Classification of human chromosome 21 gene-expression variations in Down syndrome: impact on disease phenotypes.
Down syndrome caused by chromosome 21 trisomy is the most common genetic cause of mental retardation in humans. Disruption of the phenotype is thought to be the result of gene-dosage imbalance. Variations in chromosome 21 gene expression in Down syndrome were analyzed in lymphoblastoid cells derived from patients and control individuals. Of the 359 genes and predictions displayed on a specifically designed high-content chromosome 21 microarray, one-third were expressed in lymphoblastoid cells. We performed a mixed-model analysis of variance to find genes that are differentially expressed in Down syndrome independent of sex and interindividual variations. In addition, we identified genes with variations between Down syndrome and control samples that were significantly different from the gene-dosage effect (1.5). Microarray data were validated by quantitative polymerase chain reaction. We found that 29% of the expressed chromosome 21 transcripts are overexpressed in Down syndrome and correspond to either genes or open reading frames. Among these, 22% are increased proportional to the gene-dosage effect, and 7% are amplified. The other 71% of expressed sequences are either compensated (56%, with a large proportion of predicted genes and antisense transcripts) or highly variable among individuals (15%). Thus, most of the chromosome 21 transcripts are compensated for the gene-dosage effect. Overexpressed genes are likely to be involved in the Down syndrome phenotype, in contrast to the compensated genes. Highly variable genes could account for phenotypic variations observed in patients. Finally, we show that alternative transcripts belonging to the same gene are similarly regulated in Down syndrome but sense and antisense transcripts are not.
Aït Yahya-Graison
E
E
Neurobiologie et Diversité Cellulaire, Unité Mixte de Recherche 7637 du Centre National de la Recherche Scientifique et de l'Ecole Supérieure de Physique et de Chimie Industrielles de la Ville de Paris, France.
Aubert
J
J
Dauphinot
L
L
Rivals
I
I
Prieur
M
M
Golfier
G
G
Rossier
J
J
Personnaz
L
L
Creau
N
N
Bléhaut
H
H
Robin
S
S
Delabar
J M
JM
Potier
M-C
MC
D001483:Base Sequence; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D004314:Down Syndrome / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D014158:Transcription, Genetic
Genome Res. 2004 Jul;14(7):1258-67
15231742
Genome Res. 1997 Jan;7(1):47-58
9037601
Hum Mol Genet. 2007 Apr 1;16(7):774-82
17339268
Genome Biol. 2005;6(13):R107
16420667
Am J Obstet Gynecol. 2002 Aug;187(2):457-62
12193943
Eur J Hum Genet. 1993;1(2):114-24
8055322
Genome Res. 1996 Aug;6(8):747-60
8858350
Am J Hum Genet. 1991 Jul;49(1):207-35
1829580
J Neurochem. 2006 Apr;97 Suppl 1:104-9
16635258
Am J Hum Genet. 2007 Mar;80(3):502-9
17273971
Genomics. 2003 May;81(5):457-67
12706104
J Korean Med Sci. 2005 Feb;20(1):82-7
15716609
Ann Hum Genet. 2004 Nov;68(Pt 6):546-54
15598213
Nucleic Acids Res. 1984 Dec 21;12(24):9349-65
6096825
Hum Mol Genet. 2003 Aug 15;12(16):2013-9
12913072
Nat Rev Genet. 2004 Oct;5(10):725-38
15510164
Biochem Biophys Res Commun. 1975 Dec 1;67(3):904-9
1201080
Behav Genet. 2006 May;36(3):439-53
16502135
Biochem Biophys Res Commun. 2006 Aug 11;346(4):1303-6
16806076
Nat Genet. 2007 Feb;39(2):226-31
17206142
Biochim Biophys Acta. 2004 Dec 24;1739(1):81-7
15607120
J Comput Biol. 2001;8(6):625-37
11747616
J Neural Transm Suppl. 2001;(61):11-34
11771737
Genomics. 1998 Feb 15;48(1):12-23
9503011
Gene. 2005 Dec 30;364:90-8
16310977
Am J Med Genet A. 2006 Jun 1;140(11):1164-71
16691587
Hum Mol Genet. 2005 Dec 1;14(23):3741-9
16251198
Bioinformatics. 2006 Apr 1;22(7):775-8
16428264
Hum Mol Genet. 2005 Feb 1;14(3):373-84
15590701
Genomics. 2002 Jun;79(6):824-32
12036297
C R Hebd Seances Acad Sci. 1959 Mar 16;248(11):1721-2
13639368
Science. 1994 Dec 23;266(5193):1999-2002
17836517
Ann Neurol. 2004 Dec;56(6):808-14
15562430
Hum Mol Genet. 2004 Jul 1;13(13):1333-40
15138197
Science. 2002 May 3;296(5569):916-9
11988577
Indian J Dermatol Venereol Leprol. 2003 Nov-Dec;69(6):423-4
17642958
Nucleic Acids Res. 2006 Jul 19;34(12):e87
16855282
Gene. 2003 Oct 30;318:137-47
14585506
Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9440-5
12883005
Genome Res. 2004 Jul;14(7):1268-74
15231743
Proc Natl Acad Sci U S A. 1982 Feb;79(4):1200-4
6803235
Nature. 2000 May 18;405(6784):311-9
10830953
BMC Med Genet. 2006 Mar 15;7:24
16539728
Trends Genet. 2005 Apr;21(4):219-26
15797617
Nat Genet. 2002 Dec;32 Suppl:496-501
12454644
Nat Genet. 2003 Mar;33(3):422-5
12567189
Genome Res. 2004 Feb;14(2):247-66
14762061
Genetics. 1979 Aug;92(4):1211-29
17248947
Hum Mol Genet. 2002 Dec 15;11(26):3249-56
12471051
Nature. 2006 Nov 23;444(7118):444-54
17122850