This course introduces you to the basic biology of modern genomics and the experimental tools that we use to measure it. We'll introduce the Central Dogma of Molecular Biology and cover how next-generation sequencing can be used to measure DNA, RNA, and epigenetic patterns. You'll also get an introduction to the key concepts in computing and data science that you'll need to understand how data from next-generation sequencing experiments are generated and analyzed. This is the first course in the Genomic Data Science Specialization.
Molecular Biology Structures
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Из курса от партнера Johns Hopkins University
Introduction to Genomic Technologies
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Overview
In this Module, you can expect to study topics of "Just enough molecular biology", "The genome", "Writing a DNA sequence", "Central dogma", "Transcription", "Translation", and "DNA structure and modifications".
Познакомьтесь с преподавателями
Steven Salzberg, PhDProfessor
Biomedical Engineering, Computer Science, and Biostatistics
Jeff Leek, PhDAssociate Professor, Biostatistics
Bloomberg School of Public Health
In this lecture, we're going to talk about molecular biology structures,
by which I mean structures in the DNA and other molecules inside the cell that
you need to know about to understand the rest of the course.
So these are mostly terms and, and descriptions of functions that,
that go on inside every cell of your body that kind of govern how,
how, how you're molecular, how molecular biology works and how genetics works.
So let's start with DNA.
So DNA itself, as we've said before, is this very, very long molecule.
It's inside every cell in your body.
In humans we have 23 chromosome pairs, each of those are very,
very long molecules of DNA.
So the DNA itself, if you stretched it out,
would be about two meters long inside each cell.
Cells are, are, of course, microscopic.
So in order to fit into a cell it has to be wrapped up in very,
a very efficient way.
So it's actually wrapped around other molecules called histones in what you can
see as sort of this beads on a string, just, structure, on the, on the left.
And those histones are wrapped together in these organized
slightly longer structures.
And those together, are, are then coiled up and super coiled in, in even
bigger structures which eventually form the chromosomes that you see on the right.
So DNA is, is coiled around itself,
the coils are then coiled around themselves in a very complicated way.
Now for DNA to be transcribed and translated,
it has to unwrap itself a bit so we'll talk a little bit more about that next.
So, another kind of structure a very different kind of structure is not so
much a physical one, but a sequence structure.
And that's what we call repeats, so you'll hear a lot about repeats in,
in data analysis of DNA.
So we just need to know what these terms are.
And there are many different kinds of repeats.
Broadly speaking, we could call them,
we could classify them in two different, two different types.
Tandem repeats, which are repeats of sequence, identical sequence,
that occur one after the other.
And here's an example of a five base repeat ATTCG
that occurs three times in a row.
And these then, by the way tandem repeats don't have to be identical.
And they can be very long.
There are cases where you have sequences that are hundreds of base pairs long
that occur thousands of times in a row.
And in fact the centromeres inside of each in,
in each chromosome comprise largely of repeats that are on the order
of 180 base pairs long that occur hundreds of thousands of times in a row.
So repeats can get very long and complicated.
We also have interspersed repeats which really just means the same idea,
repetitive sequence that's identical or near identical.
But it's scattered around across the chromosomes in widely separate places and
across different chromosomes.
And these repeats will cause, sometimes cause problems for
other types of analysis because they all look so similar to each other.
And if you have a very short sequence, remember when we read DNA
sequences we're only reading a few hundred base pairs at a time, so,
it's not unusual to get a sequence which consists entirely of repeats.
And that means we don't really know where it came from,
because repeats occur all over the genome.
So there's also structures of RNA that are important to understand.
So a typical human messenger RNA,
which is what we get our proteins from, looks like this.
We have some sequence which is shown in green which is the coding sequence.
And sometimes when we talk about MRNA or
RNA we're only talking about what encodes proteins, that's just the green part.
But it's important to understand that actually the part that copied from
the DNA, the transcribed portion of the DNA which goes into messenger RNA
is longer than that.
So, typically you'll have some stretch at the beginning of the, of the messenger RNA
that's not translated, and we call that the UTR or untranslated region.
And because it's at the beginning,
and remember, the beginning is the 5 prime end, we call it the 5 prime UT, UTR.
And on the other end we have the 3 prime UTR which is usually a longer stretch for
various reasons.
That's also not translated.
And somewhere in the middle, is the coding sequence.
So we want to know what the protein sequence is, if we can identify the UTR's
and get rid of those, then we can read off the coding sequences from that,
we can directly translate our amino acid sequences.
And another important, very important feature of eukaryotic cells,
not just human cells, is that they get, they get a poly-A tail added to them.
So after transcription occurs, after you copy the RNA into, the DNA into RNA,
and remove the introns, a long series of A's gets added.
And we're going to use that as, as a, as a,
kind of a hook to grab these out of the cell with some technologies.
So things are a little more complicated than what I just showed, so
actually the DNA that gets transcribed is much longer than that picture.
So DNA gets transcribed into RNA and
that DNA that eventually produces a protein includes introns as well.
So in this picture you see a gene with five exons shown in different col,
as different colored rectangles.
In between those exons are sequences that we call introns.
Those are actually chopped out or spliced out and discarded by the cell,
recycled by the cell.
And the remaining parts, the exons,
are the part that get translated into a protein.
So that coding sequence on the previous slide was just the exons
concatenated together.
But an important feature of this, one thing that it allows the cell to do,
this structure, is that, well, you're,
while you're in the process of splicing out and removing the, the introns,
you can do, you can do different things with putting the exons together.
You can combine them in different combinations.
So that's called alternative splicing.
And this is very, a very common phenomenon.
When it was first discovered it was considered to be a very unusual and
a probably rare phenomenon, but
now we know that over 90% of human genes undergo some form of alternative splicing.
Meaning that even when you know the complete sequence of the DNA and
even when you know what gets transcribed into RNA,
you still have more work to do to figure out exactly what proteins might be formed.
So by forming different combinations of exons into different mature messenger
RNAs, you can make different proteins from the same original gene part of the genome.
So, proteins themselves have structure, and these have been studied for
many decades.
Proteins themselves are the string of amino acids; however,
these are long proteins comprised of amino acids.
Sort, long se, molecules comprised of amino acids.
Not nearly as long as DNA,
typical proteins are a few hundred to a few thousands amino acids long.
And they form very complicated structures but
they have some secondary structure as well so when the two common secondary
structures of proteins form are called beta sheets and alpha helices.
So the amino acids themselves can form these sort of flat structures called
sheets or beta sheets.
And they can also coil up into these helical structures that are called
alpha helices.
And you see examples of those over on the left.
And on the right, you see examples of many different proteins,
actual protein structures and there are thousands and
thousands of proteins whose structures have been solved.
That is biophysicists have figured out what the mature structure of those
proteins is.
And their structure confers upon them their function.
So this is why we study their, study their structure.
So it's important in understanding protein function to know which parts of
the protein are say, buried on the inside of the structure and which ones are on
the outside, which are probably the more active parts of the protein.
So that's protein structure.
So another aspect of molecular structure are, so,
sort of aspect of structure is transcription factors.
So we, we, even when we know what the genes are,
remember every cell in your body has the same genes, but cells behave differently.
Skin cells behave very differently from blood cells.
So why is that?
That's because different genes are turned on.
Different genes are active in different cells.
So one way that you control the activity of cells is there are proteins that
are also of course encoded by your genome, that go back and bind to the DNA itself,
bind to those chromosomes, and can control the expression of proteins.
That is, you can have a gene, whose, whose product is a protein,
we would call this a transcription factor, that goes and binds upstream or
downstream, usually upstream of another gene.
And can accelerate the production of that gene, or decelerate or inhibit the,
the, the production of that gene.
So these are called transcription factors.
And they're a very, very important control mechanism that the cell uses to decide
how much of a protein to produce.
And finally, one other kind of important structure or
mechanism is epigenetic structures or epigenetic mechanisms.
So epigenetic means, sort of beyond genetics.
That is, these are, these are factors that are outside the DNA itself,
the directly inherited material, but nonetheless, control something about how
your, how your cell functions and how your genes are expressed.
And one important very important epigenetic structure is a methyl group.
So DNA can get tagged with these methyl groups, then we say the DNA is methylated.
And an interesting factor of this methylation is that it can get
passed on through the cell cycle.
So once you've tagged the DNA with this methylation you can,
you can then, enha, then when the cell divides, the same positions can get,
can get methylated in the daughter cells that are produced from that.
And these methylation marks, we now know, also, are, are,
a controlling factor that affects how much of a gene, or when a gene is expressed.
So methylation marks are an important factor and they are outside of the normal,
the normal genetic factors in that they are they are passed,
they are not part of the DNA, but they are inherited,
if you want to think of it that way, from one cell to another.
It's important to realize they are not inherited when a new,
a new individual is produced,
they're just inherited as cells divide to produce new cells of the same type.
So, epigenetic mechanisms are another type of structure that we have to,
that we have, that we study and
we talk about and use as a way of understanding the function of the cell
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