Genome Variation Flashcards
What is a genetic bottleneck?
A sharp reduction in the size of a population due to environmental events such as famines, earthquakes etc or human activities such as genocide.
Diversity in the form of genetic variation is reduced.
What are somatic cells?
Somatic: Any cell of the body except sperm and egg cells.
Are somatic cells diploid or haploid?
Diploid - two sets of chromosomes, one inherited from each parent
Are somatic cell mutations inheritable?
No - Mutations in somatic cells can affect the individual, but they are not passed on to offspring.
What are germline cells?
A germ line is the sex cells (eggs and sperm)
Are germline cells diploid or haploid?
Haploid - they contain a single set of chromosomes.
Are germline cell mutations inheritable?
Yes - can be inherited as mutation in egg/sperm is passed to offspring
Are somatic or germline mutations more common?
Somatic
What are the 2 factors that influence uncorrected errors in genetic variation?
- Exogenous factors
- Endogenous factors
Example of exogenous factors?
Radiation, chemicals - mostly somatic
Examples of endogenous factors?
- Segregation (Aneuploidies e.g. Downs Syndrome)
- Recombination (Translocation)
- DNA replication errors (mispaired bases, slippage)
- Inadequate DNA repair mechanisms (mismatch repair, base excision repair)
What are the 2 classes of variation?
- Variation that does not alter the DNA content (number of nucleotides is unchanged)
- Variation that results in a net loss or gain of DNA sequence - can be large (whole chromosome) or small (single nucleotide)
What are examples of variation that does not alter the DNA content?
- Single nucleotide replacements
- Balanced translocations or inversions
What is ‘neutral variation’?
The majority of mutations have neither negative nor positive effects on the organism in which they occur –> no obvious effect on phenotype
E.g. Silent point mutations
Why are silent point mutations ‘neutral’?
They do not change the amino acids in the proteins they encode
What is a single nucleotide variant (SNV)? How does it differ from a single nucleotide polymorphism (SNP)?
SNV: a variation in a single nucleotide without any limitations of frequency
SNP: a type of SNV (a substitution of a single nucleotide at a specific position in the genome) that is present >1% of population
What is the most common SNV?
C –> T
What is a SNV that is more common than 0.01 (1%) known as?
Polymorphism
What is a SNV that is less common than 0.01 (1%) known as?
Rare variant
What are ‘indels’?
An insertion or deletion of one or more nucleotides
What is Restriction Fragment Length Polymorphisms (RFLPs)?
A technique that exploits variations in homologous DNA sequences (polymorphisms) in order to distinguish individuals, populations, or species or to pinpoint the locations of genes within a sequence.
Detected through the differing locations of restriction enzyme sites.
What are restriction enzymes?
Type of nuclease enzymes - a protein that recognises a specific, short nucleotide sequence and cuts the DNA only at that specific site, which is known as restriction site or target sequence
What are CNVs?
Large indels - change in copy number of sequences (repeats) greater than 100 nucleotides in length
Sections of the genome are repeated and the number of repeats in the genome varies between individuals.
What type of variation are CNVs?
Structural - it is a type of duplication or deletion event that affects a considerable number of base pairs.
What is the most abundant type of variation?
SNVs
What are SNPs?
DNA sequence variation occurring when a single nucleotide (A, C, T or G) in the genome differs between members of a species (or between paired chromosomes in an individual)
What is minor allele frequency?
The frequency of the less common variant in a population (the frequency at which the second most common allele occurs in a given population)
What is an allele?
An allele is a variant form of a gene.
An individual inherits two alleles for each gene, one from each parent. If the two alleles are the same, the individual is homozygous for that gene. If the alleles are different, the individual is heterozygous.
What are intronic/intergenic variants?
Mutation between genes (intergenic) or between exons (intronic)
Do intronic/intergenic variants affect resulting protein directly?
No - but could affect regulation of transcription or splicing
What are coding ‘exonic’ variants?
Mutations in coding region - likely to have an effect
What are the 3 types of ‘exonic’ variants?
- Missense mutation
- Nonsense mutation
- Silent mutation
What is a missense mutation?
A point mutation in which a single nucleotide change results in a codon that codes for a different amino acid.
i.e. an amino acid change
Is a missense mutation synonymous or nonsynonymous?
Nonsynonymous as the amino acid sequence is altered
What is a nonsynonymous mutation?
A nucleotide mutation that alters the amino acid sequence of a protein
What is a nonsense mutation?
A stop mutation
A change of amino acid to a stop codon, which causes a protein to terminate or end its translation earlier than expected
What is a silent mutation?
The codon for an amino acid is changed but the same amino acid is still coded for
E.g. GGC and GGU both code for Glycine
Is a silent mutation synonymous or nonsynonymous?
Synonymous as does not alter amino acid sequence
What is a synonymous mutation?
Does not alterer amino acid sequence
What are simple repeats?
DNA stretches consisting of short, tandemly repeated nucleotide motifs that show high level of length polymorphism due to insertion or deletion mutations of one or more repeat types
What are simple repeats also known as?
- Microsatellites
- Variable number of tandem repeats (VNTRs)
- Short tandem repeats (STRs)
- Simple sequence repeats (SSRs)
Why do microsatellites have a higher mutation rate than other areas of DNA?
Unstable and prone to replication slippage
What diseases are caused by microsatellites?
Huntington’s disease, Fragile X syndrome
Are simple repeats subject to genetic anticipation?
Yes
What accounts for a large proportion of CNVs?
Non-coding genes
What genes are enriched for CNV regions (CNVR)?
Immune response, drug metabolism, olfactory receptor genes
Why are immune response genes enriched with CNV regions?
Need to be extremely diverse in order to respond to wide range of pathogens
E.g. immunoglobulin and T-cell receptor genes
What are olfactory receptor genes enriched with CNV regions?
Need to be diverse in order to respond to large number of sensory inputs they receive
What are olfactory receptors?
Are expressed in the cell membranes of olfactory receptor neurons and are responsible for the detection of odorants which give rise to the sense of smell.
Are genes such as: protein phosphorylation, signal transduction, protein degradation, transcriptional machinery and regulation enriched in copy number stable or copy number variable genes?
Copy number stable - these genes are essential for survival (unlike olfactory receptors)
Does the majority of genetic variation have an effect on our phenotype?
No - most is neutral and has negligible or no effect on phenotype
Difference in mutations between functionally constrained and not functionally constrained parts of our DNA?
Not constrained (about 90% of our genome): Generally permissive of variation and mutations are common
Constrained (about 10% of our genome): Mutation not as common as not as permissive
What happens if mutations within the constrained portion are strongly deleterious?
They will be quickly eliminated by natural selection
Only mutations that have, at worst, a mildly negative effect will be observed as segregating in the population
Survival of mutations causing late onset disease vs early onset?
Late onset: not subject to negative purifying selection and can be more frequent
Early onset: will not persist
When does positive selection of CNVs occur?
When variation is thought to be beneficial
E.g. The human AMY1A gene –> individuals in populations that have high-starch diets have significantly more AMY1A gene copies
Is most human genetic variation found within populations or between human populations?
Within populations (85-90% of human genetic variation is found within populations
Even when the most distinct populations are considered, individuals are frequently more similar to members of other populations than to members of their own population
Non-African populations have fewer low frequency variants. What does this reflect?
Recent bottlenecks
Is most variation silent?
YES
How do bottlenecks affect variation?
Reduce variation
How does positive selection affect diversity?
Reduces diversity in response to environmental adaptations (e.g. sunlight exposure, diet)
Is the genetic change seen in an SNP the same as the genetic change seen in an SNV?
Yes
What is the most common type of genetic variation?
SNPs
How can SNPs change the length of a protein?
May change a codon to a stop codon -> would shorten length of protein
What is an example of a mononucleotide repeat?
CCCCCC
Are genetic repeat sequences different in length between individuals?
Yes
CNVs are more common near the centromeres and telomeres. Why is this?
Near the centromere and telomere there are lots of complex and simple repeat regions. At mitosis/meiosis, those repeats can lead to duplications and deletions occurring.
In what % of the genome do CNVs occur?
4-10%
Are CNVs evenly distributed across the genome?
No
Are CNVs usually benign?
No
Is genetic variation greater within non-African populations?
No - greater within African populations
