Patologia Molecular

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Text of Patologia Molecular

Harvy Mauricio Velasco P Gentica Humana UNAL

1* 1015 clulas adultas 2*1017 divisiones celulares 6 *109 nucletidos para cada divisin l l celular 1*10 -6 -8 Eficiencia de la l DNA polimerasa li

Proliferacin, Divisin y apoptosis

Noxas externas

Oncogenes y Genes supresores

Reparacin del DNA

UN GEN SE ENCUENTRA AFECTADO

GENERADAS POR LA EVOLUCIONNOVEDAD ADAPTACION ENFERMEDAD MUERTE

ERRORES EN LA REPLICACIONDNA POLIMERASA

TAMAO DE DNA3.000 3 000 MILLONES DE pb

AGRESION DIRECTA A DNA DEGRADACION INTERNA DE NUCLEOTIDOS

MUTACION Cualquier cambio en el material gentico(DNA nuclear y mitocondrial), que se herede a las generaciones siguientes.

POLIMORFISMO Variacin V i i gentica ti que tiene ms de una variante i t allica en una i secuencia DNA Frecuencia >1%

MUTACIONES GERMINALESEl cambio en el DNA se da en l lnea parental en t l celulas germinales y esta mutacin se HEREDA

MUTACIONES SOMATICASMutacin M t i que no compromete lneas germinales En un tejido especifico

GERMINALES

SOMATICAS

ESPONTANEAS

INDUCIDAS POR EL AMBIENTE O EN EL LABORATORIO

A GRAN ESCALA O MUTACIONES CITOGENETICAMENTE VISIBLES

A PEQUEA ESCALA O CITOGENETICAMENTE INVISIBLES

EXISTE ALTERACION DE ALGUNOS DE LOS COMPONENTES DEL MATERIAL GENETICO O EN EL FLUJO DE INFORMACION DEL DNA HACIA PROTEINAS ERROR EN LA EXPRESION DE LA INFORMACION GENETICA

TIPO SUSTITUCION DELECION INSERCION

DEFINICION Reemplazo de una(s) base(s) por otra(s) Perdida P did o eliminacin d uno o li i i de ms nucletidos Uno o ms nucletidos estn adicionados en una secuenciaTransposicin con duplicacin de material gentico Transposicin sin duplicacin (translocacin)

MUTACIONES

Sustitucin de bases

Inserciones

Deleciones

Transiciones Transversiones

1 o pocos nucletidos

1 o pocos nucletidos

Sustitucin sinnima (neutra) i i ( t ) y no sinnima Conversin gnica, mltiple sustitucin de bases

Expansin de i l tripletas

Grandes deleciones

Otras grandes inserciones: elementos transponibles ibl

En el marco de lectura

Transiciones: Pirimidina por p pirimidina (C-T)Ms comunes (ISLAS ( CpG)

Transversiones: p p Purina por pirimidina o viceversa

Purina por purina (AG)

A

C

G

T

SINNIMAS (SILENCIOSAS): Neutral No cambia secuencia a.a. En DNA no codificante Ms comn en DNA codificante En DNA codificante cambia el A.A. en posicin 3 de codn

NO SINNIMAS Altera secuencia TIPOSDeletreas Sin efecto Efecto benfico

Mayor frecuencia Transversiones que transiciones Mayor frecuencia en secuencias no codificantes Cualquier secuencia puede p tener sustituciones

No sinnimas Sinonimias Sinnimas

Algunas sustituciones en secuencias no codificantes afectan la expresin

p e q n r u s a a e z c r m a M a c M d U a c U o T n a N T S A m O d A q U d C n e C u S e O n C T O d N O m N o S a e N T E S E c U S c V a r E f S a C o A R u m M d T V n N e O o A c O n N S n V T e N E S m A S e S E d p V n E N e A S s S d a o E E p z m f e a r e d x a r o p a e d r n a e 3 a s e a y n p 2 o d g s a n c p o c s a n c c o d n o n c o d o n

SUSTITUCIONES

Gene Histone H3 Histone H4 Actin Aldolase A HPRT Insulin -Globin -Globin Albumin Ig VH Growth hormone Ig Interferon-1 Interferon-

No. of codons 135 101 376 363 217 51 141 144 590 100 189 106 159 136

Nonsynonymous 0.00 0.00 0 00 0.01 0.07 0.13 0.13 0.55 0.80 0.91 1.07 1.23 1.87 2.21 2.79

Synonymous 6.38 6.12 6 12 3.68 3.59 2.13 4.02 5.14 3.05 6.63 5.66 4.95 5.66 5.88 8.59

MUTACIONES QUE GENERAN GANANCIA O PERDIDA DE MATERIAL GENETICO DNA CODIFICANTE Y NO CODIFICANTE INVOLUCRA GENERALMENTE REPETICIONES CORTAS EN TANDEM FENOMENOS DE RECOMBINACION

Short Tandem Repeats (STRs)AATG

7 repeats 8 repeats

Homologous equal crossover can result in fusion genes. The example shows how intragenic equal crossover occurring between alleles on nonsister chromatids can generate novel fusion genes composed of adjacent segments f t from the t th two alleles. Note that similar exchanges between genes on sister chromatids do not l i i l result in genetic novelty because the gene sequences on the interacting sister chromatids would be expected to be identical.

Unequal crossover and unequal sister chromatid exchange cause insertions and deletions. The examples illustrate unequal pairing of chromatids within a tandemly repeated array. U d Unequal crossover l involves unequal pairing of nonsister chromatids followed by chromatid breakage and rejoining. Unequal sister chromatid exchange involves unequal pairing of sister chromatids followed by chromatid breakage and rejoining. For the sake of simplicity, the breakages of the chromatids are shown to occur between repeats, but of course breaks can occur within repeats. Note that both types of exchange are reciprocal - one of the participating chromatids l ti i ti h tid loses some DNA, while the other gains some.

Unequal crossover in a tandem repeat array can result in sequence homogenization. Note that the initial spread of the novel sequence variant to the same position in the chromosomes of other members of a sexual population p p can result by random genetic drift. Once the mutation has achieved a reasonable population frequency (left panel) it can spread to other positions within the array (right panel). This can occur by successive gain of mutant repeats as a result of unequal crossover (or unequal sister chromatid exchanges) and occasional loss of normal repeats. Eventually the mutant repeat can replace the original repeat sequence at all positions within the array, leading to sequence homogenization for the mutant repeat. Such sequence homogenization is thought to result in species-specific concerted evolution for repetitive DNA sequences. UEC unequal crossover. UEC, l

Tandem gene duplication can result from unequal crossover or unequal sister chromatid exchange, facilitated by short interspersed repeats. The double arrow indicates the extent of the tandem gene duplication f d li ti of a segment t containing gene A and flanking sequences. Original mispairing of chromatids ld b f ili db hi h could be facilitated by a high degree of sequence homology between nonallelic short repeats ( 1, R2). Note that p (R ) the same mechanism can result in large-scale deletions.

Gene conversion involves a nonreciprocal sequence exchange between allelic or nonallelic genes. (A) Interallelic gene conversion. Note the nonreciprocal nature of the sequence exchange - the donor sequence is not altered but the acceptor q p sequence is altered by incorporating sequence copied from the donor sequence. (B) Interlocus gene conversion. This is facilitated by a high degree of sequence homology between nonallelic sequences, as in the case of tandem repeats (C) Mismatch repeats. repair of a heteroduplex. This is one of several possible models to explain gene conversion. The model envisages invasion by one strand of the donor sequence (-) to form a heteroduplex with the complementary (+) ( ) strand of the acceptor sequence, thereby displacing the other strand of the acceptor. Mismatch repair enzymes recognize the mispaired bases in the heteroduplex and correct' the mismatches so that the (+) acceptor sequence i is converted' to b d' be perfectly complementary in sequence to the (-) donor strand. Subsequent replication of the (-) acceptor strand and sealing of nicks results in completion of the conversion.

LUGARES DE DNASECUENCIAS CODIFICANTES DEL GEN

CARACTERISTICA

SECUENCIAS INTRAGENIAS NO CODIFICANTES

SECUENCIAS REGULADORAS FUERA DE EXONES

La mayora patolgicas (sustituciones) (1ra y 2da posicn) Sitios mas susceptibles : islas CpG cerca a hotspots Menor porcentaje mutacional (10 15%) (10-15%) Afecta regiones intronicas En las regiones promotoras de los g genes ( (antes del Exon 1) ) Alteracin en la metilacin

Mutations at conserved splice donor (SD) or splice acceptor (SA) sequences (see Figure 1.15 for consensus sequences) result in (A) intron retention where there is failure of splicing and an intervening intron sequence is not g q excised; or in exon skipping where the spliceosome brings together the splice donor and splice acceptor sites of nonneighbouring exons. (B) Sequences that are very similar to the consensus splice donor or splice acceptor sequences may coincidentally exist in introns and exons (sd and sa). These sequences are not normally used in splicing and so are known as cryptic splice sites. A mutation can activate a cryptic splice site by making the sequence more like the consensus splice donor or acceptor sequence and the cryptic splice site can now be recognized and used by the spliceosome (activation of the cryptic splice site). S Fi li i ) See Figures 9.12 and 9 13 9 12 d 9.13 for examples of activation of an exonic and an intronic cryptic splice site, respectively

GANANCIA DE INTRON

PERDIDA DE EXON

GENERACION DE INSERCIONES O DELECIONES EN EL DNA PRODUCIENDO MUTACIONES TIPO FRAMESHIFT

Location and nature of mutation Effect on gene function Extragenic mutation Normally none

Comments Rare mutations may result in inactivation of distant regulatory elements required for normal gene expression (see Figure 8.23)

Multigene deletion Whole gene deletion Whole gene duplication

Abolition

Associated with contiguous gene syndromes (see Figure 16.9)

Abolition Can have effect due to altered gene Large duplications including the peripheral myelin protein 22 gene can cause Charcot-Mariedosage Tooth syndrome (see Figure 16.7)

Whole exon deletion Within exon

Abolition or