Nucleic Acids Research 2006 34(Database Issue):D25-D28; doi:10.1093/nar/gkj009
Nucleic Acids Research, 2006, Vol. 34, Database issue D25-D28
© The Author 2006. Published by Oxford University Press. All rights reserved
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HUMHOT: a database of human meiotic recombination hot spots
K. T. Nishant1,
Chetan Kumar2 and
M. R. S. Rao1,2,*
1Department of Biochemistry, Indian Institute of Science Bangalore 560012, India
2Jawaharlal Nehru Center for Advanced Scientific Research Jakkur, Bangalore 560064, India
*To whom correspondence should be addressed. Tel: +91 80 22082865; Fax: +91 80 23622766; Email: mrsrao{at}jncasr.ac.in
Received July 29, 2005. Revised September 2, 2005. Accepted September 12, 2005.
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ABSTRACT
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Meiotic recombination occurs preferentially at certain regions
in the genome referred to as hot spots. The number of hot spots
known in humans has increased manifold in recent years. The
identification of these hot spots in humans is of great interest
to population and medical geneticists since they influence the
structure of Linkage Disequilibrium and Haplotype blocks in
human populations, whose patterns have applications in mapping
disease genes. HUMHOT is a web-based database of Human Meiotic
Recombination Hot Spots. The database comprises DNA sequences
corresponding to the hot spot regions from the literature that
have been mapped to a high resolution (<4 kb) in humans.
It also provides flanking sequence information for the hot spot
region along with references describing the hot spot. The database
can be queried based on hot spot identity, chromosome position
or by homology to user-defined sequences. It is also updated
with new hot spot sequences as they are discovered and provides
hyperlinks to commonly used tools for estimating recombination
rates, performing genetic analysis and new advances in our understanding
of meiotic hot spots. Public access to the HUMHOT database is
available at
http://www.jncasr.ac.in/humhot.
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INTRODUCTION
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Meiotic recombination is initiated at the prophase stage of
meiosis I through the formation of double strand breaks (DSBs)
by the Spo11 endonuclease (
1,
2). The non-random distribution
of DSBs that initiate the recombination events results in the
formation of hot spots where the recombination frequency between
markers exceeds the average recombination frequency for the
entire genome. A segment of DNA that undergoes recombination
at the genome average rate can also be considered a hot spot
if it is embedded in a recombinationally suppressed region of
the genome. Hot spots have been observed to be 1–3 kb
wide in yeast, mice and humans (
3) and unlike the
chi sequence
in
Escherichia coli (
4), no primary DNA sequence determinant
of hot spot activity has been identified in eukaryotes. In recent
years, a large number of human meiotic recombination hot spots
have been identified due to the development of methods to analyze
sperm DNA (
5) and population genetics approaches (
6). Comparison
of the molecular features of meiotic recombination hot spots
between yeast, mice and humans reveals a high degree of similarity
and suggests overlapping roles for both the DNA sequence and
chromatin configuration in the establishment of a hot spot (
3,
7,
8).
It has been estimated that the human genome is likely to contain
as many as 50 000 meiotic hot spots on the basis of the distribution
of hot spots in the MHC region and from the large-scale identification
of recombination hot spots on specific chromosomes (
3).
Recombination hot spots in humans frequently delimit the extent of haplotype blocks in populations as observed from the correlation between sperm crossover hot spots and regions showing LD breakdown on two different chromosomal locus (9–11). This has resulted in a role for meiotic hot spots in association mapping of loci contributing to phenotypic traits since they help define haplotype blocks that reduce the number of markers required for such analysis. However, a few exceptions in this paradigm have also emerged recently (9,12) which also support the argument that hot spots are very fluid features of the genome on evolutionary time scales (13).
The HUMHOT database has been conceived with the idea to store all meiotic recombination hot spot sequences identified in humans by a database managing system. It currently stores 132 human meiotic recombination hot spot sequences identified till date through sperm typing or population genetics based approaches. Users can query the database based on hot spot identity (locus name) or chromosome number. It is also possible to perform a homology search, which determines whether the sequence submitted exists as a hot spot sequence in the database. The database stores various details for every hot spot sequence, such as locus name, chromosome number, hot spot sequence in FASTA format, flanking sequence information in GCG format, hyperlinks to the respective reference papers on PubMed, and accession numbers to get further sequence details from the GenBank or ENCODE databases, as the case may be. The sequences are also available in a downloadable flat file version so that users can easily store them and perform additional operations on them. The database also provides information on bibliographic knowledge about hot spots and recent published literature in this field.
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DATABASE STRUCTURE
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The Database Management System that we are using is PostgreSQL
since it is freely available and also used by the server at
JNCASR. The software has been coded with PHP, HTML and Javascript
as the higher languages. The database houses information about
the various hot spot sequences in the form of tables (
Figure 1)
and flat files. The table ‘Hotspot’ which houses
details of the sequences has the following information stored
for every such sequence: Locus Name, Chromosome Number, Accession
Number, Hot spot Region in base pairs, Date of Data Entry, Reference
ID, Hot spot Sequence and Flanking Sequence information and
URL to the corresponding accession web page in the GenBank.
Locus Name is the primary key of the above table. Another table
called the ‘Reference Table’ stores the Reference
ID, name of the author and the URL to the web page where the
particular paper is available. The primary key of this table
is the Reference ID, which is also the foreign key for the Hotspot
table. The ‘Administrator’ table houses information
about the Administrator and maintain session ids. The Message
table stores the Recombination news messages and their respective
URL's. There is provision for storing three news items at a
time.
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Figure 1 Database design and operation. The database has been designed using PostgreSQL. It comprises four tables—Hotspot table which stores details of all the sequences, Reference table for storing reference articles describing the hot spots, Message table for inserting recombination news and the Administrator table which provides a secure login feature for the Administrator and maintains the session id. The database is quick in responding to a query since the queries to the database are being carried out simultaneously on a maximum of two tables (Hotspot table, Reference table) only.
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DATABASE ACCESS AND WEB QUERY INTERFACE
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The website is extremely user friendly and offers easy navigability
options across the web pages through a drop down horizontal
menu bar, with appropriate directional and error messages at
each step.
Search features
The HUMHOT web interface provides access to the database contents in three ways through the ‘search database’ option (Figure 2). The user can either enter the hot spot locus name or a chromosome number or use the homology interface that queries all sequences in the HUMHOT database. In cases in which a search identifies more than one database entry, the names of all corresponding hits are displayed for the user to choose (Figure 3). The locus name should match the hot spot name as entered in the database while the chromosome number entered can specify the chromosome arm also. For a given match, the hot spot sequence in FASTA format and the sequence flanking the hot spot in GCG format are presented along with links to the reference describing the hot spot and through the accession number to the relevant database (GenBank, ENCODE). A printable version and flat file format of the hot spot and flanking sequence can also be generated.
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Figure 2 Screen shot showing the multiple query forms generated from the drop down menu under the ‘search database’ option. Selecting a menu from the ‘Search database’ drop down box opens a simple form in which the user can specify the hot spot locus name, chromosome number or paste a query sequence to search the database.
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Figure 3 Sample output of the HUMHOT database following search for hot spots on chromosome 3. The output lists all hot spots in the database on chromosome 3. Selecting any of the hot spots under the field hot spot locus opens up a new page containing the hot spot sequence, flanking sequence, reference and accession number. The hot spot region indicated is with respect to the flanking sequence.
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Additional database contents
The website also provides information about various aspects
of meiotic hot spots, such as different classes of hot spots,
motifs associated with hot spots, molecular features of hot
spots, methods used to map hot spots and an illustration of
the meiotic recombination process in different species. The
‘Recombination Tool Box’ provides easy access to
different software and websites on the internet dedicated to
computing recombination rates and other kinds of genetic analysis.
The ‘Useful Links’ button on the menu bar allows
users to access other websites which could be helpful for DNA
sequence analysis and sequence format conversions, since the
database comprises DNA sequences. Users can also know as to
when the database was last updated by clicking on the date,
which appears right below the ‘Last Updated’ button
on the home page. This action would open a new page where the
details of all of the sequences that were updated would be displayed
in a tabular form. To keep visitors updated on recent information
on hot spots, the ‘Recombination News’ section has
been provided. The scrolling news message is hyperlinked to
the respective article on PubMed.
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FUTURE DEVELOPMENTS
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The website provides secure access to the Administrator to modify
and update the database as and when new human meiotic hot spot
sequences are identified. Researchers working on meiotic recombination
are also welcome to submit published data on new human meiotic
hot spot sequences by email to the corresponding authors. We
plan to expand the HUMHOT database to include all human meiotic
hot spot sequences along with an additional information on the
methods used to map the hotspots. We also intend to improve
the usefulness of the database by including a direct link from
the hot spot regions to the haplotype map available for the
corresponding chromosomal region on the human HapMap webpage.
This would be done in the near feature.
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CITING HUMHOT
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Authors who make use of the HUMHOT database as a tool for their
published research can cite this paper as reference, and quote
the HUMHOT home page URL,
http://www.jncasr.ac.in/humhot.
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ACKNOWLEDGEMENTS
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The authors thank Gilean McVean, University of Oxford for providing
the hot spot positions in the chromosome 20 dataset and Xuegong
Zhang, Tsinghua University for providing recombination rate
estimates for genes in the Seattle SNP database. The authors
are thankful to Ms Sheethal (Network Administrator, JNCASR,
Bangalore) for assistance with the uploading and better working
of website. Funding to pay the Open Access publication charges
for this article was provided by JNCASR.
Conflict of interest statement. None declared.
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Footnotes
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Correspondence may also be addressed to K. T. Nishant. Tel:
+91 80 22932547; Fax: +91 80 23600118; Email:
knis{at}biochem.iisc.ernet.in
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors
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REFERENCES
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ABSTRACT
INTRODUCTION