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Dog10K: The International Consortium of Canine Genome Sequencing

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PERSPECTIVES
BIOLOGY & BIOCHEMISTRY
Dog10K: the International Consortium of Canine Genome Sequencing
Guo-Dong Wang1,2, Greger Larson3, Jeffrey M. Kidd 4, Bridgett M. vonHoldt 5,
Elaine A. Ostrander6,and Ya-Ping Zhang1,2,
Dogs (Canis lupus familiaris) were the
rst species to enter into a domestic rela-
tionship with people [1] and are a source
of fascination all over the world, not only
due to their history of domestication and
dispersal along with human beings [2],
but also because of their diverse pheno-
types and behaviors, driven by both ar-
ticial and natural selection [3]. Dogs
and humans have oen been subjected to
similar selection pressures [4], and these
shared evolutionary trajectories have led
to the emergence of the same common
disorders including heart disease, neuro-
logic disorders, diabetes and cancer [5].
e worldwide canine genetics ge-
nomics communities recently formed
the International Consortium of Canine
Genome Sequencing, also called the
Dog10K Consortium (hp://www.
dog10kgenomes.org), to address major
research questions regarding the ge-
netic underpinnings of domestication,
breed formation, aging, behavior and
morphologic variation, and to advance
our understanding of human and ca-
nine health [6]. is collaboration was
originally conceived by the Chinese
Academy of Sciences in 2016 with an
initial plan to organize sample selection
and collection, sequencing technology,
bioinformatics, analysis and logistics,
toward the goal of generating and sharing
whole-genome sequence (WGS) data
from 10 000 dogs and wild canids to
improve the utility of the canine model
system. An initial meeting was held in
the summer of 2016 in the Academic
Summit of Dog Genomes, featuring 25
participants representing 9 countries and
18 institutions (Fig. 1a), and the second
meeting was held on 26 May 2019 at the
10th International Conference on Ca-
nine and Feline Genetics and Genomics
(Fig. 1b) with 15 participants represent-
ing 13 institutions.
e primary goals of this collabora-
tive endeavor are to generate WGSs of
10 000 canine/canids within 5 years, re-
ne the existing reference genome from
Figure 1. (a) Initial meeting of the Dog10K Consortium in Beijing, 2016 (Courtesy of Yunyun Zheng).
(b) Second meeting of the Dog10k Consortium in Bern, 2019 (Courtesy of Guo-Dong Wang).
a Boxer, create new reference genomes
from additional canids and apply the data
to a myriad of scientic questions. e re-
sulting catalog will contain comprehen-
sive high-density genomic data, includ-
ing single nucleotide variants (SNVs),
structural variants (SVs), which include
copy number variations (CNVs), and
C
e Author(s) 2019. Published by Oxford University Press on behalf of China Science Publishing & Media Ltd. is is an Open Access article distributed under the terms of the Creative
Commons Aribution License (hp://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original
work is properly cited.
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612 Natl Sci Rev, 2019, Vol. 6, No. 4 PERSPECTIVES
mobile element insertions (MEIs). Us-
ing these data, the possibility now ex-
ists to expand our knowledge of wild
and domestic canids, and enhance stud-
ies of biology, disease susceptibility and
evolution. We aim to sequence each
genome to at least 20×coverage, which
provides optimal coverage with mini-
mal error rates. De novo genome assem-
bly will be undertaken for both breed
dogs and wild canids using a variety
of technologies, including Pacic Bio-
sciences long-reads (PacBio) (100×),
Bacterial Articial Chromosome (BAC)-
end sequencing, optical mapping (Bio-
nano Saphyr), phased haplotypes (60x
by the 10x genomics platform), chro-
mosome conformation (Hi-C), etc. We
will sequence mRNAs, long non-coding
RNAs and circle RNAs in pituitary, liver,
hippocampus, ovarian and prefrontal cor-
tex samples, and a full-length transcrip-
tome through PacBio using a mix of the
above tissues for the annotation of the
reference genome. To address research
questions, the Consortium denes the
roles of participants and its interaction
with the larger scientic community.
SAMPLE ACQUISITION FOR
PHYLOGENY, DOMESTICATION,
AND PHENOTYPIC AND
CLINICAL TRAITS
Integral to the success of Dog10K is the
principle that sample collection will be
extensive, covering all established breeds
throughout the world, as well as village
dogs, wild canids, and niche or non-
registered dog populations that fall out-
side the formal denition of a recognized
breed. e laer can be used as outgroups
to improve detection of ancestral versus
derived alleles. e wild canids and vil-
lage dogs will help the demographic his-
tory and occurrence of admixture at the
early stages of dog domestication to be
deciphered. Niche population dogs will
reveal the natural selection events that
occurred when dogs traveled alongside
humans during early human civilizations.
Studies of established breeds will facili-
tate genetic studies of breed morphology,
behavior and disease susceptibility. e
Consortium is also sampling pedigrees
spanning three generations for both dogs
and wolves to generate deep, compre-
hensive genome sequence information,
which will further enable an improved in-
ference of evolutionary rates in canids.
BIOINFORMATIC ANALYSIS
AND DATA DISTRIBUTION
e Consortium will build a standard
pipeline for SNV calling based on the
Genome Analysis Toolkit (GATK) best
practices [7] and will produce analysis-
ready BAM les for each sample. Vari-
ant discovery will proceed from the BAM
les and produce variant calls, which in-
volves the generation of G.VCF les by
the HaplotypeCaller for each sample and
the production of variant calls by Geno-
typeGVCFs, combining all individuals.
e output will be in VCF format for the
further ltering of variants, renement of
genotypes and annotation. We will also
use a combination of methods to call the
SVs, CNVs and MEIs. Basic population
genetic analysis will be performed to infer
nuclear diversity, haplotypes recombina-
tion maps and other parameters.
Data sharing is a crucial component
of the Consortium. e FASTQ, BAM
and G.VCF les will be stored and shared
through the Genome Sequence Archive
(hp://gsa.big.ac.cn/). FASTQ les
will be stored and shared through the
Sequence Read Archive (hps://www.
ncbi.nlm.nih.gov/sra/). At the same
time, we will use iDog (hp://bigd.
big.ac.cn/idog/) to share omics data [8],
[i.e. the data set of variations (SNVs,
CNVs, SVs and MEIs), haplotype, gene
expression, parameters of population
genetics, etc.]. All data sets will be
continuously updated throughout the
duration of the project. Meanwhile,
we will update the progress of the
dog10K Consortium on the website
(hp://www.dog10kgenomes.org) and
incorporate a variety of metadata,
including information regarding the
number of samples collected, gender,
geography, progress to date and other
sample-aliated information. All co-
operating organizations and related
partners’ information will also be avail-
able on the website. For data generated
by other means and incorporated into
Dog10K, links will be established to the
original websites where primary data and
additional analyses are located.
POPULATION GENOMIC- AND
WGS-BASED CASE-CONTROLS
ANALYSIS
Dogs adapted to novel environments as
they dispersed across continents with
people and oen hybridized with local
wild canids as they did so. We will assess
the strength and timing of selection at the
rst stage of dog domestication, and will
identify articial selection that aected
early breeding processes. Dog10K data
will allow for signatures of selection to
be associated with specic traits and local
adaptation processes in wild canid popu-
lations to be identied, both of which will
serve as a basis for investigating the po-
tential role of polygenic selection in ca-
nines, none of which have been studied
to date. We will also explore the com-
plex paerns of admixture among wild
and domestic canid species, and search
for genomic regions depleted of admixed
ancestry and adapted introgression. Full
genomes from diverse populations will
provide new data to test ideas on the dis-
tribution of selection, which are integral
to evolutionary models of demography
and adaptation.
Strong articial selection has resulted
in 450 globally recognized breeds with
distinct traits related to morphology, in-
cluding body size, leg length, skull shape,
etc. [9]. Dog10K will expand that ap-
plicability by developing an exhaustive
catalog of genetic variation to enable
the generation of an accurate imputation
panel for dog genome-wide association
studies, in much the same way that the
1000 Genomes Project has improved the
study of low-frequency variants in hu-
man association studies [10,11]. Refer-
ence sequence data on all breeds will pro-
vide the scientic community with an
ability to perform matched WGS-based
case-controls analysis, either directly or
through imputation, as has recently been
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PERSPECTIVES Wang et al.613
successfully demonstrated for breed stan-
dard traits. e transition of the process
to studies of disease will be permied by
this large data set. is aim is important,
since the link between canine and human
health has generated the most interest
within the biomedical community. Ad-
vancing our understanding of common
human diseases through studies of com-
parable diseases based on genomic ap-
proaches is key to the overall success of
Dog10K.
INTERNATIONAL
COLLABORATION
Dog10K aims to integrate quickly with
ongoing sequencing and analysis eorts.
For instance, the data set under construc-
tion includes the sequencing and subse-
quent analysis of 722 canids [9] and rare
breeds from isolated locations through-
out the world [12]. Other ongoing eorts
in the general dog community fall into
three categories. First, several research
groups are studying domestication, inde-
pendent of Dog10K [13,14]. e integra-
tion of WGS data from such studies will
rapidly expand the utility of the Dog10K
data set, permiing greater understand-
ing of the selection events that have led
to specic behaviors in domestic dogs
as well as domestication itself [15]. Sec-
ond, there are scientic programs focused
on studies of ancient dog DNA (sum-
marized in [16]). Such studies will pro-
vide insights into the links between wild
canids and domesticated dogs, and will
therefore be integrated into Dog10K. It is
hoped that, simultaneously, the Dog10K
reference data set will prove useful for
studies of ancient canines. Finally, there
are several ongoing eorts to build de
novo reference genomes based on at least
12 distinct dog breeds or wild canids
[17]. e aim of Dog10K is to produce
an integrated reference genome with the
caliber of the human genome. By both
aiding the community with its advanced
bioinformatics as well as directly integrat-
ing data produced by various research
groups, this is sure to happen.
CONCLUSION
e Dog10K Consortium will gener-
ate a comprehensive data set of unpar-
alleled complexity and power. is ef-
fort will result in a resource that will
prove invaluable to a wide range of elds,
including comparative genomics, veteri-
nary science, evolutionary biology, med-
ical research and conservation genetics.
Dog10K will thus elevate the dog to its
rightful place as a premier genetic system
for revealing fundamental insights into
evolution, health and biology; therefore,
Dog10K will be a valuable partner for the
growing number of researchers who are
investigating dogs as a viable model for
studies of disease susceptibility, progres-
sion, treatment response and gene ther-
apy outcomes [18,19].
FUNDING
is work was supported by a number of entities,
including grants from the National Natural
Science Foundation of China (91731304 and
31621062), the Breakthrough Project of Strategic
Priority Program of the Chinese Academy of
Sciences (XDB13000000), the Intramural Pro-
gram of the National Human Genome Research
Institute of the National Institutes of Health to
E.A.O., a CAS International Collaborating Grant
(152453KYSB20150002 to G.-D.W.), and a
Young Innovation Promotion Association Award
(to G.-D.W.).
Conict of interest statement. None declared.
Guo-Dong Wang1,2, Greger Larson3, Jeffrey
M. Kidd 4, Bridgett M. vonHoldt 5,
Elaine A. Ostrander6,and Ya-Ping Zhang1,2,
1State Key Laboratory of Genetic Resources and
Evolution, Kunming Institute of Zoology, Chinese
Academy of Sciences, China
2Center for Excellence in Animal Evolution and
Genetics, Chinese Academy of Sciences, China
3Palaeogenomics and Bio-Archaeology Research
Network, School of Archaeology, University of
Oxford, UK
4Department of Human Genetics and Department
of Computational Medicine and Bioinformatics,
University of Michigan Medical School, USA
5Ecology & Evolutionary Biology, Princeton
University, USA
6National Human Genome Research Institute,
National Institutes of Health, USA
Corresponding authors.
E-mails: eostrand@mail.nih.gov;
zhangyp@mail.kiz.ac.cn
REFERENCES
1. Ni Leathlobhair M, Perri AR and Irving-Pease EK
et al. Science 2018; 361: 81–5.
2. Freedman AH and Wayne RK. Annu Rev Anim
Biosci 2017; 5: 281–307.
3. Ostrander EA, Wayne RK and Freedman AH et al.
Nat Rev Genet 2017; 18: 705–20.
4. Wang GD, Xie HB and Peng MS et al. Annu Rev
Anim Biosci 2014; 2: 65–84.
5. Ostrander EA, Dreger DL and Evans JM. Annu Rev
Anim Biosci 2018; 7: 449–72.
6. Ostrander EA, Wang G-D and Larson G et al. Natl
Sci Rev 2019; 6: 257–74.
7. DePristo MA, Banks E and Poplin R et al. Nat
Genet 2011; 43: 491–8.
8. Tang B, Zhou Q and Dong L et al. Nucleic Acids
Res 2018; 47: D793–800.
9. Plassais J, Kim J and Davis BW et al. Nat Com-
mun 2019; 10: 1489.
10. Genomes Project, C, Auton A and Brooks LD et al.
Nature 2015; 526: 68–74.
11. Sudmant PH, Rausch T and Gardner EJ et al. Na-
ture 2015; 526: 75–81.
12. Parker HG, Dreger DL and Rimbault M et al. Cell
Rep 2017; 19: 697–708.
13. Kukekova AV, Johnson JL and Xiang X et al. Nat
Ecol Evol 2018; 2: 1479–91.
14. Freedman AH, Schweizer RM and Ortega-
Del Vecchyo D et al. PLoS Genet 2016; 12:
e1005851.
15. vonHoldt BM, Cahill JA and Fan Z et al. Sci Adv
2016; 2: e1501714.
16. Larson G, Karlsson EK and Perri A et al. Proc Natl
Acad Sci USA 2012; 109: 8878–83.
17. Wang G-D, Shao X-J and Bai B et al. Natl Sci Rev
2019; 6: 110–22.
18. Zou Q, Wang X and Liu Y et al. J Mol Cell Biol
2015; 7: 580–3.
19. Lee BC, Kim MK and Jang G et al. Nature 2005;
436: 641.
National Science Review
6: 611–613, 2019
doi: 10.1093/nsr/nwz068
Advance access publication 29 May 2019
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