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IV. Evolution of human populations

A. Patterns of Human Genetic Variation
Many traits and genes show large differences in and among human populations around the world. Key Question: How is such variation distributed is there more variation within or among different human populations?

Distribution of Human Genetic Variation

Variation Within and Between Groups

Variation within = 0% Variation between = 100%

Variation within = 100% Variation between = 0%

Variation within = 89% Variation between = 11%

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Variation Between or Within Populations?

Apportionment of Human Genetic Diversity Studies of blood groups and other genetic markers show ~ 10% of the total human variation exists between geographic regions, with 90% existing within geographic regions.

Variation between = 10% Variation within = 90%

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Genetic Divergence among Human Populations

Genetic Distance is a measure of average relatedness between populations
It is used to understand the effects of genetic drift and gene flow, random evolutionary processes. Selection is non-random, so the genes used for measuring genetic distance are chosen to be evolutionarily neutral, i.e., not under selection.

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Genetic Divergence among Human Populations

Genetic distances to Native Americans

At smaller values, populations are more similar At larger values, they are more dissimilar

Based on allele frequencies for 120 genes

Oceania

Genetic distances on a phylogeny

America

East Asian

Central/Southern Asia European Middle Eastern Africa

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Geographic Distance vs. Genetic Distance

Isolation by Distance Between Human Populations
The hypothesis for the expected relationship between geographic distance and genetic distance is the isolation by distance model. Genetic similarity is assumed to be a function of gene flow, the more gene flow between two populations, the more similar they are genetically.

The closer two populations are geographically, the more gene flow between them, and the smaller the genetic distance. The opposite is true the farther they are apart.

Genetic Divergence among Human Populations

expected with ibd*

actual genetic distances

* ibd isolation by distance

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Contrast between genetic and phenotypic similarity

Genetic relatedness
Based on 120 genes

Morphological traits

Phenotypic similarities are not necessarily a good indicator of genetic ones

Genetic Relatedness: isolation by distance

What might be an explanation for the differences between these patterns?

Phenotypic: Skin color

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B. Natural Selection in Human Populations

Natural Selection and Disease

Natural Selection and Climate

Natural Selection and Culture Change

Variation among human populations for disease prevalence

phenylketonuria

Cystic fibrosis

Founder effect

Tay Sachs

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Natural Selection and Disease

Malaria is the strongest known force for evolutionary selection in the recent history of the human genome.
Malaria is caused by a group of parasites in the genus Plasmodium (Protistan Kingdom, Phylum Apicomplexa) Alternating high fevers & shaking chills, flu-like symptoms, and anemia Human malaria is mainly due to 4 species of Plasmodium. P. falciparum is the most dangerous cerebral malaria

Plasmodium is transmitted to humans only by mosquitoes in the genus Anopheles (over 100 species are known to be vectors).

Natural selection and malaria

Malaria is the strongest known force for evolutionary selection in the recent history of the human genome.

Over 200 Million people become ill each year with falciparum malaria 30 million more are infected with other forms of Plasmodium Over 600 Thousand people die every year from malaria

In some regions, every member of a community may be infected

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Natural selection and malaria

Malaria is implicated as the driving force for the evolution of the most common human Mendelian diseases

The most common and familiar is sickle cell anemia due to the hemoglobin S allele

However, there are at least 5 other known red blood cell mutations that appear to be favored against malaria

Natural selection and malaria

Coevolution of Plasmodium falciparum and humans
76-160 MYA 200 MYA 9-10 MYA

50000

27000

10000

Plasmodium species

P falciparum (humans) P reichenowii (chimps) P malariae P falciparum P falciparum P ovale current form increased virulence P vivax
200000 100000 8 MYA 5 MYA 80000 70000 40000 10000

Mammals Hominoids diverge from chimps

Homo sapiens out of Africa

Homo sapiens

Blood group O in hominids mutation from A

hemoglobins S and C G6PD Thalassemia Hb E

Agriculture

4000

2000

3200

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Hemoglobin, Sickle Cell, and Malaria

(a) Frequency of sickle-cell allele (b) Distribution of malaria

Hemoglobin, Sickle Cell, and Malaria

The most widely studied anti-malarial mutation is the hemoglobin S allele (HbS), the sickle cell allele. The distribution of the allele is related to the prevalence of certain forms of malaria. A person who has two HbS alleles has sickle cell anemia. As we saw previously, there is a selective advantage for heterozygous people in a malarial environment. There is a cost to this adaptation, however an increased proportion of individuals get sickle cell anemia, which can be itself fatal. This is an indication of the strength of natural selection imposed by malaria.

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Hemoglobin, Sickle Cell, and Malaria

Change in frequency of the HbS Allele in presence of malaria
Relative fitnesses AA = 88

AS = 100 SS = 14
Initial S mutation

S allele frequency increases very rapidly in this scenario but it only rises to a frequency of ~13%

Relationship between death rates and frequency of S allele

Deaths from malaria or sickle cell alone

Deaths from malaria and sickle cell combined

balance between opposing selective forces

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Other hemoglobin mutations

There are two additional structural mutations of the -globin chain that also map geographically to regions where malaria is endemic.

HbE is found in Southeast Asia, up to 50% frequency in some isolated populations

Malarial region

Other hemoglobin mutations

HbC is found in West Africa, with high allele frequencies in Burkina Faso and Mali, where it protects against severe malaria

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Other hemoglobin mutations

Unlike HbS, HbC provides more protection against malaria in the homozygous state (CC) than in heterozygous state (AC) Because of this, HbC is projected to replace the HbS allele in malarial habitats such as Burkina Faso, in perhaps as few as 50 generations! *

* Hedrick 2004. J Evol Biol.

More Natural Selection and Malaria The Duffy Blood Group

The Duffy antigen - a strong receptor for blood cell invasion by Plasmodium vivax. One allele, FY*O does not produce the antigen protein in blood cells. Individuals homozygous for Duffy negative allele (FY*O) are completely resistant to malaria caused by Pl. vivax. Areas where the Duffy negative allele frequency is high, have no vivax malaria.
FY *O mutation
note that the mutation is actually in the regulatory region for this gene gene

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The Duffy Blood Group

In China, there is some evidence for the reverse situation there is some evidence for strong selection for the FY *A allele Which region on this graph is the best potential evidence for strong selection?
C B

Regions of reduced variation

ABO Blood Groups and malaria

Distribution of B and O Blood Groups

Frequency of O increases and frequency of B decreases in African malarial regions

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Natural Selection and The ABO Blood Groups

0.80

% of patients with mild vs. severe malaria

Mild
0.60

Severe

0.40

0.20

0.00

AB

Blood Group
Pathirana et al. 2005. Ann. Trop. Med. & Parasit.

Possible model for Blood type O malarial advantage

Differences in blood cell adhesiveness?

Cells with A or B antigens may attach to walls of capillaries, allowing parasite to mature and release more merozoites. Blood group O cells do not attach.

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Natural Selection and the ABO Blood Groups

ABO Blood Type and Infectious and Noninfectious Disease Blood type A is more susceptible to smallpox, type B seems more susceptible to infant diarrhea, and type O seems more susceptible to bubonic plague. People with blood type O have a greater chance of getting duodenal and stomach ulcers. People with blood type A have a greater chance of getting certain types of cancer.

Natural Selection and the ABO Blood Groups

Diagnosis Stomach cancer Colon cancer Pancreatic cancer Duodenal ulcer Gastric ulcer Thromboembolism

# patients 55434 7435 817 26039 22052

# controls 1852288 183286 108408 407518 448354

Comparison A:O A:O A:O O:A O:A A, AB, B : O

Relative Incidence* 1.22 1.11 1.24 1.35 1.17 1.60

*frequency in patients/frequency in controls

Meier Human Evolutionary Biology chap 13

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More Natural Selection and Malaria Thalassemia

Thalassemia due to deficiencies in production of -globin or -globin chains of the hemoglobin molecule. A large number of different mutations can cause it.
chains

Normal hemoglobin protein

chains

-hemoglobins -hemoglobins

Homozygous thalassemia results in severe disease - severe anemia, enlargement of the heart, liver, and spleen, and skeletal deformation - and can be fatal. Heterozygotes are healthy other than mild anemia.

- and - Thalassemias
Despite the very strong selection against homozygotes, thalassemias are the most common Mendelian diseases of humans and a major global health problem over 70 million people are affected.

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Why is thalassemia effective against malaria?

Malaria greatly reduces hemoglobin concentrations, causing life-threatening anemia for children with hemoglobin below 5g/dl
- normal - heterozygotes - homozygotes

Children 5 yrs old or younger

Children with thalassemia produce smaller but more red blood cells than average, maintaining hemoglobin levels.
Wambua et al 2006. PLoS Medicine 3:e158

Thalassemias, sickle-cell and malaria

Are different anti-malarial alleles effective in combination?
A recent study looked at the joint effects of hemoglobin S and -thalassemia in Kenya, where both occur at high frequency. Individuals who had both sickle-cell (HbAS) and -thalassemia had malarial rates similar to individuals who had neither. Suggests that their combined effects cancel out any benefits.

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