12 - How the human genome sequence has changed medicine

Question 1

Following the human genome project how was comparative genomics and evolution studied?

Answer 1

Many species genomes sequenced

Comparisons with other species now possible to determine:
- Evolutionary relatedness.
- Evolutionary changes in genes/ proteins.

Question 2

What was found by studying comparative genomics and evolution? (2 things)

Answer 2

1. Many pathways are highly conserved across species:

• Ribosome proteins.
• tRNAs.
• ABC transporters.

2. Higher organisms have selective expansion in particular protein families and domains:

• 850 genes with human-specific features.
• 50+ entirely human-specific genes.

Question 3

What is an examples of a gene showing evidence for fast/ recent evolution in humans involving HIV?

Answer 3

Natural resistance to HIV infection:

• Homozygous for ∆32 mutation in CCR5 gene.
• Unusual as the prevalence of this mutation would require a millennia however HIV has only been around since the 1970s.
• Likely due to ∆32 being selected for in ancestral population against earlier HIV-like epidemics.

Question 4

What are LD blocks?

Answer 4

Haploid genotype = Haplotype

Formed by a collection of linked marker alleles on one chromosome that are inherited together

Over very short distances haplotypes tend to remain intact as not disrupted by meiotic recombination

these regions are LD blocks - linkage disequilibrium blocks.

Question 5

What is the evidence for humans having originated in Africa and from there moved out to populate the rest of the world?

Answer 5

African populations today are far more genetically diverse than the rest of the world.

African populations show the highest levels of genetic polymorphisms.

This suggests humans originated in Africa as it shows the African populations have had longer to accumulate more genetic diversity than non-African populations.

Question 6

What role does genetics play in the future of pharmacy?

Answer 6

Individual variation in the outcome of drug treatments is often mediated by genetic differences.

By tailoring therapy to individual genotypes the most effective medicine based on a person’s genetic makeup can be provided.

Question 7

What is an example of personalised medicine in Cystic fibrosis?

Answer 7

In cystic fibrosis DF508 is the most common mutation in europe resulting in no protein being produced.

5% of mutations just damage the function of the protein

Ivacaftor can be used to restore protein function when it is present.

Question 8

What is an example of personalised medicine regarding the Flucloxacillin antibiotic?

Answer 8

8.5 in 100,000 uses have a serious liver reaction - drug-induced liver injury (DILI).

A particular SNP marker is very significantly associated with DILI risk from Flucloxacillin.

This SNP is in complete linkage disequilibrium (LD) with HLA-B*5701 immune cell surface protein.