Comparative genomics of ape malaria parasites and the emergence ...
Transcript of Comparative genomics of ape malaria parasites and the emergence ...
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Comparative genomics of ape malaria parasites
and the emergence of human malaria
Paul Sharp
Institute of Evolutionary Biology
and
Centre for Immunity, Infection
& Evolution
University of Edinburgh
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Background .....
Beatrice HahnUniversity of Pennsylvania
2013 National Academy of Sciences USA
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Faecal samples (in RNAlater)
from which:
- host DNAmtDNA – species
amelogenin (X vs Y)
microsatellites
- viral antibodies
- viral nucleic acids
Samples from wild apes (for SIV)
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Sample sites
Chimpanzees, Bonobos, Gorillas (>5000 samples)
Other pathogens?
SFV, HBV
Plasmodium?
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Anopheles mosquitoes
Plasmodium falciparum
The malaria parasites: Plasmodium
Plasmodium species are protozoa
(Phylum Apicomplexa)
- transmitted by Anopheles mosquitoes
Plasmodium species infecting humans:
P. falciparum Africa, Asia
P. vivax Asia
P. malariae Africa
P. ovale Africa
P. knowlesi SE Asia (monkeys)
Other Plasmodium species known infecting
other mammals, and birds and reptiles
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Phylogeny of malaria parasites
Phylogeny from: HAYAKAWA et al. (2008) Mol.Biol.Evol.25:2233
Plasmodium species
infecting humans
Laverania
Sub-genus Laverania(BRAY 1958,1962)
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Ape Plasmodium species:
Parasites from chimpanzees and gorillas
Eduard Reichenow in Cameroon ~1917
Saul Adler, Donald Blacklock
in Sierra Leone ~1922
- three morphologically distinct species:
Human parasite Ape parasite
P. falciparum P. reichenowi
P. malariae P. rhodaini
P. vivax OR P. ovale P. schwetzi
ONE isolate in culture
no samples
no samples
What might we find in apes?
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Sub-genus Laverania (BRAY 1958,1962)
- co-divergence?
- common ancestor at ~7 Myr ago ? ESCALANTE & AYALA (1994) PNAS 91:11373
Laverania
Plasmodium reichenowi from chimpanzees
Origin of Plasmodium falciparum ?
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Plasmodium sequence amplification
Plasmodium
mitochondrial genome
950 bp cytB gene
3.4 kb half genome
3.3 kb half genome
apicoplast genome
390 bp clpC gene
nuclear genome
780 bp ldh gene
Weimin Liu Yingying Li
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Plasmodium gaboni
Laverania
Blood samples from 17 chimpanzees (Gabon) – wild-born pets
Detected Plasmodium (PCR and microscopy) in 2 chimpanzees
PCR: full length mtDNA (6 kb) for one, cytB (866bp) for second
OLLOMO et al. (2009) PLoS Path. 5:e1000446
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new samples from
chimpanzees
“The origin of malignant malaria”
= chimpanzees
Blood/tissue samples from
94 chimpanzees
(Cote d’Ivoire, Cameroon)
Detected Plasmodium
in 7 chimpanzees
(3 wild)
PCR: cytochrome b (mtDNA)
RICH et al. (2009) PNAS 106:14902
Laverania
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KRIEF et al. (2010) PLoS Path. 6:e1000765
“The origin of malignant malaria”
= bonobos
Bonobos from Kinshasa sanctuary
Bonobo Plasmodium had drug-resistance mutations
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“Our results corroborate the recent proposal that
P.falciparum likely originated from P.reichenowi following a
host transfer.”
“... gorillas are naturally infected by ....
P.falciparum”
PRUGNOLLE et al. (2010) PNAS 107:1458
Laverania
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cytB +coxI(mtDNA)
Blood samples from 113 chimpanzees; 17 gorillas (Cameroon)
Plasmodium sequences from: 12 chimpanzees; 2 gorillas;
Laverania
DUVAL et al. (2010) PNAS 107:10561
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Plasmodium from apes
PROBLEMS:
1. Limited sample sizes
2. Mostly captive apes
3. PCR errors
- chimaeric sequences
SOLUTIONS:
1. Faecal samples from wild apes
2. Single genome amplification (SGA)
CONFUSION: - How many Plasmodium (Laverania) species ?
- Which are natural hosts ?
- Origin of Plasmodium falciparum ?
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cytB
[also
apDNA
& nDNA]
Sequences from:
Gorilla
Nigerian chimpanzees
Central chimpanzees
Eastern chimpanzees
Others (incl. humans)
Laverania
Laverania
chimpanzee
gorilla
chimpanzee
gorilla
chimpanzee
gorilla
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Origin of Plasmodium falciparum
Human Plasmodium falciparum
from Western gorillas
(Gorilla gorilla)
Similar strains found in
(captive) bonobos, chimps and a monkey
are of immediate human originLIU et al. (2010) Nature 467:420
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Laverania genome sequences
Laverania
P.reichenowi
P.praefalciparum
P.billcollinsi
P.blacklocki
P.gaboni
P.adleri
Laverania
Origin of Plasmodium falciparum
genomic features?
Determinants of host specificity
among sympatric Chimpanzee
and Gorilla parasites ?
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Selective Whole Genome Amplification
SWGA = Selective Whole Genome Amplification
MspJI, FspEI digestion Phi29 polymerase
Primer selection: identify motifs that are common in Plasmodium falciparum
but rare in the human genome
LEICHTY & BRISSON (2014)
70,000-fold enrichment
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SESH SUNDARARAMAN
Selective Whole Genome Amplification
Laverania
P.reichenowi x1
P.praefalciparum
P.billcollinsi
P.blacklocki
P.gaboni x2
P.adleri
Laverania
P.reichenowi P.gaboni P.gaboni
Sample SY57 SY75 SY37
Assembly 18.9 Mb 18.5 Mb 15.3 Mb
Core genes 4670 4689 4071
=98.3% =98.7% =85.7%
Subtelomeric 235 222 108
genes =23.8%
Chimpanzee parasite
genome sequences
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FIKK kinase gene family
FIKK = Phe:Ile:Lys:Lys
One gene in P. vivax, P. knowlesi
& rodent malarias
20 genes in P. falciparum
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FIKK kinase gene family
FIKK = Phe:Ile:Lys:Lys
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FIKK kinase gene family
Expression profile(P. falciparum)
FIKK = Phe:Ile:Lys:Lys
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Interspecies divergence
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Chromosome 4
P. falciparum v P. reichenowi
P. falciparum v P. gaboni
P. reichenowi v P. gaboni
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Horizontal gene transfer
EBA165RH5
standard topologyunusual topology
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Chromosome 4
P. falciparum v P. reichenowi
P. falciparum v P. gaboni
P. reichenowi v P. gaboni
Rh5 : parasite ligand essential for blood
stage growthCROSNIER et al. (2011) Nature 480:534
- Rh5 binds human basigin
- binding essential for erythrocyte
invasion
REDDY et al. (2015) PNAS 112:1179
- CyRPA also essential
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Horizontal gene transfer
P. falciparum = P. reichenowi (P. gaboni different)
P. falciparum = P. gaboni (P. reichenowi different)
CyRPA protein coding region
signal sequence
CyRPA gene
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Within species diversity
species N Π Π Π Π ΠΠΠΠ4
P. falciparum 12 0.0005 0.0008
P. reichenowi 2 0.0036 0.0090
P. gaboni 2 0.0041 0.0107
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Transmission dynamics too weak to maintain parasite
in hunter-gatherer populations [CARTER & MENDIS 2002]
Timescale of P. falciparum in humans ?
Richard Carter
HbC mutation offers resistance to P.falciparum malaria
arose <5 kyr ago [WOOD et al. 2005]
G6PD A- allele offers resistance to P.falciparum malaria
arose ~ 4-12 kyr ago [TISHKOFF et al. 2001]
Anti-P.falciparum mutations in humans are young
NEAFSEY et al. (2012) Nature Genetics
max diversity among 5 genome sequences: 9.59 x 10-4 subs/site
(4-fold degenerate sites)
“commonly accepted mutation rate for eukaryotes”: 2.2 x 10-9 /site/yr
218 kyr (452 kyr)
“similar to a mutation rate estimate for Plasmodium”: 2.1 x 10-9/site/replication
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Replication rate of Plasmodium falciparum
MOSQUITO:
14 reps in 10-28 days
LIVER:
15 reps in 5 days
BLOOD:
4-168 days
at 7 reps per 4 days
+ 12 days
TRANSMISSION CYCLE:
36 replications in 31-49 days
to
323 replications in 195 days
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Chimpanzees and gorillas have:
- very high prevalence of Plasmodium
- mostly multiply infected
(similar to humans in areas of
hyper-endemicity)
Six species of Laverania parasites
in wild apes:
three in gorillas, three in chimpanzees
Conclusions
Plasmodium in African apes
Plasmodium falciparum
- originally transmitted to humans
from gorillas
- perhaps very recently ?
Comparative genomics of Laverania species:
- Unique features of Laverania genomes
- HGT in the precursor of P. falciparum
- Greatly reduced diversity in P. falciparum
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University of
Pennsylvania
Beatrice Hahn
Weimin Liu
Yingying Li
Sesh Sundararaman
Jerry Learn
Dorothy Loy
Duston Brisson
George Shaw
Rick Bushman
Washington University
Crickette M. Sanz
David B. Morgan
University of New Mexico
Martin N. Muller
University of Minnesota
Emily Wroblewski
Joann Schumacher-Stankey
Michael L. Wilson
Anne Pusey
Lilian Pintea
Jane Goodall Institute/
Gombe National Park
Jane Goodall
Shadrack Kamenya
Sanaga-Yong Sanctuary
Sheri Speede
VaccineApe
Peter D. Walsh
Philip J. Kranzusch
University of Kisangani
Bosco Ndjango
Acknowledgements
Primate samples:
University of Montpellier
Martine Peeters
Ahidjo Ayouba ++
Sanger Center, Cambridge
Julian Rayner
Nagasaki University Richard Culleton
University of Edinburgh
Lindsey Plenderleith
Richard Carter
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D
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Comparative genomics of ape malaria parasites
and the emergence of human malaria
Paul Sharp
Institute of Evolutionary Biology
and
Centre for Immunity, Infection
& Evolution
University of Edinburgh