Explore the significance of DNA mutation and genetic polymorphism in evolution. Learn about different types of mutations, their causes, and repair mechanisms. Discover the role of mutations in diseases such as cancer.
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Genetic variability • is increasedby – mutation – sexualreproduction meiosis (generation of gametes) - homologousrecombination (crossing over) - independentassortment of homologous chromosomes fertilisation - significance
DNA Mutation(causinganychange) DNA variants, alleles (anycodingornon-codingsequence) Genetic (DNA) polymorphism
Significance of mutation (forall species) Withoutmutation, evolutionwouldnot be possible. This is becausemutationsprovidethe "rawmaterial" uponwhichthemechanisms of naturalselectioncanact.
Regardingthevariants…. • normalorwildvariant (allele) is themost frequentin a • population • polymorphism (orpolymorphic) is thevariant (allele) ifits • frequency is › 1 % inthepopulation • (havingno effectonphenotype) • formerly: • mutation (ormutant) is thevariant(allele) • (formerly: ifitsfrequency is ‹ 1 % • inthepopulation / diseasecausing, it has a • negativeconnotation) • Human Genom Variation Society offered: • „sequencevariant„ or vagy „allelicvariant” • Mutation: somaticmutationsorgermlinemutations (recent) • Polymorphism: in a populationwhenthefrequency is known
Long way from mutation to polymorphism Appearance of new variant by mutation Survival of rare allele Increase in allele frequency after population expand New allele is fixed in population as novel polymorphism
Repair of double strand breaks (DSB) may result loss of nucleotides = deleterious Sisterchromatid (after S phase) orlikeinmeiosis, homologous chromosome is usedas template = safety
Multicellularcellcycle M-phase cytokinesis mitosis M G1 G2 Go G2 Restriction point - Growth factors - anchorange Checkpoints: Restrictionpoint G2 M (spindle) S Interphase
Function and activity of checkpointmachinery G1 G2 M DNA damage free kinetochors notcomplete DNA replication sensor protein kinases transducer effector s t o p of c e l l c y c l e repair
Ataxiatelangiectasia (ATM=sensor) Itsmutationcausesrare, neurodegenerative, inheriteddisease (AR), thataffectsmanyparts of the body and causesseveredisability, characterizedbyradiosensitivity and differenttumors.
Site of mutations - intheorganism Somatic- insomaticcells localized-inheritedwithincells of an organism (mosaicism: tumors, antibodydiversity, etc.) higherindividingcells Generative– inprimordialgerm line inheritedfromone generationtothenextone
Function and mutations Back mutation or reversionis a point mutation that restores the original sequence and hence the original phenotype. Lethal mutationsare mutations that lead to the death of the organisms which carry the mutations. Gain-of-function mutations- change the gene product such that it gains a new and abnormal function. These mutations usually have dominant phenotypes. Loss-of-function mutations - gene product having less or no function. Phenotypes associated with such mutations are most often recessive. Exception is when the reduced dosageof a normal gene product is not enough for a normalphenotye (this is calledhaploinsufficiency). Dominant negative mutations- the altered geneproductactsantagonistically to the wild-type allele. These mutations are characterised by a dominant phenotype. In humans, dominant negative mutations have been implicated in cancer (e.g. mutations in genes p53,ATM).
Fitness and mutations • Most areneutral – duringevolutionlatermay be harmful • orbeneficial • Somearebeneficial– • - harmfulonemutates back towild • - gettingbeneficialfunction • – diversity of antibody • - CCR532 – HIV resistency • - sicklecellanemia – malaria • resistency • Someareharmful – causingdiseases (allmonogenic • inheriteddiseases)
Size of mutations Large Genomemutation= change of chromosomenumber Medium Chromosomemutations= change of chromosomestructure Small genemutations= ranging from a change of singlenucleotideto a whole gene (notvisible) Affectingthelenght of DNA Deletion (singlebaseorshorter-longersequences) Insertion (singlebaseorshorter-longersequences- repetitive more insertionthandeletion No effectonthelength of DNA nucleotidesubstitution Cytogenetics
Repetitive insertions • Tandem repeats • Satellite DNA • pericentromeric heterochromatin • Minisatellite (VNTR) • 10-60bp • Telomere • Microsatellite (STR=short tandem repeats) • 2- somebp • good markers of kinship • Repeat number expansion diseases • Interspersed repeats • SINEs (Short Interspersed Elements), • LINEs (Long …) e. g. L1
Huntingtin MATLEKLMKAFESLKSFQQQQQQQQQQQQQQQQQQQQQQQPPPP PPPPPPPQLPQPPPQAQPLLPQPQPPPPPPPPPPGPAVAEEPLHRPK KELSATKKDRVNHCLTICENIVAQSVRNSPEFQKLLGIAHELFLLCSDD... • 350 kD protein • ubiquitously expressed • function unknown • correlation between repeatsize and age of onset and theseverity of disease (Huntington chorea) Huntington healthy
PolyglutaminePolyalanine disordersdisorders • CAG repeats • Neurodegenerativedisorders • Differentproteins • Gain of functionmutations • Variablelength • Expansion • Replicationalslippage • GCX repeats • Developmentalabnormalities • Transcriptionfactors • Loss of functionmutations • Constantlength • Stable • Unevencrossing over
MediumInDelmutations Deletion Pl. Hypodontia(Deletion of Pax 9) Insertion (retro)transposons Eg. L1 hemophilia A L1 is a LINE: Long Interspersed Elements
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