Welcome to ALE-HSA21
ALE-HSA21, AnaLysis of Expression of HSA21, is an integrated and a user-friendly relational database, which provides detailed information about various aspects of genes mapping on chromosome 21, such as gene structure, expression, nucleotide variations and association to diseases. In particular, the resource contains:
Human chromosome 21 (HSA21) is the smallest acrocentric chromosome and represents 1.5% of the entire human genome, spanning about 50 million base pairs. It has been the second human chromosome sequenced. Precisely, in 2000 the Human Genome Project has revealed the almost complete sequence of this chromosome, allowing to identify 127 genes and 59 pseudogenes, and to predict the presence of 98 putative genes localized on it. This achievement was a turning point to understand the pathologic and physiologic role of the genes mapping on this chromosome, providing unprecedented opportunities to elucidate the molecular mechanisms of monogenic disorders and genetic conditions related to single HSA21 genes or the entire chromosome. In the last decade, genetic research moved crucial steps toward the functional characterization of the coding sequence of this chromosome, in combination with a more precise identification of the regulatory elements. However, the nucleotide sequences of the centromeric DNA and of the short arm are still unknown due to the presence of repetitive elements and of heterochromatic DNA. To date, the most comprehensive genome annotation publicly available has been provided by GENCODE. The GENCODE release used in this project is the version 12, whose tracks have been downloaded from UCSC Genome Browser (http://genome.ucsc.edu/) database. Gene annotation has been integrated with RefSeq genes as well as with miRBase and Ensembl entries for microRNAs. Therefore, the final annotation reported in ALE-HSA21 includes all protein-coding and non-coding transcripts annotated on HSA21, further containing a Section containing tracks of novel transcripts identified during our project and submitted to the European Nucleotide Archive at EMBL. Other than hosting a comprehensive annotation of all HSA21 transcripts, ALE-HSA21 integrates a large amount of useful information regarding HSA21 genes, as well as detailed computational predictions of regulatory sequences and proteins binding to these within gene promoters, exons, introns, and 3’UTRs, of both annotated and newly identified HSA21 transcripts.
Chromosome 21 and Human Genetic Diseases
Several human diseases have been associated to structural and functional changes of HSA21 genes. It emphasizes the relevance of a deep characterization of this chromosome, indicating the need of a systematic revision of gene annotations. In particular, high-resolution structural analyses have led to the identification of key HSA21 genes, as well as of aberrations and sequence variations implicated in common human disorders. In addition, the employment of animal models and genome-wide expression studies revealed that altered expression of genetic elements mapping on this chromosome are associated to pathological conditions. To date, many diseases have been related - directly or indirectly - to structural and functional alterations of HSA21. Primarily, three copies of HSA21 determine a severe genetic condition, known as trisomy 21 or Down syndrome (DS). Down syndrome (OMIM 190685) is a complex human genetic condition caused by the trisomy of the entire chromosome 21, or a critical portion of it (“Down syndrome critical region”, DSCR, 21q22.3). In 1866, John Langdon Down first described this pathological condition and some distinctive phenotypic features of affected people. The cause of DS remained unknown until 1959, when Dr. Jerome Lejeune identified the presence of 47 chromosomes in the cells of an affected individual. The presence of three copies of HSA21 determines complex and variable phenotypes, with typical alterations affecting mainly the nervous, immune and hematopoietic systems. Frequent clinical manifestations are psychomotor retardation, dysmorphic facial features, congenital heart defects, and an increased incidence of hearing loss, hematologic malignancies, early-onset Alzheimer-like disease and severe abnormalities of the immune system. To date, no specific therapeutic approach with proven effectiveness is available to overcome the clinical deficit. The primary cause of the syndrome is assumed to be the dosage imbalance of HSA21 genes, although intricate interactions of multiple genes, epigenetic and environmental factors are involved in DS pathogenesis. Indeed, altered gene expression has been related to pathological manifestations of DS. Nonetheless, unknown effects - both direct and indirect - of the trisomy on global gene expression, suggest the presence of interactions with other factors, which need to be identified. Therefore, to date, a more accurate characterization of HSA21 genes - combined to the identification of functional elements involved in their regulation - are definitely needed to explore the molecular basis of the DS pathology. However, alteration of many genes mapping to HSA21 have been related to distinct monogenic disorders, such as: progressive myoclonus epilepsy (OMIM 254800) , autoimmune polyendocrine syndrome, type I (OMIM 240300) amytrophic lateral sclerosis, (OMIM 105400, 147450) holocarboxylase synthetase deficiency (OMIM 253270; 609018) microcephalic osteodysplastic primordial dwarfism, type II (OMIM 210720) long QT syndrome 5 (OMIM 613695) Jervell and Lange-Nielsen syndrome 2 (OMIM 612347) homocystinuria, (OMIM 236200; 613381) leukocyte adhesion deficiency, type I (OMIM 116920) Knobloch syndrome (OMIM 267750) and nonsyndromic deafness (OMIM 605511; 601072; 614035; 614861). Moreover, it has been documented the association between nucleotide variations in some HSA21 genes and complex disorders, including Alzheimer's disease, bipolar disease, familial combined hyperlipidemia. In addition, chromosomal rearrangements involving HSA21 have been associated with other syndromes, such as Erondu-Cymet syndrome, several types of cancer - above all acute lymphoblastic and myeloid leukemia - and different pathological states (psychomotor retardation, delayed development and altered facial features). Therefore, a detailed knowledge of all HSA21 transcribed regions, and of regulatory sequences located upstream, downstream and/or within the coding regions of HSA21 genes, is of crucial interest for clinical practice, as well as basic research. Accurate and validated gene annotations are fundamental to reconsider the functional impact of nucleotide variations falling in genomic regions previously marked as “non-genic”. Moreover, correctly annotating UTRs, crucial for genetic and epigenetic regulation, as well as identifying novel tissue or cell-specific coding and non-coding transcripts would have a significant impact on genetics research. This HSA21 "transcript-centric” database aims to be a comprehensive and helpful web resource for basic researchers and clinicians interested in Down syndrome as well as in other HSA21-related human diseases.