genome variation Flashcards
what is karyotyping?
process of sorting chromosomes into their matched pairs
important technique for investigating chromosomal disorders
what are macro level differences in the genome
generally associated with disease
- aneuploidy
- translocations
what are micro/molecular level differences in the genome
sometimes associated with disease
- point mutation
- deletion
ie coding variants such as hair, height
what is exome
where the coding genes are found (about 2% of the genome)
what does polymorphic mean
position on the genome that varies between individuals (a variant)
what is a reference sequence
a consensus (general agreement) that tells us what we expect to see in the genome - used to determine whether there are any genetic variants (polymorphisms)
what are the three main causes for variations
- single nucleotide polymorphism (SNPs)
- microsatellites
- copy number variants
what is SNP?
substitution of a single nucleotide at a specific position in the genome
high in frequency, happens in 1 in every 300 nucleotides
bi allelic
What does it mean to be biallelic?
2 possible alleles
What does triallelic mean
3 possible alleles
If there are >3 possible alleles what term do we use to describe the genotype?
multiallelic
What is the major allele?
the most common allele for a given SNP
What is the minor allele?
the less common allele for a SNP
What is the minor allele frequency (MAF)?
frequency at which the second most common allele occurs in a given population
how are SNPs formed?
during mismatch repair system during DNA replication (mitosis)
Although there are mismatch repair mechanisms which should correct these mistakes, some don’t get corrected and we end up with a SNP
Where are SNPs found?
Majority not in exome bc exome has strong selective pressure to not incorporate mutations which lead to detriment in people
Where in a gene may an SNP be found and what is the impact?
No amino acid change (synonymous) Amino acid change (non-synonymous/missense) Stop codon (nonsense) Splice sit UTR (gene expression)
promoter - affects protein expression
what is the only way for SNPs to disappear?
if they have a deleterious effect or population annihilation
otherwise, SNPs never disappear
What is a missense point mutation?
A point mutation where a single nucleotide change results in a codon that codes for a different amino acid
> type of nonsynonymous substitution
an example of a disease associated with missense mutation
Sicke cell anaemia
codon GAG -> GTG
Glu -> Val
Beneficial in places where malaria is rife (heterozygote advantage)
How do we define a polymorphism?/ when is SNV described to be a mutation or polymorphism?
polymorphism = If minor allele freqy >1% mutation = MAF is <1%
rare polymorphism = MAF 1-5%
Common polymorphism: MAF >5%
Outline the features of a variant
All variants start off from a mutation and are rare
- Evoly forces affect whether or not a variant remains rare
- Rare variant may be damaging and/or recent
what are SNV/Ps called when proven to be pathogenic?
point mutations
Summarise SNVs
Millions in genome
A position in genome at which the base can vary
Can be anywhere in the genome (genic or non-genic)
May do nothing, may affect a trait, may be associated with disorder
Generally bi-allelic
Due to mutation and mismatch repair
These are base substitutions
When pathogenic, may call point mutations
What is a microsatellite?
repetitive DNA sequences usually several base pairs in length, composed of non-coding DNA and are not parts of genes, used as genetic markers to follow the inheritance of genes in families. Where a particular unit is repeated n number of times and varies between individuals = tandem repeats (one after another) - highly variable in terms of actual quantity
what is a STR?
a short tandem repeat is a micrsatellite
Can be variation in number of repeats between people
Reference often smallest allele but a range is often quoted
how do STR/ microsatellites occur?
when the polymerase slips from the template strand during replication (error in DNA replication causing microsatellite expansion)
causes the new strand to unpair (release) from the template strand, and is the main reason for codon expansion
Where in the genome are microsatellites found?
Part of the 98% of the genome not coding for protein
- Intronic or UTR: may affect gene expression
- Intergenic
Exonic
- Extra amino acids in protein
- pathogenic example?
expansion disorders
Expansion disorders, e.g. Huntington’s = trinucleotide repeat expansion disorder, basically a “bad” microsatellite
What is a copy number variation (CNV)
An entire chunk is repeated - a duplication or deletion of a very large chunk on one of the two diploid chromosomes (paternal or maternal)
What is the simplest type of Copy number variation?
the presence or absence of a gene.
An individual’s genome could therefore contain two, one, or zero copies
What causes multiple copies of a variation?
Duplication of a genomic segment
could result in diploid copy numbers of two, three, or four.
how does CNV occur?
During non-allelic homologous recombination in meiosis
Misaligning - they shift out of alignment due to sequence similarity along the chromosome (often because viral/bacterial genome incorporate into ours through evolution)
Only a problem when recombination occurs around that segment leading to exchange of material between the chromosomes: so gametes contain duplication or deletion
What is the result of allelic recombination during meiosis?
Allelic recombination is good! – shuffling of alleles
But non-allelic recombination results in duplication/deletion and copy number change
Outline the features of CNVs
Intergenic
But quite large (>1kb) so often affect one or more genes (parts of genes)
12% of genome is copy number variation
Microdeletion disorder eg, deGeorge syndrome
Give examples of pathogenic CNVs
Microdeletion disorders, e.g. diGeorge syndrome
How do we determine if biallelic variants are common?
If biallelic, the frequency of the minor allele is relatively high. 2 different alleles are biallelic (2 possible alleles ie, GT not GG or AC not CC).
Population frequency
Ie. proportion of chromosomes that carry each allele in the population
What are the effects of variants?
Can be beneficial
Can be pathogenic
Most are neutral
can be used as markers to help find disease-causing genes and mutations
How commonly do variants associate with disease?
Common variants don’t usually cause diseases, and can contribute to physical trait associations. But can also also contribute to susceptibility to diseases. Ie HIV, aging, sexual desire, anxiety, allergies, height, sense of smell etc
