Medical genetics

What causes genetic diseases and how?

Genetic variants due to mutations. Mutations change the amino acid sequence, changing the shape of the protein, resulting in non-functional proteins

For any given trait, how many genotype combinations are there, and how many phenotype combinations are there?

There are 3 possible genotype combinations (AA, Aa, aa) and 2 possible phenotype combinations (affected or unaffected)

How many de novo mutation events occur each generation?

30 mutations which occur early in development and will be present in every cell of someone’s body

Why do variants which cause disease rarely persist many generations?

They result in a selection disadvantage, and are bred out of populations

Describe the characteristics of a Mendelian disease.

Disorder is caused by a single variant, with complete penetrance and high risk

What is the common disease, common variant hypothesis?

Diseases are caused by combinations of many low penetrance variants

What is the common disease, rare variant hypothesis?

Diseases can be caused by combinations of few moderately penetrant variants. Rarer in populations

What is the 1000 genome project?

Project to sequence 1000 genomes in order to compare them.

What numerical findings did the 1000 genome project make (5 numbers)

Average genome contains 4-5 million variants, 625,000 indels, 1000 large deletions, 150 loss of function genes and 20-30 changes that are linked to specific diseases

What is better than just sequencing a genome?

Genome annotations which demonstrate which variants cause disease

What 3 characteristics of a variant mean it is more likely to cause disease?

It causes a frameshift or stop gain, it is nonsynonymous, it is a coding variant

Why are there few key genes with loss of function variants?

LoF in these genes would be incompatible with life

What is complete penetrance?

An assumption of Mendelian genetics that all individuals with a given genotype will develop a given phenotype

What is a phenocopy?

When an environmentally induced phenotype resembles a genetic disease

What is variable expressivity?

The observable phenotype differs between individuals

What is an indel?

An SNP which causes frameshifts and changing protein structure

What is a pathogenic variant?

Change to DNA has a big, direct impact on protein that is essential to function

What is a benign variant?

Change to a DNA sequence with little effect on protein function

What is a synonymous variant?

When there is a change to the DNA, but no change to the amino acid and protein coded for

How is the LCT gene an example of changes in genetic variation?

The LCT gene makes us lactate tolerant, its presence coincided with dairy farming and famines