The Genom of Homo sapiens.pdf

Chromosome 21 and Down Syndrome: The Post-Sequence EraS.E. ANTONARAKIS, A. REYMOND, R. LYLE, S. DEUTSCH, AND E.T. DERMITZAKISDivision of Medical Genetics, NCCR Frontiers in Genetics, University of Geneva Medical Schooland University Hospitals, SwitzerlandTrisomy 21, the etiology of Down syndrome (DS), isthe most common cause of genetic mental retardation,and a model for the numerous aneuploidy syndromes. DSwas first described by John Langdon Down in 1866(Down 1866), and the trisomy for a group G acrocentricchromosome was recognized by Lejeune et al. in 1959(Lejeune et al. 1959). Many recent studies have used humanchromosome 21 as a model for genomic studies suchas determination of haplotype block (Patil et al. 2001),identification of transcribed sequences (Kapranov et al.2002), and comparative genomics (Frazer et al. 2003).DS can be viewed as a collection of various phenotypesthat are directly or indirectly related to the supernumerarycopy of genes or other functional DNA elementson human chromosome 21 (Hsa21). The entirephenotypic expression of the syndrome is therefore apolygenic disease in which all primarily of the contributinggenes map to Hsa21. One striking clinical observationis that for the majority of the DS phenotypes thepenetrance is variable; i.e., not all DS patients manifestall the phenotypes. For example, the characteristic atrioventricularseptal heart defect (AVSD) is only present in16% of patients with DS. In addition, the degree ofseverity of the phenotypes varies among patients; for example,the IQs of affected individuals vary from the low20s to the 70s.The working hypotheses to explain the phenotypicvariability include the following:1. There are two categories of genes on Hsa21; thosethat are dosage-sensitive and contribute to the phenotypesof DS, and those that are not dosage-sensitiveand therefore do not contribute to any of the phenotypes.2. The effect of the dosage-sensitive genes could eitherbe allele-specific or allele-nonspecific. In other words,the combination of certain but not all alleles could becontributory to the phenotype. This could be eitherqualitative (alleles with amino acid variation) or quantitative(alleles with variation in gene expression/proteinlevels). In the latter case, a threshold effect of totaltranscript output or amount of protein could beenvisaged: A phenotype is only present if the totaltranscript/protein level of the three alleles reaches acritical amount.3. The effect of the dosage-sensitive genes could eitherhave a direct or indirect effect on the phenotype. Theindirect effect may be due to the interaction of Hsa21genes or gene products with non-Hsa21 genes or geneproducts. This interaction could again be allele-specific;maybe only certain combinations of non-Hsa21alleles contribute to susceptibility of specific phenotypes.Therefore, the global dysregulation of the individualtranscriptome or proteome could contribute tothe DS phenotypes.4. Triplication of certain conserved non-genic sequences(CNGs, see below) on Hsa21 may contribute to the DSphenotypes. This contribution could also be allelespecific.The completion of the sequence of chromosome 21(Hsa21) and the comparison of these sequences withthose of other mammalian genomes, such as mouse, providean unprecedented opportunity to identify not onlythe protein-coding sequences, but also other functionalsegments of Hsa21. In addition, the study of populationvariation of Hsa21 will reveal functional variation (quantitativeor qualitative) that may contribute to the variousphenotypes of DS. Finally, the development of an expressionatlas of all mouse orthologs of the Hsa21 geneshas provided another useful tool for prioritizing the candidategenes that may be involved in the various phenotypesof trisomy 21. These studies will serve as model forthe other partial or full aneuploidies. In this paper, webriefly discuss three different aspects of Hsa21/DS researchin our laboratory.CONSERVED NON-GENIC SEQUENCESThe completion of the sequencing of Hsa21 (Hattori etal. 2000) and the mouse genome (Mural et al. 2002; Waterstonet al. 2002) provided for the first time the opportunityto compare the two and to recognize functionallyconserved genomic elements. We compared the 33.5-Mbgenome of Hsa21q with the syntenic mouse genomic regionson Mmu16, Mmu17, and Mmu10; the initial goalwas to complete the genic annotation of Hsa21 by recognizingnovel genes (coding or noncoding RNAs), and/orto update and correct the description of known genes.This is of importance because the full gene catalog is necessaryfor the understanding of the molecular pathophysiologyof DS. We used the program PipMaker (Schwartzet al. 2000) and focused on sequences ≥100 nucleotides inlength and ≥70% identity without gaps. A total of 3491such sequences were identified, and only 1229 of thosecorresponded to exons of previously known genes. Themapping position of the remaining 2262 conserved se-Cold Spring Harbor Symposia on Quantitative Biology, Volume LXVIII. © 2003 Cold Spring Harbor Laboratory Press 0-87969-709-1/04. 425