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Slide 1: BREVIA GENÓMICA PARA PSIQUIATRAS Carlos Y Valenzuela
Slide 2: Gregorio Mendel, fundador de la genética.
Slide 3: + ALLÁ ESPIRITUALISMO GENOMA AMBIENTE CIRCUNSTANCIAS HISTORIA SOLO + ACÁ MATERIALISMO
Slide 4: Niveles de organización de los seres humanos El cuerpo humano tiene 100 trillones de células Cada célula presenta un núcleo Cada núcleo contiene 23 pares de cromosomas Cada par cromosómico se origina de uno de la madre y uno del padre. Los cromosomas contienen ADN altamente condensado. Los genes son segmentos de ADN que contienen la información para las características biológicas de los seres humanos
Slide 5: Estructura molecular de ADN.
Slide 6: Mapa parcial de genes humanos.
Slide 7: Hebra no transcrita 5’ 3’ Hebra transcrita Exón: 5’ 1 2 3’ ARN Transcripción 5’ CAP 3’ Adición Poli (A) Procesamiento del ARN 5’ y splicing núcleo Transporte citoplasma Traducción 5’ 5’ AAAA 3’ 3 3’ 5’ AAAA 3’ Crecimiento de la cadena polipeptídica AAAA 3’ Ribosoma Ensamblaje de la proteína Polipéptido completo Traspaso de la información hereditaria desde el ADN hasta una proteína
Slide 8: Portada del Time que muestra a los dos científicos líderes en la secuenciación del genoma humano.
Slide 9: ¿SON LAS ENFERMEDADES (CONDUCTAS, ACTITUDES, EMOCIONES, AFECTOS, VALORACIONES) UN FENOTIPO? Un fenotipo es un carácter o rasgo con alguna determinación genética. Debe poderse pesquisar sin ambigüedad. No toda enfermedad lo es. Pensemos en la evolución de la Diabetes, desde fluir mucho (poliuria) después dulce o insípida al gusto, hiperglicemia, curva de tolerancia a la glucosa, insulino-dependiente. Los fenotipos se han ido precisando (disección fenotípica) Aun sin la precisión definitiva se ha aplicado el método genético a las enfermedades y se las puede clasificar en diferentes tipos.
Slide 10: For most of the DSM-III disorders the etiology is unknown. The approach taken in DSM-III is atheoretical with regard to etiology or pathophysiological process except for those disorders for which this is well established and therefore included in the definition of disorder. The major justification for the generally atheoretical approach taken in DSM-III with regard to etiology is that the inclusion of etiological theories would be an obstacle to use of the manual by clinicians of varying theoretical orientations, since it would not be possible to present all reasonable etiological theoriesof eachdisorder….BecauseDSM-III is generally atheoretical with regard to etiology, it attempts to describe comprehensively what the manifestations of the mentaldisordersare,andonlyrarelyattempts toaccount for how the disturbances come about…This approach can be said to be ‘‘descriptive’’ in that the definitions of the disorders generally consist of descriptions of the clinical features of the disorders. (American Psychiatric Association, 1980, pp. 6–7) Zucker KJ. Arch Sex Behav (2010) 39:217–220
Slide 11: A psychiatric nosology that was, by and large, agnostic with regard tounderlying causal mechanisms was deemed preferable to a theoretical model that was no longer satisfying to many researchers and practitioners. Advances in biological psychiatry, the emergence of competing psychologic models of development and disorder, and the increasing availability of alternative approaches to therapeutics all contributed to a paradigm crisis in the discipline’s nosological manual.
Slide 12: Since 1980, one overarching vision was that the manual, if organized around descriptively neutral diagnostic criteria, could be utilized by a diverse array of clinicians and researchers from many disciplines. Acommon and transparent language, so it has been held, should facilitate communication in a rapidly developing field (see Spitzer & Klein, 1978).
Slide 13: The DSM-V Task Force has, as its mission, a number of major tasks. These include, but are not limited to, the following: (1) literature reviews of current diagnostic entities; (2) literature reviews of proposed new diagnostic categories; (3) incorporation of feedback from advisors and the scientific community at large, as well as other interested stakeholders; (4) examination of relevant secondary data sets; (5) proposals for field trials to test revised diagnostic criteria; and (6) revision to the text that accompanies each diagnosis.
Slide 14: Table 6 Proposed revision to the DSM-IV diagnostic criteria for Gender Identity Disorder in Children A. A strong discomfort with one’s gender identity (in relation to the assigned sex at birth), of at least 6 months duration, as manifested by at least six of the following indicators (including A1) (1) a frequently stated desire to be the other sex or a frequently stated insistence that he or she is the other sex (2) in boys, a strong preference for cross-dressing or simulating female attire; in girls, a strong preference for wearing only stereotypical masculine clothing and a strong rejection in the wearing of culturally normative feminine clothing (3) a strong preference for cross-sex roles in make-believe or fantasy play (4) a strong preference for the stereotypical toys, games, or activities of the other sex (5) a strong preference for playmates of the other sex
Slide 15:    TIPOS DE ENFERMEDADES GENETICAS Anomalías cromosómicas: ej: Sind. De Down Enfermedades monogénicas: ej: hipercolesterolemia familiar, fenilquetonuria, albinismo. Enfermedades multifactoriales: ej: malformaciones congénitas, hipertensión arterial, diabetes mellitus.  Enfermedades mitocondriales: ej: neuropatía óptica de Leber, epilepsia mioclónica.   Susceptibilidad genética para otras patologías
Slide 16: METODOLOGÍA DEL ESTUDIO GENETICO DE LAS ENFERMEDADES (CARACTERES) Análisis de contingencia familiar Disección fenotípica (física y molecular) Estudio de genealogías Método de mellizos Análisis segregacional Análisis de asociación con marcadores (desequilibrio de ligamiento y asociación uncional) Mapeo de genes con marcadores Análisis de productos moleculares y funciones bioquímicas. Técnicas citológicas y citogenéticas Análisis de secuencias aminoacídicas y de bases con bancos de datos La extraordinaria ayuda de los SNP (single nucleotide polymorphism)
Slide 21: Genotypic interaction between DRD4 and DAT1 loci is a high risk factor for attentiondeficit/hyperactivity disorder in Chilean families. Carrasco X, Rothhammer P, Moraga M, Henriquez H, Chakraborty R, Aboitiz R, Rothhammer F. Am J Med Genet B Neuropsychiatr Genet. 2006 Jan 5;141(1):51-4. Attention-deficit/hyperactivity disorder, ADHD [MIM 126452], is a common, highly heritable neurobiological disorder of childhood onset, characterized by hyperactivity, impulsiveness, and/or inattentiveness. As part of an ongoing study of ADHD, we carried out a family-based discordant sib-pair analysis to detect possible associations between dopamine receptor D4 (DRD4) and dopamine transporter 1 (DAT1) polymorphisms and ADHD in Chilean families. Both loci individually classified as homozygotes or heterozygotes for the DRD4 7-repeat and DAT1 10-repeat alleles, did not exhibit genotype frequency differences between affected children and their healthy siblings (Fisher's exact test P > 0.25 in both cases). However, the simultaneous presence of both DRD4 7-repeat heterozygosity and DAT1 10 allele homozygosity were significantly higher (34.6%) in cases (26), compared with their unaffected siblings (25) (4%; Fisher's exact test P = 0.0096; odds-ratio, OR = 12.71). Increased density of dopamine transporter in ADHD brains, along with abundance of 7-repeat D4 receptors in prefrontal cortex, which is impaired in ADHD patients, make the observed gene-gene interaction worthy of further incisive studies.
Slide 22: Fig. 3. Influence of genetic polymorphisms on gene expression levels, brain activation, and social behavior. (A) Within prairie voles, subtle microsatellite length variation upstream of the avpr1a transcription start site is associated with differences in V1a receptor expression patterns and behavior. (B) Allele length in an analogous microsatellite polymorphism upstream the human AVPR1A locus predicts V1a mRNA expression levels in the hippocampus (27), and longer alleles are also correlated with higher levels of amygdala activation during a face-viewing task (31). Error bars indicate SE. Donaldson ZR, Young LJ Science 13/3/2009