Genome Variation Flashcards
How many bases does the human genome contain?
→ 3 billion bases
How much of the genome codes for proteins?
→ 2%
What are 2 examples of macro level differences associated with disease?
→ Aneuploidy
→ Translocations
What are micro level differences associated with disease?
→ point mutation
→ SCA
How much DNA is the same between 2 people?
→ 99.7%
What is a variant?
→ Any position in the genome that varies between individuals
Polymorphic
What does a reference sequence do?
→ Summarize what base the vast majority of people have at that position (expected base sequence)
What is a reference allele?
→ The most common and major allele
What are all the assumptions of what is normal and a variant based on?
→ the human genome mapping project
What is a SNP?
→ change in a single base
How many SNVs are there in the human genome?
→ 17 million
How are SNVs generated?
→ Faulty replication of DNA during mitosis
→ Mismatch repair mechanisms change base on template strand to match the synthesising strand.
→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 the frequency of a SNP in an individual?
→ 1 in every 1000 bases differ from the reference sequence
Describe the faulty replication that leads to a SNV/SNP in a strand that is GTTC (1) and the other strand (2) is CGGT
→ Two strands separate during replication
→ 2nd A in strand two of (1) gets replaced with a G
→ The mismatch repair mechanism identifies this and corrects it so the bases are a Watson Crick pair
→ The T on (1) is replaced with a C on the template strand
→ The bases match but it is not the original sequence
→If this change occurs in the gametes and isn’t deleterious then it will get passed on to the next generation
What does biallelic mean?
→ Two possible alleles present at a site
In what 3 regions can SNVs be in?
→ Genes
→ promoter
→ Non coding region
What 4 changes can SNVs cause within genes?
→ Synonymous
→ Non-synonymous
→ Nonsense
→ Affect where splicing occurs
What are the two things that can cause SNVs to disappear?
→ Deleterious effect
→ Population annihilation
Why is it better to use the term SNV and not polymorphism?
→ Polymorphism can imply no pathogenic effect
What change does Sickle cell anaemia have?
→ Codon GAG to GTG
→ Glutamic acid to valine
What is the criteria for an allele to be a polymorphism?
→ if the minor allele frequency is > 1%
→ at least one every 100 has a non reference allele then it can be called a polymorphism
What is the criteria for an allele to be a mutation?
→ Minor allele frequency of less than 1%
What is the criteria for a rare polymorphism?
→ 1-5%
What affects whether a variant remains or not?
→ Evolution
Why are rare variants damaging or recent?
→ rarity means the individuals don’t reproduce
→ mortality/ can’t reproduce
→ recent means they haven’t had the chance to reproduce
Why do all variants start off rare?
→ They take time to spread if they are not damaging
How do new alleles arise?
→ Mutation
What is gene flow?
→ Migration leading to the introduction of a variant into another population
What is genetic drift?
→ Random change in variant allele frequency between generations
What is selection and why does it occur?
→ Non- random change in a variant allele frequency between generations
→ because the presence is either pathogenic (negative selection)
→ or beneficial (positive selection)
When are genetic variants most likely to be neutral?
→ If they are within the non coding region
→ If they are a gene that has minor effects eg pigmentation and not developmental
What is a microsatellite?
→ An area that is repeated (many repeating base pairs)
What are microsatellites also called?
→ Short tandem repeats
What are microsatellites like across individuals?
→ Highly variable
Why are microsatellites not biallelic?
→ they are multiallelic
→ Can be 10 or 12 different alleles
→ There can be more than 1 repeat it is not binary
Describe the polymerase slippage model
→ Polymeras slips and causes the new strand to unpair from the template
→ If the slip happens at a region that has many repeats it has many identical codons to reattach to
→ The new strand may reattach to the template at the wrong codon
→ It can reattach at a more distant point than it was attached to before
→ because of this the new strand forms a bubble of unpaired bases
→ The repair mechanisms open the bubble and replace the baes
Where in the genome can microsatellites be found in?
→ Intronic - UTR
→ Intergenic
→ Exonic
What type of disorder is Huntingtons?
→ Trinucleotide repeat expansion disorder
CAG unit is incorporated and increases in length
What is a copy number variant?
→ Variation in the number of copies of the same gene between people
What is the simplest type of copy number variant?
→ Presence or absence of a gene
How many copies does a normal person have of a gene and why?
→ 2
→ there are a pair of homologous chromosomes and every locus should be diploid (mother and father)
Describe non allelic homologous recombination in meiosis
→ Sometimes chromosomes misalign
→ You can get sequence similarity between different parts of the chromosomes
→ When chromosomes align they look for sequence similarity
→The presence of duplicated sequences can “trick” the recombination machinery to initiate a crossover event
→ There can be deletion of one and a copy number change in the other
Why are there some identical parts of genes in maternal and paternal chromosomes?
→ Viral or bacterial genomes that have been incorporated through evolution
What % of the genome is a copy number variant?
→ 12%
What is an example of a microdeletion disorder?
→ diGeorge syndrome
List the types of genetic variants and their incidence
→ SNP - 17 million detected
→ Microsatellites - 3%
→ CNV - > 2000 identified
What do common variants contribute to?
→ Personality
→ looks
→ sporting ability
What are some diseases/trait associations that come from common variants?
→ height
→ allergies
→ Haemochromatosis → diabetes → alzheimers → anxiety → Dyslexia → Memory → sexual desire → ageing → nicotine dependance
What are the three possible effects of variants?
→ Beneficial
→ Pathogenic
→ Most are neutral
What can variants be used for?
→ Markers to help find disease causing genes and mutations
What is the frequency for mutation?
If less than 1%
