1994–2015: 21 Years of Achievements
HapMap and 1000 Genomes: High-resolution
maps of human genetic variation
f2 variants
bAllele sharing within and between populations: Sharing
c
of f2 variants, those found exactly twice
WHAT WAS KNOWN
40
20
60
40
20
2
0
0
0
0.01
0.02
0.05 0.10 0.20
0.50
0.01
0.02
0.05 0.10 0.20
0.50
Variant frequency
Variant frequency
n A pair of human genomes vary, on average,
at one position every 1000 base pairs
n Most of these differences result from common
genetic variants (present in at least 1 in 20
individuals)
n However, most genetic variants are rare (found
in fewer than 1 in 100 individuals) and often
restricted to a particular geographical region
n Genetic variation has a particular structure arising
from the interplay between recombination,
demographic history and selection
n Characterising the structure of common and rare
variation is critical to designing and interpreting
studies to map the genetic basis of complex and
rare diseases
WHAT WE DID
n As part of international consortia, initially
the HapMap Project and later the 1000
Genomes Project, we carried out genome-wide
characterisation of common variation and
subsequently rare variation through SNP genotyping
and whole genome sequencing from thousands
of individuals from across the world
n We released the maps of human genomic variation
as an open-source resource, with no restrictions
on data usage
4
EUR/NatAm
0.50
MXL
PURMXL
PUR
CLM
CLM
ASW
ASW
AFR/NatAm
0.05 0.10 0.20
Variant frequency
4
6
0
AFR/EUR
0.02
6
NatAm/
NatAm
PUR
CHS YRI
GBR
PUR
YRI CLM
CHSLWK
FINGBRCHB
LWKMXLCLM
IBSFIN JPTCHBASW
ASW MXL
JPT
IBS
CEU
TSI CEU
TSI
2
EUR/EUR
60
140
140
40
120
120
20
100
100
0
80 0.01
80
c
AFR/AFR
b
60
Median length of haplotype
identity between two
chromosomes that share
variants of a given frequency
in each population
80
The average proportion of variants that are new (compared with the
4
pilot phase of the project) among
those found in regions inferred to
have different ancestries
within ASW, PUR, CLM and MXL populations
c
Population abbreviations: ASW, people with
African ancestry in Southwest United States;
CEU, Utah residents with ancestry from
Northern and Western Europe; CHB, Han
Chinese in Beijing, China; CHS, Han Chinese
South, China; CLM, Colombians in Medellin,
Colombia; FIN, Finnish in Finland; GBR, British
from England and Scotland, UK; IBS, Iberian
populations in Spain; LWK, Luhya in Webuye,
Kenya; JPT, Japanese in Tokyo, Japan; MXL,
people with Mexican ancestry in Los Angeles,
California; PUR, Puerto Ricans in Puerto Rico;
TSI, Toscani in Italia; YRI, Yoruba in Ibadan,
Nigeria. Ancestry-based groups: AFR,
African; AMR, Americas; EAS, East Asian;
EUR, European
2
0
AFR/AFR
AFR/AFR
EUR/EUR
EUR/EUR
NatAm/
NatAm
NatAm/
NatAm
AFR/EUR
AFR/EUR
AFR/NatAm
AFR/NatAm
EUR/NatAm
EUR/NatAm
b
TSI
100
Percent variants novel per sample (%)
Percent variants novel per sample
(%)
Percent
variants novel per sample (%)
across the entire sample, within and between populations. Each row represents the distribution
140populations for the origin of samples sharing an f2 variant with the target populationMXL
across
PUR
CHS YRI
GBR
(indicated by the left-hand
side).
The
grey
bars represent the average number of f2 variants
PUR
CHB LWK CLM
FIN
6
CLM
carried
each population
120by a randomly
ASW in MXL
JPT genome
IBS chosen
ASW
CEU
Shared haplotype length (kb)
Shared haplotype length (kb)
Shared haplotype length (kb)
GBR
FIN
GBR
IBS
FINCEU
IBSTSI
CEU
CHS
TSICHB
CHS
JPT
CHB
YRI
JPTLWK
YRIASW
LWK
PUR
ASW
CLM
PUR
MXL
CLM
MXL
f2 variants
MXL
CLM
PUR
ASW
LWK
YRI
a
aJPT
CHB
MXLCHS
TSI
CLMMXL
CEU
PURCLM
IBS
PUR
ASW
FIN
LWKASW
GBR
YRI LWK
JPTYRI
CHBJPT
CHSCHB
TSI CHS
CEUTSI
IBS CEU
FINIBS
GBRFIN
GBR
f2 variants
GBR
FIN
IBS
CEU
TSI
CHS
CHB
JPT
YRI
LWK
ASW
PUR
CLM
MXL
a
n We developed tools for manipulating data, standards
for data sharing and methods for interpreting
and using genetic variation in the study of human
disease, as well as gaining many insights into the
demographic and evolutionary history of humans
WHAT THIS ADDS
n The final release of the 1000 Genomes project is
a validated haplotype map from 2,504 individuals
consisting of 88m single nucleotide polymorphisms,
3.6m short insertions and deletions, and more than
60,000 larger structural rearrangements
n We found that individuals from different populations
carry different profiles of rare and common variants
n We showed that low-frequency variants show
substantial geographic differentiation, which is
further increased by the action of purifying selection
n We found that each individual carries
hundreds
Figure
3
of rare non-coding variants at conserved sites,
including transcription-factor-binding sites, multiple
loss-of-function variants that knock-out gene
function and a handful of variants known to cause
genetic disorders when present in two copies
n This publicly-available resource enables analysis of
Figure 3in individuals
common and low-frequency variants
Figure 3
from diverse, including admixed, populations
REFERENCES
A haplotype map of the human
genome.
The International HapMap
Consortium. Authors include
G A McVean [Project Leader],
P Donnelly [Principal
Investigator] & L R Cardon
[Principal Investigator]
Nature 2005 437, 1299–132.
A second-generation human
haplotype map of over 3.1
million SNPs.
The International HapMap
Consortium. Authors include
G A McVean [Project Leader],
P Donnelly [Principal
Investigator] & L R Cardon
[Principal Investigator]
Nature 2007 449, 851–861.
A map of human genome
variation from population-scale
sequencing.
The 1000 Genomes Project
Consortium [authors include
P Donnelly, G A McVean,
A Auton, Z Iqbal, G Lunter,
J L Marchini & S Myers]
Nature 2010 467, 1061–1073.
An integrated map of genetic
variation from 1,092 human
genomes.
The 1000 Genomes Project
Consortium. Authors include
G A McVean, P Donnelly,
G Lunter, J L Marchini, S Myers,
A Gupta-Hinch, Z Iqbal,
I Mathieson, A Rimmer,
D K Xifara & A Kerasidou
Nature 2012 491, 56–65.
A global reference for human
genetic variation.
The 1000 Genomes Project
Consortium.
Nature 2015 526, 68–74.