Mutation rates in man Flashcards
What are the different levels of mutation?
Chromosomal - aneuploidy
Genomic regional - translocational/inversion
Whole gene level - whole gene deletion/duplication
Nucleotide level - change, deletion, duplication, change of nucleotide sequence
What are germline mutations?
Can be inherited by offspring
What are somatic mutations?
Postzygotic mutation
these are not inherited
When are mutations heritable in all situations?
Heritable at the cellular level
Do mutations occur in hotspots and what are the main mechanisms of molecular hotspots?
Yes:
Transitions of CpG dinucleotides
Slipped mispairing at DNA replication
What is the CpG mechanism hotspot?
Transitions at CpG dinucleotides
Methylation of cytosine ( to 5- methyl cytosine) next to a guanine is the major form of DNA modification
What is the slipped mispairing hotspot?
Slipped mispairing at DNA replication
- changes in repeat number in a microsatellite repeat
- offspring has an allele of a different size than either parent
can occur at increased frequency due to defective mismatch repair - mutator phenotype, seen at multiple loci
-e.g. colon cancer
What did Weinberg notice about achondroplasia and why was this?
That it is most often the last born children with the disease which is supposedly due to there being a higher mutation rate in older men so more sperm mutations.
Does the type and frequency of mutation differ between males and females?
Yes since many mutations occurring on the X chromosome are inactivated in females.
What is Achondroplasia and where does this mutation occur?
ACH is a fully penetrant dominant disease (dwarfism)
Occurs at the CpG dinucleotide of methylcytosine to thymine
What do these six conditions have in common: Crouzon Pfeiffers syndromes MEN 2A MEN2B Apert syndrome Achondroplasia
All of paternal origin
All single base mutations
6 conditions involve 3 genes.
What is the cause of high male mutation rate?
many more cell divisions in male gametogenesis than females.
DNA replication/repair is the majority of mutations so expect a higher rate.
predicted increase of genetic load with age.
predicted increased frequency of paternally derived mutations.
What does a greater number of replications in males vs female gametogenesis predict?
An increased frequency of paternally derived mutations
An increased genetic load with age
What does accurate DNA sequencing of the whole human genome allow us to do?
Compare the mutations in both parents with offspring
Therefore get an estimate of new mutations produced in each generation.
What does every additional year of paternal age result in, in terms of mutations in the offspring?
per every additional year, there are on average an extra 2 mutations in the offspring
How many mutations are transmitted in maternal figures?
Always 15 mutations in offspring regardless of age
Is there an acceleration rate of mutation with paternal age?
Yes
Why is there an accelerating rate of mutation?
Reduced fidelity of DNA repair and replication mechanisms
Cell death in old age might be compensated by increased number of cell divisions
Accumulation of mutagens
What are the exceptions to the paternal age effect?
Neurofibromatosis I
Duchenne Muscular Dystrophy
Both are extremely large genes (55-59 exons) and hence mutation rates are very high as there are many deletions.
Why are deletions common in large genes?
They have the space to take them out. Such deletions in smaller genes would be lethal and therefore not observed.
Why are small chromosomal deletions not age dependent?
They occur through a different mechanism.
Rate of occurrence of deletions is higher in females than males
What are special about these loci:
FGFR2, FGFR3 and RET ?
Mutation exclusively paternal
Unique to spermatogenesis
Paternal age effect is observed
Mutations are all gain of function and confer a selective advantage.
What other mutation type shows a sex bias?
Trinucleotide repeats:
Eg. Huntingtons disease (CAG 11-34 repeats)
Paternally derive loci have more repeats than maternally derived ones
Is mutation rate determined by evolution?
Mutation rates as a balance between benefit and liability:
too low leads to a species that is not adaptive
- too high leads to a species in which there is disease
