Clin Genet 2000: 57: 349–358Printed in Ireland. All rights reser6ed

Original Article

Somatic segregation errors predominantlycontribute to the gain or loss of a paternalchromosome leading to uniparental disomyfor chromosome 15

WP Robinson, SL Christian, BD Kuchinka, MS Penaherrera, S Das, SSchuffenhauer, S Malcolm, AA Schinzel, TJ Hassold, DH Ledbetter.Somatic segregation errors predominantly contribute to the gain or lossof a paternal chromosome leading to uniparental disomy for chromo-some 15.Clin Genet 2000: 57: 349–358. © Munksgaard, 2000

Paternal uniparental disomy (UPD) for chromosome 15 (UPD15),which is found in �2% of Angelman syndrome (AS) patients, is muchless frequent than maternal UPD15, which is found in 25% of Prader–Willi syndrome patients. Such a difference cannot be easily accountedfor if ‘gamete complementation’ is the main mechanism leading toUPD. If we assume that non-disjunction of chromosome 15 in malemeiosis is relatively rare, then the gain or loss of the paternal chromo-some involved in paternal and maternal UPD15, respectively, may bemore likely to result from a post-zygotic rather than a meiotic event.To test this hypothesis, the origin of the extra chromosome 15 wasdetermined in 21 AS patients with paternal UPD15 with a paternalorigin of the trisomy. Only 4 of 21 paternal UPD15 cases could beclearly attributed to a meiotic error. Furthermore, significant non-ran-dom X-chromosome inactivation (XCI) observed in maternal UPD15patients (pB0.001) provides indirect evidence that a post-zygotic erroris also typically involved in loss of the paternal chromosome. Themean maternal and paternal ages of 33.4 and 39.4 years, respectively,for paternal UPD15 cases are increased as compared with normal con-trols. This may be simply the consequence of an age association withmaternal non-disjunction leading to nullisomy for chromosome 15 inthe oocyte, although the higher paternal age in paternal UPD15 ascompared with maternal UPD15 cases is suggestive that paternal agemay also play a role in the origin of paternal UPD15.

Wendy P. Robinsona, SusanL. Christianb, BrianD. Kuchinkaa, MariaS. Penaherreraa, Soma Dasc,Simone Schuffenhauerd,Susan Malcolme, AlbertA. Schinzelf, Terry J. Hassoldg

and David H. Ledbetterc

a Department of Medical Genetics,University of British Columbia, and the B.C.Research Institute for Children’s andWomen’s Health, Vancouver, Canada,b Department of Psychiatry, University ofChicago, Chicago, IL, USA, c Departmentof Human Genetics, University of Chicago,Chicago, IL, USA, d Kinderpoliklinik derUniversitat Abteilung fur PadiatrischeGenetik, Munchen, Germany, e MolecularGenetics Institute, Institute for Child Health,London, UK, f Institut fur MedizinischeGenetik der Universitat Zurich, Switzerland,g Department of Genetics and The Centerfor Human Genetics, Case WesternReserve University School of Medicine,Cleveland, OH, USA

Key words: Angelman syndrome – meiosis– mosaicism – non-disjunction –Prader–Willi syndrome – uniparentaldisomy – X-chromosome inactivation

Corresponding author: Wendy P. Robinson,Ph.D., B.C. Research Institute for Chil-dren’s and Women’s Health, Room 3086,950 West 28th Ave., Vancouver B.C.,Canada V5Z 4H4. Tel: +1 604 8753229;fax: +1 604 8752496; e-mail:wendyr@unixg.ubc.ca

Uniparental disomy (UPD) is the situationwhereby both homologues of a chromosome pairhave originated from a single parent (1). UPD mayarise through multiple mechanisms including 1)gamete complementation – the chance fertilizationof a disomic egg with a sperm nullisomic for thesame chromosome (or vice versa); 2) trisomic

zygote rescue – early somatic loss of a paternalchromosome from a conceptus with a trisomy aris-ing from one paternal and two maternal chomo-somes (and vice versa); and 3) compensatory UPD– a somatic event leading to replacement of anabnormal or absent chromosome with the normalhomologue (see (2) for review). Although all of

349

Robinson et al.

these mechanisms are known to occur, rarely canone accurately determine the mechanism of originin a particular case of UPD. Knowing the mecha-nism could provide useful clinical information con-cerning the potential that mosaicism with anothercell line might have an influence on the phenotype.

Maternal UPD15 is found in �25% of Prader–Willi syndrome patients and paternal UPD15 isfound in �2% of Angelman syndrome (AS) pa-tients (3). Based on a 1/20000 incidence of thesesyndromes, the frequency of maternal and paternalUPD15 can be estimated as 1/80000 and 1/1000000 births, respectively (4). The relative lackof paternal UPD15 cases as compared with mater-nal UPD15 seems likely to be related to the lowerrate of non-disjunction in male meiosis as com-pared with female meiosis (5, 6). Because the originof UPD as a result of gamete complementationrequires the occurrence of a non-disjunction eventin the meiosis of both parents, this mechanismcannot explain the estimated 10-fold excess of ma-ternal as compared with paternal UPD15. It is,therefore, hypothesized that a post-zygotic gain orloss of the paternal chromosome in paternal andmaternal UPD15, respectively, is more likely tohave occurred.

MethodsPatient ascertainment

A total of 21 paternal UPD15 cases were ascer-tained through routine molecular diagnosis of ASpatients. Four cases were included in previous pub-lications (7–9); however, more detailed markertyping is presented here. Of the 17 ‘new’ cases, 13were diagnosed in Chicago, USA, 1 in Zurich,Switzerland, 1 in London, UK and 2 in Munich,Germany. Cases of maternal UPD15 were ascer-tained through the investigation of Prader–Willisyndrome patients and a summary of the molecu-lar data on most has been published (10). Detailsof the controls used in X-chromosome inactivation(XCI) studies are presented elsewhere (11). Detailsof control data from a Swiss population used inparental age comparisons are also given elsewhere(12).

Cytogenetic analysis

Cytogenetic analysis was performed in the refer-ring laboratories by conventional G-banding. Inothers, only fluorescence in situ hybridization(FISH) was performed using commercially avail-able probes, SNRPN, D15S10, D15S11 orGABRB3 with a 15q22 control probe (PML) (Vy-sis, Downer’s Grove, IL, USA). Most transloca-

tions or rearrangements of chromosome 15 wouldbe detected using this FISH test. However, thepresence of a small supernumerary isodicentric15(pter-q11:q11-pter) chromosome could poten-tially be missed using this method alone.

DNA studies

Microsatellite polymorphisms were detected bypolymerase chain reaction (PCR) amplification, asdescribed previously (13). In total, 50 loci spanning15q were used in the analyses with 15–25 of thesemarkers typed in any one patient (see Table 3 forthe more commonly used markers). The Centred’Etude du Polymorphisme Humain (CEPH) malegenetic map used for marker distances (Tables 3and 4) is based mostly on data obtained onlinefrom http://cedar.genetics.soton.ac.uk/. However,for the region from D15S541 through D15S165,data from Robinson and Lalande (14) were usedinstead of the online map, owing to inconsistencieswith known published maps of this region (15).

If both the UPD15 case and the parent transmit-ting two chromosomes 15 are heterozygous, this isreferred to as non-reduction of parent of originheterozygosity (or heterodisomy). Non-reductionof markers close to the centromere is indicative ofa meiosis I (MI) error. Reduction to homozygosity(or isodisomy) of markers near to the centromereis classified as either a meiosis II (MII) error, ifother markers elsewhere along the chromosomeare heterozygous, or a somatic error, if all markersthroughout the chromosome show reduction tohomozygosity. D15S541, D15S542 or D15S1035(the most proximal markers to the centromere) wasinformative in all cases except AS 381, for whichthe most proximal informative marker wasD15S128.

Misclassification of a non-disjunction event as asomatic error may occur if insufficient markers aretyped, thus leading to failure to detect a doublecrossover. To evaluate the degree of interference inmale meiosis, we haplotyped the 8 CEPH referencepedigrees for chromosome 15 markers as describedpreviously (10). Among 15 double crossovers iden-tified in male meioses, only 3 were identified as lessthan or potentially less than 30 cM and none oc-curred between markers less than 24 cM apart.This is consistent with studies of interference onchromosomes 9 and 19, for which doublecrossovers rarely occurred over less than 20 cM inmale meiosis (16, 17). We, therefore, divided chro-mosome 15 into 7 marker clusters – I: D15S541-D15S128 (0–4 cM); II: D15S1365-GABRA5(4–6 cM); III: D15S1048-D15S129 (17 cM); IV:D15S1028-D15S117 (43 cM); V: D15S108-

350

Uniparental disomy for chromosome 15

D15S114 (47–51 cM); VI: FES-D15S100 (60–67 cM); and D15S120-D15S642 (80–83 cM). Withthe exception of AS381, each patient was informa-tive for at least one marker in each of these clus-ters and the maximum gap in coverage in any onepatient was 26 cM.

The degree of skewed XCI was estimated usingan assay based on a methylation sensitive HpaIIrestriction site located near the human androgenreceptor (AR) gene (18). Quantification of the re-sulting bands was performed as detailed previ-ously (19).

Results and discussionOrigin of the paternal chromosomes in paternal UPD15

Of the 21 UPD15 cases analyzed as part of thisstudy, 17 (81%) showed homozygosity for markersthroughout the entire chromosome arm, whichwas suggestive that the additional paternal chro-mosome arose through a post-zygotic somaticevent rather than an error at meiosis (Tables 1and 3). The extensive marker coverage makes itunlikely that any double crossovers were missed.Markers within the most proximal 4 cM and distal3 cM were informative in all cases. The maximumgap in coverage was 37 cM in AS381, while in allother patients it was 26 cM. It is not possible,however, to formally exclude the chance that theseerrors arose as either pre-meiotic somatic eventsor as MII errors following a non-recombinant MI.

These results show a higher frequency of so-matic origin than might be concluded from thepreviously published cases of paternal UPD15(Table 2). Some previous reports suffer from as-certainment bias because the presence of an ab-normality involving chromosome 15 could bothincrease the chance that a diagnosis of AS wouldbe suspected and make the case of greater interestfor publication. If single case reports are excludedand only those cases ascertained and published aspart of a series of cases (7, 20–22) are summa-rized together with the present results, then only 6of 34 total cases (18%) had a proven meioticorigin.

Chromosome abnormalities and UPD15

In this series, three cases were associated with achromosome abnormality: one 15q isochromo-some; one Robertsonian translocation betweenchromosomes 14 and 15; and one supernumeraryisodicentric chromosome containing chromosome15 centromeres. Another case (V117) showed evi-dence of a faint additional band by DNA analysisat D15S541, which may have been either maternal

or paternal in origin. This would be consistentwith mosaicism for a small supernumerary chro-mosome derived from proximal 15, which was notdetected cytogenetically (FISH but not conven-tional G-banding was performed in this case). Allof these abnormalities have been reported previ-ously in association with both maternal and pater-nal UPD15 (Tables 1 and 2) (4). Although clearlyincreased, the risk of finding UPD when theseabnormalities are found prenatally is difficult topredict from the limited data available. Two casesof paternal UPD have been the result of aberrantMI segregation associated with translocations be-tween chromosome 15 and a non-acrocentricchromosome (Table 2). Such errors have not beenreported in maternal UPD15. However, it shouldbe noted that these were not balanced transloca-tions but rather derivative chromosomes similar toRobertsonian translocations, in that the entirelong arm of chromosome 15 was translocated tothe recipient chromosome. There is no evidence tosuggest that balanced reciprocal translocations forany chromosome are at increased risk of UPD(23).

Recombination and paternal meiotic non-disjunction

To investigate the role of recombination in pater-nal meiotic errors, detailed marker analysis is pre-sented for four cases of paternal UPD15 ofmeiotic origin (see Table 4). Further analysis of apreviously published case of trisomy 15 (5467) (24,25) is also included. Based on both genetic andchiasma-based maps, it is expected that two chias-mata would occur between the two chromosome15 homologues in the majority of male meioses(26). The observed number of transitions (Table 4)is consistent with expectations (27). It is, however,noteworthy that, in S467, a recombination eventoccurred between two markers (D15S123 andD15S1006) for which no male or female recombi-nation is apparent in the CEPH family-based ge-netic map. This exchange was confirmed both byrepeating these marker amplifications and by typ-ing nearby adjacent markers. Furthermore, noneof the four MI cases showed any transitions in theproximal 43 cM of the q-arm, in contrast to thethree MII errors. A reduction in recombination inthe centromeric region has been associated withmaternal MI non-disjunction of chromosomes 15,16 and 21 (10, 28, 29) and an increase in recombi-nation in the proximal region has been associatedwith maternal MII non-disjunction of chromo-some 21 (30). It is possible that the same effectoccurs for meiotic non-disjunction of autosomesin males.

351

Robinson et al.

352

Tabl

e1.

Sum

mar

yof

pate

rnal

UPD

15or

triso

my

15ca

ses

–th

isst

udy

Cas

ec(re

fere

nce)

Orig

inPr

oxim

alin

form

ative

mar

ker

No.

info

rmat

ivem

arke

rs*

Kary

otyp

eM

ater

nala

geSe

xPa

tern

alag

e(y

ears

)(y

ears

)

New

case

s–

UPD

15V8

5M

eios

isI

D15

S541

13FI

SH-N

3540

FR.

M.

Mei

osis

ID

15S5

427

45,X

Y,de

r(14;

15)(q

10;q

10)

NA

NA

MV9

6M

eios

isII

D15

S542

1346

,XX

3537

FV1

22M

eios

isII

D15

S103

516

FISH

-N33

38M

1040

4So

mat

icD

15S5

4112

46,X

Y27

28M

V26

Som

atic

D15

S541

1146

,XY

NA

NA

MV2

7So

mat

icD

15S5

4211

46,X

XN

AN

AF

V28

Som

atic

D15

S542

1045

,XY,

i(15;

15)(q

10)

NA

NA

MV5

6So

mat

icD

15S5

4211

46,X

YN

AN

AM

V82

Som

atic

D15

S541

13FI

SH-N

NA

NA

MV8

9So

mat

icD

15S5

4311

47,X

X,+

psu

dic(

15;1

5)(q

11;q

11)

NA

32F

V108

Som

atic

D15

S541

13FI

SH-N

NA

NA

FV1

09So

mat

icD

15S5

4210

Not

test

ed34

36M

V115

Som

atic

D15

S541

12FI

SH-N

2828

MV1

17So

mat

icD

15S5

4114

FISH

-NN

AN

AF

V118

Som

atic

D15

S541

1246

,XX

NA

NA

FAS

381

Som

atic

D15

S128

7N

otte

sted

4553

F

New

data

–pr

evio

usly

publ

ished

UPD

15AS

112;

Botta

niet

al.(

7)So

mat

icD

15S5

418

46,X

X43

45F

AS13

6;Bo

ttani

etal

.(7)

Som

atic

D15

S541

846

,XX

3143

FAS

182;

Robi

nson

etal

.(8)

Som

atic

D15

S541

1247

,XY,

+ps

udi

c(15

;15)

(q11

;q11

)30

40M

4884

;Cha

net

al.(

9)So

mat

icD

15S5

4111

46,X

Y31

40M

*No.

ofm

arke

rshe

tero

zygo

usin

the

fath

eran

din

form

ative

todi

stin

guish

‘redu

ctio

n’fro

m‘n

on-r

educ

tion’

.N

A=

data

not

avai

labl

e.FI

SH-N

=no

rmal

byFI

SHbu

tG

-ban

ded

kary

otyp

eno

tpr

efor

med

.

Uniparental disomy for chromosome 15

353

Tabl

e2.

Sum

mar

yof

prev

ious

lypu

blish

edpa

tern

alU

PD15

not

part

ofth

isst

udy

Cas

ec

(refe

renc

e)Pa

tern

alag

e(y

ears

)Se

xO

rigin

Prox

imal

info

rmat

ivem

arke

rN

o.in

form

ative

mar

kers

*Ka

ryot

ype

Mat

erna

lage

(yea

rs)

Publ

ished

UPD

1536

Mal

colm

etal

.(20

)–W

1F

Mei

osis

ID

15S1

13

46,X

X32

FN

AN

A45

,XX,

der(6

;15)

(p25

.3;q

11.1

)Sm

eets

etal

.(33

)1

D15

S10

Mei

osis

IN

ASm

ithet

al.(

21)(

c31

)M

Mei

osis

ID

15S1

12

45,X

Y,de

r(14;

15)(q

10;q

10)**

19 2426

MM

eios

isI

Smith

etal

.(34

)D

15S1

12

45,X

Y,de

r(8;1

5)(p

23.3

;q11

)F

NA

NA

Zack

aiAJ

HG

57:A

106

45,X

X,de

r(13;

15)(q

10;q

10)p

atM

eios

isI

NA

NA

29G

yfto

dim

ouet

al.(

35)

FM

eios

isII

D15

S11

846

,XX

3622

Pras

adan

dW

agst

aff(

36)

FSo

mat

icD

15S8

177

46,X

X14

F26

46,X

X36

6D

15S5

41So

mat

icH

arpe

yet

al.(

37)

3134

MM

alco

lmet

al.(

20)–

D1

?D

15S2

42

46,X

YM

Nic

holls

etal

.(38

)26

33?

46,X

Y3

D15

S10

NA

Free

man

etal

.(39

)M

?D

15S2

43

45,X

Y,i(1

5;15

)(q10

)31 22

25F

?Sm

ithet

al.(

21)

c28

D15

S11

346

,XX

2832

M?

Smith

etal

.(21

)c

29D

15S1

33

46,X

YF

2546

,XX

312

D15

S98

?Sm

ithet

al.(

21)

c30

3834

FSm

ithet

al.(

22)

c42

?D

15S1

131

46,X

XM

2831

Smith

etal

.(22

)c

4346

,XY

?D

15S5

414

25G

illess

en-K

aesb

ach

etal

.(40

)M

?D

15S1

83

46,X

Y25

*No.

ofm

arke

rshe

tero

zygo

usin

the

fath

eran

din

form

ative

todi

stin

guish

‘redu

ctio

n’fro

m‘n

on-r

educ

tion’

.**

A.Sm

ith,p

erso

nalc

omm

unic

atio

n.N

A=

data

not

avai

labl

e.?=

Insu

ffici

ent

mar

kers

type

dto

dete

rmin

eor

igin

;all

info

rmat

ivem

arke

rssh

owed

are

duct

ion

toho

moz

ygos

ity.

Robinson et al.

354

Tabl

e3.

Sum

mar

yof

mar

ker

data

inpa

tern

alU

PD15

case

scl

assifi

edas

som

atic

erro

rs

V26

V27

V28

V56

V82

V89

V108

V109

V115

V117

V118

AS38

1AS

112

AS13

6AS

182

4884

1040

4

R*

*R

*R

*R

Rc

D15

S541

0R

RR

RR

RR

RR

R*

RR

*D

15S5

420

D15

S103

5*

R0

D15

S543

*R

RR

0.9

R*

RD

15S1

12.

8*

*D

15S1

28R

RR

RR

R4.

1D

15S2

10R

4.1

RD

15S1

365

RR

R*

R*

RD

15S1

224.

5R

D15

S113

5.6

D15

S97

*R

5.6

RR

RR

*R

RG

ABRB

3*

5.6

RR

R*

RR

RG

ABRA

5R

6.2

D15

S822

R*

D15

S104

8R

R*

17R

RD

15S1

031

17*

D15

S165

RR

R*

RR

R*

RR

17R

*R

RR

D15

S129

RR

RR

R43

D15

S102

8R

R*

D15

S123

R*

R*

R43

R*

RR

R*

RR

D15

S100

643

CYP

19*

R*

RR

43R

RR

RR

D15

S101

643

RR

RR

RR

*R

*R

RR

*R

D15

S117

RR

*43

RD

15S9

8R

D15

S108

*R

**

RR

*47

RR

RR

RR

RR

*D

15S1

020

47D

15S1

53R

R*

48D

15S1

25R

RR

48R

*R

R*

RR

R*

R*

R50

D15

S131

D15

S204

R*

RR

*R

D15

S114

RR

51D

15S1

16R

*R

*FE

SR

R*

RR

RR

R60

RR

RR

RR

RR

64IP

M15

RR

RR

RR

RR

RR

RR

D15

S100

*67

RR

R*

*R

RR

D15

S120

80D

15S9

66*

*R

RR

**

83D

15S8

7**

**

RR

R83

RR

R*

**

*R

D15

S642

83R

RR

R

R=

redu

ctio

nto

hom

ozyg

osity

.*=

mar

ker

unin

form

ative

.c

=a

fain

ter

seco

ndba

ndw

asse

enat

this

mar

ker

(see

text

).

Uniparental disomy for chromosome 15

Table 4. Recombination of paternal meiotic errors

Transition events are outlined with boxes.N=non-reduction of paternal heterozygosity to homozygosity.R= reduction to homozygosity.*=marker uninformative.GRY is patient from Gryftodimou et al. (35).WI is patient from Malcolm et al. (20).5467 is a trisomy 15 case.

XCI and UPD15

Non-random XCI, defined as \90% inactivationof one parental X, is present in the fetal tissues ofmore than half of the evaluated cases of pre-natallydiagnosed mosaicism resulting from ‘trisomiczygote rescue’ but in only about 2% of newborncontrols (19, 31). As an indirect test of ‘trisomiczygote rescue’, we have, therefore, evaluated XCIstatus in 4 paternal and 38 maternal UPD15 cases(Table 5). Additional cases were uninformative forthe AR test because they were either male, female

but homozygous, or female with alleles too close insize to perform accurate dosage analysis. Theseresults confirm our previous findings in maternalUPD15 cases, with 24% showing extremely skewedXCI (\90% inactivation of one X) (pB0.005). Asonly those cases of trisomic zygote rescue with arelatively late origin of the diploid cell line willresult in skewed XCI, a post-zygotic loss of thepaternal chromosome has probably occurred in alarge proportion of maternal UPD15 cases. Incontrast, all four paternal UPD15 cases showedrandom XCI. Although the numbers are small, this

355

Robinson et al.

Table 5. Non-random XCI in UPD15

Degree of skewing (%) Paternal UPD15 (n=4) Maternal UPD15 (n=38) Controls (n=98)

56 (57)450–69 22 (58)37 (38)70–89 0 7 (18)

9* (24)90–100 0 5 (5)

* pB0.005 compared with controls (Fisher’s exact test).Percentages are shown in parentheses.

Table 6. Parental age data

Mean age difference (=paternal age−maternal age)Mean paternal ageMean maternal age

33.4** (n=13)Paternal UPD15 39.4** � (n=14) 6.5* �� (n=13)35.3** (n=84)33.2** (n=108)Maternal UPD15 2.2 (n=83)

2.9 (n=123)Controls 28 (n=123) 30.9 (n=123)

* pB0.01, ** pB0.001 compared with controls (Student’s t-test).� pB0.05, �� pB0.001 compared with maternal UPD15 (Student’s t-test).

would be consistent with the hypothesis that, in thissituation, the maternal chromosome 15 is ‘lost’through a meiotic rather than a post-zygotic error.

Parental ages and UPD15

The mean maternal and paternal ages of 33.4 (n=13) and 39.4 (n=14) years are much higher thanthose reported for normal births in most popula-tions and higher than our Swiss controls (Table 6).The paternal age is also higher for the paternalUPD15 as compared with the maternal UPD15cases in our study (pB0.05). Proper evaluation ofthese data is difficult as the paternal UPD15 pa-tients data have come from multiple countries andare therefore not from the same population as thecontrol group. Furthermore, both the mean mater-nal and paternal ages for those cases evaluated aspart of this study are significantly higher (pB0.01)than the parental ages for the other paternalUPD15 cases reported in the literature (see Table 2).Interestingly, the fathers were on average 6.5 yearsolder than the mothers in the paternal UPD15group, as compared with only 2.2 years in a groupof maternal UPD15 patients (pB0.05). However,once again the two populations are not directlycomparable, and this difference was only 4.1 yearswhen the other published paternal UPD15 cases areconsidered. Because the paternal errors are predom-inantly believed to be the result of post-zygoticevents, it seems likely that the age effect is mostlyowing to an association between maternal age andnon-disjunction leading to nullisomy for chromo-some 15 in oocytes. Studies of pre-implantationembryos suggest that monosomy occurs as often astrisomy for most chromosomes studied and is also

associated with increased maternal age (32).Nonetheless, the apparently higher paternal ages inthe paternal UPD15 group leaves open the possibil-ity that what appears to be a post-zygotic duplica-tion of the paternal chromosome may be influencedby paternal age, either because these are indeederrors originating prior to fertilization or becausean age-related abnormality in the chromosome pre-disposes it to a post-fertilization error.

Summary

Humans produce trisomic conceptions at a remark-ably high rate, mostly as a result of a propensity oferrors in maternal meiosis (6). A high frequency ofearly post-fertilization errors in humans is alsoapparent from studies of human pre-implantationembryos (32). An early post-zygotic gain or loss ofa chromosome may provide a means to ‘rescue’ apregnancy that would otherwise not survive. Ourstudies of UPD15 are consistent with this scenarioin that most cases of UPD15 appear to have arisenfrom a mosaic blastocyst. In the case of maternalUPD15, it appears that a trisomic cell line is oftenpresent but is eliminated by selection from signifi-cant contribution to fetal tissues. On the otherhand, in paternal UPD15, a putative monosomiccell line is presumably present but would be ex-pected to be non-viable and eliminated in earlydevelopment. The clinical consequence of thesefindings is that abnormalities owing to low-leveltrisomic cells would likely be limited to maternalUPD15.

AcknowledgementsThis work was supported by MRC grant cMA-13694.

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