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Flashcards in 6. Genome Variation Deck (19):

What is polymorphic?

A genetic variant


How do we know what is normal and what is a variant?

The human genome mapping project aimed to provide a complete human genome sequence.


What is SNV?

Single nucleotide variant (the same as SNP)
• High frequency
• Majority not in exome
• Generally bi-allelic (can be tri-allelic)
• Can be anywhere in the genome (genic or non-genic)
• May do nothing, may affect a trait, may be associated with disorder - When pathogenic, may call point mutations
• Due to mutation (base substitutions) and mismatch repair during DNA replication
- Mismatch repair is the process where there is a mismatch made during DNA replication (wrong base) and then the original strand is repaired to match the mistake and hence in this position you will find 2 different bases. ~ if this change occurs in the gametes and isn't deleterious then it will get passed on to the next generation
• As time goes on it can spread through the population.


What is bialleic?

Pertaining (relating) to both alleles (both alternative forms of a gene)


In which regions of the DNA can SNVs be found? and their effects?

• Gene
- No amino acid change (synonymous)
- Amino acid change (non-synonymous/missense)
- Stop codon (nonsense)
- Splice site
- UTR (gene expression)

• Promoter
- Protein expression

• Non-coding region


What is MAF?

• Minor allele frequency (MAF) – refers to the frequency at which the second most common allele occurs in a given population
• If the MAF is less between 1-5% then it is rare.
• If the MAF is bigger than 5%, then it is common
• Evolutionally forces affect whether or not a variant remains rare (rare variants may be damaging and/or recent)


How do SNV and evolutionary forces interact? - the different processes.

• GENE FLOW - migration leading to introduction of that variant into another population
• GENETIC DRIFT - Randomchange in variant allele frequency between generations
• SELECTION - Non-random chane in variant allele frequency between generations because presence of one allel/genotype is pathogenic (negative selection) or beneficial (positive selection).


Where are genetic variants most likely to be neutral?

• Depends on the type of variant (lots of variants in every gene –some pathogenic, some not; depends on the environment)
• e.g. If in a developmental gene, they are most likely pathogenic. If in a pigmentation gene, they may not be what we would refer to be pathogenic, but account for variation.


Is every genome exactly 300mb?

No, because of STR (short tandem repeats) ~ STR = microsatellites = simple sequence repeat (SSR).
These are when DNA motifs are repeated, e.g. 2 or more nucleotides repeated. - the number of repeats is highly variable between individuals.


What does 12/7 mean in terms of the DNA sequence?

the 12 in front shows the alleles and the whole thing (12/7) shows the genotype.


How is microsatellite expansion caused in the region of the Huntington gene?

• This is caused by the process of polymerase slippage - when the polymerase slips from the template strand during replication.
• This occurs when a DNA sequence is present in more than one copy on the chromosome. - in this case, there is a repeat of the CAG (glutamine).
• The slippage causes the new strand to unpair from the template stand. So, when the new strands tries to reattach to the new strand, it may reattach at the wrong copy (which is usually the one that is further back than the one where the polymerase slipped). ~ As a result, the new strand forms a loop of unpaired bases.
• The polymerase will add an extra glutamine as it passes over the CAG, causing expansion.
• The polymerase slippage can also decrease the size of the microsatellite - but this happens less often.


Where are microsatellitse found?

• Part of the 98% of genome not coding for protein
- Intronic or UTR: may affect gene expression
- Intergenic

• Exonic
- Usually adds extra amino acids in protein ~ can be pathogenic like Huntington's


What is CNV?

• Copy number variant (CNV)
• You can get copies big chunks of a DNA sequence, or even a deletion.
• This happens a lot, but the results may not cause a big problem.

• The simplest type of copy number variation is the presence or absence of a gene. - An individual’s genome could therefore contain two, one, or zero copies.
• Duplication of a genomic segment
could result in diploid copy numbers of two, three, or four.

• CNVS may be intergenic
- But – quite large (>1kb) so often affect one or more genes (parts of genes)


What is non-allelic homologous recombination in meiosis

• This is different to allelic recombination
• Different regions of the homologous chromosomes are identical, which can cause misalign of the chromosomes and during crossover, it can cause deletion in one chromosome and duplication in the other, copy number change.


Summary of the different types of common genetic variant

• Single Nucleotide Polymorphisms (SNPs) ~17 million identified; ~3 million/genome
• Microsatellites ~3% of the genome
• Copy Number Variants (CNVs) >2000 identified; ~100 per genome
• Everyone “has” every variant, what may differ between individuals is the genotype


How common are biallelic variants?

• If biallelic, the frequency of the minor allele is relatively high
- Population frequency
- i.e. proportion of chromosomes that carry each allele in the population


What are common variants and disease/trait associations?

• Most common variants not causing Mendelian, monogenic disorders.
• Majority are probably neutral (particularly intergenic variants).
• May well impact upon complex, non-Mendelian disorders and undoubtedly contribute to general individual variation (personality, sporting ability, looks etc)


What are variant effects? Can they be useful?

• Can be beneficial
• Can be pathogenic
• Most are neutral
• They can be used as markers to help find disease-causing genes and mutations
- Autozygosity mapping & linkage studies (Microsatellites, SNPs)
- Association analysis (SNPs, CNVs)


The book analogy.

• Whole book = genome
• Chapter = chromosome
- Delete or duplicate chapter and you can really mess the story up
• Paragraph = CNV
- Delete or duplicate a paragraph and, as long as it’s not key, you can make do
• Sentence = microsatellite
- Accidentally repeat several words within that sentence, you elongate it, it’s annoying but not fatal to the plot (unless its key)
• Letter = SNP
- Typos often barely change the meaning at all