DNA variation

Question 1

What is a variant?

Answer 1

Any position in the genome that varies between individuals is considered a variant

Question 2

What is a SNV?

Answer 2

A change in a single base

occurs approximately once in every 300 bases

Question 3

How are SNVs generated?

Answer 3

During DNA replication, the two strands separate and are used as templates to synthesise complimentary strands. When synthesising this strand, instead of incorporating an A, a G is incorporated. The mismatch repair system will identify this mistake and correct it so that the bases are a standard Watson-Crick base pair. However, instead of correcting the G, it replaces the T with a C, so we end up with either a T or a C in this position. If these changes occur in the gametes and aren’t deleterious, it will get passed onto the next generation and can spread throughout the population over time

Question 4

Where can SNVs end up in the genome and what effect can they have?

Answer 4

The gene:

• no amino acid change
• amino acid change (missense)
• stop codon
• splice split
• UTR

The promoter:
- protein expansion

The non-coding region:
- unknown

Question 5

What is the difference between mutations and polymorphisms?

Answer 5

If the minor allele frequency is less than 1%, it is a mutation.

If it is more than 1%, it is a polymorphism,

So we use the term variant as it is safer

Question 6

How do evolutionary forces affect SNVs?

Answer 6

Gene flow:
migration leading to the 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 because the presence of one allele/genotype is pathogenic/beneficial

Question 7

Describe the polymerase slippage model

Answer 7

During replication, polymerase slippage and subsequent reattachment may cause a bubble to form in the new strand. Slippage is thought to occur in sections of DNA with repeated patterns of bases (such CAG).

Then, DNA repair mechanisms realign the template strand with the new strand and the bubble is straightened out. The resulting double helix is thus expanded.

Question 8

What are microsatellites?

Answer 8

A set of short, repeated DNA sequences in tandem at a particular locus on a chromosome. They vary in number in different individuals, and thus are used for genetic fingerprinting.

Microsatellites may be in the part of the 98% of the genome not coding for protein, or may be exonic.

Question 9

What are CNVs?

Answer 9

Copy number variants - a phenomenon in which sections of the genome are repeated and the number of repeats in the genome varies between individuals

Question 10

How do CNVs come about?

Answer 10

Through non-allelic homologous combination in meiosis

this results in duplication/deletion and thus a copy number change

Question 11

Where are CNVs found?

Answer 11

They can be intergenic, but they are quite large, so they often affect one or more genes (part of genes)

Question 12

List the different types of common genetic variants

Answer 12

SNPs - 17 million identified, 3 million in the genome

Microsatellites - 3% of the genome

CNVs - 2000 identified, 100 per genome

Question 13

What are some of the effects of variants?

Answer 13

Can be…

• beneficial
• pathogenic
• most are neutral

Question 14

How can we use variants?

Answer 14

As markers to help find disease-causing genes and mutations, such as autozygosity mapping, and association analysis