Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/14023
El Genoma Humano. Un Sistema Altamente Complejo
Martínez-Frías, María Luisa ISCIII
Boletín del ECEMC: Rev Dismor Epidemiol 2007; V (nº 6): 82-91
Since the completion of the sequence of the human genome, knowledge of the structure and function of DNA is growing dramatically. However, at the same time, studies are showing an impressive complexity in the structural and functional aspects of DNA. One of the first findings was the identification of frequent DNA variants known as Single Nucleotide Polymorphisms (SNP). More recently, and particularly since 2004, a high degree of fine scale structural variations in the human genome are being identified, which at present are globally called Copy Number Variations/variants (CNVs). As these CNVs are quite frequent, they have been considered polymorphisms, and are responsible for a greater individual variability than SNPs, with a genetic variation estimated in 1/800 bp, while the SNPs vary in 1/1,200 bp. The CNVs are classified into those altering the number of DNA copies, such as insertions, deletions, and duplications, and those affecting its position (translocations) or its orientation (inversions). In addition, according to the number of repeat copies and, therefore, size, CNVs are classified as (Table 2): Large-scale Copy Variations (LCV), Intermediate-sized Structural Variants (ISV) and Low Copy Repeats (LCR). Although there are evidences that the CNVs, even including genes, do not necessarily have adverse effects on individuals who carry them, they may have adverse consequences even when they only include non-coding DNA (ncDNA). Some of them could alter meiotic chromosome pairing giving rise to gametes carrying unbalanced chromosome constitutions. In addition, there are several publications showing that some CNVs are related with malformations and syndromes (holoprosencephaly19, Peters anomaly24, Townes-Bröcks syndrome25, Cleidocranial dysplasia19, Campomelic dysplasia21-23, and other skeletal dysplasias26), that are due to position-effect and other types of effects such as alteration of gene dosage or the presence of unbalanced chromosomal alterations. In 2006, Redon et al.9, published a map with the global variation in copy numbers in each of the 46 chromosomes of the human genome. These results parallel the identification of new transcriptional processes, that have also increased since the recognition that the number of genes in the human genome is slightly more than 1/4 of previous estimates. Several studies have recently shown that nearly the whole human genome is transcribed, and that about 98% of the human genome that is transcribed represents non-coding RNA (ncRNA). This has led to many questions regarding their functional meaning, its relationship with RNA coding proteins, and its implications in the regulation and structural organization of the genome. But, at the same time, there has been an increasing knowledge on the function of different ncRNAs that shows an intricate pattern of interrelations and imbrications. Functionally, these ncRNAs are separated into two groups. One includes the housekeeping ncRNAs that is necessary for the normal function of the cells, such as RNA of transference, nuclear RNAs, ribosomal RNAs, etc. The other group includes the ncRNAs regulators that are expressed in embryonic development during cell differentiation, or as response to different stimuli, and can affect the expression of other genes. Among these are the riboswitches and others that participate in regulating gene expression and transcription and post-transcription processes such as microRNA (miRNA) and interference RNA (iRNA). Recent studies have observed that miRNA can use the interference pathway to activate genes, which is a surprising finding41-42. Structural and functional investigations on the different ncRNAs have shown that several of them are related with some human diseases and defects (Table 4). In addition, this year, studies on introns, which are a source of miRNA in different animals (D. melanogaster, C. elegans), have identified a different class of miRNA precursors, called "mirtrons" whose function is yet unknown. However, recent studies have suggested that they may function in the regulatory biological network, and that they may also exist in other species43-44. The recent publication of the results of the pilot study of the ENCODE Project (ENCcyclopedia Of DNA Elements)27-28, has offered a highly complex structural and functional view of the human genome and in the structure of RNAs36, as well as the implications in the alternative transcription (splicing). In relation with this last process, the current results on the function of the alternative proteins suggest that it may not be exactly as previously considered37. All these findings have led to the revision of previous concepts, starting by the "dogma" of the gene definition. The proposed definition, which represents a good example of the complexity of the human genome, is as follows: The gene is a union of genomic sequences encoding a coherent set of potentially overlapping functional products.30 This article presents a simplified general review of the most recent findings summarized above, reviewing: a) the structural variations of DNA and functional elements of the human genome, and b) the types and function of different RNAs. Finally, as a reflection, it is clear that the DNA code is much more than the lecture of the combination of the four bases (adenine, guanine, thymine, and cytosine), and although our knowledge of their structure and function it is still very small, its high level of complexity is becoming increasingly evident. New information shows multiple and complex frameworks of different functional networks, whose products are not the sum of their components, but "emergent behaviors" in relationship with the other parts of the whole system, although its laws are still unknown. All these aspects are concordant with the characteristics of the so called "complex systems or chaotic systems". These, as the chaos theory postulates, do not have absence of order or causality, but a particular interrelationship that gives rise to new levels that are subject to their own emergent rules. Thus, it is possible that the rules that command the human genome are not physically or mathematically different from those that conduct the "Complex systems" regulating nature.
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