nosce te ipsum: the human genomemcb.berkeley.edu/courses/mcb140/syllabus/urnov_lectures/...1 1...
TRANSCRIPT
1
1M
CB1
40, 1
2-1-
06
Nos
ce te
ipsu
m:
the
hum
an g
enom
e3.
3 bi
llion
base
pai
rs
2M
CB1
40, 1
2-1-
06
Dec
lara
tion
of In
depe
nden
ceW
HE
N in
the
Cou
rse
of h
uman
Eve
nts,
it b
ecom
es n
eces
sary
for o
neP
eopl
e to
dis
solv
e th
e P
oliti
cal B
ands
whi
ch h
ave
conn
ecte
d th
em w
ith a
noth
er, a
nd to
ass
ume
amon
g th
e P
ower
s of
the
Ear
th, t
he s
epar
ate
and
equa
l Sta
tion
to w
hich
the
Law
s of
Nat
ure
and
of N
atur
e's
God
ent
itle
them
, a d
ecen
t Res
pect
to th
e O
pini
ons
of M
anki
nd re
quire
s th
at
they
sho
uld
decl
are
the
caus
es w
hich
impe
l the
m to
the
Sep
arat
ion.
WE
hol
d th
ese
Trut
hs to
be
self-
evid
ent,
that
all
Men
are
cre
ated
equ
al, t
hat t
hey
are
endo
wed
by
thei
r C
reat
or w
ith c
erta
in u
nalie
nabl
e R
ight
s, th
at a
mon
g th
ese
are
Life
, Lib
erty
and
the
Pur
suit
of H
appi
ness
--Th
at to
sec
ure
thes
e R
ight
s, G
over
nmen
ts a
re in
stitu
ted
amon
g M
en,
deriv
ing
thei
r jus
t Pow
ers
from
the
Con
sent
of t
he G
over
ned,
that
whe
neve
r any
For
m o
f Gov
ernm
ent b
ecom
es d
estru
ctiv
e of
thes
e E
nds,
it is
the
Rig
ht o
f the
Peo
ple
to a
lter o
r to
abo
lish
it, a
nd to
inst
itute
new
Gov
ernm
ent,
layi
ng it
s Fo
unda
tion
on s
uch
Prin
cipl
es, a
nd o
rgan
izin
g its
Pow
ers
in s
uch
Form
, as
to th
em s
hall
seem
mos
t lik
ely
to e
ffect
thei
r S
afet
y an
d H
appi
ness
. Pru
denc
e, in
deed
, will
dic
tate
that
Gov
ernm
ents
long
est
ablis
hed
shou
ld n
ot b
e ch
ange
d fo
r lig
ht a
nd tr
ansi
ent C
ause
s; a
nd a
ccor
ding
ly a
ll E
xper
ienc
e ha
th s
hew
n, th
at M
anki
nd a
re m
ore
disp
osed
to s
uffe
r, w
hile
Evi
ls a
re s
uffe
rabl
e, th
an to
righ
t the
mse
lves
by
abol
ishi
ng th
e Fo
rms
to w
hich
they
are
acc
usto
med
. But
whe
n a
long
Tra
in o
f Abu
ses
and
Usu
rpat
ions
, pur
suin
g in
varia
bly
the
sam
e O
bjec
t, ev
ince
s a
Des
ign
to re
duce
them
und
er a
bsol
ute
Des
potis
m, i
t is
thei
r Rig
ht, i
t is
thei
r Dut
y, to
thro
w
off s
uch
Gov
ernm
ent,
and
to p
rovi
de n
ew G
uard
s fo
r the
ir fu
ture
Sec
urity
. Suc
h ha
s be
en th
e pa
tient
Suf
fera
nce
of th
ese
Col
onie
s; a
nd s
uch
is n
ow th
e N
eces
sity
whi
ch
cons
train
s th
em to
alte
r the
ir fo
rmer
Sys
tem
s of
Gov
ernm
ent.
The
His
tory
of t
he p
rese
nt K
ing
of G
reat
-Brit
ain
is a
His
tory
of r
epea
ted
Inju
ries
and
Usu
rpat
ions
, all
havi
ng in
di
rect
Obj
ect t
he E
stab
lishm
ent o
f an
abso
lute
Tyr
anny
ove
r the
se S
tate
s. T
o pr
ove
this
, let
Fac
ts b
e su
bmitt
ed to
a c
andi
d W
orld
. H
E h
as re
fuse
d hi
s A
ssen
t to
Law
s, th
e m
ost
who
leso
me
and
nece
ssar
y fo
r the
pub
lic G
ood.
HE
has
forb
idde
n hi
s G
over
nors
to p
ass
Law
s of
imm
edia
te a
nd p
ress
ing
Impo
rtanc
e, u
nles
s su
spen
ded
in th
eir O
pera
tion
till h
is
Ass
ent s
houl
d be
obt
aine
d; a
nd w
hen
so s
uspe
nded
, he
has
utte
rlyne
glec
ted
to a
ttend
to th
em.
HE
has
refu
sed
to p
ass
othe
r Law
sfo
r the
Acc
omm
odat
ion
of la
rge
Dis
trict
s of
P
eopl
e, u
nles
s th
ose
Peo
ple
wou
ld re
linqu
ish
the
Rig
ht o
f Rep
rese
ntat
ion
in th
e Le
gisl
atur
e, a
Rig
ht in
estim
able
to th
em, a
nd fo
rmid
able
to T
yran
ts o
nly.
HE
has
cal
led
toge
ther
Le
gisl
ativ
e B
odie
s at
Pla
ces
unus
ual,
unco
mfo
rtabl
e, a
nd d
ista
ntfro
m th
e D
epos
itory
of t
heir
publ
ic R
ecor
ds, f
or th
e so
le P
urpo
se o
f fat
igui
ng th
em in
to C
ompl
ianc
e w
ith h
is
Mea
sure
s. H
E h
as d
isso
lved
Rep
rese
ntat
ive
Hou
ses
repe
ated
ly, f
or o
ppos
ing
with
man
ly F
irmne
ss h
is In
vasi
ons
on th
e R
ight
s of
the
Peo
ple.
HE
has
refu
sed
for a
long
Tim
e,
afte
r suc
h D
isso
lutio
ns, t
o ca
use
othe
rs to
be
elec
ted;
whe
reby
the
Legi
slat
ive
Pow
ers,
inca
pabl
e of
the
Ann
ihila
tion,
hav
e re
turn
ed to
the
Peo
ple
at la
rge
for t
heir
exer
cise
; the
S
tate
rem
aini
ng in
the
mea
n tim
e ex
pose
d to
all
the
Dan
gers
of I
nvas
ion
from
with
out,
and
the
Con
vuls
ions
with
in.
HE
has
end
eavo
ured
to p
reve
nt th
e P
opul
atio
n of
thes
e S
tate
s; fo
r tha
t Pur
pose
obs
truct
ing
the
Law
s fo
r Nat
ural
izat
ion
of F
orei
gner
s; re
fusi
ng to
pas
s ot
hers
to e
ncou
rage
thei
r Mig
ratio
ns h
ither
, and
rais
ing
the
Con
ditio
ns o
f new
A
ppro
pria
tions
of L
ands
. H
E h
as o
bstru
cted
the
Adm
inis
tratio
n of
Jus
tice,
by
refu
sing
his
Ass
ent t
o La
ws
for e
stab
lishi
ng J
udic
iary
Pow
ers.
HE
has
mad
e Ju
dges
dep
ende
nt o
n hi
s W
ill a
lone
, for
the
Tenu
re o
f the
ir O
ffice
s, a
nd th
e A
mou
nt a
nd P
aym
ent o
f the
ir S
alar
ies.
HE
has
ere
cted
a M
ultit
ude
of n
ew O
ffice
s, a
nd s
ent h
ither
Sw
arm
s of
Offi
cers
to
harr
ass
our P
eopl
e, a
nd e
at o
ut th
eir S
ubst
ance
. H
E h
as k
ept a
mon
g us
, in
Tim
es o
f Pea
ce, S
tand
ing
Arm
ies,
with
out t
he c
onse
nt o
f our
Leg
isla
ture
s. H
E h
as a
ffect
ed to
re
nder
the
Mili
tary
inde
pend
ent o
f and
sup
erio
r to
the
Civ
il P
ower
. H
E h
as c
ombi
ned
with
oth
ers
to s
ubje
ct u
s to
a J
uris
dict
ion
fore
ign
to o
ur C
onst
itutio
n, a
nd u
nack
now
ledg
ed
by o
ur L
aws;
giv
ing
his
Ass
ent t
o th
eir A
cts
of p
rete
nded
Leg
isla
tion:
FO
R q
uarte
ring
larg
e B
odie
s of
Arm
ed T
roop
s am
ong
us;
FOR
pro
tect
ing
them
, by
a m
ock
Tria
l, fro
m
Pun
ishm
ent f
or a
ny M
urde
rs w
hich
they
sho
uld
com
mit
on th
e In
habi
tant
s of
thes
e S
tate
s: F
OR
cut
ting
off o
ur T
rade
with
all
Par
ts o
f the
Wor
ld:
FOR
impo
sing
Tax
es o
n us
w
ithou
t our
Con
sent
: FO
R d
epriv
ing
us, i
n m
any
Cas
es, o
f the
Ben
efits
of T
rial b
y Ju
ry:
FOR
tran
spor
ting
us b
eyon
d S
eas
to b
e tri
ed fo
r pre
tend
ed O
ffenc
es:
FOR
abo
lishi
ng
the
free
Sys
tem
of E
nglis
h La
ws
in a
nei
ghbo
urin
g P
rovi
nce,
est
ablis
hing
ther
ein
an a
rbitr
ary
Gov
ernm
ent,
and
enla
rgin
g its
Bou
ndar
ies,
so
as to
rend
er it
at o
nce
an E
xam
ple
and
fit In
stru
men
t for
intro
duci
ng th
e sa
me
abso
lute
Rul
es in
to th
ese
Col
onie
s: F
OR
taki
ng a
way
our
Cha
rters
, abo
lishi
ng o
ur m
ost v
alua
ble
Law
s, a
nd a
lterin
g fu
ndam
enta
lly
the
Form
s of
our
Gov
ernm
ents
: FO
R s
uspe
ndin
g ou
r ow
n Le
gisl
atur
es, a
nd d
ecla
ring
them
selv
es in
vest
ed w
ith P
ower
to le
gisl
ate
for u
s in
all
Cas
es w
hats
oeve
r. H
E h
as
abdi
cate
d G
over
nmen
t her
e, b
y de
clar
ing
us o
ut o
f his
Pro
tect
ion
and
wag
ing
War
aga
inst
us.
HE
has
plu
nder
ed o
ur S
eas,
rava
ged
our C
oast
s, b
urnt
our
Tow
ns, a
nd d
estro
yed
the
Live
s of
our
Peo
ple.
HE
is, a
t thi
s Ti
me,
tran
spor
ting
larg
e A
rmie
s of
fore
ign
Mer
cena
ries
to c
ompl
eat t
he W
orks
of D
eath
, Des
olat
ion,
and
Tyr
anny
, alre
ady
begu
n w
ith
circ
umst
ance
s of
Cru
elty
and
Per
fidy,
sca
rcel
y pa
ralle
led
in th
em
ost b
arba
rous
Age
s, a
nd to
tally
unw
orth
y th
e H
ead
of a
civ
ilize
d N
atio
n. H
E h
as c
onst
rain
ed o
ur fe
llow
Citi
zens
ta
ken
Cap
tive
on th
e hi
gh S
eas
to b
ear A
rms
agai
nst t
heir
Cou
ntry
, to
beco
me
the
Exe
cutio
ners
of t
heir
Frie
nds
and
Bre
thre
n, o
r to
fall
them
selv
es b
y th
eir H
ands
. H
E h
as
exci
ted
dom
estic
Insu
rrec
tions
am
ongs
t us,
and
has
end
eavo
ured
to b
ring
on th
e In
habi
tant
s of
our
Fro
ntie
rs, t
he m
erci
less
Indi
an S
avag
es, w
hose
kno
wn
Rul
e of
War
fare
, is
an
undi
stin
guis
hed
Des
truct
ion,
of a
ll A
ges,
Sex
es a
nd C
ondi
tions
. IN
eve
ry s
tage
of t
hese
Opp
ress
ions
we
have
Pet
ition
ed fo
r Red
ress
in th
e m
ost h
umbl
e Te
rms:
Our
repe
ated
P
etiti
ons
have
bee
n an
swer
ed o
nly
by re
peat
ed In
jury
. A P
rince
, who
se C
hara
cter
is th
us m
arke
d by
eve
ry a
ct w
hich
may
def
ine
a Ty
rant
, is
unfit
to b
e th
e R
uler
of a
free
P
eopl
e. N
OR
hav
e w
e be
en w
antin
g in
Atte
ntio
ns to
our
Brit
ish
Bre
thre
n. W
e ha
ve w
arne
d th
em fr
om T
ime
to T
ime
of A
ttem
pts
by th
eir L
egis
latu
re to
ext
end
an u
nwar
rant
able
Ju
risdi
ctio
n ov
er u
s. W
e ha
ve re
min
ded
them
of t
he C
ircum
stan
ces
of o
ur E
mig
ratio
n an
d S
ettle
men
t her
e. W
e ha
ve a
ppea
led
to th
eir n
ativ
e Ju
stic
e an
d M
agna
nim
ity, a
nd w
e ha
ve c
onju
red
them
by
the
Ties
of o
ur c
omm
on K
indr
ed to
dis
avow
thes
e U
surp
atio
ns, w
hich
, wou
ld in
evita
bly
inte
rrup
t our
Con
nect
ions
and
Cor
resp
onde
nce.
The
y to
o ha
ve
been
dea
f to
the
Voi
ce o
f Jus
tice
and
of C
onsa
ngui
nity
. We
mus
t,th
eref
ore,
acq
uies
ce in
the
Nec
essi
ty, w
hich
den
ounc
es o
ur S
epar
atio
n, a
nd h
old
them
, as
we
hold
the
rest
of
Man
kind
, Ene
mie
s in
War
, in
Pea
ce, F
riend
s. W
E, t
here
fore
, the
Rep
rese
ntat
ives
of t
he U
NIT
ED
STA
TES
OF
AM
ER
ICA
, in
GE
NE
RA
L C
ON
GR
ES
S, A
ssem
bled
, app
ealin
g to
th
e S
upre
me
Judg
e of
the
Wor
ld fo
r the
Rec
titud
e of
our
Inte
ntio
ns, d
o, in
the
Nam
e, a
nd b
y A
utho
rity
of th
e go
od P
eopl
e of
thes
e C
olon
ies,
sol
emnl
y P
ublis
h an
d D
ecla
re, T
hat
thes
e U
nite
d C
olon
ies
are,
and
of R
ight
oug
ht to
be,
FR
EE
AN
D IN
DE
PE
ND
EN
T S
TATE
S; t
hat t
hey
are
abso
lved
from
all
Alle
gian
ce to
the
Brit
ish
Cro
wn,
and
that
all
polit
ical
C
onne
ctio
n be
twee
n th
em a
nd th
e S
tate
of G
reat
-Brit
ain,
is a
nd o
ught
to b
e to
tally
dis
solv
ed; a
nd th
at a
s FR
EE
AN
D IN
DE
PE
ND
EN
T S
TATE
S, t
hey
have
full
Pow
er to
levy
War
, co
nclu
de P
eace
, con
tract
Alli
ance
s, e
stab
lish
Com
mer
ce, a
nd to
do
all o
ther
Act
s an
d Th
ings
whi
ch IN
DE
PE
ND
EN
T S
TATE
S m
ay o
f rig
ht d
o. A
nd fo
r the
sup
port
of th
is
Dec
lara
tion,
with
a fi
rm R
elia
nce
on th
e P
rote
ctio
n of
div
ine
Pro
vide
nce,
we
mut
ually
ple
dge
to e
ach
othe
r our
Liv
es, o
ur F
ortu
nes,
and
our
sac
red
Hon
or.
3M
CB1
40, 1
2-1-
06
D. o
. I.:
6,81
0 ch
arac
ters
1 hu
man
gen
ome:
484
,581
DoI
uni
ts
Har
twel
l et a
l.: 9
00 p
ages
1 hu
man
gen
ome:
538
Har
twel
l uni
ts
1 H
artw
ell =
1.2
5 in
ches
1 hu
man
gen
ome
prin
ted
at D
oI d
ensi
ty a
ndbo
und
into
Har
twel
l uni
ts w
ill ri
se to
…
672
inch
es =
22
feet
or 4
.1 F
yodo
r uni
ts(1
Fyo
dor u
nit =
5 fe
et 1
1 in
ches
)
4M
CB1
40, 1
2-1-
06
0.3%
of
the
geno
me
U. L
aem
mli
2
5M
CB1
40, 1
2-1-
06
C-v
alue
par
adox
Am
ount
of D
NA
= f
(org
anis
m c
ompl
exity
)1.
hum
an (3
.3×1
09)>
fly >
yea
st >
bac
teria
2.A
mph
ibia
> >
> h
uman
3.Tu
lip =
10x
hum
an [s
ic!]
4.A
moe
ba d
ubia
= 20
0x h
uman
5.B
road
bea
n =
4x k
idne
y be
an6.
Lily
= 1
00x
Ara
bido
psis
→un
icel
lula
r org
anis
ms
are
unde
r sel
ectiv
e pr
essu
re to
hav
e sm
all g
enom
es
6M
CB1
40, 1
2-1-
06
How
to m
easu
re th
e “c
ompl
exity
” an
d co
mpo
sitio
n of
a g
enom
e1.
She
ar th
e D
NA
to a
siz
e of
abo
ut 4
00 b
p.2.
Den
atur
e th
e D
NA
by
heat
ing
to 1
00o C
.3.
Slo
wly
coo
l and
take
sam
ples
at d
iffer
ent t
ime
inte
rval
s.4.
Det
erm
ine
the
% s
ingl
e-st
rand
ed D
NA
at e
ach
time
poin
t. Th
e sh
ape
of a
"Cot
" cur
ve fo
r a g
iven
spe
cies
is a
fu
nctio
n of
two
fact
ors:
1.
the
size
or c
ompl
exity
of t
he g
enom
e 2.
the
amou
nt o
f rep
etiti
ve D
NA
with
in th
e ge
nom
e
http
://w
ww
.nds
u.no
dak.
edu/
inst
ruct
/mcc
lean
/pls
c431
/euk
aryc
hrom
/euk
aryo
3.ht
m
7M
CB1
40, 1
2-1-
06
C0t
curv
e
hum
an
http
://w
ww
.nds
u.no
dak.
edu/
inst
ruct
/mcc
lean
/pls
c431
/euk
aryc
hrom
/euk
aryo
3.ht
m
8M
CB1
40, 1
2-1-
06
“Why
seq
uenc
e ju
nk?!
”
~50%
of g
enom
e is
repe
titiv
e D
NA
~5%
of g
enom
e is
gen
esG
enom
e se
quen
cing
cos
ts $
1 a
base
.=
3.3
billi
on d
olla
rs to
seq
uenc
e th
e ge
nom
e
S. B
renn
er –
Fugu
(puf
ferfi
sh) –
com
pact
ge
nom
e!
3
9M
CB1
40, 1
2-1-
06
Say
aga
in?
Li e
t al.
Nat
ure
409:
847
(200
1).
10M
CB1
40, 1
2-1-
06
Rep
eats
: ~45
% o
f gen
ome
Land
er e
t al.
(200
1) N
atur
e 40
9: 8
60.
11M
CB1
40, 1
2-1-
06
Rep
etiti
ve D
NA
in th
e H
GO
gen
e (m
utat
ion
caus
es a
lkap
tonu
ria –
A. G
arro
d, 1
902)
12M
CB1
40, 1
2-1-
06
L1 (L
INE
) –no
n-LT
R
retro
trans
poso
n“L
1s a
ccou
nt d
irect
ly o
r ind
irect
ly fo
r abo
ut
one-
third
of t
he h
uman
gen
ome…
”
Kaz
azia
n an
d G
oodi
er C
ell 1
10: 2
77 (2
002)
.
4
13M
CB1
40, 1
2-1-
06
Alu
(SIN
E) –
7SL
RN
A g
ene
•7S
L –
com
pone
nt o
f the
SR
P•
Mos
t Alu
ele
men
ts a
re in
activ
e•
A fe
w A
lu e
lem
ents
can
stil
l ret
ropo
se, a
re
mut
agen
ic, a
nd c
ause
dis
ease
:W
alla
ce e
t al.
(Col
lins)
(199
1)A
de
novo
Alu
inse
rtion
resu
lts in
neu
rofib
rom
atos
is ty
pe 1
N
atur
e. 1
991
Oct
31;
353(
6347
):864
-6.
14M
CB1
40, 1
2-1-
06
The
cost
of s
exua
l rep
rodu
ctio
n
•S
exua
l rep
rodu
ctio
n fa
vors
Tn
prop
agat
ion
beca
use
the
fitne
ss o
f a tr
ansp
oson
is
twic
e th
at o
f its
hos
t•
Pos
itive
cor
rela
tion
betw
een
depe
nden
ce
on s
ex fo
r rep
rodu
ctio
n an
d Tn
ag
gres
sive
ness
in g
erm
line
•V
erte
brat
es, o
f cou
rse,
are
obl
igat
e se
xual
ou
tcro
sser
s
T.H
. Bes
tor (
2003
) Tre
nds
Gen
et. 1
9: 1
85
15M
CB1
40, 1
2-1-
06
Sim
ple
poin
t
Mus
t map
gen
ome
befo
re s
eque
ncin
g it:
indi
vidu
al s
eque
nce
read
< 1
,000
bp
16M
CB1
40, 1
2-1-
06
“gen
etic
”
5
17M
CB1
40, 1
2-1-
0618
MC
B140
, 12-
1-06
19M
CB1
40, 1
2-1-
0620
MC
B140
, 12-
1-06
6
21M
CB1
40, 1
2-1-
06
RFL
PV
NTR
STR
SN
PS
TSE
ST
22M
CB1
40, 1
2-1-
06
23M
CB1
40, 1
2-1-
06
Gro
ss c
hrom
osom
e st
ruct
ure:
G-b
andi
ng (u
se G
iem
sa s
tain
)
= sp
lit k
aryo
type
into
300
ban
ds
24M
CB1
40, 1
2-1-
06
7
25M
CB1
40, 1
2-1-
06
Dr.
Thom
as R
ied,
NC
I/NIH
:
SK
Y (s
pect
ral k
aryo
typi
ng)
26M
CB1
40, 1
2-1-
06
Mar
ker:
a D
NA
seq
uenc
e th
at o
ccur
s so
mew
here
in th
e hu
man
geno
me
in a
kno
wn
loca
tion
rela
tive
to o
ther
mar
kers
.
For a
mar
ker t
o be
use
ful,
we
need
a w
ay to
det
ect i
t.
27M
CB1
40, 1
2-1-
06
Res
trict
ion
fragm
ent
leng
thpo
lym
orph
ism
(RFL
P)
11.6
28M
CB1
40, 1
2-1-
0611
.7
8
29M
CB1
40, 1
2-1-
0630
MC
B140
, 12-
1-06
The
first
map
Bot
stei
n D
, Whi
te R
L, S
koln
ick
M, D
avis
RW
. Am
J H
um G
enet
198
0 32
(3)
Con
stru
ctio
n of
a g
enet
ic li
nkag
e m
ap in
man
usi
ng re
stric
tion
frag
men
t len
gth
poly
mor
phis
ms.
We
desc
ribe
a ne
w b
asis
for t
he c
onst
ruct
ion
of a
gen
etic
link
age
map
of
the
hum
an g
enom
e. T
he b
asic
prin
cipl
e of
the
map
ping
sch
eme
is to
de
velo
p, b
y re
com
bina
nt D
NA
tech
niqu
es, r
ando
m s
ingl
e-co
py D
NA
pr
obes
cap
able
of d
etec
ting
DN
A s
eque
nce
poly
mor
phis
ms,
whe
n hy
brid
ized
to re
stric
tion
dige
sts
of a
n in
divi
dual
's D
NA
. Eac
h of
thes
e pr
obes
will
def
ine
a lo
cus.
Loc
i can
be
expa
nded
or c
ontra
cted
to
incl
ude
mor
e or
less
pol
ymor
phis
m b
y fu
rther
app
licat
ion
of
reco
mbi
nant
DN
A te
chno
logy
. Sui
tabl
y po
lym
orph
ic lo
ci c
an b
e te
sted
fo
r lin
kage
rela
tions
hips
in h
uman
ped
igre
es b
y es
tabl
ishe
d m
etho
ds;
and
loci
can
be
arra
nged
into
link
age
grou
ps to
form
a tr
ue g
enet
ic m
ap
of "D
NA
mar
ker l
oci."
Ped
igre
es in
whi
ch in
herit
ed tr
aits
are
kno
wn
to
be s
egre
gatin
g ca
n th
en b
e an
alyz
ed, m
akin
g po
ssib
le th
e m
appi
ngof
th
e ge
ne(s
) res
pons
ible
for t
he tr
ait w
ith re
spec
t to
the
DN
A m
arke
r lo
ci, w
ithou
t req
uirin
g di
rect
acc
ess
to a
spe
cifie
d ge
ne's
DN
A.F
or
inhe
rited
dis
ease
s m
appe
d in
this
way
, lin
ked
DN
A m
arke
r loc
i can
be
used
pre
dict
ivel
y fo
r gen
etic
cou
nsel
ing.
31M
CB1
40, 1
2-1-
06
Con
stru
ctio
n of
a h
igh-
reso
lutio
n ge
netic
map
32M
CB1
40, 1
2-1-
06
PC
R
Kar
y B
. Mul
lis
9
33M
CB1
40, 1
2-1-
06
VN
TRs:
var
iabl
e nu
mbe
r tan
dem
repe
ats
(STR
: sho
rt ta
ndem
repe
at --
sam
e, b
ut s
horte
r)
34M
CB1
40, 1
2-1-
0611
.12
35M
CB1
40, 1
2-1-
0611
.12
36M
CB1
40, 1
2-1-
06
Cen
tre d
’Etu
de d
u P
olym
orph
ism
e H
umai
n
517
indi
vidu
als
40 th
ree-
gene
ratio
n fa
mili
es
5,26
4 S
SLP
s (s
peci
fical
ly, S
TRs)
Gen
otyp
ed e
very
one
for e
ach
one
(gas
p).
10
37M
CB1
40, 1
2-1-
0638
MC
B140
, 12-
1-06
230/
225
227/
223
230
/ 223
39M
CB1
40, 1
2-1-
065.
1240
MC
B140
, 12-
1-06
11
41M
CB1
40, 1
2-1-
06
By
~200
1, th
ere
wer
e 8,
031
STR
s.
2-3
mar
kers
at ~
eve
ry c
entim
orga
n (1
,000
,000
bp!
!)
NO
T G
OO
D E
NO
UG
H
42M
CB1
40, 1
2-1-
06
STS
:
sequ
ence
-tagg
ed s
ite:
a un
ique
seq
uenc
e in
the
hum
an g
enom
e.
43M
CB1
40, 1
2-1-
0644
MC
B140
, 12-
1-06
Two
map
sG
enet
ic m
apTw
o ge
nes
(loci
) on
the
sam
e ch
rom
osom
e w
ill b
ecom
e se
para
ted
if a
reco
mbi
natio
n ev
ent o
ccur
s be
twee
n th
em.
Rec
ombi
natio
n is
gov
erne
d by
ru
les
of m
eios
is: t
he g
enet
ic
dist
ance
bet
wee
n tw
o lo
ci is
a
com
plex
func
tion
of th
e ac
tual
di
stan
ce b
etw
een
two
loci
.
Phy
sica
l map
Nat
ure,
shm
atur
e.S
hear
the
DN
A ra
ndom
ly (b
y X
-ra
ys):
two
gene
s (lo
ci) b
ecom
e se
para
ted
if a
brea
k oc
curs
be
twee
n th
em.
Shea
ring
is g
over
ned
by ru
les
of
phys
ics
(ahe
m, t
he P
oiss
on
dist
ribut
ion
= $1
00) –
loci
that
are
fu
rther
apa
rt w
ill te
nd to
bec
ome
sepa
rate
d m
ore
frequ
ently
–ph
ysic
al d
ista
nce
betw
een
two
loci
mea
sure
d th
is w
ay is
mor
e ac
cura
te.
12
45M
CB1
40, 1
2-1-
06
Rad
iatio
n hy
brid
map
ping
(con
stru
ctio
n of
a h
igh-
reso
lutio
n ph
ysic
al m
ap)
46M
CB1
40, 1
2-1-
06
47M
CB1
40, 1
2-1-
06
The
best
par
t
Con
trol l
evel
s of
radi
atio
n co
ntro
l fra
gmen
t siz
e C
ON
TRO
L R
ES
OLU
TIO
N O
F M
AP
Nam
e: ra
diat
ion
avg.
siz
e re
solu
tion
Gen
eBrid
ge 4
: 30
00 ra
d 25
,000
,000
bp
1 M
bS
tanf
ord
G3:
10,
000
rad
2,40
0,00
0 bp
0.
25 M
bS
tanf
ord
TNG
: 50,
000
rad
? <
100
kb
48M
CB1
40, 1
2-1-
06
13
49M
CB1
40, 1
2-1-
06
RH
map
ping
Scie
nce.
200
1 Fe
b 16
;291
(550
7):1
298-
302.
Our
stra
tegy
invo
lved
an
initi
al e
lect
roni
c an
alys
is o
f gen
omic
DN
A
sequ
ence
to e
limin
ate
repe
titiv
e D
NA
seq
uenc
es, f
ollo
wed
by
an
auto
mat
ed s
elec
tion
of o
ligon
ucle
otid
e pr
imer
s to
gen
erat
e P
CR
pr
oduc
ts 9
0 to
350
bp
in le
ngth
und
er a
sin
gle
set o
f rea
ctio
n co
nditi
ons,
as
desc
ribed
(9).
PC
R p
rodu
cts
wer
e as
saye
d by
eth
idiu
m b
rom
ide
stai
ning
afte
r ag
aros
e ge
l ele
ctro
phor
esis
. An
STS
was
judg
ed s
ucce
ssfu
l whe
n th
e pr
imer
s pr
oduc
ed a
dis
tinct
PC
R p
rodu
ct o
f the
exp
ecte
d si
ze fr
om to
tal
hum
an D
NA
and
faile
d to
pro
duce
a p
rodu
ct o
f thi
s si
ze fr
om e
ither
ha
mst
eror
mou
sege
nom
ic D
NA
. W
e ge
nera
ted
a to
tal o
f 41,
234
hum
an S
TSs
that
met
thes
e cr
iteria
. Of
thes
e S
TSs,
14,
953
wer
e sc
ored
on
rode
nt-h
uman
hyb
rid s
omat
ic c
ell
map
ping
pan
els
to d
eter
min
e th
eir c
hrom
osom
al lo
catio
n(1
0, 1
1).
A to
tal o
f 14,
041
of th
ese
14,9
53 S
TSs
(94%
) cou
ld b
e as
sign
ed to
a
uniq
ue h
uman
chr
omos
ome.
Th
ese
14,0
41 c
hrom
osom
e-sp
ecifi
c S
TSs,
as
wel
l as
the
rem
aini
ng
26,2
81 S
TSs
not s
core
d on
the
chro
mos
omal
map
ping
pan
el, w
ere
used
to c
onst
ruct
a h
igh-
reso
lutio
n R
H m
ap o
f the
hum
an g
enom
e as
de
scrib
ed b
elow
. 50
MC
B140
, 12-
1-06
Gen
erat
e 41
,234
STS
s
Ass
ign
them
all
to c
hrom
osom
es
Mak
e la
rge
num
ber o
f hum
an-h
amst
er R
H li
nes
Gen
otyp
e ea
ch o
ne fo
r eac
h S
TS
Map
them
as
if th
is w
ere
a cr
oss
51M
CB1
40, 1
2-1-
06
Res
ult
Can
inte
grat
e ge
netic
and
phy
sica
l map
!!!
52M
CB1
40, 1
2-1-
06
14
53M
CB1
40, 1
2-1-
06
BA
C
Bac
teria
l arti
fical
chr
omos
ome
–la
rge
piec
e of
som
e ot
her g
enom
e th
at is
sus
tain
able
in
bac
teria
.
CH
OR
I:S
plit
entir
e ge
nom
e in
to B
AC
s an
d or
der
BA
Cs
by S
TSs.
54M
CB1
40, 1
2-1-
06
Fing
erpr
intin
g
Run
242
-wel
l gel
s.O
n ea
ch o
ne, 5
0 m
arke
r lan
es a
nd 1
92
BA
Cs,
eac
h di
gest
ed w
ith th
e sa
me
rest
rictio
n en
zym
e –
patte
rn o
f ban
ds
uniq
ue fo
r eac
h B
AC
.
55M
CB1
40, 1
2-1-
0610
.10
56M
CB1
40, 1
2-1-
06
Fing
erpr
int @
CH
OR
I
15
57M
CB1
40, 1
2-1-
06
And
?
Do
20,0
00 fi
nger
prin
ts a
wee
k.N
ow, g
enot
ype
each
BA
C fo
r kno
wn
STS
s!!
58M
CB1
40, 1
2-1-
0610
.7
STS
STS
59M
CB1
40, 1
2-1-
0610
.11
60M
CB1
40, 1
2-1-
06
Fina
lly (w
ell,
not e
xact
ly)…
Onc
e th
e ph
ysic
al a
nd g
enet
ic m
aps
of th
e ge
nom
e ha
ve b
een
inte
grat
ed, t
he
geno
me
is “b
roke
n” d
own
into
“sm
all
piec
es” a
nd e
ach
can
be s
eque
nced
.R
eass
embl
y of
the
com
plet
ed s
eque
nce
from
the
piec
es b
ecom
es p
ossi
ble
beca
use
each
pie
ce c
onta
ins
know
n m
arke
rs w
hose
rela
tions
hip
to m
arke
rs in
ot
her p
iece
s is
kno
wn.
16
61M
CB1
40, 1
2-1-
06La
nder
et a
l. (2
001)
Nat
ure
409:
860
.
6 ye
ars…
62M
CB1
40, 1
2-1-
06
Hum
an W
hole
-Gen
ome
Sho
tgun
Sequ
enci
ng
“…Th
e cr
ux o
f our
pla
n in
volv
es h
igh-
qual
ity,
sem
iaut
omat
ed s
eque
ncin
g fro
m b
oth
ends
of v
ery
larg
e nu
mbe
rs o
f ran
dom
ly s
elec
ted
hum
an g
enom
ic D
NA
fra
gmen
ts. D
NA
of h
igh
mol
ecul
ar w
eigh
t pur
ified
from
at
leas
t a fe
w d
iffer
ent h
uman
don
ors
wou
ld b
e sh
eare
d, s
ize-
sele
cted
, and
clo
ned
into
E.c
oli.
Inse
rt si
zes
wou
ld fa
ll in
to
two
clas
ses.
Lon
g in
serts
wou
ld b
e 5-
20 k
b in
siz
e an
d w
ould
be
clon
ed in
to p
lasm
id, p
hage
, or p
ossi
bly
cosm
id
vect
ors.
Sho
rt in
serts
wou
ld b
e 0.
4-1.
2 kb
in s
ize
and
wou
ld
be c
lone
d in
to p
lasm
id v
ecto
rs. R
ead
leng
ths
wou
ld b
e of
su
ffici
ent m
agni
tude
so
that
the
two
sequ
ence
read
s fro
m
the
ends
of t
he s
hort
inse
rts o
verla
p. …
Sta
ndar
d, g
el-
base
d m
etho
ds w
ould
be
utili
zed
to g
ener
ate
at le
ast
30bi
llion
nuc
leot
ides
of r
aw s
eque
nce
(10-
fold
cov
erag
e of
th
e ge
nom
e).”
Web
er a
nd M
yers
(199
7) G
enom
e R
es. 7
: 401
.
63M
CB1
40, 1
2-1-
06
The
key
idea
–pa
ired-
end
read
s
“Seq
uenc
ing
from
bot
h en
ds o
f rel
ativ
ely
long
in
sert
subc
lone
s is
an
esse
ntia
l fea
ture
of t
he p
lan.
…
Seq
uenc
e in
form
atio
n fro
m b
oth
ends
of
rela
tivel
y lo
ng in
serts
dra
mat
ical
ly im
prov
es th
e ef
ficie
ncy
of s
eque
nce
asse
mbl
y. In
con
trast
to
sing
le s
eque
nce
read
s fro
m o
ne e
nd o
f sho
tgun
su
bclo
nes,
the
pairs
of s
eque
nce
read
s fro
m b
oth
ends
hav
e kn
own
spac
ing
and
orie
ntat
ion.
Use
of
rela
tivel
y lo
ng in
sert
subc
lone
s al
so a
ids
in th
e as
sem
bly
of s
eque
nces
con
tain
ing
inte
rspe
rsed
re
petit
ive
elem
ents
.”
Web
er a
nd M
yers
(199
7) G
enom
e R
es. 7
: 401
.64
MC
B140
, 12-
1-06
17
65M
CB1
40, 1
2-1-
06
twasbrilligandtheslithytovesdidgyreandgimble
↓B
reak
into
sm
all b
its a
nd s
eque
nce:
wasb
yto
dgim
yrea
(and so on)
How
to a
ssem
ble
into
com
plet
e se
quen
ce?
Wha
t is
the
linka
ge re
latio
nshi
p of
eac
h bi
t to
ever
y ot
her
one?
Wha
t is
thei
r rel
ativ
e or
ient
atio
n an
d di
stan
ce?
66M
CB1
40, 1
2-1-
06
twasbrilligandtheslithytovesdidgyreandgimble
↓B
reak
into
larg
e bi
ts: sb
rilligandthe
hytovesdidgyreandgi
wasbrilligandtheslithyto
↓R
ead
just
the
end
of e
ach
larg
e bi
t:sb??????????he
hy???????????????gi
wa????????????????????to
Now
you
kno
w th
at wa
and to
are
on th
e sa
me
piec
e of
D
NA
, and
you
kno
w th
eir o
rient
atio
n! A
pply
this
info
to
the
shot
gun
sequ
ence
dat
a.
67M
CB1
40, 1
2-1-
0610
.13
68M
CB1
40, 1
2-1-
06
The
Cel
era
geno
me
Nin
e m
onth
s. T
wen
ty s
even
milli
on s
eque
nce
read
s (5
x co
vera
ge).
“For
our
ass
embl
y op
erat
ions
, the
tota
l com
pute
in
frast
ruct
ure
cons
ists
of 1
0fo
ur-p
roce
ssor
SM
Ps
with
4gi
gaby
tes
of m
emor
y pe
r clu
ster
(Com
paq'
s E
S40
, Reg
atta
) and
a 1
6-pr
oces
sor N
UM
A
mac
hine
with
64
giga
byte
s of
mem
ory
(Com
paq'
s G
S16
0, W
ildfir
e). T
he to
tal c
ompu
te fo
r a ru
n of
th
e as
sem
bler
was
roug
hly
20,0
00C
PU
hou
rs.”
18
69M
CB1
40, 1
2-1-
06
Impo
rtant
Cel
era
took
the
unfin
ishe
d pu
blic
gen
ome
sequ
ence
dat
a, s
hred
ded
thos
e da
ta, a
nd
used
thos
e in
the
asse
mbl
y.
70M
CB1
40, 1
2-1-
06
The
key
poin
t of d
ispu
te
PG
P: C
eler
a di
d no
t ach
ieve
a tr
ue “w
hole
ge
nom
e sh
otgu
n as
sem
bly”
of t
he h
uman
ge
nom
e be
caus
e th
ey re
lied
too
muc
h on
(p
ublic
ly a
vaila
ble)
dat
a fro
m th
e pu
blic
ly
fund
ed h
uman
gen
ome
proj
ect.
Cel
era:
that
is n
ot w
hat h
appe
ned.
71M
CB1
40, 1
2-1-
06
PN
AS
99:
371
2 (2
002)
.
72M
CB1
40, 1
2-1-
06
PN
AS
99:
414
5 (2
002)
.
19
73M
CB1
40, 1
2-1-
06
Ther
e is
, unf
ortu
nate
ly, a
lot o
f bad
blo
od in
th
e hu
man
gen
ome
sequ
enci
ng “c
omm
unity
”
Ric
hard
Pre
ston
, The
New
Yor
ker 6
/12/
02:
“… “C
raig
Ven
ter i
s an
***
****
. He’
s an
idio
t. H
e is
a
thor
n in
peo
ple’
s si
des
and
an e
gom
ania
c,” a
se
nior
sci
entis
t in
the
Hum
an G
enom
e P
roje
ct s
aid
to m
e re
cent
ly.”
For t
he re
cord
: in
my
pers
onal
opin
ion,
Dr.
Ven
ter
is a
ver
y gi
fted
scie
ntis
t and
the
wor
k by
Cel
era
on
the
hum
an g
enom
e is
a m
ajor
con
tribu
tion
to
biol
ogy.
= F
DU
74M
CB1
40, 1
2-1-
06
Rea
ding
Jam
es S
hrev
e“T
he G
enom
e W
ar”
John
Sul
ston
“The
Com
mon
Thr
ead”