

And in the mitochondria is a small

ring of DNA called mitochondrial DNA and that comes exclusively from the mother.

How does it come exclusively from the mother?

Remember that when the sperm cell and the ovary come together, the sperm is tiny.

It's just a little collection of DNA, where the egg cell has a nuclear and

has a cytoplasm, so it's the cytoplasm of the egg cell

that transmits the mitochondrial DNA from generation to generation.

So your mother's mother's mother's mother's mother's mother's mother's

mother's mother's mitochondrial DNA is your mitochondrial DNA.

We can track maternal lineage that way.

This slide shows what we call the central dogma of modern genetics.

The central dogma is that the information that we want to use to transmit

from generation to generation is contained in DNA,

is encoded in DNA in ways in which I will talk about in a moment.

The DNA itself can be copied.

It can be copied to make other DNA molecules.

It can also be copied to make a single strand copy of itself called RNA.

RNA looks much like DNA, you can see it looks like a single strand as opposed to

a double strand so it's a template obviously.

And the four baeis, the As, Cs, Ts, and

Gs that make up DNA are shown with the DNA molecule.

The same four bases make up RNA except we refer to the T as a U.

Instead of Thymadine we call it Uridine because it's a different chemical.

But the T and the U serve similar functions in RNA and DNA.

RNA then serves as a template from which proteins can be made.

And it's proteins that do all the work in our body.

Proteins that make up the structure of our body so that we have collagen proteins and

hair proteins and nail proteins.

Proteins that do work like heart contraction or thinking or eye color,

all of those are proteins, proteins in the liver that chew up food as we digest.

Every function that you can think of in your body

is really a function of proteins.

And proteins are made up of also fundamental building blocks.

Not A, C, T, and G or A, C,

A, C, G, and U, but fundamental building blocks called amino acids.

And there are 20 amino acids.

So each protein is a collection, a string of amino acids,

and the amino acids that are selected for it in each protein are encoded in

the DNA in ways in which I'll tell you about right now.

So here is a long strand of DNA and that strand happens to encode a protein.

We call that strand a gene.

It turns out that most DNA does not encode proteins.

Most DNA is what we call non-coding, and

its job in life is to actually regulate the process whereby genes are translated

into proteins through ways in which we are just beginning to understand now.

So about one percent of all the DNA in each cell, actually encodes proteins.

The way it works is that there are specific regions of DNA that

are recognized as so-called promoter regions.

Promoters allow, a set of molecules called RNA polymerase to bind.

And what RNA polymerase does is two things.

It unwinds the DNA, and when it unwinds the DNA it

also creates a copy as you can see on the bottom cartoon here.

And each strand of DNA serves as a template for

creating a single strand of RNA.

The RNA is made in the nucleus because that's where DNA lives.

The RNA is then exported from the nucleus Into the cytoplasm.

It's called messenger RNA.

And messenger RNA is then translated into proteins.

So this is the structure of a gene, and again, the details become important,

not the entire sequence encodes a protein, only a piece of the sequence.

Actually, usually a minority of the sequence.

So a gene can be a very, very long structure, over hundreds of thousands of

base pairs of DNA, and yet the coding region of that gene

could just be a thousand or 2,000 based pairs with a lot of intervening sequences.

So when message our RNA gets made from DNA we get a very, very, very long string.

And each string consists of coding regions that we call exons and

intervening regions between the coding regions that are called introns.

I've drawn them here showing them at roughly the same size,

but in fact, introns are generally much much larger than exons.

So this is what's called a pre-messenger RNA molecule.

It's an exact copy of the entire gene, intervening sequence, exons, and

then a little bit of sequence at the upstream part and the downstream part.

So that this pre-messenger RNA molecule that undergoes a process called splicing.

And splicing then results in deletion of all the intronic material and

a sequence of messenger RNA that will encode a protein.

And it's shown here as these five little green blocks.

They're slightly different colors,

just to show the exons as they come out of the pre-messenger RNA.

Now, that's one way of splicing.

But it turns out splicing can also result in different messenger RNA sequences.

So here's an example of splicing where that big green blob in the middle

of the exon three is deleted.

So we have a different messenger RNA that has a different sequence and

will encode a different protein.

In this way one gene can encode multiple different proteins,

sometimes with quite different function.

So the way it works is the messenger RNA is then exported

to the cytoplasm where a structure called a ribosome attaches to the messenger RNA,

and beings to translate the code,

the A, C, G, and U code into proteins.

Each three letter code is called a codon and

each three letter code encodes a single amino acid.

A structure called transfer RNA attaches itself to each three letter code,

and each transfer RNA molecule carries a different amino acid.

So in this particular sequence, each RNA molecule which comes from DNA

then translates into a unique protein sequence and generates a protein.

As the ribosome moves down the message RNA the protein gets longer and longer and

longer as each of it's single amino acid is added until you have

a fully formed protein.

This slide shows the way in which the messenger RNA bases the A, C,

G, and U combined in triplets to encode 1 of 20 individual amino acids.

Now, it turns out that there are four nucleotides in RNA,

and they can combine in 64 different ways to make triplet codons.

So, there's what's called redundancy in the genetic code.

That is a UUU triplet encodes the amino acid phenylalanine, abbreviated here Phe.

But a UUUC also encodes phenylalanine and

you can see that for example arginine is CG and then anything.

CGU, CGC, CGA, or CGG.

So this is what's called redundancy in the genetic code.

And it means that if there's a DNA change, the messenger RNA might be different,

but the amino acid that is encoded might not be changed at all.

And we'll come back to that in one moment.

So after a string of protein is made,

one cartoon in my cartoons have shown that it looks like spaghetti.

There's a sort of floppiness to it.

But in fact, proteins assume structure.

Two common structures are what's called an alpha helix and it looks like a helix.

And the other structure is called a beta-pleated sheet and

it looks like a pleated sheet as in a cartoon.

Those structures then come together to form a protein with some rigidity.

Many proteins move around a little bit and

they move around as they accomplish their function.

You can see in that complicated cartoon of the protein

where there's lots a little pockets and

one of the things that happens is drugs for example can bind in those pockets.

And one of the other things that can happen is that proteins bind to each

other, to create giant multi-protein complexes.

And it's the multi protein complexes that actually accomplish the function

that the protein is designed to do like contract the heart or

to digest a piece of food.

So that's the idea.

So let's come back to this string of amino acids that I showed you before, and

remember the string is the sequence of amino acids.

It comes from the sequence of the messenger RNA, and

that in turns comes from the DNA that sits in the nucleus, and it carries the code.

So in a liver cell there's some DNA molecules,

some genes that are turned on and make messenger RNA and then make protein.

In a heart cell it may be a different collection of genes.

So not every single gene is expressed in every single piece of tissue, and

that's one of the functions of the long non-coding regions of DNA to tell the cell

which particular gene it should turn on at what particular time to make proteins.

Now imagine there are changes in the DNA molecule.

So some of those changes will be in the coding region.

And, for example, there could be a little deletion of sequence of DNA.

And if there's a deletion of the sequence,

what might happen is that the protein would look different.

You might be missing all those five or six amino acids in light gray.

Will that make the same protein?

Will it work the same way?

It might not.

And that, in turn might cause a disease,

it might contribute to a disease, it might cause an unusual reaction to a drug.

That's one sort of DNA variation that we'll be talking about a lot

in this course.

And commonest form of DNA variation is a variation in a single base pair.

And if that variation occurs in the coding region of a gene,

it can result in change in a single amino acid.

That's indicated here by the little red arrow.

That's one amino acid that's changed in its sequence.

That could change the function of that protein drastically.

Or could do nothing.

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Genetics Definitions, Part I

Case Studies in Personalized Medicine

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