Ulf

Lese

r

Wis

sens

man

agem

ent

in d

er

Bioi

nfor

mat

ik

Mol

eku

larb

iolo

gisc

he

Dat

enba

nke

nG

rund

lage

n de

r M

olek

ular

biol

ogie

Ulf

Lese

r:M

olek

ular

biol

ogis

che

Dat

enba

nken

, Vor

lesu

ng, S

oSe

2003

2

50th

anni

vers

ary

•25

.4.1

953

-Ja

mes

Wat

son,

Fra

ncis

Cric

k-

„Mol

ecul

ar S

truc

ture

of N

ucle

ic

Acid

s “-

Nat

ure,

1 p

age

-„T

his

stru

ctur

e ha

s tw

o he

lical

ch

ains

eac

h co

iled

arou

nd th

e sa

me

axis

“

•Ba

sed

on w

ork

by W

ilkin

s&

Fran

klin

Ulf

Lese

r:M

olek

ular

biol

ogis

che

Dat

enba

nken

, Vor

lesu

ng, S

oSe

2003

3

Cells

Ulf

Lese

r:M

olek

ular

biol

ogis

che

Dat

enba

nken

, Vor

lesu

ng, S

oSe

2003

4

Her

itabl

e In

form

atio

n

•Ce

ll nu

cleu

s

•Ch

rom

osom

es

•D

NA

•Th

e bl

uepr

int

of li

fe

Ulf

Lese

r:M

olek

ular

biol

ogis

che

Dat

enba

nken

, Vor

lesu

ng, S

oSe

2003

5

Des

oxyr

iboN

ucle

icA

cid

•Ch

rom

osom

e: s

trin

g of

DN

A•

Onl

y 4

diff

eren

t nu

clei

c ac

ids

•Fi

xed

pairs

: A-

T, G

-C•

Sam

e m

echa

nism

in a

ll sp

ecie

s

Ulf

Lese

r:M

olek

ular

biol

ogis

che

Dat

enba

nken

, Vor

lesu

ng, S

oSe

2003

6

Stru

ctur

e of

DN

A

Que

lle:

http

://w

ww

.nhg

ri.ni

h.go

v/

5’

3’

3’

5’

Nucleotide

Base

Ulf

Lese

r:M

olek

ular

biol

ogis

che

Dat

enba

nken

, Vor

lesu

ng, S

oSe

2003

7

DN

A St

rand

s

•D

NA

sing

le o

r do

uble

str

ande

d•

DN

A ha

s fix

ed o

rient

atio

n -

read

fro

m 5

’to

3’-

Stra

nds

are

antip

aral

lel

5’…

TACT

GAA

…3’

3’…

ATG

ACTT

…5’

Ulf

Lese

r:M

olek

ular

biol

ogis

che

Dat

enba

nken

, Vor

lesu

ng, S

oSe

2003

8

DN

A Rep

licat

ion

•M

itosi

s: C

ell r

eplic

atio

n•

Mei

osis

: Sp

ecie

s re

plic

atio

n

Ulf

Lese

r:M

olek

ular

biol

ogis

che

Dat

enba

nken

, Vor

lesu

ng, S

oSe

2003

9

Spec

ies

•Pr

okar

yote

s: c

ell n

ucle

us, d

iffer

entia

l spl

icin

g,

gene

reg

ulat

ion,

com

plex

ity•

Mod

el o

rgan

ism

Ulf

Lese

r:M

olek

ular

biol

ogis

che

Dat

enba

nken

, Vo

rlesu

ng, S

oSe

2003

10

Gen

ome

•Se

t of

all

gene

s of

a s

peci

es is

its

geno

me

•H

uman

s-

App.

3.3

00.0

00.0

00 b

p-

22 c

hrom

osom

es +

2

sex

chro

mos

omes

-Le

ngth

50–

250

MB

Ulf

Lese

r:M

olek

ular

biol

ogis

che

Dat

enba

nken

, Vo

rlesu

ng, S

oSe

2003

11

Hum

an G

enom

e Pr

ojec

t

•D

NA:

~

3.3

00.0

00.0

00 b

ase

pairs

•H

uman

Gen

ome

Proj

ect:

Seq

uenc

ing

the

com

plet

e H

uman

Gen

ome

(sch

edul

ed 2

005)

•W

orld

-wid

e Ef

fort

(G

erm

any:

sin

ce 1

996)

•“F

inis

hed”

in 2

000

-Ra

pid

impr

ovem

ent

in t

echn

olog

y-

Com

mer

cial

com

pani

es ju

mpe

d on

it (

Cele

ra)

•“A

lmos

t” f

inis

hed

in 2

001

•“R

eally

” fin

ishe

d in

200

3

Ulf

Lese

r:M

olek

ular

biol

ogis

che

Dat

enba

nken

, Vo

rlesu

ng, S

oSe

2003

12

Sequ

enci

ng a

Gen

ome

gatcaattatagttgacttcagtcctgcctgattcatctcca

aaaatgtagtctgcctgattcatctcccaaaaatgtagctc

cgcttaaaggagctttcaagttgggggtggtgggccattc

agtgttgtcactaacagatgcatcttgtgggggtaaaatgt

cccaaagtatcttttcttgcttatgttcataagggcgctggtc

tggaatgtgccacatctgttctcactctgccatggactcctg

gaccctctgtgtgtccctttgtatcctggtagcgagtgagtc

ctcatgatttatcatcctcatgctgggcctctgtatagatga

•Br

eak

it up

into

ver

y sm

all p

iece

s•

Read

the

seq

uenc

e on

e-by

-one

•As

sem

ble

the

piec

es t

o co

ntig

s

Ulf

Lese

r:M

olek

ular

biol

ogis

che

Dat

enba

nken

, Vo

rlesu

ng, S

oSe

2003

13

Wha

t do

es D

NA

tell

us ?

actt

tcct

cg g

cagc

ggta

g gc

gaga

gcac

gcg

gagg

agc

gtgc

gcgg

gg g

cccc

ggga

gac

ggcg

gcgg

tgg

cggc

gcg

ggca

gagc

aa g

gacg

cggc

g ga

tccc

actc

gca

cagcagc

gcac

tcgg

tg c

cccg

cgca

g gg

tcgc

gatg

ctg

cccg

gtt

tggc

actg

ct c

ctgc

tggcc

gcct

ggac

gg c

tcgg

gcgc

t gg

aggt

accc

act

gatg

gta

atgc

tggc

ct g

ctgg

ctgaa

cccc

agat

tg c

catg

ttct

g tg

gcag

actg

aac

atgc

aca

tgaa

tgtc

ca g

aatg

ggaag

tggg

attc

ag a

tcca

tcag

g ga

ccaa

aacc

tgc

attg

ata

ccaa

ggaa

gg c

atcc

tgcag

tatt

gcca

ag a

agtc

tacc

c tg

aact

gcag

atc

acca

atg

tggt

agaa

gc c

aacc

aacca

gtga

ccat

cc a

gaac

tggt

g ca

agcg

gggc

cgc

aagc

agt

gcaa

gacc

ca t

cccc

acttt

gtga

ttcc

ct a

ccgc

tgct

t ag

ttgg

tgag

ttt

gtaa

gtg

atgc

cctt

ct c

gttc

ctgac

aagt

gcaa

at t

ctta

cacc

a gg

agag

gatg

gat

gttt

gcg

aaac

tcat

ct t

cact

ggcac

accg

tcgc

ca a

agag

acat

g ca

gtga

gaag

agt

acca

act

tgca

tgac

ta c

ggca

tgttg

ctgc

cctg

cg g

aatt

gaca

a gt

tccg

aggg

gta

gagt

ttg

tgtg

ttgc

cc a

ctgg

ctgaa

gaaa

gtga

ca a

tgtg

gatt

c tg

ctga

tgcg

gag

gagg

atg

actc

ggat

gt c

tggt

ggggc

ggag

caga

ca c

agac

tatg

c ag

atgg

gagt

gaa

gaca

aag

tagt

agaa

gt a

gcag

aggag

gaag

aagt

gg c

tgag

gtgg

a ag

aaga

agaa

gcc

gatg

atg

acga

ggac

ga t

gagg

atggt

gatg

aggt

ag a

ggaa

gagg

c tg

agga

accc

tac

gaag

aag

ccac

agag

ag a

acca

ccagc

gcca

acga

ga g

acag

cagc

t gg

tgga

gaca

cac

atgg

cca

gagt

ggaa

gc c

atgc

tcaat

gacc

gccg

cc g

cctg

gccc

t gg

agaa

ctac

atc

accg

ctc

tgca

ggct

gt t

cctc

ctcgg

•D

NA

is ju

st a

str

ing:

[AC

TG]*

•In

hum

ans,

mos

t D

NA

is c

onsi

dere

d ju

nk•

All D

NA

is r

eplic

ated

, but

...

•...

onl

y D

NA

that

is t

rans

form

ed in

to

„som

ethi

ng“

mat

ters

Ulf

Lese

r:M

olek

ular

biol

ogis

che

Dat

enba

nken

, Vo

rlesu

ng, S

oSe

2003

14

Cent

ral D

ogm

a

The

Cent

ral D

ogm

a of

Mol

ecul

arG

enet

ics

Ulf

Lese

r:M

olek

ular

biol

ogis

che

Dat

enba

nken

, Vo

rlesu

ng, S

oSe

2003

15

Gen

e /

prot

ein

func

tions

•St

ruct

ure

-ce

ll w

all,

mem

bran

es, o

rgan

elle

s, ..

.•

Sign

al t

rans

duct

ion

-Si

gnal

rec

ogni

tion

(out

side

cel

l), t

rans

duct

ion,

and

re

actio

n•

Enzy

mat

ic c

atal

ysis

-Su

ppor

t fo

r ch

emic

al r

eact

ions

: re

spira

tion,

m

etab

olis

m, p

rote

in c

onst

ruct

ion/

deco

nstr

uctio

n, ..

.•

Tran

spor

t-

mRN

Afr

om n

ucle

us t

orib

osom

es, p

rote

ins

from

ribos

omes

to c

ell w

ell,

...

Ulf

Lese

r:M

olek

ular

biol

ogis

che

Dat

enba

nken

, Vo

rlesu

ng, S

oSe

2003

16

Inte

ract

ion

of g

enes

/ p

rote

ins

KEG

G, 1

998

Pat

hw

ays

•M

etab

olic

pa

thw

ays

•Reg

ulat

ory

path

way

s•

Sign

al

tran

sduc

tion

path

way

s

Ulf

Lese

r:M

olek

ular

biol

ogis

che

Dat

enba

nken

, Vo

rlesu

ng, S

oSe

2003

17

DN

A an

d G

enes

•G

enes

are

cod

ing

regi

ons:

DN

A ->

RN

A (

-> P

rote

in)

•Su

bjec

t to

evo

lutio

nary

prin

cipl

es:

mut

atio

n, s

elec

tion

•M

utat

ion

mig

ht c

hang

e ph

enot

ype

-ge

netic

dis

ease

•Co

mpl

ex r

egul

atio

n m

echa

nism

s

Ulf

Lese

r:M

olek

ular

biol

ogis

che

Dat

enba

nken

, Vo

rlesu

ng, S

oSe

2003

18

No.

of

gene

s do

esn‘

t m

ean

... 3000

MB

30.0

00M

ouse

100

MB

18.0

00C.

ele

gans

1600

0 M

BW

heat

180

MB

13.0

00Fl

y33

00 M

B30

.000

Hum

anG

enom

e si

zeN

o of

gen

esSp

ecie

s

•G

enom

ic r

earr

ange

men

ts &

dup

licat

ions

•In

activ

atio

n•

Gen

e tr

ansf

er

Ulf

Lese

r:M

olek

ular

biol

ogis

che

Dat

enba

nken

, Vo

rlesu

ng, S

oSe

2003

19

Gen

otyp

e -

Phen

otyp

e

•G

enes

are

diff

eren

t be

twee

n in

divi

dual

s-

Alle

les

•G

enot

ype:

se

t of

gen

es o

f an

indi

vidu

al•

Phen

otyp

e: a

ppea

ranc

e of

an

indi

vidu

al

-Vi

sual

fea

ture

s, b

ehav

iora

l fea

ture

s, s

usce

ptib

ility

to

dise

ases

, ...

•G

enot

ype

dete

rmin

es p

heno

type

-To

wha

t ex

tend

?

Ulf

Lese

r:M

olek

ular

biol

ogis

che

Dat

enba

nken

, Vo

rlesu

ng, S

oSe

2003

20

From

Gen

es t

o Pr

otei

ns

•G

enes

are

tra

nscr

ibed

into

mRN

A•

Post

-Pro

cess

ing

(spl

icin

g)•

mRN

Ais

tra

nsla

ted

into

pro

tein

s•

Post

-pro

cess

ing

•Co

de n

ot

univ

ersa

l

Ulf

Lese

r:M

olek

ular

biol

ogis

che

Dat

enba

nken

, Vo

rlesu

ng, S

oSe

2003

21

Alte

rnat

ive

Splic

ing

One

gen

e –

one

prot

ein

is m

ostly

wro

ng

Ulf

Lese

r:M

olek

ular

biol

ogis

che

Dat

enba

nken

, Vo

rlesu

ng, S

oSe

2003

22

Hum

an G

enom

e

•Ap

p. 3

0.00

0 ge

nes

•Le

ngth

fro

m 1

00bp

–2M

B (in

tron

s+ex

ons)

•Le

ngth

avg

. 140

0 bp

s (o

nly

exon

s)-

Avg.

pro

tein

leng

th 4

47 a

min

o ac

ids

•Av

gge

ne h

as 9

exon

s•

Onl

y 3%

of

hum

an g

enom

e is

cod

ing

-Re

st „

junk

“ ?

-M

any

repe

ats,

tra

nspo

sons

, low

-com

plex

ity s

eque

nce

-Re

gula

tory

ele

men

ts

Ulf

Lese

r:M

olek

ular

biol

ogis

che

Dat

enba

nken

, Vo

rlesu

ng, S

oSe

2003

23

Gen

e st

ruct

ure

Ulf

Lese

r:M

olek

ular

biol

ogis

che

Dat

enba

nken

, Vo

rlesu

ng, S

oSe

2003

24

Prot

eins

•Pr

otei

ns m

ake

(alm

ost)

eve

ryth

ing

-M

etab

olis

m-

Sign

al g

ener

atio

n, t

rans

port

atio

n, r

ecog

nitio

n, a

nd

reac

tion

-Ce

llula

r st

ruct

ures

-Re

gula

tion

of g

ene

expr

essi

on•

Prot

ein

sequ

ence

-Am

ino

acid

s-

20-le

tter

alp

habe

t-

300-

500

AA lo

ng

Ulf

Lese

r:M

olek

ular

biol

ogis

che

Dat

enba

nken

, Vo

rlesu

ng, S

oSe

2003

25

Prot

ein

Fold

ing

•Pr

otei

ns f

old

into

3D

-str

uctu

re•

Com

plex

and

dyn

amic

pro

cess

•M

ain

prob

lem

in b

ioin

form

atic

s•

„Fun

ctio

n fo

llow

s st

ruct

ure“

Ulf

Lese

r:M

olek

ular

biol

ogis

che

Dat

enba

nken

, Vo

rlesu

ng, S

oSe

2003

26

Prot

ein

stru

ctur

e

•Pr

imar

y:aa

sequ

ence

•Se

cond

ary:

H

elix

es &

she

ets

•Te

rtia

ry:

3D-S

truc

ture

•Q

uart

ary:

Pr

otei

n co

mpl

exes

Ulf

Lese

r:M

olek

ular

biol

ogis

che

Dat

enba

nken

, Vo

rlesu

ng, S

oSe

2003

27

From

Gen

otyp

e to

Phe

noty

p

Mol

ecul

arSt

ruct

ure

Bio

chem

ical

Inte

ract

ion

Phen

otyp

eG

enot

ype

Ulf

Lese

r:M

olek

ular

biol

ogis

che

Dat

enba

nken

, Vo

rlesu

ng, S

oSe

2003

28

The

„-om

ics“

in L

ife S

cien

ce

•G

enom

e-

All D

NA

sequ

ence

in a

cel

l-

Cons

tant

•Tr

ansc

ripto

me

-Al

lmRN

Ain

a c

ell a

t gi

ven

time

-Va

ries

grea

tly w

ith c

ell t

yp, e

nviro

nmen

tal c

ondi

tions

, de

velo

pmen

tal s

tage

, sex

, ...

of c

ells

•Pr

oteo

me

-Al

l pro

tein

s in

a c

ell a

t gi

ven

time

-Ev

en m

ore

com

plex

tha

n tr

ansc

ripto

me:

life

spa

n, in

tera

ctio

n,

post

-tra

nsla

tiona

lmod

ifica

tions

, ...

•M

etab

olom

e-

All n

on-p

rote

in t

hing

s in

a c

ell a

t gi

ven

time