Nucleic Acids Research, 2009, Vol. 37, Database issuePublished online 26 November 2008
The HuRef Browser: a web resource for individual
Nelson Axelrod*, Yuan Lin, Pauline C. Ng, Timothy B. Stockwell, Jonathan Crabtree,
Jiaqi Huang, Ewen Kirkness, Robert L. Strausberg, Marvin E. Frazier, J. Craig Venter,
Saul Kravitz and Samuel Levy*
J. Craig Venter Institute, 9704 Medical Center Drive, Rockville, MD 20850, USA
Received October 27, 2008; Revised November 4, 2008; Accepted November 5, 2008
The HuRef Genome Browser is a web application
for the navigation and analysis of the previously pub-
lished genome of a human individual, termed HuRef.
The browser provides a comparative view between
the NCBI human reference sequence and the HuRef
assembly, and it enables the navigation of the HuRef
genome in the context of HuRef, NCBI and Ensembl
annotations. Single nucleotide
indels, inversions, structural and copy-number var-
iations are shown in the context of existing func-
comparative view. Demonstrated here are some
potential uses of the browser to enable a better
understanding of individual human genetic variation.
The browser provides full access to the underlying
reads with sequence and quality information, the
genome assembly and the evidence supporting the
identification of DNA polymorphisms. The HuRef
Browser is a unique and versatile tool for browsing
genome assemblies and studying individual human
sequence variation in a diploid context. The browser
is available online at http://huref.jcvi.org.
The first two drafts of human genome sequences were
published by the Human Genome Sequencing consortium
(1) and Celera Genomics (2) in 2001. These two genome
assemblies were created as consensus sequences from a
population of multiple individuals and DNA variations
were identified in the form of single nucleotide poly-
morphisms (SNPs) (3). We sequenced the genome of a
single individual and employed long range haplotype
sequence, referred to as HuRef (4). This genome sequence
assembly is unique in that it is constructed from the DNA
of a human individual and the diploid phasing of the
assembly has been determined in greater than 80% of
the genome. The analysis of the diploid human genome
produced a rich and complex picture of human sequence
variation. We reported variations in the form of SNPs,
block substitutions, indels, variable number tandem
repeats (VNTRs), inversions and other complex variants.
The detail and complexity of the datasets generated by
genome sequencing and assembly projects necessitate
visualization tools to provide composite displays that
synthesize all of the underlying data.
There aretwo types ofgenome browsers most relevant to
our project: assembly browsers and annotation browsers.
There are a number of genome assembly browsers that are
publicly available, including the NCBI Assembly Viewer,
Hawkeye (5), TAMPA (6) and EagleView (7). These brow-
sers are designed largely to enable users to detect, interro-
gate and correct errors of assembly, and are primarily used
to refine the assembly process.
There are a number of genome annotation browsers
available for the visualization and analysis of genome
sequence annotations, including the UCSC Genome
Browser (8), Ensembl Genome Browser (9), NCBI
Sequence Viewer and GBrowse (10). These browsers pro-
vide many useful features for viewing genome sequences,
annotations and variants. However, due to the highly
coupled nature of the genome assembly and annotation
processes, errors in assemblies are often propagated as
errors in annotations. The accuracy of genome annota-
tions, especially with regard to complex sequence varia-
tion, is nearly impossible to examine using annotation
browsers. There are reported cases of incorrectly anno-
tated genes or mischaracterized sequence variations that
are due to errors in assembly (11).
During the analysis of the HuRef genome, we found
that existing genome browsers were not designed to
study complex, large-scale sequence variation and its
*To whom correspondence should be addressed. Tel: +1 301 795 7382; Fax: +1 301 294 3142; Email: email@example.com
Correspondence may also be addressed to Samuel Levy. Tel: +1 301 795 7382; Fax: +1 301 294 3142; Email: firstname.lastname@example.org
? 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/
by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
relation to the assembly and annotation of an individual
human genome. To this end, we developed the HuRef
genome browser. It is a unified, high-performance frame-
work that integrates the functionality of annotation
and assembly browsers, and incorporates assembly-to-
assembly genome comparison views, haplotype views
and multiple sequence alignment capabilities.
The HuRef genome browser is a unique visualization
tool enabling the analysis of human sequence variation
complexity within an individual and between an individual
and areference genome. The analysis of the HuRef genome
determined that non-SNP sequence variation is responsible
for 22% of all variant events, but accounts for 74% of all
variant bases. Consequently, the annotation and assembly-
to-assembly comparison (ATAC) views in the HuRef
browser enable users to intuitively analyze indels and
other types of large-scale sequence variants including
inversions, transpositions, VNTRs and copy-number var-
iations (CNVs). The assembly view provides the basis for
judging the quality of the assembly, confirming structural
variants, determining the possible presence of alternate
alleles and interpreting the potential significance of a
given variation in the context of sequence annotations.
Finally, incorporating the multiple sequence alignment of
the underlying assembly and the pairwise alignment of an
individual to a reference genome helps to interrogate both
heterozygous and homozygous sequence variation.
The HuRef database
The HuRef database consists of approximately 32 million
DNA reads sequenced using Sanger dideoxy chemistry,
assembled into 4528 scaffolds and 4.1 million DNA varia-
tions identified by genome analysis (4). These variants
include SNPs, block substitutions, short and large indels,
inversions, rearrangements, and copy-number changes.
The data sources comprising the assembly and annotation
of the HuRef genome, including the HuRef genome
assembly (version 6), HuRef sequence variants and the
HuRef haplotype blocks have been previously described
(4,12). Additionally, the consensus module of the Celera
Assembler produces a multiple sequence alignment of the
reference sequence (12,15) that has been stored in the
HuRef database, and made accessible by the Sequence
The HuRef database contains external data sources,
including the reference sequence of the human genome
(NCBI version 36), the gene annotation of the NCBI
human reference sequence (Ensembl version 41), dbSNP
variants (build 126), OMIM Annotations (13), Gene
Ontology (14) and HUGO Gene nomenclature. These
external data sets are mapped to the NCBI and HuRef
coordinate systems using the ATAC sequence alignment
tool (15–17). Additionally, the HuRef database maintains
a direct sequence annotation of the HuRef assembly by
aligning genes in the RefSeq collection (18). There are
approximately 1000 genes predicted by the RefSeq anno-
tation that are uniquely annotated on the HuRef genome.
The HuRef SNPs and indels in coding regions were
classified using our internal tool, SNP Classifier, accord-
ing to their position on any given transcript such as in a
promoter, splice site, UTR, exonic or intronic region, and
the effects of these variants on translation such as causing
a synonymous or non-synonymous substitution, frame-
shift or protein truncation. Tandem repeats were identified
on the HuRef and NCBI reference sequences using the
default parameters for Tandem Repeats Finder (19).
The HuRef Browser software
The HuRef Genome Browser is an n-tier web application
built on standards-based, open source technologies to
facilitate software reuse and exchange of scientific infor-
mation. The HuRef database was designed to solve the
dual challenge of using open, standard and sensible biolo-
gical data formats while delivering a high-performance
web-based data resource. Our solution was to implement
an optimized data warehouse schema to serve as the read-
only data access layer of the browser application, built on
top of the Chado (20) database schema which serves to
manage the primary source of the data and the transac-
tional data operations.
The Chado database schema enables us to use standard
ontologies for the typing of annotations and relationships
(14), which provides for the proper semantic encoding
of complex biological information, and allows us to lever-
age existing open-source tools and software. The HuRef
database uses the open-source PostgreSQL RDBMS in
keeping to our commitment to standards-compliant,
The data and logic tiers are implemented in object-
oriented Perl, and the BioPerl (21) Graphic Modules are
utilized in the presentation layer. We use the MultiPanel
module from Sybil (http://sybil.sourceforge.net/) to gener-
ate images of the genome assembly-to-assembly mappings.
kit.org/) to build a high-performance web application that
provides the rich, user-experience of a thick-client applica-
tion. The HuRef Browser is currently hosted on a single,
2-CPU Enterprise Red Hat Linux 5.0 server, running the
Apache 2 HTTP server.
The HuRef Browser and database is available as an
open-source project under the GNU General Public
License (GPL) license at https://sourceforge.net/projects/
The HuRef Browser is a web application for the naviga-
tion and analysis of an individual human diploid genome.
The browser provides a comparative view between the
HuRef and NCBI human sequences enabling the exami-
nationof small-to-large scale
between any two assemblies. Users can navigate the
HuRef genome assembly and sequence variations, and
compare it with the NCBI human assembly in the context
of the NCBI (18) and Ensembl (9) gene annotations. The
browser has tracks representing the haplotype blocks from
which diploid genome sequence can be inferred and the
Nucleic Acids Research, 2009, Vol. 37, Database issueD1019
relation of variants to gene annotations. The Sequence
Alignment view displays the underlying sequence reads
of the HuRef assembly, and the haploid phasing of the
assembly is shown in precise detail.
Featuresof the HuRef Browser
Users can search the HuRef Browser using: HUGO gene
names; RefSeq, NCBI Gene, Ensembl or dbSNP acces-
sions; HuRef supercontig or contig locations; read identi-
fiers; or NCBI chromosome coordinates. Alternatively,
users can navigate to a region by selecting a chromosome
band of interest in the karyotype view. Users can navigate
in the vicinity of any genomic region via the pan and zoom
controls. The views are configurable by the user, and any
tracks can be turned on and off by a drop-down menu and
rearranged by drag and drop controls.
ATAC tool to align the HuRef and NCBI human
genome consensus sequences, and the resulting pairwise
alignments are shown in the ATAC view. This view is
designed to enable the visualization of complex, large-
scale sequence variations including indels, inversions,
rearrangements, VNTRs and other structural variants
(Figure 1). Ungapped alignments between the genome
assemblies are linked by either blue (same orientation)
or pink (opposite orientation) blocks.
comparisonview. We used the
Assembly view. The assembly view displays a contig or
supercontig region of the HuRef assembly, and its under-
lying clones, reads and sequence annotations (Figure 2).
A supercontig is a collection of ordered and oriented con-
tigs, sometimes referred to as a scaffold. The assembly
information is useful for the identification of structural
variations such as large indels and inversions, to identify
alternate alleles in the HuRef assembly, or to identify
potential misassemblies. The assembly is displayed using:
(i) a contig track which displays the tiling of contigs for
any scaffold region, (ii) a histogram track of read cover-
age, (iii) a histogram track of clone coverage and (iv)
tracks to display the individual clones and reads. The
HuRef consensus has been annotated by the NCBI
RefSeq group (18). The NCBI gene models and RefSeq
mRNAs are displayed as tracks in the same context as the
Assembly view, along with tracks for the various types of
The underlying clone layout is useful to identify com-
pressions and expansions, and assess the local accuracy of
an assembly. The clone tracks are separately displayed and
categorized according to their mate pair status: satisfied,
stretched, compressed, externally mated, unknown mate
and unassembled mate. Satisfied clones are defined by
the furthest endpoints of the clone pair being placed
within 3 SDs of the mean insert distance of its library.
Stretched and compressed clones are cases where the
clone ends are greater or less than the satisfied clone dis-
There are a number of patterns that are often associated
with alternate alleles in the HuRef assembly that can be
inspected using the browser. For example, a reduction in
read coverage is often indicative of a heterozygous indel.
A region with a number of externally placed clones that all
share the same external contig assembly can be indicative
of a large indel or structural variation. The assembly view
enables the identification of these types of patterns, and to
explore haplotype variability from single base pair SNPs
to indels and large-scale sequence variations.
Annotation view. The annotation view displays Ensembl
genes, dbSNP variants, HuRef variants and HuRef
Haplotype Blocks as separate
Differences in glyph color and shape are used to distin-
guish HuRef variants based upon their type and predicted
functional impact (Supplementary Table 1). The annota-
tion view is useful for understanding sequence variation
within the context of genome annotation, to identify var-
iants of interest, to review and compare the HuRef and
Figure 1. Representing complex sequence variation in the assembly
comparison view. The ATAC view represents the mapping between
two consensus sequences. In this example, the NCBI reference
genome is represented as the teal rectangle on top, and the HuRef
supercontig or contig that has the best match to the NCBI reference
region is shown as the green and/or yellow rectangles at the bottom.
Shaded lines represent the mapping between the two reference
sequences, and the blue or pink fill color is use to denote the same
or reverse orientation of the HuRef supercontig or contig with respect
to the NCBI chromosome location. (A) Deletion of NCBI sequence
with respect to the HuRef genome. (B) Insertion of HuRef supercontig
sequence with respect to NCBI human reference. (C) Rearrangement
of the HuRef supercontig with respect to the NCBI reference.
(D) Inversion of HuRef with respect to NCBI reference. (E) HuRef
assembly contains a ?10kb scaffold that potentially represents an alter-
nate haplotype to the larger supercontig that is the best match to this
region on the NCBI reference.
Nucleic Acids Research, 2009,Vol. 37,Database issue
dbSNP variants, and to inspect the Ensembl and NCBI
gene annotations on either the HuRef or NCBI reference
frame. Differences between the de novo annotation of
HuRef and the mapped annotation on the NCBI human
reference can be readily found using the HuRef Browser.
The large-scale sequence variation found in the HuRef
genome may lead to the identification of novel genes or
alternate transcript forms (Supplementary Figure 2).
Figure 2. Assembly view showing a 3kb Indel. This view represents the underlying structure of the HuRef assembly with tiers representing the contig
layout, sequence read and clone coverage organized by their mate pair criteria. This example shows a 3kb deletion on HuRef with respect to the
NCBI reference genome. This indel ranges from 4–9? sequence read coverage and 10–25? clone coverage consisting of entirely well-placed clones.
There are no stretched or compressed clones in this region which provides confidence in the quality of the assembly.
Figure 3. Annotation view. This view represents annotations on the reference sequence, including gene models, haplotype blocks, SNPs, indels,
assembly comparison differences and complex sequence variations found on HuRef, as well as known variants from dbSNP. Glyph shape is used to
distinguish between heterozygous and homozygous SNPs, and color is used to denote predicted impact on the encoded protein product. This example
shows a 467bp insertion on HuRef with respect to the NCBI reference sequence in the terminal coding exon of this Zinc-finger gene. The yellow and
pink square glyphs in the HuRef SNPs tier represent heterozygous SNPs that introduce a synonymous and non-synonymous amino acid change,
respectively. The pink circles represent homozygous SNPs, or differences between HuRef and the NCBI reference sequence, that introduce non-
synonymous amino acid substitutions. See supplemental figure S1 for more detail on glyph shape and color.
Nucleic Acids Research, 2009, Vol. 37, Database issueD1021
Browser components. A selected feature or region of inter-
est can be further analyzed using the components that are
accessible at the bottom of the main browser window. The
tabs in this portion of the browser page are: (i) feature
inspector: this displays detailed information of any feature
including coordinate locations, external database identi-
fiers, links to related Web resources and the ability to
export any feature in FASTA format (Supplementary
Figure 3). (ii) Seq alignment: this displays the multiple
sequence alignment of the NCBI consensus aligned to
the sequence and associated quality values of the HuRef
consensus and underlying sequence reads (Figure 4). The
multiple sequence alignment can be examined to inspect
variant calls and to determine the zygosity of the consen-
sus at any position. (iii) GFF table: this displays the anno-
tations visible in the Annotation View as a table that can
be readily exported in GFF format (Supplementary
Figure 4). (iv) SNP analysis: the SNP analysis component
displays the predicted impact of the HuRef variants on
functional sequence considering all overlapping transcript
forms in a given region of interest (Supplementary
Figure 5). (v) SNP evidence: this component provides
the set of evidence criteria used for variant identification
including read and clone placement, read coverage, read
orientation to confirm a given variant in both sequencing
directions, read and consensus quality values, and clone
statistics (Supplementary Figure 6). (vi) SNPs in repeats:
this component lists repeat features that overlap any
Annotations: this lists all external database references
including OMIM and Gene Ontology links/assignments
of genes and other annotations for a given region of inter-
est. All of the datasets for these components can be
exported in standard formats.
Examplesof using thebrowser
The HuRef Browser provides an easy way for users to
identify variants of structural or functional interest in a
genome, to check an individual’s genotype, to examine the
underlying evidence for any variant, to assess the impact
of a variant on a particular protein product, or to verify
genome assembly. The ability to provide accurate geno-
type calls whose underlying supporting evidence can be
examined is paramount when providing a personal geno-
mics profile to an individual. This is especially true for
genotypes whose implication in genetic diseases has been
Example 1. Analysis of a heterozygous SNP associated
with night blindness. CACNA2D4 is a gene that encodes
a regulatory subunit in the voltage-dependent calcium
channel complex that mediates ion influx to the cell.
A C-to-A transversion was identified (23) that introduces
a premature stop codon (TAC ! TAA) and truncates
one-third of the open reading frame. This truncation has
been shown to cause retinal cone dystrophy, an autosomal
recessive condition. Upon navigating to this gene in the
browser, users will notice a red round glyph in the HuRef
SNPs track in the Annotation View representing a hetero-
zygous variant that causes a frameshift or protein trunca-
tion according to our variant analysis (Supplementary
Figure 1). The Sequence Alignment view of this G/T
SNP shows ten reads that overlap the variant column, of
which two support the alternate T allele, indicating that
the HuRef donor is heterozygous for this variation and is
a carrier of this recessive disorder. The predicted func-
tional impact of the variant can be obtained by using
the SNP Analysis component that confirms that the var-
iant truncates the open reading frame of this protein-
Example 2. Analysis of a 14kb inversion in a TNF recep-
tor gene. There is a 14kb inversion in the HuRef donor
on chromosome 1 from 2.47 to 2.49 MB (Supplementary
Figure 2). This inversion fully spans the genic region of
TNFRSF14, a member of the Tumor Necrosis Factor
receptor superfamily. This gene plays a key role in
Figure 4. Sequence alignment view showing haplotype phasing. The sequence alignment of the 30intronic region of LOC400713, a Zinc finger
gene on chromosome 19, shows three, closely-spaced SNP sites that have been phased to represent the diploid sequence of HuRef. This view
includes the haploid sequences that overlap a given region, and color is used to highlight the variant columns and to show the phasing of variants.
The haplotype assembly phases the three heterozygous SNPs in the haplotype block with the ‘A’ haplotype containing the A, T and G alleles, and
the ‘B’ haplotype containing the G, C, T alleles for these three SNPs. Notice that the HuRef consensus is a mixed G, C, G allele and the correct
phasing can only be observed by inspecting the haplotype sequences. The NCBI chromosome consensus is representative of the G, C and T
Nucleic Acids Research, 2009,Vol. 37,Database issue
regulating the immune response to infection, and is
involved in lymphocyte activation. The inversion is con-
tained in a 2.3MB contig with 23? and 27? clone cover-
age spanning the 50and 30breakpoints of the inversion,
respectively, with a read in the inversion and its mate in
the non-inverted region. This provides a significant degree
of confidence in the inversion call. It is possible that this
insertion may affect TNFRSF14 regulation if this gene is
cis-regulated by upstream or downstream sequences,
although further analysis is required.
In 2001, two versions of the human genome were pub-
lished, both of which were comprised of a mosaic of
an ethnically diverse population of individuals. Because
of the composite nature of these genomes, the individ-
ual haplotype sequences were almost entirely lost.
Subsequently, the genome sequences of Dr Craig Venter
and Dr James Watson were published (4,22). This has
signified a new era of human genomics and it is expected
that thousands of personal human genomes will be pub-
licly available in the near future. We can begin to unravel
the unique traits and disease propensities that are encoded
in an individual’s double-stranded DNA on a genome-
wide scale as this data becomes available.
In this article, we present the HuRef Genome Browser,
a new web resource that provides open, public access to
the de novo assembly and annotation of an individual
diploid human genome (4). The HuRef Browser enables
the analysis of the complete spectrum of sequence varia-
tion, from SNPs to indels, rearrangements, VNTRs and
CNVs. It brings together the visual analytic tools of
assembly, annotation and synteny viewers in an easy-to-
use, integrated framework.
The underlying evidence, especially the assembly, which
forms the basis of the subsequent annotation and analysis
processes, is open and publicly available to the scientific
community. This is especially important in the analysis of
personal genomes because of the significant implications
that some disease-associated genotypes may have to an
individual donor. Due to the complexity of the human
genome and limitations in technologies and algorithms,
the cloning, sequencing, assembling and data analysis pro-
cesses can lead to errors in the automated detection of
sequence variation. Therefore, it is prudent to verify gen-
otypes by a full examination of the sources of evidence.
The HuRef Browser is designed to facilitate this kind of
detailed examination by providing the variant evidence-
related data, including the placement and status of reads
and clones assembled into contigs and scaffolds, the
sequence alignment, quality values and other measures
that are associated with accurate variant detection meth-
ods. This information serves the scientific community to
make the correct analysis of an individual genome based
upon all of the available information.
It is now feasible to sequence individual human gen-
omes on a large scale given the dramatic increase in
the efficiencies of DNA sequencing. Researchers are gen-
erating individual human sequence data at an ever-
increasing rate (4,22,24–26), motivating the need for
effective, high-performance visualization tools to study
sequence assembly and variation in a population of
Supplementary Data are available at NAR Online.
The authors would like to thank Gennady Denisov for his
help in the development of the sequence alignment cap-
abilities. Brian Walenz for his valuable comments and
contributions towards the assembly comparison displays.
Kelvin Li for his support and the use of his variant classi-
fication software. We wish to express our gratitude to
Stephen Scherer and Lars Feuk at The Centre for
Applied Genomics at The Hospital for Sick Children, as
well as Lisa Stubbs at the Lawrence Livermore Laboratory
for their valuable suggestions to improve the user interface
and information layout of the browser. Lastly, we would
like to thank Tom Emmel and Hank Wu for their support
in administering the IT system resources.
This work was supported by the J. Craig Venter Institute.
Funding for open access charge: J. Craig Venter Institute.
Conflict of interest statement. None declared.
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