Types of mutations Flashcards
what are the small scale mutations?
a. point mutation
b. substitutions
c. inversion
d. insertion
e. deletion
what are the large scale mutations?
chromosomal rearrangements
a. deletion, replication, inversion, translocation
what are copy number variations?
A type of genetic variation where the number of copies of a particular gene/region of a genome differs from one individual to another
what are mobile genetic element (transposable element)-induced mutations?
Sequences of DNA that can change their position within the genome –> the ability to move/”transpose” can lead to various types of mutations and genetic variations
how can point mutations be classified by?
amino acid changes (synonymous vs nonsynonymous mutations) and DNA sequence changes (transition vs transversion mutations)
what are transition mutations?
Purine → purine ; pyrimidine → pyrimidine
what are transversion mutations?
Purine → pyrimidine ; pyrimidine → purine
which bases are purines and which bases are pyrimidines?
purines: G, A
pyrimidine: C, T
synonymous mutations
A change in a nucleotide in the DNA sequence that codes for amino acids in a protein sequence but does NOT change the encoded amino acid sequence
aka silent mutation
nonsynonymous mutations and the different subtypes?
mutations in a single nucleotide that RESULTS in an amino acid sequence change
a. missense
b. nonsense/stop-gain
c. stop-loss
d. start-loss
e. start-gain
how many different mutation sequence context types are there?
96: 16 sequence contexts (=4x4 different DNA bases for the two positions) and 6 (combining complementary strand sequences) point mutation types → 16 * 6 = 96 mutation sequence context types
missense mutations
mutations in a single nucleotide that results in a substitution of a different amino acid –> a change in the protein encoded
can alter the function of the protein
nonsense mutations
the original amino acid is changed to a stop codon –> results in truncated or nonfunctional protein
what is an example of a nonsense mutation?
TP53 R213: a point mutation in the TP53 gene located on chromosome 17 at position 213 of the protein (7578212th position on Chr 17) where arginine (R) is replaced by a stop codon → causes premature termination of translation process and results in a truncated nonfunctional TP53 protein
stop-loss mutation
the loss of the normal stop codon –> results in abnormal elongation of a protein’s C-terminus until the next stop codon is encountered
start-loss mutation
the start codon (ATG) is lost –> eliminates gene function
start-gain mutation
a point mutation that creates a new start codon (ATG) upstream of the original starting site
if new ATG is CLOSE enough to the original one and in frame, it will be used to initiate translation → adding amino acids to the amino terminus of the original protein
If it is out of frame, it will NOT affect translation of the original protein
generally has low impact on gene function
how many possible numbers of different point mutation types with respect to DNA sequence change?
6 distinct ones: C –> G, C –> A, C –> T, T–> A, T –> C, T –> G
what is the start codon?
ATG
what are the three stop codons?
TAG - UAG
TAA - UAA
TGA - UGA
–> usually codes to Ter
what are the results of insertion and deletions on genes?
a. frameshift mutation that changes the reading frame
b. splice site mutation where splicing usually occurs → would change the transcript so introns could be inserted to mature mRNA molecules
frameshift mutation
changes where translation begins and affects downstream amino acids –> significantly altered or nonfunctional protein
splice site mutation
a mutation at the intron-exon junctions (splice sites) of a gene –> retention of introns and exclusions of exons in mature mRNA –> proteins missing crucial regions or contains nonfunctional sequences
what does an amino acid consist of?
a carboxylic acid group, an amino group, and a side chain (denoted as R)
how many different codons are there?
64: 444 = 64 different codons (possible combinations of 3 nucleotides)
how many possible reading frames does a single-stranded DNA sequence have? what about double-stranded DNA sequence?
3: can start translating the DNA strand into RNA template from the 1st nucleotide, 2nd, or 3rd
6
What does COSMIC stand for and what is its definition?
Catalogue Of Somatic Mutations In Cancer
Definition: an online expert-curated database of somatically acquired mutations found in human cancer and somatic mutation mechanisms causing human cancer
what are somatic mutations and their common causes?
somatic mutations: mutations that can occur in all body’s cells EXCEPT for germ cells (sperm, egg) and occur over an individuals life and are NOT hereditary (cannot be inherited or passed down)
common causes:
DNA damage or modification
DNA replication errors
Defective DNA repair
Mutagen exposures
Enzymatic modification of DNA
Exposures (ie. tobacco smoking)
–> leaves mutational signatures
what are mutational sequences?
specific patterns/alterations in the DNA sequence that arise from mutations
Signature 1?
One of the earliest identified mutational signatures cataloged in the COSMIC database
found in all cancer types and in most cancer samples
Proposed etiology: the result of an endogenous mutational process initiated by spontaneous deamination of 5-methylcytosine (the loss of an amine group from C → converting into T
5-methylcytosine undergoes deamination → leads to a C → T transition during DNA replication) associated with small numbers of small insertions and deletions in most tissue types
the number of Sig1 mutations correlates with age of cancer diagnosis
serves as a potential biomarker for age-related mutational accumulation
Signature 4?
specifically linked to tobacco exposure and has been found in various cancers associated with tobacco use/exposure
proposed etiology: associated with smoking (mutagenic effects of tobacco-related compounds are thought to primarily damage DNA bases, especially Guanine G)
exhibits transcriptional strand bias for C –> A mutations, especially CC –> AA dinucleotide substitutions
Sig29 also found in cancers associated with tobacco chewing
what is the deamination of 5-methylcyotsine?
Leads to a C→T transition mutation during replication; if DNA is left unrepaired, the newly synthesized DNA strand will incorporate an A instead of a G
How does the transcriptional strand bias for C –> A mutations found in Sig4 relate to transcription-coupled nucleotide excision repair (TC-NER)?
Sig4 exhibits transcriptional strand bias for C>A mutations, compatible with the notion that damage to guanine is repaired by transcription-coupled nucleotide excision repair
These mutations preferentially occur on the DNA strand that is being actively transcripted into RNA
This bias supports the hypothesis that transcription-coupled nucleotide excision repair (TC-NER) is involved in repairing DNA damage caused by tobacco exposure → the repair machinery preferentially targets damaged bases on the transcribed strand
What is the full name of TCGA and its definition?
The Cancer Genome Atlas
Definition: a landmark cancer genomics program, molecularly characterized over 20,000 primary cancer and matched normal samples spanning 33 cancer types
a. Joint effort between the National Cancer Institute and the National Human Genome Research Institute that began in 2006
b. Generated over 2.5 petabytes of genomic (ie. mutations, copy number variations), epigenomic (methylation patterns), transcriptomic (ie. gene expression profiles) and proteomic data (study of proteins, their structions, functions, and modifications)
d. data has already led to improvements in our ability to diagnose, treat, and prevent cancer and will remain publicly available
What is the difference between COSMIC and TCGA?
COSMIC focuses on somatic mutations in human cancer. It’s special in that it catalogs mutational signatures each associated with different mutations or exposures (ie. Signature 1 is linked to the deamination of 5-methylcytosine)
TCGA also catalogs genetic mutations in human cancers but contains a much broader dataset that has not only somatic mutations, but also include genomic, epigenomic, transcriptomic, and clinical data pertaining to the specific cancer type
What is the cBioPortal for Cancer Genomics?
A powerful web application that provides visualization, analysis and download of large-scale cancer genomics data sets
A web application platform that facilitates data exploration and analysis through the use of a variety of visualization and analytical tools (ie. comparative analyses, survival analysis)
what are the definitions for point mutations, substitution, inversion, insertion, and deletions?
point mutation: a single base substitution (a subset of substitution)
substitution: when one or more bases is replaced by the same number of bases
inversion: when a segment of chromosome is REVERSED end to end
Insertion: a base is added to the DNA sequence
Deletion: a base is removed from the DNA sequence
How many mutation signatures for COSMIC (v2: Mar 2015)?
30 single base substitutions mutation signatures (including sig1 and sig4)
what is the timeline and key developments in COSMIC?
Version 1. (2013) 20 signatures (only SBS)
V2. (2015) 30 signatures (only SBS)
V3. (Feb 2020) 49 signatures (SBS, DBS, small Indels)
V3.1. (June 2020) 54 signatures (SBS, DBS, small Indels)
What is TCGA’s PanCancer Atlas
In April 2018, TCGA research network marked the end of the TCGA program by publishing the Pan-Cancer Atlas: a collection of cross-cancer analyses delving into overarching themes on cancer, including cell-of-origin patterns, oncogenic processes and signaling pathways
The TCGA data provides…
Our current understanding of the disease
How basic research is changing patient treatment
The future of multi-omic studies in cancer
