Natural gene-expression variation in Down syndrome modulates the outcome of gene-dosage imbalance.
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.
Department of Genetic Medicine and Development, University of Geneva Medical School and University Hospitals of Geneva, Geneva, Switzerland.
Paola
P
Prandini
Samuel
S
Deutsch
Robert
R
Lyle
Maryline
M
Gagnebin
Celine
C
Delucinge Vivier
Mauro
M
Delorenzi
Corinne
C
Gehrig
Patrick
P
Descombes
Stephanie
S
Sherman
Franca
F
Dagna Bricarelli
Chiara
C
Baldo
Antonio
A
Novelli
Bruno
B
Dallapiccola
Stylianos E
SE
Antonarakis
D000782:Aneuploidy; D002460:Cell Line; D002472:Cell Transformation, Viral; D002891:Chromosomes, Human, Pair 21; D004314:Down Syndrome / Q000235:genetics*; D005347:Fibroblasts; D018628:Gene Dosage; D015870:Gene Expression; D020869:Gene Expression Profiling; D014644:Genetic Variation; D006801:Humans; D008214:Lymphocytes; D020133:Reverse Transcriptase Polymerase Chain Reaction