1000 Genomes Project

1000 Genomes Project
The 1000 Genomes Project (abbreviated as 1KGP), launched in January 2008, was an international
research effort to establish by far the most detailed catalogue of human genetic variation. Scientists planned
to sequence the genomes of at least one thousand anonymous participants from a number of different ethnic
groups within the following three years, using newly developed technologies which were faster and less
expensive. In 2010, the project finished its pilot phase, which was described in detail in a publication in the
journal Nature.[1] In 2012, the sequencing of 1092 genomes was announced in a Nature publication.[2] In
2015, two papers in Nature reported results and the completion of the project and opportunities for future
research.[3] [4]
Many rare variations, restricted to closely related groups, were identified, and eight structural-variation
classes were analyzed.[5]
The project unites multidisciplinary research teams from institutes around the world, including China, Italy,
Japan, Kenya, Nigeria, Peru, the United Kingdom, and the United States. Each will contribute to the
enormous sequence dataset and to a refined human genome map, which will be freely accessible through
public databases to the scientific community and the general public alike.[2]
By providing an overview of all human genetic variation, the consortium will generate a valuable tool for
all fields of biological science, especially in the disciplines of genetics, medicine, pharmacology,
biochemistry, and bioinformatics.[6]
Background
Since the completion of the Human
Genome Project advances in human
population genetics and comparative
genomics have made it possible to gain
increasing insight into the nature of
genetic diversity.[7] However, we are
just beginning to understand how
processes like the random sampling of
gametes, structural variations
(insertions/deletions (indels), copy
number variations (CNV), Changes in the number and order of genes (A-D) create genetic
retroelements), single-nucleotide diversity within and between populations.
polymorphisms (SNPs), and natural
selection have shaped the level and
pattern of variation within species and also between species.[8][9][10][11]
Human genetic variation
The random sampling of gametes during sexual reproduction leads to genetic drift — a random fluctuation
in the population frequency of a trait — in subsequent generations and would result in the loss of all
variation in the absence of external influence. It is postulated that the rate of genetic drift is inversely
proportional to population size, and that it may be accelerated in specific situations such as bottlenecks,
where the population size is reduced for a certain period of time, and by the founder effect (individuals in a
population tracing back to a small number of founding individuals).[8]
Anzai et al. demonstrated that indels account for 90.4% of all observed variations in the sequence of the
major histocompatibility locus (MHC) between humans and chimpanzees. After taking multiple indels into
consideration, the high degree of genomic similarity between the two species (98.6% nucleotide sequence
identity) drops to only 86.7%. For example, a large deletion of 95 kilobases (kb) between the loci of the
human MICA and MICB genes, results in a single hybrid chimpanzee MIC gene, linking this region to a
species-specific handling of several retroviral infections and the resultant susceptibility to various
autoimmune diseases. The authors conclude that instead of more subtle SNPs, indels were the driving
mechanism in primate speciation.[9]
Besides mutations, SNPs and other structural variants such as copy-number variants (CNVs) are
contributing to the genetic diversity in human populations. Using microarrays, almost 1,500 copy number
variable regions, covering around 12% of the genome and containing hundreds of genes, disease loci,
functional elements and segmental duplications, have been identified in the HapMap sample collection.
Although the specific function of CNVs remains elusive, the fact that CNVs span more nucleotide content
per genome than SNPs emphasizes the importance of CNVs in genetic diversity and evolution.[10]
Investigating human genomic variations holds great potential for identifying genes that might underlie
differences in disease resistance (e.g. MHC region) or drug metabolism.[12]
Natural selection
Natural selection evolution of a trait can be divided into three classes. Directional or positive selection refers
to a situation where a certain allele has a greater fitness than other alleles, consequently increasing its
population frequency (e.g. antibiotic resistance of bacteria). In contrast, stabilizing or negative selection
(also known as purifying selection) lowers the frequency or even removes alleles from a population due to
disadvantages associated with it with respect to other alleles. Finally, a number of forms of balancing
selection exist; those increase genetic variation within a species by being overdominant (heterozygous
individuals are fitter than homozygous individuals, e.g. G6PD, a gene that is involved in both Hemolytic
anaemia and malaria resistance) or can vary spatially within a species that inhabits different niches, thus
favouring different alleles.[13] Some genomic differences may not affect fitness. Neutral variation,
previously thought to be “junk” DNA, is unaffected by natural selection resulting in higher genetic
variation at such sites when compared to sites where variation does influence fitness.[14]
It is not fully clear how natural selection has shaped population differences; however, genetic candidate
regions under selection have been identified recently.[11] Patterns of DNA polymorphisms can be used to
reliably detect signatures of selection and may help to identify genes that might underlie variation in disease
resistance or drug metabolism.[13][14] Barreiro et al. found evidence that negative selection has reduced
population differentiation at the amino acid–altering level (particularly in disease-related genes), whereas,
positive selection has ensured regional adaptation of human populations by increasing population
differentiation in gene regions (mainly nonsynonymous and 5'-untranslated region variants).[11]
It is thought that most complex and Mendelian diseases (except diseases with late onset, assuming that older
individuals no longer contribute to the fitness of their offspring) will have an effect on survival and/or
reproduction, thus, genetic factors underlying those diseases should be influenced by natural selection.
Although, diseases that have late onset today could have been childhood diseases in the past as genes
delaying disease progression could have undergone selection. Gaucher disease (mutations in the GBA
gene), Crohn's disease (mutation of NOD2) and familial hypertrophic cardiomyopathy (mutations in
MYH7, TNNT2, TPM1 and MYBPC3) are all examples of negative selection. These disease mutations are
primarily recessive and segregate as expected at a low frequency, supporting the hypothesized negative
selection. There is evidence that the genetic-basis of Type 1 Diabetes may have undergone positive
selection.[15] Few cases have been reported, where disease-causing mutations appear at the high
frequencies supported by balanced selection. The most prominent example is mutations of the G6PD locus
where, if homozygous G6PD enzyme deficiency and consequently Hemolytic anaemia results, but in the
heterozygous state are partially protective against malaria. Other possible explanations for segregation of
disease alleles at moderate or high frequencies include genetic drift and recent alterations towards positive
selection due to environmental changes such as diet or genetic hitch-hiking.[12]
Genome-wide comparative analyses of different human populations, as well as between species (e.g.
human versus chimpanzee) are helping us to understand the relationship between diseases and selection and
provide evidence of mutations in constrained genes being disproportionally associated with heritable
disease phenotypes. Genes implicated in complex disorders tend to be under less negative selection than
Mendelian disease genes or non-disease genes.[12]
Project description
Goals
There are two kinds of genetic variants related to disease. The first are rare genetic variants that have a
severe effect predominantly on simple traits (e.g. Cystic fibrosis, Huntington disease). The second, more
common, genetic variants have a mild effect and are thought to be implicated in complex traits (e.g.
Cognition, Diabetes, Heart Disease). Between these two types of genetic variants lies a significant gap of
knowledge, which the 1000 Genomes Project is designed to address.[6]
The primary goal of this project is to create a complete and detailed catalogue of human genetic variations,
which in turn can be used for association studies relating genetic variation to disease. By doing so the
consortium aims to discover >95 % of the variants (e.g. SNPs, CNVs, indels) with minor allele frequencies
as low as 1% across the genome and 0.1-0.5% in gene regions, as well as to estimate the population
frequencies, haplotype backgrounds and linkage disequilibrium patterns of variant alleles.[16]
Secondary goals will include the support of better SNP and probe selection for genotyping platforms in
future studies and the improvement of the human reference sequence. Furthermore, the completed database
will be a useful tool for studying regions under selection, variation in multiple populations and
understanding the underlying processes of mutation and recombination.[16]
Outline
The human genome consists of approximately 3 billion DNA base pairs and is estimated to carry around
20,000 protein coding genes. In designing the study the consortium needed to address several critical issues
regarding the project metrics such as technology challenges, data quality standards and sequence
coverage.[16]
Over the course of the next three years, scientists at the Sanger Institute, BGI Shenzhen and the National
Human Genome Research Institute’s Large-Scale Sequencing Network are planning to sequence a
minimum of 1,000 human genomes. Due to the large amount of sequence data that need to be generated
and analyzed it is possible that other participants may be recruited over time.[6]
Almost 10 billion bases will be sequenced per day over a period of the two year production phase. This
equates to more than two human genomes every 24 hours; a groundbreaking capacity. Challenging the
leading experts of bioinformatics and statistical genetics, the sequence dataset will comprise 6 trillion DNA
bases, 60-fold more sequence data than what has been published in DNA databases over the past 25
years.[6]
To determine the final design of the full project three pilot studies were designed and will be carried out
within the first year of the project. The first pilot intends to genotype 180 people of 3 major geographic
groups at low coverage (2×). For the second pilot study, the genomes of two nuclear families (both parents
and an adult child) are going to be sequenced with deep coverage (20× per genome). The third pilot study
involves sequencing the coding regions (exons) of 1,000 genes in 1,000 people with deep coverage
(20×).[6][16]
It has been estimated that the project would likely cost more than $500 million if standard DNA sequencing
technologies were used. Therefore, several new technologies (e.g. Solexa, 454, SOLiD) will be applied,
lowering the expected costs to between $30 million and $50 million. The major support will be provided by
the Wellcome Trust Sanger Institute in Hinxton, England; the Beijing Genomics Institute, Shenzhen (BGI
Shenzhen), China; and the NHGRI, part of the National Institutes of Health (NIH).[6]
In keeping with Fort Lauderdale principles (http://www.genome.gov/pages/research/wellcomereport0303.p

df) Archived (https://web.archive.org/web/20131228183230/http://www.genome.gov/pages/research/wellc
omereport0303.pdf) 2013-12-28 at the Wayback Machine, all genome sequence data (including variant
calls) is freely available as the project progresses and can be downloaded via ftp from the 1000 genomes
project webpage (http://www.1000genomes.org/data).
Human genome samples
Based on the overall goals for the

project, the samples will be chosen to
provide power in populations where
association studies for common
diseases are being carried out.
Furthermore, the samples do not need
to have medical or phenotype
information since the proposed
catalogue will be a basic resource on
human variation.[16]
For the pilot studies human genome

samples from the HapMap collection
Locations of population samples of 1000 Genomes Project.[17]
will be sequenced. It will be useful to
Each circle represents the number of sequences in the final
focus on samples that have additional
release.
data available (such as ENCODE
sequence, genome-wide genotypes,
fosmid-end sequence, structural variation assays, and gene expression) to be able to compare the results
with those from other projects.[16]
Complying with extensive ethical procedures, the 1000 Genomes Project will then use samples from
volunteer donors. The following populations will be included in the study: Yoruba in Ibadan (YRI),
Nigeria; Japanese in Tokyo (JPT); Chinese in Beijing (CHB); Utah residents with ancestry from northern
and western Europe (CEU); Luhya in Webuye, Kenya (LWK); Maasai in Kinyawa, Kenya (MKK);
Toscani in Italy (TSI); Peruvians in Lima, Peru (PEL); Gujarati Indians in Houston (GIH); Chinese in
metropolitan Denver (CHD); people of Mexican ancestry in Los Angeles (MXL); and people of African
ancestry in the southwestern United States (ASW).[6]
ID Place Population Detail
Detail (https://catalog.coriell.org/1/NHGRI/Collectio
ASW * African Ancestry in SW USA ns/1000-Genomes-Collections/African-Ancestry-in-
SW-USA-ASW)
ACB * African Caribbean in Barbados ns/1000-Genomes-Collections/African-Caribbean-in
-Barbados-ACB)
BEB Bengali in Bangladesh ns/1000-Genomes-Collections/Bengali-in-Banglade
sh-BEB)
GBR British from England and Scotland ns/1000-Genomes-Collections/British-from-England
-and-Scotland-UK-GBR)
CDX Chinese Dai in Xishuangbanna, China ns/1000-Genomes-Collections/Chinese-Dai---Xishu
angbanna-CDX)
CLM Colombian in Medellín, Colombia ns/1000-Genomes-Collections/Colombian-in-Medelli
n-Colombia-CLM)
ESN Esan in Nigeria ns/1000-Genomes-Collections/Esan-in-Nigeria-ES
N)
FIN Finnish in Finland ns/1000-Genomes-Collections/Finnish-in-Finland-FI
N)
GWD Gambian in Western Division – Mandinka ns/1000-Genomes-Collections/Gambian-in-Western
-Division--Mandinka-GWD)
Gujarati Indians in Houston, Texas,
GIH * ns/1000-Genomes-Collections/Gujarati-Indians-in-H
United States
ouston-TX-USA-GIH)
CHB Han Chinese in Beijing, China ns/1000-Genomes-Collections/Han-Chinese-in-Beiji
ng-China-CHB)
CHS Han Chinese South, China ns/1000-Genomes-Collections/Han-Chinese-South-
China-CHS)
IBS Iberian populations in Spain ns/1000-Genomes-Collections/Iberian-populations-i
n-Spain-IBS)
ITU * Indian Telugu in the U.K. ns/1000-Genomes-Collections/Indian-Telugu-in-the-
UK-ITU)
JPT Japanese in Tokyo, Japan ns/1000-Genomes-Collections/Japanese-in-Tokyo-J
apan-JPT)
KHV Kinh in Ho Chi Minh City, Vietnam ns/1000-Genomes-Collections/Kinh-in-Ho-Chi-Minh-
City-Vietnam-KHV)
LWK Luhya in Webuye, Kenya ns/1000-Genomes-Collections/Luhya-in-Webuye-Ke
nya-LWK)
MSL Mende in Sierra Leone ns/1000-Genomes-Collections/Mende-in-Sierra-Leo
ne-MSL)
Mexican Ancestry in Los Angeles CA
MXL * ns/1000-Genomes-Collections/Mexican-Ancestry-in
United States
-Los-Angeles-CA-USA-MXL)
PEL Peruvian in Lima, Peru ns/1000-Genomes-Collections/Peruvian-in-Lima-Pe
ru-PEL)
PUR Puerto Rican in Puerto Rico ns/1000-Genomes-Collections/Puerto-Rican-in-Puer
to-Rico-PUR)
PJL Punjabi in Lahore, Pakistan ns/1000-Genomes-Collections/Punjabi-in-Lahore-Pa
kistan-PJL)
STU * Sri Lankan Tamil in the UK ns/1000-Genomes-Collections/Sri-Lankan-Tamil-in-t
he-UK-STU)
TSI Toscani in Italia
ns/1000-Genomes-Collections/Toscani-in-Italia-TSI)
YRI Yoruba in Ibadan, Nigeria ns/1000-Genomes-Collections/Yoruba-in-Ibadan-Nig
eria-YRI)
Utah residents with Northern and Western

Detail (https://catalog.coriell.org/1/NIGMS/Collectio
CEU * European ancestry from the CEPH
ns/CEPH-Resources)
collection
* Population that was collected in diaspora
Community meeting
Data generated by the 1000 Genomes Project is widely used by the genetics community, making the first
1000 Genomes Project one of the most cited papers in biology.[18] To support this user community, the
project held a community analysis meeting in July 2012 that included talks highlighting key project
discoveries, their impact on population genetics and human disease studies, and summaries of other large-
scale sequencing studies.[19]
Project findings
Pilot phase
The pilot phase consisted of three projects:
low-coverage whole-genome sequencing of 179 individuals from 4 populations

high-coverage sequencing of 2 trios (mother-father-child)
exon-targeted sequencing of 697 individuals from 7 populations
It was found that on average, each person carries around 250–300 loss-of-function variants in annotated
genes and 50-100 variants previously implicated in inherited disorders. Based on the two trios, it is
estimated that the rate of de novo germline mutation is approximately 10−8 per base per generation.[1]
See also
Biology portal
Human Genome Project

HapMap Project
Personal genomics
Population groups in biomedicine
1000 Plant Genomes Project
List of biological databases
References
1. Abecasis GR, Altshuler D, Auton A, Brooks LD, Durbin RM, Gibbs RA, et al. (October 2010).
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(2008) http://www.nih.gov/news/health/jan2008/nhgri-22.htm
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American Anthropological Association (2004)
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"Comparative sequencing of human and chimpanzee MHC class I regions unveils
insertions/deletions as the major path to genomic divergence" (https://www.ncbi.nlm.nih.gov/
pmc/articles/PMC164652). Proceedings of the National Academy of Sciences of the United
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"Global variation in copy number in the human genome" (https://www.ncbi.nlm.nih.gov/pmc/
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13. EE Harris et al., The molecular signature of selection underlying human adaptations,
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14. Bamshad M, Wooding SP (February 2003). "Signatures of natural selection in the human
genome". Nature Reviews. Genetics. 4 (2): 99–111. doi:10.1038/nrg999 (https://doi.org/10.1
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15. Corona E, Dudley JT, Butte AJ (August 2010). Hawks J (ed.). "Extreme evolutionary
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16. Meeting Report: A Workshop to Plan a Deep Catalog of Human Genetic Variation, (2007)
http://www.1000genomes.org/sites/1000genomes.org/files/docs/1000Genomes-
MeetingReport.pdf
17. Oleksyk TK, Brukhin V, O'Brien SJ (2015). "The Genome Russia project: closing the largest
remaining omission on the world Genome map" (https://www.ncbi.nlm.nih.gov/pmc/articles/P
MC4644275). GigaScience. 4: 53. doi:10.1186/s13742-015-0095-0 (https://doi.org/10.118
6%2Fs13742-015-0095-0). PMC 4644275 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4
18. C. King (2012) The Hottest Research of 2011. Science Watch
http://archive.sciencewatch.com/newsletter/2012/201203/hottest_research_2012/
19. 1000 Genomes Project Community Analysis Meeting http://1000gconference.sph.umich.edu/
External links
1000 Genomes (http://www.1000genomes.org/) - A Deep Catalog of Human Genetic
Variation - official web page
International HapMap Project (http://www.hapmap.org/) Archived (https://web.archive.org/we
b/20140416084248/http://www.hapmap.org/) 2014-04-16 at the Wayback Machine - official
web page
Human Genome Project Information (http://www.ornl.gov/sci/techresources/Human_Genom
e/home.shtml)
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1000 Genomes Project

Human genetic variation

In keeping with Fort Lauderdale principles (http://www.genome.gov/pages/research/wellcomereport0303.p

Human genome samples

Based on the overall goals for the

For the pilot studies human genome

Utah residents with Northern and Western

* Population that was collected in diaspora

The pilot phase consisted of three projects:

low-coverage whole-genome sequencing of 179 individuals from 4 populations

Human Genome Project

Retrieved from "https://en.wikipedia.org/w/index.php?title=1000_Genomes_Project&oldid=1160866783"

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