Further Mapping And Human Haplotypes

Question 1

Haplotype

Answer 1

A group of alleles in an organism that are inherited together from a single parent

They are often discussed in the context of tightly linked Single Nucleotide Polymorphisms (SNPs)

Question 2

HapMap project

Answer 2

Before we were able to sequence DNA as quickly and cheaply as today, The International HapMap Project aimed to locate about 3 million human SNPs.

Today, we have identified about 10 million SNPs in the human genome. The basic principle of mapping is that closely linked SNPs will be
passed on together.

Question 3

Genome Wide Association Study (GWAS)

Answer 3

This method uses many different genomes from 2 different groups of individuals

First group share a particular trait (for example high blood pressure) and the second group is a control group

If a particular locus is associated with the phenotype of interest individuals who share the trait will share the same genetic variant.

Typically GWAS tests the association to SNPs

Question 4

Manhattan Plots

Answer 4

GWAS studies produced this

On X axis = SNP location in chromosome order
Y axis = the probability the SNP is associated with the trait of interest

The peaks correspond to regions of association

Used extensively to map variants associated to human diseases such as Systemic lupus erythromatosus, Schizophrenia and
type-2 diabetes.

GWAS can also be used to study the location of loci associated with continuous traits such as height (although in this trait we have been less successful)

Question 5

Genome project today

Answer 5

We can directly sequence the human genome. This is now cheap and fast
In Dec 2018 Genomics England completed the 100,000 Genome project

These were mostly NHS patients with rare diseases such as cancers and their families

This will improve our understanding of the genetics of these disease

NHS is now running the 5 million genome project

Question 6

Sickle cell haplotypes

Answer 6

All individuals have the same mutation, but individuals vary in the combination of SNPs around the mutation

There’s 5 different haplotypes which suggest that there are 5 different origins to the mutation:
- Benin Cameroon
- Central African Republic
- Saudi Arabia
- India
- Senegal

Sickle cell mutation likely arose due to natural selection because it gave resistance to malaria

The 5 haplotypes have evolved independently

Portuguese being a former empire has many of
these haplotypes in its population; shows the significance of migration on allele frequencies.

Question 7

Haplotypes on House Flies

Answer 7

House flies used to be controlled with the pesticide DDT. A haplotype arose which gave resistance to DDT.
A selective sweep selected for this haplotype and is now present all around the world.

Question 8

Haplotypes and human skin colour

Answer 8

Melanin is the colour pigment - the amount of melamine produced in different populations has been selected for;
- natural selection has driven a gradient of dark coloured skins near the equator and lighter coloured skins at more extreme latitudes.
- this is because darker skin arose in humans as protection form UV radiation in open habitats
- darker skins protect against the incidence of skin cancers.
- Folic acid strongly absorbs UV and decreases in concentration.
- Lighter skinned pregnant women therefore more likely to have offspring with spina bifida in high UV environments.

Question 9

Haplotypes and Vitamin D

Answer 9

• Darker pigment was lost in more extreme latitudes because they are unable to make vitamin D.
• This vitamin is produced when the skin absorbs UV, but individuals with darker skin cannot absorb enough UV.
• Vitamin D deficiency commonly associated with rickets, the highest incidence of which is
  in darker skin individuals.
  Vitamin D deficiency is also associated with increases in infections, lung
  disease, autoimmune diseases, cancers mental disorders.
• You also see the effect in the UK where
  northern latitudes are exposed to lower levels of UV; Scotland historically had the highest level of
  rickets in the UK.

Question 10

Alleles for skin colour

Answer 10

• Many different alleles selected for skin colour. SLC24A5 first discovered in zebrafish.
• In humans it is associated with two different SNP variants A/G found across the world.
• The A variant more common in Europe associated with white skin, the ancestral G variant common in Africa associated with dark skin. The darker skin allele is also found in Asian populations, but their skin colour is modified in
  other ways.