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More 19 genes

Brazilian team participates in the discovery of new components of the chromosome responsible for Down syndrome

Understanding the genetic mechanisms involved in Down syndrome, as far as several kinds of cancer are concerned, involves the identification of the genes of the human chromosome 21 (HC21), the trisomy of which is responsible for the syndrome. A team from the Ludwig Institute for Cancer Research – together with researchers from four Swiss institutes – has just identified 19 new genes of the HC21. 127 genes had already been characterized, and the existence of another 98 was expected. Published in the Genomics magazine in June, the work by the team resulted in a 9.5% increase in the count of HC21 genes.

None of the 19 new genes identified had been foreseen by the Consortium for Mapping and Sequencing the Chromosome 21, nor by the Ensembl consortium, which were at the forefront of this work. But while the group was preparing the article, Celera Genomics, from the United States, reported having identified three of the same 19 genes, boosting the trustworthiness of the study, which includes a descriptive table of the new genes and of the proteins of their RNA (ribonucleic acid). It was noted that the majority of the substances of the new genes show no significant similarity with any protein so far characterized.

The group’s objective was to perfect the genetic annotation of the HC21, assessing the degree of precision of the current methods for gene identification by computer analysis. To do so, a database was set up with all the available mapping of the chromosome, including the forecasts, and instruments were incorporated to facilitate the discovery of genes. The analysis of this material, supported by ample documentation on experiments, made it possible to identify the 19 genes and another four transcription units of the HC21.

Convinced that computer analysis is not sufficiently sensitive and needs to be coupled with experimental data, the researchers believe that, from now on, genetic identification will depend on lining up the finalized genomes with sequences obtained by means of RNAs validated in experiments. The data obtained by the Brazilians suggests, for example, that the current identification techniques contain countless false data, arising from unidirectional errors – false positive data and false negatives.

All the 19 genes identified codify foreseen proteins, with an average size of 121 residues – extremely lower than the 575 or 469 previously foreseen. The problem is, the group believes, that the most usual forecasts contain an excessive number of pseudogenes, as was corroborated in the case of the human genome: originally estimated at between 45,000 and 140,000 genes, in the recently concluded sequencing, the forecast dropped to 35,000. Extrapolating the data from their work, the researchers go further: “If the number of HC21 genes comes to between 218 and 250, we can foresee that the total number of human genes lies between 21,500 and 24,500”, the article, signed by 16 researchers, reports – those taking part from the Ludwig Institute were Anamaria Camargo, Fabiana Bettoni, Rapahel Parmigiani, Sandro de Souza and Andrew Simpson.

The discovery of 19 genes of one chromosome already well studied – the first to be mapped, in 2000 – shows that the identification of the complete human transcriptome (the set of proteins) may not be based on the genetic forecast alone. The article warns: “The definitive gene annotation of the human genome is going to call for a gene by gene approach, coupled with corroboration in experiments”.

With the advances in the mapping of the HC21, the expectation is to detect the contribution of each gene in the various manifestations of Down’s syndrome. New studies should also contribute towards clarifying the suspicion – suggested by epidemiological studies – that the bearers of the syndrome may be protected against certain kinds of cancer, which have a much larger incidence in the population at large.