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 localized on chromosome 21, such as gene annotation, prediction and structure, proteins, expression, regulation, variations and diseases association. In particular, this resource contains:

  • detailed gene description, including (for each splice variant) reference number, genomic coordinates, information about encoded protein and the involvement in human genetic diseases;
  • sequences of coding exons, introns, 5' and 3' UTRs and promoters, easily downloadable for each transcript, including novel splice isoforms, extended 5' and 3' UTRs for some HSA21 genes, identified in our RNA-Seq study and validated by RT-PCR;
  • systematic in silico characterization of transcription factors' binding sites in gene promoters, exonic and intronic regulatory elements of splicing and miRNAs' regulatory binding sites in 3' UTRs;
  • catalogue of single nucleotide polymorphisms.
  • Chromosome 21

    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 revealed the almost complete sequence of this chromosome, identifying 127 known genes, 98 predicted genes and 59 pseudogenes localized on it. This achievement was a turning point to understand the pathophysiological role of 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 to a more precise identification of its regulatory elements. However, the sequence of centromeric DNA and of the short arm is still unknown due to the presence of repetitive elements and eterochromatic 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 were 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 the tracks of novel transcripts during our project and submitted to the European Nucleotide Archive at EMBL (the number of different classes of transcripts collected in ALE-HSA21 is reported in the Table below). Besides the comprehensive annotation of all HSA-21transcripts, ALE-HSA21 collects a large amount of related information, as well as detailed computational predictions of regulatory elements 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 and crucial genes localize on it, emphasizing the relevance of biological characterization of this chromosome and the need of a correct revision of gene annotations for genetic studies. 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 implications. To date, different pathological human conditions 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, infections, hematologic malignancies and early-onset Alzheimer-like disease. To date, no specific therapeutic approach with proven effectiveness is available to overcome the defective features of DS patients. 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, even if the altered expression of some key genes is clearly related to typical pathological manifestations of DS, unknown effects - both direct and indirect - of the trisomy on global gene expression, suggest interactions among molecular-genetic factors, which need to be identified. Therefore, to date, a more accurate characterization of entire regions and genes of HSA21 - combined to the identification of crucial functional genomic elements involved in their regulation - are definitely needed to explore the molecular basis of Down syndrome. In addition, alterations of specific genes localized on HSA21 have been related to 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, a series of 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 occurring as typical symptoms of DS, such as 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 falling within HSA21 genes, is of crucial interest for medical-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 collects data from our pilot study aimed to create a comprehensive and helpful web resource for basic researchers and clinicians interested in Down syndrome as well as in other HSA21-related human diseases.

    Updated on June 12, 2013