Genetic Variation and

Human Disease II

Human migration,
the evolution of human skin color, vitamins,
and disease predisposition

Neda Barghi
University of Veterinary Medicine Vienna
Institute of Population Genetics
 Outline of lecture

The human expansion(s) out of Africa

- Resulting patterns of local genetic variation and
adaptations

Human 1000 genome project

- Measuring and describing human genome variation
- Genome wide association studies (GWAS)

Evolution of human skin color variation

- How does it work ?
- What is the human variation ?
- What may be the evolutionary causes ?
- What can we learn ?
Why are allele frequencies of human populations different?
 The consequences of human migrations

• Serial bottleneck effect, where each migrating population comprised

a sample of the total population

• Largest human genetic variation is therefore in Africa

• Further erosion of genetic diversity by Genetic Drift

• Local effects of selection and gene flow

• Disentangling Neutral effects (Drift, Geneflow and Mutation) from

Selective effects is extremely difficult, and will remain a challenge for
the future
 Human migration

Therefore ancestral african humans clearly adapted to

various environments as they populated the world

Local changes in allele frequency

Local diseases
 1000 Genomes Project

Most detailed map of human genetic variation

Sequenced whole genomes of 1000 anonymous

participants of different ethnic backgrounds

China, Europe, Africa, and USA

 1000 Genomes Project

 Enables search for disease-related genetic

variants: association mapping
Human skin and hair color variation
Human eye (iris) color variation
 Human evolutionary diversity in
skin, hair and eye pigmentation

How does it work? (proximate causes, mechanistic logic)

What is the human variation ?

What are or may be the evolutionary reasons ?

What are the implications to human disease ?

 How ?

Proximate causes
 Skin pigmentation by Melanin
The primary determinant of skin color is a pigment called melanin

Two forms
– Pheomelanin (red to yellow in color)
- Light complexion

– Eumelanin (dark brown to black in color)

- Dark complexion

• But primary determinant of skin color is the size and number of melanin
particles

• Melanin is produced by specialized dendritic cells (called melanocytes)

in organelles (called melanosomes) that are transferred to
keratinocytes (= organelle transfer from cell to cell !)
Melanocytes in the human skin
Melanocytes in the human hair follicles
How does the melanosome makes melanin ?
Sun tan as an adaptive phenotypic plasticity
What is the human diversity in pigmentation ?
World wide human skin color distribution
Also the frequency of light hair is high
at high latitudes
 Genome wide association studies (GWAS) in humans

Phenotype: hair color

# of individuals: >10000
# SNPs scored: 528’713 SNPs
IRF4 HERC2 MC1R

Manhatten plot
chromosome location (x) vs. – log10 P-value (y)
 Non-african human populations show
multiple naturally selected loss of function
alleles for pigmentation
The human melanin synthesis shows multiple
deleterious mutations in european and asian
populations ?
Why are (early) african humans all dark skinned
?

Why did europeans and asian humans lose their

pigmented skin ?

Why do (europeans) like to expose themselves

to sunlight so much despite the damage ?

Evolutionary assumptions
and explanations
Why dark skin in
Africa?

Human adaption to savanna

environment

Control of body temperature,

sweating, loss of body hair,
exposure to sun and its
Ultra Violet Radiation (UVR)

Evolutionary hypotheses:
Protection from UVR/
skin cancer

Protection of
folic acid (vitamin B9)
from UVR ?
 Folic acid (vitamin B9)

Essential for many processes including nucleotide synthesis for DNA

replication during cell division

UV causes the breakdown of folic acid

Lack of vitamin B9 results in:

– Anemia
– Miscarriages and neural tube defects
– Diarrhea
– Nerve damage
– Weak limbs

-> Melanin selected for in early humans to protect folic acid supply ?
 Melanin blocks UV radiation….

UVR is most intense at tropical latitudes, especially in non-

forested regions

Melanin acts as a biological shield against UVR radiation

Prevents sunburn that could damage DNA and cause skin

cancer (non-melanoma and melanoma)

Seasonal tanning is a response to different levels of UV in

winter and summer (adaptive phenotypic plasticity)
– UV stimulated increase in the number and size of
melanin particles
Human migrations to
higher latitudes
caused maladaption to
local environment

Often wooded environment

with overcast weather

Lack of exposure to sun and UVR

Evolutionary hypothesis:
- Strongly melanised skin did
not allow sufficient production
of vitamin D in the skin
- Suggested evolutionary pressure to
select an array of loss of function alleles
in human pigmentation genes
(-> production of vitamin D with less
sun)
 Vitamin D

Vitamin D is synthesized in the skin upon exposure to UVB

Vitamin D may be obtained through specific diet

(eg. fish, whale or seal blubber (Inuit))

Vitamin D maintains skeletal calcium balance by promoting

calcium absorbtion in the intestine and via bone resorption.

This maintains important serum calcium and phosphate

levels allowing constant bone formation/mineralisation.
 Why do we crave the sun so much despite the
potential damage ?
Pro-opio-melano-cortin (POMC) gene

Alpha- Beta-
Melanocyte endorphin
Stimulating Hormone

Pigment 1. Analgesia
Fell et al,. 2014, Cell
production 2. Dependency
 Alternative evolutionary hypotheses

Sexual selection (for blue eyes) has been proposed

Adaption to lighter skin, hair, and eye colors may have

allowed circadian rhythm sensors (melanopsins) to get
more light at high latitudes (eg. seasonal affective disorder)
Iris pigmentation alters light intensity reaching
the retina
Retinal ganglion cells express Melanopsin

Rhodopsins
Light quality

Melanopsin
extreme light
exposure
Blue eyed show less SAD, than brown eyed humans
Iris pigmentation & Melanopsin effect on SAD?
What can we learn ?
 Medical consequences for a now globally
distributed bipedal African primate with fair skin

Multiple sclerosis

Skin cancer

Rickets (children), osteomalacia (adults)

Multiple sclerosis

occurs mainly in those

areas of the world where
sunlight is not intense

Depends on exposure to
the sun as a child
 Skin cancer
• 8000 cases per year in the UK resulting in 1800
deaths
• European Americans have 10X higher risk than
African Americans
• Australia
– Highest skin cancer rate in the world
– 380000 cases diagnosed per year
– A maladaptation since the white skin colour of most
contemporary Australians evolved at high latitudes
 Skin cancer

Most commonly diagnosed malignancy

Non-melanoma skin cancer (800’000 cases US/year)

– Different forms
– Often arises on external skin surface
– squamous cell carcinoma or a basal cell carcinoma

Melanoma
– Uncontrolled growth of melanocytes

2nd most common cancer among 20-39 age group

 Rickets

Childhood disease

vitamin D deficiency

Softening of the bones

leading to fractures or
deformities

Recent migration of dark-

skinned people to high
latitudes
 Contemporary vitamin D deficiency

Risk to African Americans

200,000 cases in the US State of Georgia

Insufficient exposure to sunlight

Phosphoric acid in soft drinks promotes hypocalcemia

 Thanks to:

Thomas Flatt
Alistair McGregor
Alex Kalinka
Dustin Penn
Kirsten Senti
 Questions:

What is the background for the 1000 Genome project ?

What are the proximate explanations for skin, hair and eye
color diversity in humans ?

What are the evolutionary hypotheses why diverse skin

colors were positively selected for in human evolution ?