Resumen de La epigenética y los estudios en gemelos en el campo de la psiquiatría
Adriana Estrella González Ramírez, Alejandro Díaz Martínez, Adriana Díaz Anzaldúa
- español
La secuencia de ADN genómico que caracteriza a nuestra especie constituye la piedra fundamental de la vida humana; parte de ella se refleja en la secuencia del ARN y a través de éste se dicta la información necesaria para que nuestras células produzcan proteínas.
La genética contribuye de manera importante a los avances en el campo médico. Los descubrimientos genéticos han permitido desarrollar estrategias para modificar, prevenir y proponer nuevas terapias para diversas enfermedades.
En el siglo XIX, Gregor Johann Mendel desarrolló un modelo teórico capaz de predecir la naturaleza y propiedades de los mecanismos de la herencia, que sigue siendo indispensable para explicar la base de la herencia humana. Otro suceso determinante en la historia de la Medicina se dio a conocer casi nueve décadas después cuando James Watson y Francis Crick describieron su modelo estructural para el ADN. Posteriormente se introdujeron la clonación posicional y la reacción en cadena de la polimerasa; más recientemente se publicó cerca del 99% de la secuencia del genoma humano. El período actual se conoce como la era post–genómica, ya que además de descifrar genomas completos, los investigadores pretenden, entre otras cosas, esclarecer los mecanismos que influyen en la activación e inactivación de los genes, lo cual en parte involucra un nivel epigenético.
En las ciencias médicas los gemelos constituyen un grupo idóneo para abordar el estudio de las enfermedades hereditarias. En este tipo de padecimientos suelen observarse similitudes entre parientes, en especial si se trata de gemelos monocigóticos. Sin embargo, aun en este tipo de hermanos se detectan diferencias importantes. Parámetros como los grados de concordancia y porcentajes de heredabilidad han puesto de manifiesto que un gemelo monocigótico puede presentar trastornos hereditarios que su co–gemelo nunca tendrá.
La epigenética es el estudio de los cambios en la función de los genes que no afectan la secuencia del ADN, por modificaciones que tienen lugar principalmente en las citosinas de éste y en las histonas de la cromatina. Se ha determinado que las modificaciones epigenéticas son mucho más frecuentes que aquellas que modifican la secuencia del ADN, por lo que constituyen uno de los fundamentos de la diversidad biológica, muestran la manera en que el ambiente puede modular la expresión genética y contribuyen así a nuestro fenotipo. Esta revisión reúne datos sobre la posible relevancia de la epigenética en el estudio de los trastornos mentales y como posible explicación parcial de las diferencias observadas entre gemelos "idénticos". Un conocimiento más profundo de los patrones epigenéticos podría contribuir a identificar factores de riesgo para estos trastornos.
- English
The sequence of the human genome integrates the keystone of our life. Part of it is transcribed to RNA, which in turn provides the information required by our cells to produce proteins. Discoveries in the genetics field have been essential to medicine and have been used to develop strategies to modify, prevent and propose new therapeutic approaches for human diseases.
In the 19th Century, Gregor Johann Mendel developed a theoretical model which was able to predict in an accurate way hereditary mechanisms; indeed, his laws still explain the basis of human inheritance. Almost ninety years later, James Watson and Francis Crick announced their double–helix model of the DNA molecule. Then, positional cloning and the polymerase chain reaction (PCR) were introduced; more recently, almost 99% of the sequence of our genome was made public.
The current period of time is known as the post–genomic era, due to the fact that researchers are not only obtaining the complete sequences of thousands of genomes, but are also searching for clues that may help understand the mechanisms that affect gene activation and deactivation, in which epigenetic factors are also involved.
In medical domains, twins constitute a suitable group to study inherited disorders. Dizygotic or fraternal twins are produced by different egg and sperm cells, and even when these two fertilization events occur simultaneously, dizygotic twins share approximately the same percentage of genetic material than any pair of siblings, that is, around 50%. Some authors have suggested that the tendency for spontaneous dizygotic twinning could be attributed to a double ovulation which is genetically determined in an autosomal dominant manner.
Monozygotic, as opposed to dizygotic twins, are produced by a single zygote whose cells are dissociated and originate two independent organisms; approximately a third of monozygotic twins are separated before the 5th day after fertilization, and the rest between the 5th and the 15th day. Most monozygotic twins are very similar; nevertheless, some few exceptions prove that in fact they actually do not have to be identical.
Relatives of a person with a mental disorder tend to share traits associated with this disease, especially if the patient and the relative are monozygotic twins. However, important differences may be detected even between each pair of identical twins.
Parameters such as concordance and heritability have shown that a monozygotic twin can develop an inherited disorder while his or her co–twin will always be disease–free. In addition to differences in susceptibility to inherited diseases, this kind of twins can display dissimilarities in somatic cell mutations (more overtly noticeable when ageing), their set of antibodies and T cell receptors, their number of mitochondrial DNA molecules, and chromosome X inactivation patterns in women, all of which are the main subject of many ongoing studies. A recent report shows that from 160 monozygotic twin pairs who were 3 to 74 years old, epigenetic patterns were identical early in life, but differences were more obvious at older ages, especially if twins were raised apart or if they had different medical history. Medical conditions, but also environmental factors such as pregnancy tobacco exposure, physical activity, and diet could contribute to differences in epigenetic patterns. It has been shown that epigenetic modifications (or epi–mutations) are more frequent than the ones that modify DNA sequence, so they are part of the fundamental causes of biological diversity, and they show how environment can modulate gene expression and contribute to our phenotype.
Even when twin studies are sometimes considered purely genetic, they also give information about the influence of environmental factors. However, it is important to consider with caution the results from this type of studies. Heritability estimates are not unchangeable facts. They depend on the sample being analyzed, the genes involved in the specific sample, the characteristics of the environmental factors which members of this group were exposed to, and the precise moment the study was done.
Epigenetics refers to changes that do not alter the DNA sequence but affect gene function due to chemical modifications which mainly occur in DNA cytosines and in chromatin–related histones. Epigenetic processes are covalent modifications which include the addition of functional groups (methyl, acetyl, phosphate, etc.) or proteins (ubiquitin, SUMO, etc.) to the DNA molecule or to associated proteins. These modifications contribute to the activation or inhibition of transcription, which leads to changes in messenger ARN expression that can ultimately influence the onset of disease.
Pseudogenes are still being excluded while new genes are being confirmed in our genome sequence, but the current estimates indicate that each one of our nucleated cells contains almost 22000 genes (excluding mitochondrial DNA) which encode for polypeptides and more than 4,000 whose final product is RNA.
Gene expression is partially controlled by DNA coiling around globular proteins called histones, which constitute a structure known as chromatin, a DNA–protein complex that represents the packaging of 3.25 billion base pairs of our genetic information. Physical and chemical chromatin modifications can also affect gene expression by changing DNA–protein interactions; in general terms, genes are inhibited when chromatin is packed and they are active when it is free. These dynamic states are controlled by epigenetic reversible modifications on DNA methylation or by changes in histones. It has been shown that subtle epigenetic differences between any two human beings are associated with dissimilar final chromatin remodeling, as well as expression/repression of genes.
In order to explain how DNA methylation controls transcription, two mechanisms have been proposed. First, the presence of a methyl group on specific sites could simply prevent transcription factors from binding the DNA. Second, some proteins contain a specific domain that recognizes and binds methylated DNA, and works as a transcription repressor.
Regarding histone modifications, acetyl group addition occurs on the amino acid lysine; there are reports that indicate that almost 14% of lysines are susceptible to acetylation. On the other hand, methyl groups bind arginines and lysines. Different combinations of covalent modifications lead to what is known as the histone code. This review gathers information about the possible involvement of epigenetics in some mental disorders and attempts to explain how it can account for differences observed between "identical" twins. Some examples of a plausible link between epigenetic modifications and mental disorders are discussed.
Regarding bipolar disorder, valproate efficacy has been linked to its inhibitory activity, suggesting that an epigenetic modification (that represses transcription of a gene) may play a role in the onset of some of the symptoms of the disease. Perhaps one of the most studied aspects regarding schizophrenia is the hypermethylation of Reelin (RELN) and GAD67 genes in the prefrontal cortex, due to the over–expression of DNMT1 (DNA methyl–trasferase 1) in GABAergic cortical interneurons. Reelin is an important protein during prenatal development of the Central Nervous System and it is relevant for the expression of cortical pyramidal neurons in the adult brain; it regulates the migration of neurons during brain development and it is essential for the correct organization and plasticity of the cerebral cortex. GAD67 is one of two molecular forms of GABA synthetizing enzymes, being GABA the main inhibitory neurotransmitter in humans.
Hypermethylation of these genes leads to transcription repression either by interference of transcription promoters by methyl groups or by MBD protein binding. The final outcome is a low production of Reelin and GAD67, a typical feature found in brains of shchizophrenic patients.
Epigenetic analyses of autism are sometimes with Rett and Angelman's syndromes. The latter are pathological conditions that share clinical features with autism, such as development retardation, language impairments and stereotypic behaviors. Rett syndrome is caused by mutations at the MECP2 gene, and Angelman's syndrome by a maternal deficiency on chromosome 15 q11–q13 region, impaired methylation of DNA or maternal mutation of the ubiquitin–protein ligase E3A (UBE3A). However, there have also been reports of patients with Angelman's syndrome or autism who have mutations at MECP2.
In conclusion, the onset of mental disorders is influenced both by environmental and genetic factors. Concordance and heritability estimates are just two of the many ways of analyzing differences between monozygotic twins. Part of the reported disparity between monozygotic twins could be caused by epigenetic factors. Epigenetic modifications could partially explain the etiology of mental disorders.
