Instability: Mutation and DNA repair Mutations DNA repair

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  • Instability: Mutation and DNA repairMutationsDNA repair

  • Instability: Mutation and DNA repairSubstitution rates vary throughout the genome.

  • Instability: Mutation and DNA repairDifferent mutation rates in primates and rodents

    Species PairSitesPercent Divergence Substitution rate (x 109)

    Human/Chimp9211.91.3 (7 myr)

    Human/Old world monkey99811.02.2 (25 myr)

    Mouse/rat388623.77.9 (15 myr)

  • Instability: Mutation and DNA repairHigher mutation rates in malesGreater number of cell divisions

  • Instability: Mutation and DNA repairSex-specific differences in mutation rates

    Gene Mutation Ratio of male/female mutations

    NF1Point4.5VHLPoint1.3RBPoint8.5ZFX/ZFYMutations in last intron6

  • Instability: Mutation and DNA repairMechanism of mutationSimple sequence repeats and strand slippage

  • Instability: Mutation and DNA repairMechanism of mutationHomologous equal crossover yields fusion genes.

  • Instability: Mutation and DNA repairMechanism of mutationUnequal crossover causes insertions and deletions.

  • Instability: Mutation and DNA repairMechanism of mutationUnequal crossover in a tandem repeat array can result in sequence homogenization.

  • Instability: Mutation and DNA repairMechanism of mutationTandem gene duplication by unequal crossover or sister chromatid exchange facilitated by short interspersed elements.

  • Instability: Mutation and DNA repairMechanism of mutationGene conversionNon reciprocal sequence exchange between allelic or nonallelic genes.

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  • Instability: Mutation and DNA repairMechanism of mutationSplicing mutationsIntron retentionExon skippingActivation of cryptic splice sites

  • Instability: Mutation and DNA repairMechanism of mutationShort tandem repeats are deletion insertion hotspots.

  • Instability: Mutation and DNA repairMechanism of mutationSpinocerebellar ataxia (SCA1) triplet repeat expansion.

  • Instability: Mutation and DNA repairMobile elements and mutationsAlu elementInsertion eventsRecombination events

  • Reverse transcription and insertion1. Usually a single master copy2. Pol III transcription to an RNA intermediate3. Target primed reverse transcription (TPRT) enzymatic machinery provided by LINEs

  • What are SINEs?1.Interspersed Elements

    2.70 - 300 Bases in Length

    3.Very High Copy Numbers(>100,000 Copies/Genome)

  • Promoter

    disrupts reading frame

    disrupts splicing

    no disruption

    ALU INSERTIONS AND MUTATION

    alters gene expression

  • ALU INSERTIONS AND DISEASE

    LOCUS

    DISTRIBUTION

    SUBFAMILY

    DISEASE

    REFERENCE

    BRCA2

    de novo

    Y

    Breast cancer

    Miki et al, 1996

    Mlvi-2

    de novo (somatic?)

    Ya5

    Associated with leukemia

    Economou-Pachnis and Tsichlis, 1985

    NF1

    de novo

    Ya5

    Neurofibromatosis

    Wallace et al, 1991

    APC

    Familial

    Yb8

    Hereditary desmoid disease

    Halling et al, 1997

    PROGINS

    about 50%

    Ya5

    Linked with ovarian carcinoma

    Rowe et al, 1995

    Btk

    Familial

    Y

    X-linked agammaglobulinaemia

    Lester et al, 1997

    IL2RG

    Familial

    Ya5

    XSCID

    Lester et al, 1997

    Cholinesterase

    one Japanese family

    Yb8

    Cholinesterase deficiency

    Muratani et al, 1991

    CaR

    familial

    Ya4

    Hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism

    Janicic et al, 1995

    C1 inhibitor

    de novo

    Y

    Complement deficiency

    Stoppa Lyonnet et al, 1990

    ACE

    about 50%

    Ya5

    Linked with protection from heart disease

    Cambien et al, 1992

    Factor IX

    a grandparent

    Ya5

    Hemophilia

    Vidaud et al, 1993

    2 x FGFR2

    De novo

    Ya5

    Aperts Syndrome

    Oldridge et al, 1997

    GK

    ?

    Sx

    Glycerol kinase deficiency

    McCabe et al, (personal comm.)

  • UNEQUAL Alu/Alu HOMOLOGOUS RECOMBINATION

  • ALU/ALU RECOMBINATION AND GERM-LINE DISEASE

    LOCUS

    DISTRIBUTION

    DISEASE

    REFERENCE

    8 x LDLR

    Kindreds

    Hypercholesterolemia

    Lehrman et al, 1985, 1987

    Yamakawa et al, 1989

    Rudiger et al, 1991

    Chae et al, 1997

    5 x -globin

    Kindreds

    -thalassaemia

    Nicholls et al, 1987

    Flint et al, 1996

    Harteveld et al, 1997

    Ko et al, 1997

    5 x C1 inhibitor

    Kindreds

    Angioneurotic adema

    Stoppa-Lyonnet et al, 1990

    Ariga et al, 1990

    C3

    Kindred

    C3 deficiency

    Botto et al, 1992

    HPRT

    Individual

    Lesch-Nyhan syndrome

    Marcus et al, 1993

    DMD

    Kindred

    Duchennes muscular dystrophy

    Hu et al, 1991

    ADA

    Individual

    ADA deficiency-SCID

    Markert et al, 1988

    Ins. Rec.

    Individual

    Insulin-independent diabetes

    Shimada et al, 1990

    Antithrombin

    Individual

    Thrombophilia

    Olds et al, 1993

    XY

    Individual

    XX male

    Rouyer et al, 1987

    Lysyl hydroxylase

    Kindreds

    Ehlers-Danlos syndrome

    Pousi et al, 1994

  • ALU/ALU RECOMBINATION AND CANCER

    LOCUS

    DISTRIBUTION

    MECHANISM

    DISEASE

    REFERENCE

    10 x

    ALL-1

    Somatic

    Alu-Alu recomb

    Dup. intron 1-6

    Acute myelogenous leukemia

    Strout et al, 1998

    So et al, 1997;

    Schichman et al, 1994

    7 x BCR/Abl

    Somatic

    X-Alu recomb.

    CML

    Jeffs et al, 1998

    Chen et al, 1989

    de Klein et al, 1986

    All-1/AF9

    Somatic

    Alu-Alu translocation

    Acute myelogenous leukemia

    Super et al, 1997

    2 x

    BRCA1

    Somatic &

    A kindred

    Alu-Alu recomb

    (del exon 17; del. Promoter)

    Breast cancer

    Puget et al, 1997

    Swensen et al, 1997

    2 x

    MLH1

    2 kindreds

    Alu-Alu recomb.

    (del exon 16)

    (exons 13-16)

    HNPCC

    Nystrom-Lahti et al, 1995

    Mauillon et al, 1996

    TRE

    Somatic

    Interchromosomal

    Alu-Alu recomb

    Ewing's sarcoma

    Onno et al, 1992

    RB

    Common

    Alu-Alu recomb.

    (799 bp del.)

    Association with glioma

    Rothberg et al, 1997

    EWS

    Subset of Africans

    Alu-Alu recomb.

    (del 2 kb)

    Protective against Ewing Sarcoma?

    Zucman-Rossi et al, 1997

  • Instability: Mutation and DNA repairDNA repairPhotodimerDNA glycosylase /AP endonucleasesE-coli mismatch repairHuman mismatch repair

  • Instability: Mutation and DNA repairDNA repairPhotodimer

  • Instability: Mutation and DNA repairDNA repairDNA glycosylase /AP endonucleases

  • Instability: Mutation and DNA repairDNA repairE-coli mismatch repairHuman mismatch repair

  • Instability: Mutation and DNA repairDNA repairHuman mismatch repair

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