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Lecture: Genome indexes used in research

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Algoritmos Aplicado ao Sequenciamento de DNA

Universidade Johns Hopkins

4.8 (415 classificações) | 16K alunos inscritos

Curso 4 de 8 no Análise de Dados GenômicosAnálise Genômica Programa de cursos integrados

We will learn computational methods -- algorithms and data structures -- for analyzing DNA sequencing data. We will learn a little about DNA, genomics, and how DNA sequencing is used. We will use Python to implement key algorithms and data structures and to analyze real genomes and DNA sequencing datasets.

Visualizar o programa do curso

Habilidades que você aprenderá

Bioinformatics Algorithms, Algorithms, Python Programming, Algorithms On Strings

Avaliações

4.8 (415 classificações)

5 stars
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MD

Nov 10, 2016

This was really fun. Really enjoyed the a-ha of the algorithms and the fun of solving the alignment and assembly problems. Feel mildly powerful after assembling a virus genome.

LK

Mar 12, 2016

Excellent intro to the computational challenges in analyzing genomic sequences.\n\nLectures and programming exercises explain algorithms very clearly even for beginners.

Na lição

Preprocessing, indexing and approximate matching

In this module, we learn useful and flexible new algorithms for solving the exact and approximate matching problems. We'll start by learning Boyer-Moore, a fast and very widely used algorithm for exact matching

Week 2 Introduction 1:34

Lecture: Boyer-Moore basics8:50

Lecture: Boyer-Moore: putting it all together6:15

Lecture: Diversion: Repetitive elements5:02

Practical: Implementing Boyer-Moore 10:01

Lecture: Preprocessing7:02

Lecture: Indexing and the k-mer index10:43

Lecture: Ordered structures for indexing8:06

Lecture: Hash tables for indexing7:13

Practical: Implementing a k-mer index 7:23

Lecture: Variations on k-mer indexes9:25

Lecture: Genome indexes used in research9:34

Lecture: Approximate matching, Hamming and edit distance6:53

Lecture: Pigeonhole principle6:37

Practical: Implementing the pigeonhole principle 9:30

Ministrado por

Ben Langmead, PhD
Assistant Professor
Jacob Pritt

Transcrição

Indexing is a very powerful idea.

As we discussed, indexing is the reason why,

when you type a query into a search engine, a worldwide web search engine,

you can get an answer back in less than a second.

Indexing is also at the core for a lot of different methods for

analyzing sequencing data and methods that solve the read alignment problem.

So the question of how to build faster and smaller and more flexible indexes,

indexes for genomes, is an active area of research right now.

And some of the advances in the last several years that have come in read

alignment, have related to how we can manage to fit the genome into an index,

into a relatively compact index so that it can fit in memory, but

we can still query it very quickly.

So, let's start by looking at the familiar K-mer Index here,

which we discussed in a previous lecture.

The idea behind the K-mer index was very simple.

We extracted every substring of length K, every K-mer,

from a reference genome, and instead of saying,

text T, I'll just say, genome here, since the genome is what we're indexing.

And we also discussed variations on that idea.

So one variation here was to extract not every K-mer, but

only some of the K-mer from the genome.

So, for example,

we could extract just the K-mer's that are at even offsets in the genome.

And to compensate for the fact that our index didn't contain

the odd K-mers anymore, we would actually query the index twice.

Once, with a K-mer from the pattern from an even offset, with respect to

the pattern and once with a K-mer from a non-offset, with respect to the pattern.

These ideas are used in many, many practical tools for

solving the read-alignment problem.

And, more generally, for bio sequence analysis.

We also discussed a variation on this idea, which we called a subsequence index.

Where we extract subsequences from the genome instead of substrings.

So subsequences are not necessarily contiguous.

So what we're extracting is this non-contiguous pattern

out from the middle of the text T.

This idea is also pretty widely used in practice.

Here's an example of a tool that uses this idea.

And as you'll explore in a programming assignment in this module,

it has an important advantage over the substring indexes,

which is basically that index filter tends to be more specific.

In other words, a larger fraction of the index hits actually lead

to matches of the pattern P within the text T.

So, here's another idea,

a new idea that seems very similar to the sub-string index.

But, it actually leads to some very different and

interesting new index data structures.

So what I have here in black is a genome.

And let's say that instead of extracting every sub-string of a certain length from

this genome and putting that into an index, we take every suffix.

So what do I mean by that?

Well, here in black is a genome, and

then in red is a list of all the suffixes of the genome.

So we'd like to extract and organize all the suffixes into some data structure that

allows us to perform rapid queries in the same way that the sub-string index did.

So one simple idea is to just take all the sub-strings, I'm sorry, all the suffixes

from the genome and then put them in alphabetical order, just like this.

So again, here in black is our genome, here in red is all the suffixes.

And we're just going to put those suffixes in alphabetical order.

And now what we have is simply a list of all the suffixes of the genome, but

they're in alphabetical order.

And if we want to query the index, we can use our old friend binary search.

So for example if our query is ab, if our pattern p is ab,

then we can use binary search to find all of the suffixes that have ab as a prefix.

Because the suffixes are in order, all of the suffixes that share some prefix,

that have the same prefix are going to be consecutive in this list.

So you may be wondering if maybe this data structure isn't perhaps too big.

Right? Because it's organizing all the suffixes

of a genome and let's say that your genome has length N.

Then if we add up the lengths of all the different suffixes of the genome,

we get this expression, which grows with the square of N.

It grows quadratically with N.

So by the time N gets to 3 billion, as is the case for

the human reference genome, it's about 3 billion characters long.

This expression, the number of characters in our index,

is just going to be far too large.

It's going to be really, really big.

Way too big to be practical.

But in fact, we can sidestep this issue with a simple trick.

So specifically,

we can represent a suffix of the genome by its offset into the genome.

Instead of representing it explicitly as a string, we can represent it as just

one integer that tells us the offset with respect to the beginning of the genome.

So for example, what do I mean?

So here are all the suffixes of a text and they're in alphabetical order and

then listed to the left of those suffixes, Is a list of integers.

And each integer corresponds to that suffix's

offset with respect to the beginning of the text.

So if the text is abaaba, then the very

first suffix, alphabetically, is the one that consists just of the character a,

and that's the suffix that's at offset 5.

And so, if we do this for all of the suffixes, we can represent

all those suffixes, in alphabetical order, with just a list of integers.

And this list is called a suffix array.

And before I say much more about the suffix array,

I should point out that to make this a useful data structure,

besides the array of integers itself, we also have to store T itself.

We have to store the genome or the text.

So we have to keep the genome around because that way we have the list which

tells us the alphabetical order of the suffixes but if we want to know what

the sequence of any particular suffix is, we also have to go look inside T.

Just knowing the offset isn't enough,

we have to know the entire string that that's an offset into.

The most important fact is that besides the genome itself,

the only thing we need to store is this list of integers.

And even though the total number of characters in all

the suffixes of the genome is a quantity that grows quadratically or

with the square of the length of the genome.

The number of integers in this list, that is the suffix array, grows only linearly.

In fact it's just equal to the length of the genome.

So this leads to a much more manageably sized and a more practical data structure.

Now the suffix array is just one example from a family of indexes,

called the suffix indexes.

And, another kind of suffix index, which is shown on the left here,

is a suffix tree.

A suffix tree is like the suffix array,

in that it organizes all of the suffixes of a text in some way.

But, unlike the suffix array, it organizes them using the principle of grouping

rather than the principle of ordering.

The suffix array put all the suffixes in order.

So, like we said before, this is like the idea behind the index of a book.

It uses ordering.

Where as the suffix tree uses grouping.

More like the aisles of a grocery store.

Another popular kind of suffix index is called the FM index,

which is shown on the right here.

The FM index is based on another idea called the Burrows-Wheeler transform,

or the BWT.

And the Burrows-Wheeler transform was originally developed for compression.

But it so happens that it's also used to build a specific kind of suffix index,

the FM index, and this index is very, very compact.

So to give an idea about how large these three data structures are, let's consider

the question of, if we used each of them to build an index of the entire human

reference genome, which again is about three billion letters long, then how large

would that data structure be, how much room would it take up on your computer?

So we can see that the size varies quite a bit from structure to structure,

the suffix tree is pretty big.

And, by the way, my estimate here is probably a pretty optimistic estimate

on how big it would be.

So depending on how you implement the suffix tree,

it could be substantially bigger and then what's written here.

But it's still not terribly big, it could fit, for example,

in the memory of a large server.

The suffix array is much smaller than that.

But the FM index is Is very compact, so the reason for

this is that the FM index really just consists primarily of the Burrows-Wheeler

transform genome which is the same exact size as the genome itself.

It's really just the genome with the characters in a different order permitted.

And since because it's so

small it can easily fit in to memory on a typical computer.

So the FM index is widely used and

is the basis for some very popular read alignment tools.

In the Bowtie and BWA families, for example, there are tools called Bowtie and

Bowtie 2, BWA, BWA-SW and BWA-MEM that all use this idea of the FM index.

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