Sequencing extinct human ancestors

The Hominid Lineage

Archaeology – “the scientific study of material remains (as fossil relics, artifacts, and monuments) of past human life and activities”

Studies the time period starting at the Paleolithic time until the advent of literacy

Archaeology

Slide Credits to Vanessa Patel

From bones, compared genomes of three different Neanderthals with five genomes from modern humans from different areas of the world

The Neanderthal Genome

Figure 1- R. E. Green et al., Science 328, 710-722 (2010)

Slide Credits to Vanessa Patel

Genomic Analysis

Stoneking, Krause, Nature Reviews Genetics 2011

Genomic Analysis

Stoneking, Krause, Nature Reviews Genetics 2011

Neanderthal Genome

Neanderthal Genome

Model-based analyses

Stoneking, Krause, Nature Reviews Genetics 2011

Neanderthal Genome

Neanderthal Genome

Denisovan – Another human relative

Denisovan – Another human relative

Out of Africa Refined

Stoneking, Krause, Nature Reviews Genetics 2011

Denisovan

Denisovan Admixture

Denisovan Admixture

Aboriginal Australian

Aboriginal Australian

Archaic African Admixtures

Signature Haplotypes: Highly diverged High LD over a long region

Archaic African Admixture

Fixation, Positive & Negative Selection

Neutral Drift Positive SelectionNegative Selection

How can we detect negative

selection?

How can we detect positive

selection?

How can we detect positive selection?

Ka/Ks ratio:Ratio of nonsynonymous tosynonymous substitutions

Very old, persistent, strong positive selection for a protein that keeps adapting

Examples: immune response, spermatogenesis

How can we detect positive selection?

X

X

X

Mutations and LD

Slide Credits:Marc Schaub

Slide Credits:Marc Schaub

Extended Haplotype Homozygozity

Chr S1 S2 S3 S4 S5 S6

S1 S2 S3 S4 S5 S6

Slide Credits:Marc Schaub

Chr S1 S2 S3 S4 S5 S6

A 1 0 1 1 1 0B 1 1 1 0 1 0C 1 0 1 1 1 0D 1 1 1 1 0 0E 1 0 0 0 1 1F 1 0 1 1 1 0G 1 0 0 1 0 0H 1 1 1 1 1 0I 1 0 1 1 1 1J 1 0 1 1 1 1

Core C

Extended Haplotype Homozygozity

Slide Credits:Marc Schaub

Chr S1 S2 S3 S4 S5 S6

A 1 0 1 1 1 0B 1 1 1 0 1 0C 1 0 1 1 1 0D 1 1 1 1 0 0E 1 0 0 0 1 1F 1 0 1 1 1 0G 1 0 0 1 0 0H 1 1 1 1 1 0I 1 0 1 1 1 1J 1 0 1 1 1 1

Core C

• 3 core haplotypes: ch0 = 101 ch1 = 111 ch2 = 100

Extended Haplotype Homozygozity

Slide Credits:Marc Schaub

Chr S1 S2 S3 S4 S5 S6

A 1 0 1 1 1 0B 1 1 1 0 1 0C 1 0 1 1 1 0D 1 1 1 1 0 0E 1 0 0 0 1 1F 1 0 1 1 1 0G 1 0 0 1 0 0H 1 1 1 1 1 0I 1 0 1 1 1 1J 1 0 1 1 1 1

Core C

• 3 core haplotypes: ch0 = 101 ch1 = 111 ch2 = 100

Extended Haplotype Homozygozity

Slide Credits:Marc Schaub

Chr S1 S2 S3 S4 S5 S6

A 1 0 1 1 1 0B 1 1 1 0 1 0C 1 0 1 1 1 0D 1 1 1 1 0 0E 1 0 0 0 1 1F 1 0 1 1 1 0G 1 0 0 1 0 0H 1 1 1 1 1 0I 1 0 1 1 1 1J 1 0 1 1 1 1

Core C

• 3 core haplotypes: ch0 = 101 ch1 = 111 ch2 = 100

Extended Haplotype Homozygozity

Slide Credits:Marc Schaub

Chr S1 S2 S3 S4 S5 S6

A 1 0 1 1 1 0B 1 1 1 0 1 0C 1 0 1 1 1 0D 1 1 1 1 0 0E 1 0 0 0 1 1F 1 0 1 1 1 0G 1 0 0 1 0 0H 1 1 1 1 1 0I 1 0 1 1 1 1J 1 0 1 1 1 1

Core C Given a core haplotype (101) and

a SNP (S6)

EHH is the conditional probability of two randomly chosen chromosomes to be homozygous from the core to S6 given that they include core haplotype 101

Extended Haplotype Homozygozity

Chr S1 S2 S3 S4 S5 S6

A 1 0 1 1 1 0B 1 1 1 0 1 0C 1 0 1 1 1 0D 1 1 1 1 0 0E 1 0 0 0 1 1F 1 0 1 1 1 0G 1 0 0 1 0 0H 1 1 1 1 1 0I 1 0 1 1 1 1J 1 0 1 1 1 1

Core C EHH is the conditional probability of two randomly chosen chromosomes to be homozygous from the core to S6 given that they include core haplotype 101

Extended Haplotype Homozygozity

Slide Credits:Marc Schaub

EHH is the conditional probability of two randomly chosen chromosomes to be homozygous from the core to S6 given that they include core haplotype 101

Chr S1 S2 S3 S4 S5 S6

A 1 0 1 1 1 0B 1 1 1 0 1 0C 1 0 1 1 1 0D 1 1 1 1 0 0E 1 0 0 0 1 1F 1 0 1 1 1 0G 1 0 0 1 0 0H 1 1 1 1 1 0I 1 0 1 1 1 1J 1 0 1 1 1 1

Core C

Extended Haplotype Homozygozity

Slide Credits:Marc Schaub

Chr S1 S2 S3 S4 S5 S6

A 1 0 1 1 1 0B 1 1 1 0 1 0C 1 0 1 1 1 0D 1 1 1 1 0 0E 1 0 0 0 1 1F 1 0 1 1 1 0G 1 0 0 1 0 0H 1 1 1 1 1 0I 1 0 1 1 1 1J 1 0 1 1 1 1

Core C

Extended Haplotype Homozygozity

Slide Credits:Marc Schaub

Study of genes known to be implicated in the resistance to malaria.

Infectious disease caused by protozoan parasites of the genus Plasmodium

Frequent in tropical and subtropical regions

Transmitted by the Anopheles mosquito

Image source: wikipedia.org

Application: Malaria

Slide Credits:Marc Schaub

Image source: NIH - http://history.nih.gov/exhibits/bowman/images/malariacycleBig.jpg

Application: Malaria

Slide Credits:Marc Schaub

Image source: CDC - http://www.dpd.cdc.gov/dpdx/images/ParasiteImages/M-R/Malaria/malaria_risk_2003.gif

Application: Malaria

Slide Credits:Marc Schaub

Source: Sabeti et al. Nature 2002.

Results: G6PD

Slide Credits:Marc Schaub

Results: G6PD

Source: Sabeti et al. Nature 2002.Slide Credits:Marc Schaub

Results: G6PD

Source: Sabeti et al. Nature 2002.Slide Credits:Marc Schaub

Results: TNFSF5

Source: Sabeti et al. Nature 2002.Slide Credits:Marc Schaub

Results: TNFSF5

Source: Sabeti et al. Nature 2002.Slide Credits:Marc Schaub

Malaria and Sickle-cell Anemia

Allison (1954): Sickle-cell anemia is limited to the region in Africa in which malaria is endemic.

Image source: wikipedia.org

Distribution of malaria Distribution of sickle-cell anemiaSlide Credits:Marc Schaub

Malaria and Sickle-cell Anemia

Hypothesis: mutation causing sickle-cell anemia positively selected for the resistance to malaria.

Currat (2002) and Ohashi (2004) identify the mutations in the African respectively Asian populations.

Slide Credits:Marc Schaub

Malaria and Sickle-cell Anemia

Single point mutation in the coding region of the Hemoglobin-B gene (glu → val).

Heterozygote advantage: Resistance to malaria Slight anemia.

Image source: wikipedia.orgSlide Credits:Marc Schaub

Slide Credits:Marc Schaub

Source: Ingram and Swallow. Population Genetics of Encyclopedia of Life Sciences. 2007.

Slide Credits:Marc Schaub

Lactose Intolerance

LCT, 5’

LCT, 3’

Source: Bersaglieri et al. Am. J. Hum. Genet. 2004.Slide Credits:Marc Schaub

Lactose Intolerance

Lactose Intolerance

Source: Catherine Janet Ellen Ingram and Dallas Mary Swallow. Population Genetics of Lactase Persistence and Lactose Intolerance advanced. Encyclopedia of Life Sciences. 2007.

Slide Credits:Marc Schaub

-13910*T associated with persistent lactose tolerance. Is this mutation causal?

Does not account for tolerance in sub-Saharan populations (Mulcare 2004).

Additional SNPs in an enhancer within 100bp are associated with lactose tolerance.

Several independent causes for lactose

tolerance (reviewed in Ingram 2009).Slide Credits:Marc Schaub

Finding the Causal Marker

Lactase persistence (litterature)Predicted lactase persistence

13910*T distribution

Source: Ingram et al. Lactose digestion and the evolutionary genetics of lactase persistence. Hum Genet. 2009 Jan;124(6):579-91.

Slide Credits:Marc Schaub

Long Haplotypes –iHS test

Less time:• Fewer mutations• Fewer recombinations

Neanderthal Immune System

Neanderthal Immune System