University of Chicago Press - Gene-Expression...

Am. J Hum. Genet., 81: 252–263, 2007

© 2007 by The American Society of Human Genetics. All rights reserved.

0002-9297/2007/8102-0007$15.00

DOI: 10.1086/519248

Article

Natural Gene-Expression Variation in Down Syndrome Modulates the Outcome of Gene-Dosage Imbalance

Paola Prandini,

Samuel Deutsch,

Robert Lyle,

Maryline Gagnebin,

Celine Delucinge Vivier,

Mauro Delorenzi,

Corinne Gehrig,

Patrick Descombes,

Stephanie Sherman,

Franca Dagna Bricarelli,

Chiara Baldo,

Antonio Novelli,

Bruno Dallapiccola, and

Stylianos E. Antonarakis

From the Department of Genetic Medicine and Development, University of Geneva Medical School and University Hospitals of Geneva (P.P.; S.D.; R.L.; M.G.; C.G.; S.E.A.), and National Center for Competence in Research (NCCR) Frontiers in Genetics, Genomics Platform, University of Geneva (C.D.V.; P.D.), Geneva; Department of Medical Genetics, Ullevål University Hospital, Oslo, Norway (R.L.); Swiss Institute of Bioinformatics, Lausanne, Switzerland (M.D.); Swiss Institute of Experimental Cancer Research, Epalinges, Switzerland (M.D.); Emory University School of Medicine, Atlanta, Georgia (S.S.); Genetics Laboratory, Galliera Hospital, Genoa, Italy (F.D.B.; C.B.); and Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS)-Casa Sollievo della Sofferenza (CSS), San Giovanni Rotondo and CSS-Mendel Institute (A.N.; B.D.), and Department of Experimental Medicine and Pathology, University of Rome “La Sapienza” (B.D.), Rome

Received March 26, 2007; accepted for publication April 27, 2007; electronically published June 20, 2007.

Address for correspondence and reprints: Dr. Stylianos E. Antonarakis, Department of Genetic Medicine and Development, University of Geneva Medical School and University Hospitals of Geneva, 1 rue Michel-Servet, 1211 Geneva, Switzerland. E-mail: [e-mail]

Down syndrome (DS) is characterized by extensive phenotypic variability, with most traits occurring in only a fraction of affected individuals. Substantial gene-expression variation is present among unaffected individuals, and this variation has a strong genetic component. Since DS is caused by genomic-dosage imbalance, we hypothesize that gene-expression variation of human chromosome 21 (HSA21) genes in individuals with DS has an impact on the phenotypic variability among affected individuals. We studied gene-expression variation in 14 lymphoblastoid and 17 fibroblast cell lines from individuals with DS and an equal number of controls. Gene expression was assayed using quantitative real-time polymerase chain reaction on 100 and 106 HSA21 genes and 23 and 26 non-HSA21 genes in lymphoblastoid and fibroblast cell lines, respectively. Surprisingly, only 39% and 62% of HSA21 genes in lymphoblastoid and fibroblast cells, respectively, showed a statistically significant difference between DS and normal samples, although the average up-regulation of HSA21 genes was close to the expected 1.5-fold in both cell types. Gene-expression variation in DS and normal samples was evaluated using the Kolmogorov-Smirnov test. According to the degree of overlap in expression levels, we classified all genes into 3 groups: (A) nonoverlapping, (B) partially overlapping, and (C) extensively overlapping expression distributions between normal and DS samples. We hypothesize that, in each cell type, group A genes are the most dosage sensitive and are most likely involved in the constant DS traits, group B genes might be involved in variable DS traits, and group C genes are not dosage sensitive and are least likely to participate in DS pathological phenotypes. This study provides the first extensive data set on HSA21 gene-expression variation in DS and underscores its role in modulating the outcome of gene-dosage imbalance.