Genome Variation

Question 1

How big is the human genome?

Answer 1

3 billion bases
About 20,000 genes
About 2% of the genome codes for protein = exome

Question 2

What are major macro-level differences associated with? Examples

Answer 2

Associated with disease (aneuploidy, translocations etc)

Question 3

What are micro or molecular level pathogenic differences associated with? Examples

Answer 3

Sometimes associated with disease (point mutation and SCA, 3bp deletion in CFTR)

Question 4

What do coding variants effect?

Answer 4

Effect traits such as height, hair colour, intelligence etc

Question 5

What is a variant?

Answer 5

Any position in the genome that varies between individuals

Question 6

Homozygous

Answer 6

Same alleles

Question 7

Heterozygous

Answer 7

Different alleles

Question 8

Reference allele

Answer 8

What you would expect the base to be at a particular position on the chromosome

Question 9

Usefulness of the human genome mapping

Answer 9

Enabled us to base all our assumptions of what we expect given positions on the genome to be hence the reference alleles.

Question 10

What is an SNP?

Answer 10

A change in a single base

Question 11

How many SNPs are there when comparing the human genome?

Answer 11

Approx. once every 300 bases

Question 12

In an individual, how many SNPs are there per base?

Answer 12

1 every 1000 bases

Question 13

How many SNVs have been identified in the human genome?

Answer 13

About 17 million

Question 14

How does a SNP occur?

Answer 14

Typically caused by faulty replication of DNA during mitosis. There is a mismatch repair mechanisms that should correct these mistakes, some don’t get corrected and end up as a SNP.

Question 15

How does the mismatch repair system work?

Answer 15

Repair the parental strand and not the new strand resulting in the T being changed for a C. This will result in variation.

Question 16

What is the polymerase slippage event?

Answer 16

• The polymerase in the template strand during replication slips.
• It causes the new strand to unpair (release) from the template strand.
• If occurs in the codon repeat region, then the new strand will reattach to the template strand and it will have many identical copies of the codon to choose from.
• With so many identical codon copies to reattach to, the new strand may reattach to the template at the wrong copy.
• The new strand forms a bubble of unpaired bases, which represents the expansion of the new strand.
• The template strand will realign with the new strand and bring the bases from the bubble back into line with the template strand.
• The brand new double helix of DNA contains more CAGs in the repeat region.

Question 17

Where are SNPs located/

Answer 17

In the 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
- Less likely to have a detrimental effect

Question 18

Why do SNPs not disappear?

Answer 18

Without a deleterious effect or population annihilation, they remain.

Question 19

Describe the distribution of the SCA variant allele in the european population

Answer 19

0.02% - 2 in every 10,000 chromosomes

Point mutation very rare in white European population

Question 20

Describe the distribution of the SCA variant allele in the african population

Answer 20

4.5% - about 1 in every 20 chromosomes

But, relatively common in black African population

Question 21

What is the heterozygous advantage of SCA?

Answer 21

Beneficial in places where malaria is rife

Question 22

What is a minor allele frequency?

Answer 22

Frequency is greater than 1 then in at least 1 in every 100 chromosomes has non-reference allele

Question 23

Describe the MAF levels in rare and common polymorphisms

Answer 23

Rare - MAF 1-5%

Common - MAF > 5%

Question 24

What affects whether a variant remains rare?

Answer 24

• All variants start off rare (via the mismatch repair system).
• Evolutionary forces affect whether or not a variant remains rare.
• Rare variants may be damaging and/or recent,
• However, some minor allele frequencies may have just occurred therefore using the 1% measure may also be accurate to distinguish between a mutation and a polymorphism.

Question 25

What are the evolutionary forces that affect SNVs?

Answer 25

• Mutations: New allele arises, now a variant
• Gene flow: migration leading to introduction of that variant into another population
• Genetic drift: Random change in variant allele frequency between generations
• Selection: Non-random change in variant allele frequency between generations.
  - Pathogenic (negative selection)
  
  • Beneficial (positive selection)

Question 26

What do genetic variants most likely cause?

Answer 26

Most likely cause a detrimental effect if they are in a gene especially in a key developmental gene.

Question 27

What is a microsatellite?

Answer 27

A short repeating sequence in the DNA unit.

Question 28

Where are microsatellites located?

Answer 28

• Part of the 98% of genome not coding for protein
  - Intronic or UTR: may affect gene expression
  - Intergenic
• Exonic
  • Extra amino acids in protein
  • Expanison disorders e.g. Huntington’s = trinucleotide repeat expanison disorder

Question 29

What is a copy number variant?

Answer 29

Large sections of the genome are repeated and the number of repeats in the genome varies between individuals

Question 30

What is the simplest type of a copy number variation?

Answer 30

The presence or absence of a gene.

Question 31

What can a duplication of a genomic segment result in?

Answer 31

It could result in diploid copy numbers of two, three, or four.

Question 32

How does the duplication or deletion of loci on chromosomes occur?

Answer 32

It occurs via non-allelic homologous recombination.

Question 33

How does non-allelic homologous recombination occur?

Answer 33

This is due to misaligned crossover driven by sequence similarity due to viral/bacterial genomes which have incorporated during evolution.

Question 34

Where are CNVs located?

Answer 34

• Intergenic
• Often affect one or more genes (parts of genes)
• About 12% of genome is CNV

Question 35

Give an example where the CNV is pathogenic?

Answer 35

In microdeletion disorders e.g. DiGeorge syndrome

Question 36

Give some types of common genetic variant

Answer 36

• SNP: 17 million identified - about 3 million/genome
• Microsatellites: about 3% of the genome
• Copy number variants: about 2000 identified

Question 37

What do most common variants cause?

Answer 37

Probably neutral (particularly intergenic variants). Most common variants do not cause mendelian, monogenic disorders.

Question 38

What are the effects of variants?

Answer 38

• Can be beneficial
• Can be pathogenic
• Most are neutral
• Used as markers to help find disease-causing genes and mutations.

Question 39

Give examples of tests that can be used to find diseases and mutations

Answer 39

Autozygosity mapping and linkage studies - microsatellites, SNPs

Association analysis - SNPs and CNVs

Question 40

Locus

Answer 40

Unique position in genome

Question 41

Allele

Answer 41

Particular form of a specific locus

Question 42

Biallelic

Answer 42

2 possible alleles

Question 43

Triallelic

Answer 43

3 possible alleles

Question 44

Multiallelic

Answer 44

> 3 alleles

Question 45

Genotype

Answer 45

An individual has 2 alleles for any autosomal locus (heterozygous/homozygous)