Colle
cting
quanti
tative
CNV
infor
matio
n usin
g aC
GHin
a Cyto
geneti
c labo
ratory
Dec
embe
r 200
9
Ant
on P
etro
v, P
h.D
. in
foQ
uant
Overv
iew
Copy num
ber a
nalysis of array CGH data
Overview of an array-‐based Cytogene
tic te
stLooking for clinically re
levant abe
rrations
Samples from
health
y individu
als and bu
ilding CN
V tracks
Abe
rration freq
uency data
HapMap
project, re
lease 3: Affym
etrixSN
P 6.0 data
Popu
latio
n-‐specific CN
V profiles
HapMap
data: 11 po
pulatio
ns
Prob
e coverage issue
CNV profile variatio
n from
one
array platform to
ano
ther
Array
-based
copy
numb
er tes
ts: da
ta ana
lysis
Data pre-‐processing
Raw measuremen
ts extracted
from
a slide
Data no
rmalized
between tw
o channe
ls (experim
ent/reference)
Log-‐ratio
measuremen
ts built and arranged
along gen
ome
Detectio
n of cop
y nu
mbe
r changes
Detectio
n of re
gion
s whe
re log-‐ratio
s significantly deviate from
zero (gains and
losses)
A ro
bust binary segm
entatio
n approach for h
igh-‐res data in infoQuant softw
are
Repo
rting of detected anom
alies
In a Cytogen
etic te
st need to determine clinical re
levance of detected aberratio
ns
Lookin
g for
clinic
ally r
elevan
t anom
alies
Know
n gene
sLook fo
r gene
s overlapp
ing with
detected anom
alies
Find
gen
es, associated with
a spe
cific class of d
isorde
rs
Know
n CN
VsPu
blicly available CN
V databases: Database of Gen
omic Variants (Toron
to)
Lack of con
trol over source
Differen
t array platforms used
In-‐hou
se CNV tracks using cho
sen platform
Build
ing C
NV tr
acks i
n copy
numb
er sof
tware
In-‐hou
se CNV track
Perform cop
y nu
mbe
r analysis on
aCG
Hdata from
individu
al sam
ples (con
trol group
)Co
llect CNV region
s for a coho
rt of con
trol sam
ples and
visualize in ro
utine Cyto
tests
Keep
upd
ating CN
V tracks as ne
w sam
ples get analyzed
CNV freq
uency profile
Compu
te freq
uency of CNVs along gen
ome based on
accum
ulated
sam
ples
Use quantita
tive inform
ation that CNV freq
uencies provide to interpret relevance of
detected
chrom
osom
al ano
malies in new
ly acquired samples
Using
CNV
track
s in C
ytogen
etic t
ests
Visualize accumulated
CNV inform
ation du
ring ro
utine tests
Visualize region
s of freq
uent CNVs whe
n review
ing data fo
r a ne
w sam
ple
to determine clinical re
levance of detected anom
alies
Furthe
r increase insight into po
ssible clinical re
levance of a detected
anom
aly using qu
antitative inform
ation provided
by CN
V freq
uencies
Cohor
ts of
health
y indi
vidual
s: the
HapM
appro
ject
The HapMap
project
The International H
apMap
Project is a partne
rship of scien
tists and
fund
ing agen
cies
from
various cou
ntries www.hapmap.org
The goal of the
International H
apMap
Project is to com
pare th
e gene
tic seq
uences of
diffe
rent individu
als to iden
tify chromosom
al re
gion
s whe
re gen
etic variants are
shared
Gen
etic data are be
ing gathered
from
differen
t hum
an pop
ulations >10
00 sam
ples in
the latest re
lease
aCGHand SN
P data were ob
tained
using differen
t array platforms from
med
ium
resolutio
n to high resolutio
n to ultra-‐high re
solutio
n over th
e years
Build
ing C
NV fr
equenc
ies ac
ross H
apMap
sample
sA large, pow
erful poo
l of d
ata
High-‐de
nsity
inform
ation provided
by Affym
etrixSN
P 6.0 arrays
CNV freq
uencies across HapMap
samples provide
a useful insight into how
freq
uently a certain ano
maly may be ob
served
in health
y individu
als
Separate gain freq
uencies and loss freq
uencies
Useful add
ition
to th
e Database of Gen
omic Variants
Filter
ing H
apMap
CNV
data
Control group
may produ
ce CNVs th
at are clinically re
levant
HapMap
sample be
low dem
onstrates a large copy num
ber loss con
firmed
by
both sets of m
easuremen
tsThe region
includ
es cancer-‐related gene
NRA
SSuch ano
malies ne
ed to
be isolated
using cop
y nu
mbe
r analysis softw
are
Filte
r CNVs by size
Whe
n compu
ting CN
V freq
uency profiles pre-‐set softw
are to disregard CNVs
larger th
an 2Mbp
, for instance
CNV
freque
ncy pr
ofiles
speci
fic to
samp
le att
ribute
Dem
ograph
ic attribu
tes may be im
portant
For e
xample: 11 diffe
rent pop
ulations in HapMap
Individu
al CNV freq
uency plots may be bu
ilt fo
r the po
pulatio
ns by aCGH
software and used
in Cytogen
etic te
sts for more targeted
reference
Probe
cover
age is
sueDifferent a
rray platforms may produ
ce slightly different C
NV profiles
-‐scale and
com
plex architecture of hum
an cop
y-‐nu
mbe
r
Affym
etrixSN
P 6.0 arrays (H
apMap
release 3)
Platform
s may con
centrate th
eir prob
e coverage on differen
t areas, hen
ce differen
t CNV
profiles. This is ty
pical for perform
ing copy num
ber analysis across array platform
s.
Othe
r sour
ces of
high
-quali
ty CN
V dat
aOther studies
CHOP: High-‐resolutio
n mapping of cop
y nu
mbe
r variatio
ns in 2,026
health
y individu
als
http://cnv.cho
p.ed
u/Wellcom
eTrust: Ultra-‐high re
solutio
n CN
V stud
y. 42 M probe
coverage, custom 2.1 M
array de
signs based on
Roche
-‐Nim
blegen
aCGH.
http://w
ww.sanger.ac.uk/hum
gen/cnv/42
mio/
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