Linkage analysis

Question 1

What is Genetic variation?

Answer 1

Genetic variation refers to differences in the DNA sequence between individuals in a population. It can either be inherited or due to environmental factors/spontaneous. (e.g. drugs, exposure to radiation).

Question 2

What are the different effects of genetic variation?

Answer 2

Depending on location and frequency, genetic variation can have many diff effects:

• Alteration of the amino acid sequence (protein) that is encoded by a gene
• Changes in gene regulation (Where and when a gene is expressed)
• Physical appearance of an individual (e.g. eye colour, genetic disease risk)
• Silent or no apparent effect (silent variants)

In linkage analysis, we utilise common (most likely silent) variation to inform us about protein-altering variation.

Question 3

Why is genetic variation important?

Answer 3

• Genetic variation underlies and determines phenotypic differences among different individuals e.g eye and hair colour, but also susceptibility to disease.
• Determines our predisposition to complex diseases and can be used to determine our response to drugs and environmental factors.
• Important in population genetics for determining ancestry and migration patterns – used to track people (ancestral human migration history)

Question 4

What are the three main mechanisms of genetic variation?

Answer 4

1. Mutation/polymorphism: Errors in DNA replication. These may affect single nucleotides or may affect larger segments of DNA e.g. whole exons, whole genes or multiple genes.
   - Germline mutations- passed onto descendants (present in germlines or germ cells). Occur in gametes
   - Somatic mutations- not transmitted to descendants. Occur in single cell of body. These variants may lead to cancer
   - De novo mutations – new mutation not inherited from either parent – present throughout body. Occur spontaneously.
2. Homologous recombination: shuffling of chromosomal segments between partner (homologous) chromosomes of a pair, resulting in new allele combinations. Important in linkage analysis as it can be used to track the inheritance of chromosomal segments and determine the likely location of a disease gene.
3. Gene flow: the movement of genes from one population to another I.e. migration. Important source of genetic variation as it introduces new alleles into the population.

Question 5

What is the difference between a mutation and a polymorphism?

Answer 5

• A mutation is a rare change in the DNA sequence that is different to the normal (reference) sequence. The ‘normal’ allele is prevalent in the population and the mutation changes this to a rare ‘abnormal’ variant.
• a polymorphism is a DNA sequence variant that is common in the population. In this case no single allele is regarded as the ‘normal’ allele. Instead there are two or more equally acceptable alternatives.

To distinguish between the two, The arbitrary cut-off point between a mutation and a polymorphism is a minor allele frequency (MAF) of 1% (i.e. for a variant to be classed as a polymorphism, the least common (minor) allele must be present in ≥1% of the population).