18.417: lecture 1

Molecular biology

instructor: Ross A. Lippert

http://www-math.mit.edu/~lippert/18.417/

The depressing truth

Ultimately, it all comes down to 3 facts:

All things eventually disappear.
Making copies can delay this.
With limited resources, what is left is that which makes good copies of itself.

To endure, copy. To really endure, copy better.

That's life.

The following patterns copy themselves in the right environment:

 main(){char q=34, n=10,*a="main() {char q=34,n=10,*a=%c%s%c; printf(a,q,a,q,n);}%c";printf(a,q,a,q,n);}

((lambda (h q) (list h (list q h) (list q q))) (quote 
 (lambda (h q) (list h (list q h) (list q q)))) (quote quote)) 

... TGAACTGCAC ACTTTCAGTC CGGTCCTCAC AGTTGAAAAG ACCTAAGCTT GTGCCTGATT ...

The first two use a computer environment.

The third, is a substring of the human genome (it is beta globin on chr 11). It uses you.

Biology is the study of life

OK, what does "life" mean?

An organism is something alive.
Organisms are composed of cells.
- Some organisms are multicellular and some are not.
Cells are composed of
- water (70%)
- big molecules (23%)
- small molecules (7%)
Big molecules are
- polymers of nucleic acids (DNA or RNA)
- polymers of amino acids (proteins)
- Polysaccharides and lipids (which I know nothing about)
Small molecules are
- free-floating bits of DNA, RNA, AA
- salts, ions, pharmaceuticals, etc.

Cells are either eukaryotic or prokaryotic depending on how their big molecules are organized.

Inside the cell

A prokaryotic cell	A eukaryotic cell

Generally, eukaryotes are much more complicated than prokaryotes.

bigger
specialized compartments/membrane-bound organelles
capable of forming multicellular organisms
DNA molecules are in chromosomal pairs

Proteins

Proteins are polymers of 20 amino acids.

Sometimes multiple proteins form a protein complex.

Enzymes are proteins/protein complexes which do things.

Deoxyribonucleic Acids (DNA)

Polymers formed from 4 nucleic acids

Adenine
Cytosine
Guanine
Thymine

Long means 1-2 meters for typical mammals

<1 million bps for most bacteria (prokaryote)
5 million bps for E.coli (prokaryote)
15 million bps for yeast (eukaryote)
3 billion base-pairs for human/mouse
17 billion base-pairs for triticum aestivum

In eukaryotes, many linear chromosomes

In prokaryotes, one circular chromosome

A more schematic DNA

Strands come in pairs.
Alternating sugar-phosphate backbone
A,T,G,C variability in the side groups
Nucleotide bonds are hydrogren bonds

For reasons to be made clear later, DNA is read from the 3' end to the 5' end.

3' ATTAGCCCAT 5'
5' TAATCGGGTA 3'

Is the string "attagcccat" bonded to its complement "atgggctaat".

Keeping DNA organized

Ribonucleic Acids (RNA)

Also polymers formed from 4 nucleic acids

Adenine
Cytosine
Guanine
Uracil

RNA is stable in single stranded form, though will H-bond to DNA other RNA or itself.

RNA is less stable than double stranded DNA. It doesn't get very long.

Folded RNA has some functional uses,

transfer RNA
ribosomes
other(???)

DNA replication

DNA strands can replicate

A replication fork is created
DNA polymerase is the enzyme responsible
DNA ligase is a helper enzyme for the lagging part of the fork

Proteins are the catalysts which make this happen

DNA is transcribed to RNA

RNA-polymerase can produce a complementary RNA strand to some sections of DNA.

The tendency of RNA-polymerase to do this is affected by

chromatin structure (in eukaryotes)
regulatory proteins

Transcribed RNA goes on to become:

messenger RNA (mRNA)
ribosomal (rRNA)
transfer RNA (tRNA)
something we don't know about (?RNA)

RNA is translated to AA

Proteins get made by

RNA moves out from the nucleus to the Ribosom
At the Ribosome tRNAs bring in amino acids
Ribosome/tRNAs catalyze the bonding of AAs

Things are a little more complicated for Eukaryotes

tRNA

tRNA comes in almost 61 flavors

typical stem loop structure
specific 3 base anticodon
specific tail at 3' for an amino acid

The codon table

ATGGAATTCTCGCTC	DNA coding strand
AUGGAAUUCUCGCUC	mRNA from 5'->3' strand
MEFSL	amino acid sequence

Second Position of Codon

F
i
r
s
t

P
o
s
i
t
i
o
n

TTT	Phe	[F]
TTC	Phe	[F]
TTA	Leu	[L]
TTG	Leu	[L]

TCT	Ser	[S]
TCC	Ser	[S]
TCA	Ser	[S]
TCG	Ser	[S]

TAT	Tyr	[Y]
TAC	Tyr	[Y]
TAA	STOP	[end]
TAG	STOP	[end]

TGT	Cys	[C]
TGC	Cys	[C]
TGA	STOP	[end]
TGG	Trp	[W]

T
C
A
G

T
h
i
r
d

P
o
s
i
t
i
o
n

CTT	Leu	[L]
CTC	Leu	[L]
CTA	Leu	[L]
CTG	Leu	[L]

CCT	Pro	[P]
CCC	Pro	[P]
CCA	Pro	[P]
CCG	Pro	[P]

CAT	His	[H]
CAC	His	[H]
CAA	Gln	[Q]
CAG	Gln	[Q]

CGT	Arg	[R]
CGC	Arg	[R]
CGA	Arg	[R]
CGG	Arg	[R]

T
C
A
G

ATT	Ile	[I]
ATC	Ile	[I]
ATA	Ile	[I]
ATG	Met	[M]

ACT	Thr	[T]
ACC	Thr	[T]
ACA	Thr	[T]
ACG	Thr	[T]

AAT	Asn	[N]
AAC	Asn	[N]
AAA	Lys	[K]
AAG	Lys	[K]

AGT	Ser	[S]
AGC	Ser	[S]
AGA	Arg	[R]
AGG	Arg	[R]

T
C
A
G

GTT	Val	[V]
GTC	Val	[V]
GTA	Val	[V]
GTG	Val	[V]

GCT	Ala	[A]
GCC	Ala	[A]
GCA	Ala	[A]
GCG	Ala	[A]

GAT	Asp	[D]
GAC	Asp	[D]
GAA	Glu	[E]
GAG	Glu	[E]

GGT	Gly	[G]
GGC	Gly	[G]
GGA	Gly	[G]
GGG	Gly	[G]

T
C
A
G

Splicing (eukaryotes)

In Eukaryotes, mRNA is modified before leaving the nucleus.

Splicing is the most significant one of these mods.

Additional ornamentation is added to the mRNA before it leaves the nucleus.

Gene structure

The structure of a general eukaryotic gene is a sequence of control regions, followed by coding regions.

Coding regions are sites where promoter of inhibitor proteins might bind.

The concatenation of the coding regions is the final product which goes to translation.

Cellular reproduction (mitosis)

We will talk about meiosis and its effects later.

But reproductive fidelity not 100%

During DNA replication, occassional changes occur.

ATCCCCA ------> ATCTCCA

insertion	vv-->vXw
deletion	vXv-->vw
substitution	vXv-->vYw

Other kinds of mutations:

large (5-10bp) indels
gene conversion
translocation
transpositions

Effects of mutations

Beneficial: new functionalities arise, resistance to malaria or HIV
Deterimental: death, debilitating or degenerative disease
Neutral: not in a coding or control region -- the majority case!

Change, competition, diversity

The history of a string

Variations in the example gene across different species

Clearly the strategy of creating cows, chickens, and carp has been asuccessful one for the beta globin pattern.

Bioinformatics/compuational biology

Computational Biology Central Dogma:

Sequence --> Structure --> Function

DNA sequence databases keep growing
About 70 species have been or are being sequenced
The data currently staggers most computational resources
It is believed that the data has value

Where do computational biology problems come from?

Supplement for experiment

Science is driven by observations.

Observations can include

a nucleotide sequence at a given location
the binding energy of a specific molecule to another
the expression and relative amount of a protein in a cell
a nucleotide sequence is a gene

Sometimes experimental devices fall short of the observation desired.

Computational techniques serve to supply hidden data.

Inferences

With sufficiently advanced technology, we can observe any fact.

Science draws inferences from observations.

Typical inferences include

two sequences are more closely related than another two
some region of the genome is undergoing selection
a set of proteins interact to support some complex function
generalizations and categorization of facts
inferences of past facts (evolutionary history)

What is computer science?

The study of automation:

What can a machine do? (will it stop with the right answer?)
How well can a machine do it? (will it stop today?)

Model machines

regular expressions
context free grammars
Turing machines
lambda calculus

It is no coincidence that many of these models are linguistic.

Originating in mathematics

deductive
abstract

This has an effect on interactions with biology which isinductive and suspicious.

What does abstract mean?

Tends to consider the details less than the generality

What does suspicious mean?

Once, when trying to be general, a detail bit him on the ass.

What does deductive mean?

Truth can be derived from other true things.
In theory there is no difference between theory and practice.

What does inductive mean?

Truth must be demonstrated repeatedly.
In practice, there is.

Complexity

The second question of CS, that of complexity, plays a central role in applications to other disciplines.

Computer science provides: Complexity Theory which is about what can and can't be done practically.

Its statements are usually asymptotic, phrased in terms of limiting behaviors: e.g. as input size gets large.

a simplifying reduction: reason about the largest cost
hardware independence: requires few specifics of the actual machine

Contingencies

what descriptors describe the difficulty of the problem?
are we in the asymptotic regime of those descriptors?
can hardware (e.g. memory hierarchy) be neglected/simplified?

O(n P(log(n)))

n times a polynomial in the logarithm of n.

Runtime very roughly proportional to database size
Most string matching problems need to run here

O(2^P(n))

2 to some power which is a polynomial of n.

the hard problems
not really hard unless n is large

What this class should be about

This class is intended to survey some of the leading results in computational biology.

some examples will be too simple
some examples will be outdated
all of them illustrate important techniques still in use

This class will emphasize sequence analysis over structural analysis.

After taking this course, you should be able to:

be able to read the current literature
be conversant in enough biology to be useful to a biologist

18.417: lecture 1

Molecular biology

instructor: Ross A. Lippert

The depressing truth

Biology is the study of life

OK, what does "life" mean?

Inside the cell

A prokaryotic cell

A eukaryotic cell

Proteins

Deoxyribonucleic Acids (DNA)

A more schematic DNA

Keeping DNA organized

Ribonucleic Acids (RNA)

DNA replication

DNA is transcribed to RNA

RNA is translated to AA

tRNA

The codon table

Splicing (eukaryotes)

Gene structure

Cellular reproduction (mitosis)

But reproductive fidelity not 100%

Change, competition, diversity

The history of a string

Variations in the example gene across different species

Bioinformatics/compuational biology

Computational Biology Central Dogma:

Where do computational biology problems come from?

Supplement for experiment

Inferences

What is computer science?

What does abstract mean?

What does suspicious mean?

What does deductive mean?

What does inductive mean?

Complexity

O(n P(log(n)))

O(2^P(n))

What this class should be about