Chapter 15: Gene mutation, DNA repair, and transposition

Dominant Negative

A mutation in an allele that encodes an inactive gene product that directly interferes with the wild tipe allele

Haploinsufficiency

One allele is mutated/inactive and the single wild-type copy is not enough for wt function of the gene product

Mutation hot spots

Regions of the genome that are more susceptible to mutations

Spontaneous Mutation in Human Germ Cells

On average, newborns have 60 new SNPs compared to their mothers/fathers. The number of SNPs increases with the father’s age

Spontaneous somatic mutation rates

Much higher than germline rates, give rise to cancer and other diseases

Replication slippage

Looping in the template strand during replication results in the polymerase skipping the looped out base pairs, ending in deletions

Replication slippage is more prevalent in ___ sequences

Tandem repeat

Tautomeric Shifts

Nucleotide proton shifts that result in chemical changes in the bases that can lead to noncomplimentary base pairing

Depurination

Loss of one nitrogenous base in an intact double helix, most often the purine base, that results in an apurinic site that might result in the random insertion of a base at this site

Deamination

An amino group in cytosine or adenine is converted to a keto group, which results in base exchange

Alkylating agents

Chemicals that donate alkyl groups (CH3 or CH2CH3) to amino or keto groups

Intercalating agents

Chemicals with dimensions and shapes that allow them to fit inbetween bound base pairs resulting in the unwinding of DNA strands. Often used as DNA stains

MMR

Mismatch repair. Nascent DNA strands are unmethlyated, MMR proteins read for mismatches on the unmethylated strand and repair them to match the template strand

Postreplication repair

Repair system used when gaps are formed due to polymerase skipping, uses the intact homologous strand to recombine and then ligase to reseal the gap on the intact strand after recombination

RecA

Recombinase A, a protein involved in homologous recombination. Essential for postreplication repair

Base excision repair

Repair pathway in which incorrect base pairings are fixed. Relies on proteins called DNA glycosylases that recognize specific bases. AP endonucleases (APE1) make the excisions

Nucleotide excision repair

Repair “bulky” lesions in DNA like pyrimidine dimers. Same concept as BER, just requires different endo/exonucleases and a different detection mechanism

XPA-G

Proteins involved in human NER, discovered by experiments in xeroderma pigmentosum

HR Repair

Homologous recombination repair. DSB ends are resected to leave 3’overhangs, overhangs invade sister chromatids, align homologous regions, synthesis occurs on both strands of the DSB, and then the halliday junction is resolved.

NHEJ

Non-homologous end joining. DDK and BRCA1 bind ends of DSB, resect them slightly, and then they are pasted back together. Thid pathway is error-prone and is active in G1 before replication

DNA transposons

Transposons that undergo transposition without an RNA intermediate, encode for transposase, possess inverted terminal repeats, and jump from one locus to another

Retrotransposons

Move via an RNA intermediate, in a “copy and paste” mechanism. RNA intermediate encodes for integrase and reverse transcriptase, RT transcribes a new dsDNA copy of the transposon (from the mRNA) and it jumps with integrase.