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Iniciadores utilizados en la identificación de virus de papiloma humano por PCR: una revisi&oacut= e;n

 

Primers used in the identification of Human Papillomavirus by PCR: a review=

3D"Interfaz
 


1

Felix Falconi Ontaneda

 

https://orcid.org/= 0000-0003-3825-5271

 

Carrera de Laboratorio Clínico, Facultad de Ciencias de la Salud, Universidad Nacional de Chimborazo, Chimborazo, Ecuador

ffalconi@unach.edu.ec<= /span> =

2

José Zaporta Ramos=

 

http= s://orcid.org/0000-0002-5509-1160

 

Carrera de Laboratorio Clínico, Facultad de Ciencias de la Salud, Universidad Nacional de Chimborazo, Chimborazo, Ecuador

andres.zaporta@espoch.edu.ec =

3

Yisela= Carolina Ramos Campi

 

http= s://orcid.org/0000-0002-2403-4139

 

Carrera de Laboratorio Clínico, Facultad de Ciencias de la Salud, Universidad Nacional de Chimborazo, Chimborazo, Ecuador

yramos@unach.edu.ec

4

Gisnella María Cedeño Cajas

 

http= s://orcid.org/0000-0001-7452-8762

 

Carrera de Laboratorio Clínico, Facultad de Ciencias de la Salud, Universidad Nacional de Chimborazo, Chimborazo, Ecuador

gcedeño@unach.edu.ec<= /span> =

 

 

 

Art&ia= cute;culo de Investigación Científica y Tecnológica=

Enviado: 27/10/2023

Revisado: 23/11/2023

Aceptado: 15/12/2023

Publicado:28/12/2023   

DOI: https://doi= .org/10.33262/anatomiadigital.v6i4.3.2830 <= /o:p>

 

 

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C&iacu= te;tese:

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Falconi Ontaneda, F., Zapor= ta Ramos, J., Ramos Campi, Y. C., & Cede&nti= lde;o Cajas, G. M. (2023). Iniciadores utilizados en la identificación de virus de papiloma humano por PCR: una revisión. Anatomía Digital, 6(4.3), 707-726. https://doi= .org/10.33262/anatomiadigital.v6i4.3.2830

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3D"Texto,3Deditorial=

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ANATOMÍA DIGITAL, es una Revista Electrónica, Trimestral,= que se publicará en soporte electrónico tiene como misió= n contribuir a la   formación de profesionales competentes con visión humanística y crítica que sean capaces de exponer sus resultados investigativos y científicos en la misma medida que se promueva mediante su intervención cambios positivos en la sociedad. https://anatomia= digital.org  

La revista es editada por la Editorial Ciencia Digital (Editorial de prestigio registrada en la Cámara Ecuatoriana de Libro con No de Afiliación 663) www.celibro.org.ec

 

 

3D"Interfaz<= /o:p>

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Esta revista está protegida bajo una licencia Creative Commons Atribución-NoCo= mercial-CompartirIgual 4.0 International. Copia de la licen= cia: https://creative= commons.org/licenses/by-nc-sa/4.0/deed.es

 

Palabras claves:

VPH, PCR, iniciadores, diseño de iniciadores, bioinformática

 

Resumen

Introducción La infección por el virus del papiloma humano (VPH) sigue siendo una de las más comunes en la población humana. Este virus cuenta con aproximadamente 200 genotipos diferentes, que se clasifi= can en términos de su capacidad oncogénica en alto y bajo riesg= o. La identificación de estos genotipos se ha realizado mediante la técnica de la reacción en cadena de la polimerasa (PCR), la cual requiere el uso de iniciadores específicos para garantizar resultados precisos. Objetivo. Recopilar secuencias de iniciadores publicados, analizarlos y organizar esta información para proveer = una lista compilada que facilite la decisión de optar por la utilización de un par de iniciadores requeridos para la detección y diagnóstico del HPV. Metodología. Se aplicó un enfoque cualitativo, de alcance descriptivo y con un diseño transversal teórico-documental, puesto que se analizó y sintetizó la literatura actualizada extraí= da de artículos científicos, relacionados con el tema de investigación, los cuales permitieron profundizar la investigación y cumplir con los objetivos planteados. Se revisaron varios artículos de publicaci&o= acute;n reciente que refieren los iniciadores utilizados. Resultados. Se muestran 17 iniciadores útiles para las variantes de alto riesgo 1= 7 y 15 para las variantes 18, así como para otras variantes. Se expone= de manera organizada diferentes aspectos a destacar en su análisis, así como características a tomar en cuenta para su diseño. Además, se mencionan las herramientas de análisis de secuencias las directrices y parámetros requeri= dos a considerar para asegurar una buena reacción de PCR. Es muy conveniente tomar en cuenta la clasificación taxonómica y estructura del VPH que permite comprender la utilización de un iniciador para un determinado gen del virus. Al momento de necesitar util= izar un determinado iniciador se sugiere tomar en cuenta los más convenientes según los valores obtenidos por las herramientas bioinformáticas y a los autores quienes probaron y publicaron secuencias de detección por PCR. Conclusión. Se mues= tran 17 iniciadores útiles para las variantes de alto riesgo 16 y 15 pa= ra las variantes 18, además de 8 para otros tipos. Además, se muestran parámetros de cada uno que permite tener criterios para decidir su selección. Área de estudio general: Salud= . Área de estudio específica: Biología molecular. Tipo de estudio: Artículo de revisi&oacu= te;n.

 

 

Keywords:

HPV, P= CR, primers, primer design, bioinformatics

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Abstract

Introduction.

Human papillomavirus (HPV) infection rem= ains one of the most common infections in the human population. This virus has approximately 200 different genotypes, which are classified in terms of t= heir oncogenic capacity into high and low risk. The identification of these genotypes has been carried out using the polymerase chain reaction (PCR) technique, which requires the use of specific primers to guarantee accura= te results. Methodology. A qualitative approach was applied, with a descriptive scope and a transversal theoretical-documentary design, since the updated literature extracted from scientific articles related to the research top= ic was analyzed and synthesized, which allowed the research to be deepened a= nd the objectives met. raised. Several recently published articles that refe= r to the initiators used were reviewed. Results. Shown are 17 useful primers for high-risk variants 17 and 15 for variants 18, as well as other variants. Different aspects to highlight in its analysis are presented in= an organized manner, as well as characteristics to take = into account for its design. In addition, sequence analysis tools, guidelines and required parameters to consider to ens= ure a good PCR reaction are mentioned. It is very convenient to take into account the taxonomic classification and structure of HPV that allows us to understand the use of a primer for a certain gene of the virus. When needing to use a certain primer, it is suggested to take into account the most conven= ient ones according to the values obtained by the bioinformatics tools and the authors who tested and published PCR detection sequences. Conclusion Shown are 17 useful primers for high-risk variants 16 and 15 for variants 18, plus 8 for other types. In addition, parameters for each one are shown that allow you to have criteria to decide your selection. General Study Area: Health. Specific area of study: Molecular biology.= Study type: Review article.

 

 

 

Introducción

= La infección por virus papiloma humano (VPH) continúa siendo de = las infecciones de transmisión sexual (ITS) más comunes en la población humana. Se han identificado aproximadamente 200 genotipos diferentes de VPH, y se los clasifica en dos categorías: VPH de alto riesgo (VPH-AR) y VPH de bajo riesgo (VPH-BR), en función de su capacidad oncogénica (1, 2).

= Los genotipos de alto riesgo corresponden a VPH 16,18, 31, 33, 35, 39, 45, 51, = 52, 56, 58, 59, 66, 68, 73 y 82 (2, 3) y los de bajo riesgo incluyen a los genotipos VPH 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81 y CP6108 <= /span> ADDIN EN.CITE  ADDIN EN.CITE.DATA 3C456E644E6F74653E3C436974653E3C417574686F723E48657373656C62657267= 20412E2053746F736963204D2E204D617263204A2E204B7261757320492E2056616E6773746= 5696E20482E204865726D616E204F2E20526F756E676520542E3C2F417574686F723E3C5965= 61723E323032333C2F596561723E3C5265634E756D3E33363C2F5265634E756D3E3C4469737= 06C6179546578743E28332C2034293C2F446973706C6179546578743E3C7265636F72643E3C= 7265632D6E756D6265723E33363C2F7265632D6E756D6265723E3C666F726569676E2D6B657= 9733E3C6B6579206170703D22454E222064622D69643D22747732307A7730746D667A747477= 65776570797639667A7A70616566657A30727839787A222074696D657374616D703D2231363= 934383034303135223E33363C2F6B65793E3C2F666F726569676E2D6B6579733E3C7265662D= 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No obstante, acorde a diferentes estudi= os, las variantes VPH 16 y VPH 18 son los genotipos más prevalentes, con altos porcentajes en las lesiones precancerosas y cáncer de cuello uterino (CCU) considerado como el tercer motivo de cáncer más frecuente en mujeres en todo el mundo, sobre todo en los países en vías de desarrollo (5, 6), por esta razón es el principal motivo de investigación epidemiológica y del desarrollo de vacunas.

= Estructuralmente el HPV tiene genoma de ADN (ácido desoxirribonucleico) circular de d= oble cadena con un tamaño de 8 kb, dividiéndose funcionalmente en = tres regiones diferentes: la región temprana (E =3D = early), la región tardía (L=3D late), y la región larga de con= trol LCR (Long Control Region). La región E está conformada por los genes E1 y E2 que regulan la replicaci&oacut= e;n y la transcripción viral, constituida por los genes E5, E6 y E7 codifican proteínas con alto poder oncogénico (7), en la región larga de control LC= R se localizan las secuencias de ADN que contienen los promotores y sitios de iniciación de replicación del genoma viral y la región= L conformada por los genes estructurales L1 y L2 codificantes de proteí= ;nas de la cápside (8-11).

= La clasificación de los virus del papiloma humano (HPV) se basa en el análisis de la secuencia de nucleótidos del gen viral L1 debi= do a su alta conservación. De esta manera, se identifica un nuevo tipo vi= ral cuando su secuencia difiere en más de un 10% de los tipos ya conocid= os, se clasifica como subtipo si la diferencia se sitúa entre el 2% y el 10%, y se considera una variante intratípica si la divergencia es inferior al 2%. Los primeros estudios de variabilidad genética se llevaron a cabo con el HPV 16, ya que es el tipo de viru= s de alto riesgo más prevalente en el cáncer de cuello uterino a n= ivel mundial, y esta investigación continúa avanzando en la actual= idad (12).Por comparación de secuencias en = la región LCR de distintos aislados virales se creó el primer árbol filogenético para los diferentes continentes, resultand= o en varias subclasificaciones: A, B, C y D para HPV 16 dentro de las variantes = se tiene las africanas (Af-1 y Af-2), asiática-americana (AA), europea = (E), asiática (As) y norteamericanas (NA), quedando el clon referencial dentro de la rama E. Del mismo modo se ha aplicado para las variantes de HP= V 18 teniendo A, B y C como linajes, mostrado en tres ramas: europea (E), africa= na (Af) y asiático-amerindia (AAI) (13-15).

= Posteriormente también se analizaron los genes virales L1 y L2 y los oncogenes vira= les E6 y E7 con lo que ha encontrado que las diferencias de la secuencia nucleotídica en estos genes podrían vincularse con cambios en= la respuesta inmune del hospedador y en el potencial oncogénico, respectivamente y se ha observado una fuerte covariación intergenética, sugiriendo que las diferencias nucleotídicas halladas en la región genómica pueden us= arse para distinguir los distintos linajes de HPV (16, 17). Concretamente de los 16 géneros = de la familia Papillomavirus, únicam= ente cinco (5) infectan a seres humanos, éstos son: Alp= hapapillomavirus, Betapapillomavirus, Gammap= apillomavirus, Mupapillomavirus y = Nupapillomavirus, que conforman la clasificación no taxonómica de "virus d= el papiloma humano” (10, 18, 19).

= Los métodos moleculares de detección y/o identificación del ADN de VPH disponibles son: Reacción en Cadena de la Polimerasa (PCR= por sus siglas en inglés) y Sistema de Captura de Híbridos (SCH).= La PCR puede utilizarse con técnicas de hibridación o con la producción de fragmentos de restricción de longitud polimórfica (RFLP) a partir de los productos de amplificación para la tipificación viral (18, 19).

= La PCR es una técnica in vitro utilizada para amplificar enzimáticamente una región específica de ADN de interés. Esta región es limitada por dos moléculas llamadas iniciadores, que son fragmentos cortos de nucleótidos que se hibridan por complementariedad a la secuencia molde del genoma problema. A partir de los iniciadores se genera una nueva cadena mostrándose cono resultado una amplificación de copias de esa región de tama&n= tilde;o especifico (amplicon) (20). El tamaño de los amplicones obtenidos de la muestra, tiene un efecto inverso sobre la eficacia de la PC= R, recomendándose que no sea superior a 200 pb.

= En la actualidad, varios iniciadores de diferentes genes de VPH han sido diseñados, pero las más comunes se basan en el gen L1 = (21); no obstante también se han publi= cado la secuencia de los iniciadores para las otras regiones mencionadas.

El propósito de este trabajo fue recopilar secuencias de iniciadores publicados, analizarlos y organizar esta información para proveer una lista compilada que facilite la decisión de optar por la utilización de un par de iniciadores requeridos para la detección y diagnóstico del HPV.

= Para que se lleve a cabo exitosamente la PCR es primordial que los iniciadores s= ean específicos. Estos iniciadores, actúan como punto de partida y unión para la ADN polimerasa durante la síntesis de ADN del fragmento a amplificar. Cada iniciador es complementario a una de las caden= as del ADN en estudio, uno de los iniciadores debe tener la misma secuencia qu= e se encuentra en una de las cadenas del ADN (iniciador sentido) y el otro deberá tener la secuencia complementaria que estará al final = del fragmento que se quiere amplificar (iniciador antisent= ido) (22).

= Previo a la realización de la reacción es indispensable analizar la secuencia de cada iniciador.

= Este análisis se lleva a cabo con herramientas bioinformáticas diseñadas para este fin. Antes de realizar el análisis de los iniciadores sentido y antisentido, es indispens= able conocer los requisitos que dichos iniciadores deben cumplir para ser considerados como óptimos y así poder utilizarlos para la reacción de PCR (23).

Características de iniciadores

Longitud del iniciador<= /i>

= Cada iniciador sentido y antisentido debe contar con= una longitud de entre 18-24 bases, ya que la cantidad de bases influye en la especificidad de la secuencia a amplificar, siempre y cuando la temperatura= de alineamiento (temperatura calculada, a partir de la cual se realizan los ensayos necesarios) haya sido probada como adecuada. La longitud del inicia= dor influye en la eficiencia del alineamiento, cuanto más largo sea el iniciador, menos eficaz será la alineación. Al unirse una men= or cantidad de iniciador a la secuencia de ADN molde en cada ciclo, se tiene c= omo consecuencia la disminución de la cantidad del producto amplificado = de forma significativa. Sin embargo, los iniciadores no deben ser demasiado cortos, ya que pueden llegar a unirse de forma inespecífica. Esto ti= ene como consecuencia, amplificados de productos no deseados y una disminución del producto de interés (23).

Especificidad

= Los iniciadores, deben ser específicos para delimitar la región q= ue se quiere amplificar y esta condición depende al menos en parte de su longitud, por lo que deben elegirse de forma que tengan una secuencia única dentro del ADN a amplificar. La ADN-polimerasa puede activarse= a diferentes temperaturas, la extensión del iniciador se produce a una temperatura inferior a la de alineamiento, pero si es demasiado baja, puede darse un alineamiento inespecífico por lo que una buena recomendación se obtiene con una temperatura de fusión de ent= re 55 a 72ºC, que corresponde a una longitud del iniciador de entre 18 y = 24 bases (23).

Temperatura de fusión (Tf o Tm)

= La Tf (Temperatura de fusión) es la temperatura a= la que la mitad de las hebras de ADN se encuentran como banda simple y la mitad como banda doble. Se sugiere que los iniciadores tengan Tf similares o muy próximas, con 5 ºC = de diferencia como máximo de lo contrario el resultado sería men= os eficaz e incluso puede no llevarse a cabo la amplificación. Esto es porque si el iniciador con la Tf mayor, funcion= a mal a temperaturas más bajas y el iniciador con la = Tf más baja, no se une a temperaturas más elevadas. Por esto se recomienda analizar los iniciadores por medio de herramienta bioinformáticas que indican la Tf de cad= a uno de ellos. De manera común se ha calculado la Tf= por medio de la fórmula Tf =3D 4 (Guanina+Citocina) + 2 (Adenina +Timina), que resulta = en una buena aproximación del valor de Tf de ca= da iniciador y se aplica para iniciadores de entre 18 y 24 bases, siendo disponible varios sitios de internet en el que se puede realizar este cálculo. De esta manera, la Tf estar&aac= ute; entre 56 – 62 ºC (24).

Temperatura de alineamiento

= En cuanto a la temperatura de alineamiento se sugiere que los iniciadores teng= an al menos 50 ºC; la relación entre temperatura de alineamiento y temperatura de fusión corresponde a la temperatura de alineamiento inferior en 5 ºC a la temperatura de fusión (T alineamiento =3D Tf= iniciador – 5 ºC).=

= No obstante, esta temperatura sirve de referencia, puesto que es posible que la temperatura de alineamiento determinada empleando esta regla no sea la apropiada y se tengan que efectuar varios ensayos para determinar la temperatura óptima de la reacción.

= En un termociclador de gradiente, se puede probar en un solo ensayo varias temperaturas y así determinar la temperatura óptima de una reacción. Una T alineamiento alta, evita la unión de los iniciadores y una T alineamiento baja, permite unión inespecí= fica de los iniciadores, obteniéndose tamaños diversos de amplific= ados que se observan como amplicones inespecí= ficos.

Secuencias complementarias del iniciador<= o:p>

= Puede haber secuencias de iniciadores que tienen ciertas regiones con capacidad p= ara formar estructuras secundarias internas (dímeros), por complementari= edad entre ellos o formación de horquillas (por tener zonas de auto homología), por lo tanto, esto debe evitarse. Se recomienda revisar,= que los iniciadores no presenten secuencias con homología interna de más de tres  pares de b= ases, y si presentan homología parcial en las regiones centrales, as&iacut= e; como, en el extremo 3’ de cualquiera de los iniciadores, pueden formar dímeros de iniciadores, que en general interfieren con el alineamien= to al ADN molde e impiden la formación del producto deseado por un mecanismo de competencia (25).

Contenido de G/C y tramos de polipirimidina (T, C) o polipuri= na (A, G)

= Se ha sugerido que el contenido de G:C (Guanina: Citocina) debe estar en el ra= ngo de entre 40 y 55%. Mientras más cantidad de G y C tenga el iniciador, mayor será Tf. Por otro lado, tambi&eacu= te;n se deben evitar secuencias de poli X (X=3D G o C o T o A), en el caso de te= ner poli G o poli C esto favorecería una hibridación inespecífica, en tanto que las secuencias de poli-A y poli-T, tramos= de polipirimidinas (T, C) y polipur= inas (A, G) pueden reducir la eficacia de la amplificación. Se recomienda= que los iniciadores tengan una mezcla diversa de nucleótidos con un contenido de GC del 50 %, que conserve la Tf apropiada. y una longitud aproximada de 20 bases.

Secuencia en el extremo 3’

= Un punto importante es la inclusión de un residuo de G o C en el extremo 3’ de los iniciadores. Extremos 3’, debido a que los triples enlaces que forman estas bases favorecen la eficacia de la reacción = ya que minimizan la posibilidad de que se abra la doble cadena formada entre el iniciador y el ADN a amplificar (23).

Análisis de iniciadores

= Los iniciadores deben de someterse previamente a análisis adecuado, caso contrario puede obtenerse poco producto, productos inespecíficos o incluso ningún producto, dado por una amplificación inespecífica y/o por la formación de dímeros de iniciadores que compiten durante la reacción.

= Para realizar el análisis de iniciadores se utilizan herramientas bioinformáticas gratuitas que se encuentran en línea. Con est= as herramientas bioinformáticas, podemos contrastar las secuencias de l= os iniciadores contra bases de datos y así caracterizarlos. Con los resultados obtenidos del análisis, determinamos si los iniciadores analizados son adecuados o no, para realizar la reacción de PCR en el laboratorio (22).

Herramientas bioinformáticas<= /o:p>

= Para el análisis de biomoléculas se disponen de varias herramientas bioinformáticas que se pueden utilizar en especial para obtener dato= s de la composición y con ello encontrar sitios de interés para la detección por técnicas moleculares. Estas plataformas tienen bases de datos con las que además de obtener la secuencia de moléculas que conforma el genoma del microorganismo, se pueden reali= zar análisis de homología de secuencias muy requeridas en el diseño de los iniciadores. Con estas herramientas se puede tomar una decisión de la utilización de algún par de iniciadores para la reacción por PCR.

= El desarrollo y optimización de las herramientas bioinformáticas para el análisis de iniciadores, así como la utilizació= ;n de bases de datos (BLAST, Clustal Omega, FASTA,= M-Coffee, PRALINE, Online Analysis= Tools, Omic Tools, Repeat<= /span> Masker, Sequence Manipulation Suite SMS, SILVA, u= niprot), ayudan al análisis de iniciadores para verificar si son altamente específicos, que conduzcan en definitiva a obtener un resultado exit= oso.

 

Metodología

= Este trabajo consistió en una revisión bibliográfica, se aplicó un enfoque cualitativo, de alcance descriptivo y con un diseño transversal teórico-documental, puesto que se analizó y sintetizó de literatura actualizada extraída= de bases de datos de investigación orientada en el área de la biología molecular. Para encontrar las publicaciones se hizo uso de palabras clave y conectores de búsqueda, acorde a los objetivos planteados. Dichas publicaciones fueron obtenidas de buscadores y bases de datos académicas como Pudmed, Academic Google, Elsevier, y Scielo.

= Se tomó en cuenta documentación de alta complejidad, actualizada= y relevante que pueda solventar las inquietudes planteadas y el alcance de es= ta investigación.

= Los artículos revisados fueron trabajos de publicación reciente (años 2020 -2023) que implicaban los iniciadores utilizados en la detección de VPH según sea éste de alto o bajo riesgo y seleccionando los artículos donde se describe la aplicación d= e la PCR mostrando los iniciadores utilizados pero que no sean de tipo aleatorio= y con un año de publicación no mayor a 5 años. Para la recolección de los datos se usó como técnica la observación de las mejores fuentes de primera mano y para organizar = la información se utilizó una hoja de cálculo de Excel en= la que se registraron los datos específicos requeridos para disponer de= una base de datos.

= Se organizó en una tabla los iniciadores para VPH de tipo 16, 18, 31, 3= 3, 52, 53 categorizados dentro de los tipos de alto riesgo, así como también los de 45, 58 y el común MY09/MY11 acorde a lo public= ado por los autores. tomados en cuenta en este trabajo.  Se verificó la existencia e= n la secuencia genómica del VPH que consta en la base de datos NCBI (National Center for Biotechnology Information= ). Luego cada iniciador fue revisado con varias aplicaciones bioinformáticas disponibles en la red diseñadas para este propósito, no obsta= nte, fue con la aplicación MFEprimer que se o= btuvo la mayoría de los resultados. Otros datos fueron directamente tomado= s de lo publicado por los autores. Los valores de los parámetros que se evidenciaron fueron: tamaño del iniciador, contenido GC (%), energía libre de Gibs (ΔG (kcal/mol= )), base en el extremo 3', promedio de la temperatura de alineamiento (Tm) y amplicon en pares de bases (pb).

= Para orientar el trabajo que corresponde hacer cuando se requiere analizar la calidad de los iniciadores se elaboró tablas que exponen las bases de datos útiles en estos casos, los tipos de iniciadores, las característica y criterios que se tienen que tomar en cuenta cuando = se diseña los iniciadores, las herramientas bioinformáticas útiles en el análisis de iniciadores, los iniciadores encontr= ados en las publicaciones, y los cálculos de los parámetros cuyos valores son decisivos para la selección apropiada del iniciador. En = este sentido, el propósito de este trabajo fue recopilar secuencias de iniciadores publicadas, analizarlos y organizarlos para proveer una lista compilada que facilite la decisión de optar por la utilizació= n de un par de iniciadores requeridos para la detección y diagnóst= ico del HPV, sirviendo para diferentes versiones de PCR que le sea útil.=

Resultados

= La selección de oligonucleótidos iniciadores se tiene que tomar = en cuenta parámetros muy importantes para que se produzca una buena reacción de PCR, adecuada hibridación con sondas y en caso de secuenciación de ADN. Por lo tanto, de este paso depende el é= xito de la detección del virus en el laboratorio con técnicas moleculares. En este sentido es necesario distinguir el tipo de iniciador q= ue se va a usar (Tabla 1)(26).

= Tabla 1: Tipos de iniciador para PCR

Ini= ciadores

Des= cripción

Universales

Específicos

Amplifican solo de un tipo de secuencia diana, es decir no pueden amplificar una región que no sea su complemento. Se complementan a una región especifica por ejemplo d= e un virus para poder detectarlo con la amplificación.

Degenerados

Tienen secuencias similares, pero no exactamente igual, amplifican el mismo gen incluso en diferentes organism= os, por lo cual pueden ayudar a estudiar las variaciones de una especie<= /o:p>

Anidados

Fuente: Guevara K., 2022 (26)

= Cada uno de este tipo de iniciadores tiene que ser consideración en base a criterios de su composición que deben ser también tomados en cuenta

= Tabla 2: Criterios a tomar= en cuenta al diseñar los iniciadores

Car= acterísticas

Cri= terios

Tamaño

De 20-25 nucleótidos (tama&ntild= e;o ideal) De 18-30 nucleótidos (Tamaño general)

Base en el extremo 3'=

Debe ser una Guanina (G) o una citosina= (C)

Temperaturas de fusión (Tm)

Entre 50 a 60ᵒC=

Contenido GC

Entre 40 al 60%

Autocomplementariedad

Debe ser evitada y así impedir la formación de estructuras secundarias y dímeros entre iniciadores.

Similaridad

Debe tener un 100% de apareamiento con = el molde

Fuente: http://bioinf.ibun.unal.edu.co/document= os/primers/primer.php#PCR%20o%20para%20Secuenciaci

Como puede observ= arse hay cierta variación en las recomendaciones respecto al tamañ= o de los iniciadores esto ha dependido de la experiencia de los resultados obten= idos por los investigadores. Mientras mayor es el tamaño del iniciador será más específico la identificación. As&iacut= e; mismo, los extremos al final del iniciador son necesarios para que las polimerasas agreguen nucleótidos para elongar la cadena, en este sen= tido es útil que los nucleótidos de Guanina o citocina son útiles por tener mayor estabilidad en la cadena razón por la = cual se toma en cuenta este parámetro. Por último, se debe verific= ar que el iniciador contenga ciertas secuencias que permita la autocomplementariedad y más bien sea complementario con la cadena molde del ADN de la mues= tra (27).

= Con estos antecedentes se revisaron varios artículos y se tomaron en cue= nta los iniciadores publicados, estos se verificaron en aplicaciones dispuestas= en plataformas y utilitarios para el análisis de los mismos mostrados e= n la tabla 3 de los cuales el que más información directa resulto = fue MFEprimer (28).

= Tabla 3: Herramientas bioinformáticas útiles para el análisis de iniciadores para PCR.

Apl= icación

Des= cripción

sit= io

TM TOOLSM

https://= dna-utah.org/tm/tool.html

In-Silico P= CR

Para validación del iniciador

http://rohsdb.cmb.usc.edu/GBshape/cgi-b= in/hgPcr

MFEprimer

https://= mfeprimer3.igenetech.com/spec

AutoDimer

https://autodimerv1.software.informer.com/

IDT, Integrated DNA Technologies, In<= /o:p>

https://www.idtdna.com/pages

Primer3plus

https://= www.primer3plus.com/

Nucleotide-BLAST

Para “alineamiento de secuencias de tipo local, ya sea de ADN, ARN o de proteínas”

http://w= ww.ncbi.nlm.nih.gov/BLAST/

SNPCheck

Busca de interferencias de SNP

https://secure.ngrl.org.uk/SNPCheck/snp= check.htm

 

 

 

 

= Tabla 3: Herramientas bioinformáticas útiles para el análisis de iniciadores para PCR. (continuación)

Apl= icación

Des= cripción

= sitio

Primer-Blast

Para diseñar iniciadores específicos para la cadena molde

https://www.ncbi.nlm.nih.gov/tools/prim= er-blast/index.cgi?GROUP_TARGET=3Don

Oligo Calc

Para cálculo de varios parámetros

http://biotools.nubic.northwestern.edu/= OligoCalc.html

Fuente: Falconi F. et al. = 2023

= Se obtuvieron 31 pares de iniciadores para HPV, 17 para los de la variante 16 = y 15 para la variante 18. También se muestra para las variantes 31, 33, 4= 5, 52, 53 y 58 según se observa en la tabla 4 (1, 29-3= 1).

= Tabla 4: Iniciadores publicados para la detección de VPH por PCR.

= =

VPH

Iniciador F (Forward)=

Iniciador R (Reverse)=

Artículo public= ado por:

AGAATGTGTGTACTGCAAGCAA= CA

Bonifaz & Rocabado, 2020

CAGATCATCAAGAACACGTAGA= GA

Bonifaz & Rocabado, 2020

TTGCAGATCATCAAGAACACGT= AGA

GTAGAGATCAGTTGTCTCTGGT= TGC

Fantin C. et al, 2023

Vijayan<= span style=3D'font-size:9.0pt;line-height:115%;font-family:"Times New Roman",s= erif; color:black;mso-themecolor:text1;background:white'> A., 2022

Kantún N. et al, 2023

Kantún N. et al, 2023

Kantún N. et al, 2023

Kantún N. et al, 2023

Kantún N. et al, 2023

CTGTGATAATTCAAATGTACAA= TC

Kantún N. et al, 2023

Kantún N. et al, 2023

Kantún N. et al, 2023

Kantún N. et al, 2023

TATTTGTGAAGAAGCATCAGTA= AC

Kantún N. et al, 2023

TATTTGTGAAGAAGCATCAGTA= AC

Kantún N. et al, 2023

Kantún N. et al, 2023

Zapana E. et al, 2022

CTCGGTTGCAGCACGAATGG

Kantún N. et al, 2023

Kantún N. et al, 2023

Kantún N. et al, 2023

Kantún N. et al, 2023

Kantún N. et al, 2023

Kantún N. et al, 2023

Kantún N. et al, 2023

Kantún N. et al, 2023

GTGCATACAAAACCGAGGATTG=

Kantún N. et al, 2023

Kantún N. et al, 2023

= Tabla 4: Iniciadores publicados para la detección de VPH por PCR. (continuación)

Item

VPH

Iniciador F (Forward)

Iniciador R (Reverse)

= Artículo public= ado por:

Kantún N. et al, 2023

GGAATTTCATTTTGRGGCTCTA= AA

Bonifaz & Rocabado, 2020

TAGAAGGTCAACCGGAATTTTC= AT

Fantin C. et al, 2023

TCGTTTTCTTCCTCTGAGTCGC= TT

Vijayan<= span style=3D'font-size:9.0pt;line-height:115%;font-family:"Times New Roman",s= erif; color:black;mso-themecolor:text1;background:white'> A K., 2022=

CAGTGAAGTGTTCAGTTCGGT<= o:p>

Zapana E. et al 2022

33

31

GAAATTGCATGAACTAAGCTCG<= /span>

Fantin C. et al, 2023

34

33

Fantin= C. et al, 2023

35

45

Fantin= C. et al, 2023

36

52

Fantin= C. et al, 2023

37

53

Fantin= C. et al, 2023

38

58

Fantin= C. et al, 2023

39

MY09/MY11

CGTCCMAARGGAWACTGATC

Bonifaz & Rocabado, 2020

MY09/MY11

Abdulsalam A. et al, 2023

Fuente: Falconi F. et al. = 2023

Los iniciadores universales muy utilizados como MY09/MY11 incluidos en la Tabla 4, así como G5/G6 (no incluidos) son út= iles en encontrar variantes intratipo de la regi&oac= ute;n L1 del genoma viral del VPH, permite su uso para un amplio espectro de genotipos, como característica de este, se observa que el iniciador contiene secuencias degeneradas (32-35).

Además, se analizó las característic= as de cada uno de los iniciadores, siendo útil en la decisión de selección de un par de estos y crear el programa correspondiente de = PCR con los datos para el termociclador. Cada parámetro mostrado en la t= abla 5 fue analizado con las herramientas bioinformáticas disponibles, en este caso la mayor parte fue realizado con MFEprimer, otros datos como los de la Tm y tamaño del amplicon fueron tomados de los publicados por los autores (Tabla 4).=

Tabla 5: Parámetros analizado= s de los iniciadores para detección de VPH por PCR.=

Item=

= Tamaño

Contenido GC (%)<= /o:p>

= ΔG (kcal/mol)

Base en el extremo 3'<= o:p>

Promedio

Tm (°C)=

=

pb

F

R

F

R

F

R

F

R

1

2

3

4

5

6

7

8

 

Tabla 5: Parámetros analizado= s de los iniciadores para detección de VPH por PCR. (continuación)=

Tamaño

Contenido GC (%)

ΔG (kcal/mol)

Base en el extremo 3'<= /span>

Promedio

Tm (°C)

=

pb

F

R

F

R

F

R

F

R

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

Fuente: Falconi F. et al. = 2023. La Tm va a depender de la concentración de sales y concentraci&oacut= e;n del iniciador en uM

= Algunos iniciadores tienen condiciones más convenientes que otros segú= ;n se observa los valores en la tabla 5, la Tm corresponde al promedio calcula= do entre los dos iniciadores (F, R), todos los iniciadores no darían posibilidad a dimerización.

Conclusiones<= o:p>

&m= iddot;      =    Para proceder a aplicar la técnica de PCR como medio de detección = de algún determinado virus como es en este caso el VPH se requiere cont= ar con un previo análisis de los iniciadores a utilizar, para asegurar buenos resultados. Este trabajo muestra lo concerniente a realizar en el análisis y las secuencias de nucleótidos útiles para el diagnóstico de VPH para los tipos reconocidos como de alto riesgo 16= y 18 y algunos de bajo riesgo.

·         Se incluye los parámetros determinados con las herramientas bioinformáticos, cuyos valores permiten tomar decisiones en la utilización de un par de iniciadores que cumpla con las características requeridas, teniendo 17 iniciadores para = las variantes 16 y 15 para las variantes 18, además de 8 pares de iniciadores para otros tipos.

·         Los criterios a elegi= r, puede ser reflexionada con los parámetros que se muestra de cada uno= de los pares de iniciadores en la tabla 5, que permite tener fundamentos para decidir su selección.

Conflicto de intereses

Los autores declaran que no existe conflicto de intereses en relación con el artículo presentado= .

= Declaraci&oacu= te;n de contribución de los autores

El artículo deberá acompañarse de una nota, que exprese la contribución de cada autor al estudio realizado.

Félix Atair Falconi Ontaneda análisis de iniciadores y redacción del artículo, José Andrés Zaporta Ramos revisión y correcciones del documento, Yi= sela Carolina Ramos Campi descarga de bibliograf&iac= ute;a, y revisión cumplimiento con las normativas de publicación, Gisnella María Cedeño Cajas revisi&oacu= te;n de normas bibliográficas

Referencias bibliográficas

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El artículo que se publica es de exclusiva responsabilidad de los autores y no necesariamente reflejan el pensamiento = de la Revista Anatomía Digital= .

 

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