week 1 reading Flashcards
define substitutions mutation
replacement of a single nucleotide by another (very common)
what is meant by the term transition?
Substitution mutation involving replacement by the same type of nucleotide - pyrimidine for a pyrimidine (C for T) or a purine for a purine (A for G)
what is meant by the term transversion?
substitution of a pyrimidine by a purine or vice versa
What is more frequent transitions of transverions?
transitions due to hotspots of CpG dinucleotides into a T
deletions
involves loss of one or more nucleotides
what can be the result of a deletion mutation?
- if this occurs in a coding sequence and involves one, two or more nucleotides that are not a multiple of three, the reading frame ill be disrupted
what can be the cause of large deletions?
unequal crossover between repeat sequences
insertions
involves addition of one or more nucleotides to a gene
what can be the consequences of insertions?
- if it occurs in a coding sequence and involves one, two, more nucleotides that are not a multiple of three, it will disrupt the reading frame
what can be the cause of a large insertion?
unequal crossover or insertions of transposable elements
define dynamic mutations
- triple repeat expansion (insertion) that make the sequence more unstable as it expands in size
- take place over number of generations within a family
what might be the reason for triplet repeat expansions?
- unequal crossover or unequal sister chromatid exchange in non-replicating DNA
- slipped-strand misfiring and polymerase slippage in replication DNA
eg. expansion (insertions) in relation to huntingtons
- expansion of CAG repeat in doing region of HTT gene and some SCA genes result in a protein with an elongated polyglutamine tract that forms toxic aggregates within certain cells
What other subdivisions for mutations are there?
according to the effect on polypeptide sequence of the encoding protein - synonymous or non-synonymous
synonymous/ silent mutations
- if it doesn’t alter polypeptide product of the gene
- eg. single base pair substitution, particularly if it occurs in the third position of a codon will often result in other triplet coding for same amino acid with no alteration in properties of resulting protein
non-synonymous mutations
- mutation leading to an alteration in encoded polypeptide
- less frequent
- likely to result in abnormal function, associated with disease or lethality
describe the three main ways in which non-synonymous mutations can occur
- missense
- nonsense
- frameshift
missense mutation
single-base pair substitution resulting in coding for a different amino acid and synthesis of an altered protein
non-conservative substitution
altered porbtein
conservative substitution
no functional effect
nonsense
substitution leading to generation of one of the stop codons will result in premature termination of translation of a peptide chain - most times shortened chain unable to retain normal biological activity
what happens to faulty mRNA transcripts containing premature termination codons due to a nonsense mutation?
degraded by the process of nonsense-mediated decay
frameshift
mutation involving insertion or deletion of nucleotides that are not. multiple of three, it will disrupt the reading frame -> frameshift
most common consequence of frameshift mutations
- result in premature stop codon downstream to the mutation
may lead to expression of truncated protein, unless the mRNA is degraded by nonsense-mediated decay
What could be the effect of mutations in non-coding DNA ? eg. promoter sequence, enhancers
affects level of gene expression (mutations in miRNA or siRNA binding sites within UTRs can also result in disease)
splicing mutations
mutations of highly conserve splice donor (GT) and splice acceptor (AG) sites result in aberrant splicing
what is the result of splicing mutations?
- loss of coding sequence (exon skipping) or retention of intronic sequence -> may lead to frameshift mutations
What are the functional effects of mutations on the protein?
- loss of function mutations
- gain of function mutations
- dominant negative mutations
loss of function mutation
- phenotypic effect
- can result in either reduced activity (hypomorph) or complete loss of gene product (null allele/ amorph)
loss of function mutations involving enzymes are inherited in what way?
autosomal/ X-linked recessive, because data;ytic activity of product of the normal allele is more than adequate to carry out the reactions of most metabolic pathways
Haploinsufficiency
- loss of function mutations in the heterozygous state
- half-normal levels of gene product results in phenotypic effects
- homozygous mutations result in more severe phenotypic effects
- eg. familial hypercholesterolemia
gain of function mutations
- increased level of gene expression or development of a new function of the gene product
- eg. point mutations or increased gene dosage - Charcot-marie-tooth disease
- more severe in homozygous state
dominant-negative mutations
- mutant gene in heterozygous state results in loss of protein activity or function as a consequence of a mutant gene product interfering with the function of the normal gene product of the corresponding allele
where are dominant-negative mutations most common in?
- in proteins that are dimers or multimers
eg. mutations in genes encoding structural proteins such as collagens can lead to osteogenesis imperfecta
Define DNA
basic template that provides blueprint for the formation and maintenance of an organism
- DNA - chromosome - genes
define chromosomes
factors that distinguish one species form another and enable transmission of genetic information form one generation to the next
- vehicle that facilitate reproduction and maintenance of a species
cytogenetics
study of chromosomes and cell division
How many chromosomes in humans?
46, abnormalities disrupts development and growth
centromere
- joins sister chromatids, consists of several hundred kilobases of repetitive DNA, responsible for movement of chromosomes at cell division
p arm
short
q arm
long
telomere
tip of each chromosome arm
- shortening part of aging process
role of telomeres
- sealing ends of chromosomes and maintaining structural integrity
- highly conserve through evolution
telomerase
- enzyme that replaces the 5’ end of the long strand during DNA replication which otherwise becomes progressively shorter until a critical length was reached when the cell could no longer divide and thus became senescent
telomeres relation to cancer
- increased activity leads to prolonged cell survival off tumour cells
morphological classification of chromosomes
- metacentric
- Acrocentric
- submetacentric
metacentric
centromere located centrally
acrocentric
centromere located terminally - formation of satellites instead of p arms
submetacentric
centromere is an intermediate position
satellites
in acrocentric chromosomes, stalk-like appendages, form nucleolus of resting interphase cell, contain multiple repeat copies of genes for ribosomal RNA
