EDIT

/**

* Copyright (C) 2007 EDIT

* European Distributed Institute of Taxonomy

* http://www.e-taxonomy.eu

*

* The contents of this file are subject to the Mozilla Public License Version 1.1

* See LICENSE.TXT at the top of this package for the full license terms.

*/

package eu.etaxonomy.cdm.model.molecular;

import java.net.URI;

import java.net.URISyntaxException;

import java.util.HashSet;

import java.util.Set;

import javax.persistence.Column;

import javax.persistence.Entity;

import javax.persistence.FetchType;

import javax.persistence.ManyToMany;

import javax.persistence.ManyToOne;

import javax.persistence.OneToMany;

import javax.persistence.Transient;

import javax.xml.bind.annotation.XmlAccessType;

import javax.xml.bind.annotation.XmlAccessorType;

import javax.xml.bind.annotation.XmlAttribute;

import javax.xml.bind.annotation.XmlElement;

import javax.xml.bind.annotation.XmlElementWrapper;

import javax.xml.bind.annotation.XmlIDREF;

import javax.xml.bind.annotation.XmlRootElement;

import javax.xml.bind.annotation.XmlSchemaType;

import javax.xml.bind.annotation.XmlTransient;

import javax.xml.bind.annotation.XmlType;

import org.apache.log4j.Logger;

import org.hibernate.annotations.Cascade;

import org.hibernate.annotations.CascadeType;

import org.hibernate.envers.Audited;

import org.hibernate.search.annotations.IndexedEmbedded;

import org.springframework.beans.factory.annotation.Configurable;

import eu.etaxonomy.cdm.common.CdmUtils;

import eu.etaxonomy.cdm.model.common.AnnotatableEntity;

import eu.etaxonomy.cdm.model.common.DefinedTerm;

import eu.etaxonomy.cdm.model.common.TermType;

import eu.etaxonomy.cdm.model.media.Media;

import eu.etaxonomy.cdm.model.reference.Reference;

/**

 * Alignment of multiple {@link SingleRead single sequences} to a consensus sequence.

 * This sequence is a part of (or the complete) DNA sequences of the related {@link DnaSample DNA Sample},

 * while

 *

 * <BR>This class holds information about both the combining process of

 * {@link SingleRead single sequences} to one consensus sequence

 * ({@link #getSingleReads() singleReads} , {@link #getContigFile() contigFile} )

 * as well as sequence related information.

 * The later includes the {@link #getConsensusSequence() sequence string} itself,

 * important genetic information about the DNA that has been sequenced

 * ({@link #getDnaMarker() marker} , {@link #getHaplotype()} haplotype) as well as

 * registration information ({@link #getGeneticAccessionNumber() genetic accession number} ),

 * citations, and barcoding information ({@link #getBoldProcessId() BOLD-id},

 * {@link #getBarcodeSequencePart() barcode sequence}, ...).

 *

 * @author m.doering

 * @since 08-Nov-2007 13:06:51

 * @author a.mueller

 * @updated 11-Jul-2013

 */

@XmlAccessorType(XmlAccessType.FIELD)

@XmlType(name = "Sequence", propOrder = {

    "dnaSample",

	"consensusSequence",

	"isBarcode",

    "barcodeSequencePart",

    "dnaMarker",

    "geneticAccessionNumber",

    "boldProcessId",

    "haplotype",

    "contigFile",

    "singleReadAlignments",

    "citations"

})

@XmlRootElement(name = "Sequencing")

@Entity

@Audited

@Configurable

//@Table(appliesTo="Sequence", indexes = { @Index(name = "sequenceTitleCacheIndex", columnNames = { "titleCache" }) })

public class Sequence extends AnnotatableEntity implements Cloneable{

	private static final long serialVersionUID = 8298983152731241775L;

	private static final Logger logger = Logger.getLogger(Sequence.class);

	//TODO move to cdmlib-ext?

	private static final String GENBANK_BASE_URI = "http://www.ncbi.nlm.nih.gov/nuccore/%s";

	private static final String EMBL_BASE_URI = "http://www.ebi.ac.uk/ena/data/view/%s";

	private static final String DDBJ_BASE_URI = "http://getentry.ddbj.nig.ac.jp/getentry/na/%s/?filetype=html";

	private static final String BOLD_BASE_URI = "http://www.boldsystems.org/index.php/Public_RecordView?processid=%s";

    @XmlElement( name = "DnaSample")

    @XmlIDREF

    @XmlSchemaType(name = "IDREF")

    @ManyToOne(fetch = FetchType.LAZY)

    @IndexedEmbedded

    private DnaSample dnaSample;

	/** @see #getContigFile() */

	@XmlElement(name = "ContigFile")

    @XmlIDREF

    @XmlSchemaType(name = "IDREF")

    @ManyToOne(fetch = FetchType.LAZY)

	@Cascade({CascadeType.SAVE_UPDATE,CascadeType.MERGE})

	private Media contigFile;

	/** @see #getConsensusSequence() */

	@XmlElement(name = "ConsensusSequence")

    private SequenceString consensusSequence = SequenceString.NewInstance();

	@XmlAttribute(name = "isBarcode")

	private Boolean isBarcode = null;

	/** @see #getBarcodeSequence()*/

	@XmlElement(name = "BarcodeSequencePart")

    private SequenceString barcodeSequencePart = SequenceString.NewInstance();

	/** @see #getGeneticAccessionNumber()*/

	@XmlElement(name = "GeneticAccessionNumber")

    @Column(length=20)

	private String geneticAccessionNumber;

	/** @see #getBoldProcessId() */

	@XmlElement(name = "BoldProcessId")

    @Column(length=20)

	private String boldProcessId;

    @XmlElementWrapper(name = "SingleReadAlignments")

    @XmlElement(name = "SingleReadAlignment")

    @XmlIDREF

    @XmlSchemaType(name = "IDREF")

    @OneToMany(mappedBy="consensusAlignment", fetch = FetchType.LAZY, orphanRemoval=true)

    @Cascade({CascadeType.SAVE_UPDATE,CascadeType.MERGE})

	private Set<SingleReadAlignment> singleReadAlignments = new HashSet<SingleReadAlignment>();

	/** @see #getDnaMarker() */

	@XmlElement(name = "DnaMarker")

    @XmlIDREF

    @XmlSchemaType(name = "IDREF")

    @ManyToOne(fetch = FetchType.LAZY)

	//no cascade as it is a defined term

	private DefinedTerm dnaMarker;

	/** @see #getHaplotype() */

	@XmlElement(name = "Haplotype")

    @Column(length=100)

	private String haplotype;

	/** @see #getCitations() */

	@XmlElementWrapper(name = "Citations")

    @XmlElement(name = "Citation")

    @XmlIDREF

    @XmlSchemaType(name = "IDREF")

    @ManyToMany(fetch = FetchType.LAZY)

    @Cascade({CascadeType.SAVE_UPDATE,CascadeType.MERGE})

	private Set<Reference> citations = new HashSet<>();

//	//should be calculated in case sequence is set

//	@XmlElement (name = "DateSequenced", type= String.class)

//	@XmlJavaTypeAdapter(DateTimeAdapter.class)

//	@Type(type="dateTimeUserType")

//	@Basic(fetch = FetchType.LAZY)

//	private DateTime dateSequenced;

//*********************** FACTORY ****************************************************/

	public static Sequence NewInstance(String consensusSequence){

		Sequence result = new Sequence();

		result.setSequenceString(consensusSequence);

		return result;

	}

	public static Sequence NewInstance(String consensusSequence, Integer length){

		Sequence result = NewInstance(consensusSequence);

		result.getConsensusSequence().setLength(length);

		return result;

	}

	public static Sequence NewInstance(DnaSample dnaSample, String consensusSequence, Integer length){

		Sequence result = NewInstance(consensusSequence);

		result.getConsensusSequence().setLength(length);

		dnaSample.addSequence(result);

		return result;

	}

//*********************** CONSTRUCTOR ****************************************************/

	protected Sequence() {}

//*********************** GETTER / SETTER ****************************************************/

	/**

	 * The {@link DnaSample dna sample} this sequencing belongs too.

	 */

	public DnaSample getDnaSample() {

		return dnaSample;

	}

	/**

	 * To be called only from {@link DnaSample#addSequence(Sequence)}

	 * @see #getDnaSample()

	 */

	//TODO implement full bidirectionality

	protected void setDnaSample(DnaSample dnaSample) {

		this.dnaSample = dnaSample;

		if (dnaSample != null && !dnaSample.getSequences().contains(this)){

			throw new RuntimeException("Don't use DNA setter");

		}

	}

	/**

	 * The resulting consensus sequence represened by this {@link Sequence sequence} .

	 * The consensus is usually computed from the {@link SingleRead single reads}.

	 * The result of which is stored in a file called {@link #getContigFile() contig file}

	 *

	 * #see {@link #getContigFile()}

	 * #see {@link #getSingleReads()}

	 */

	public SequenceString getConsensusSequence() {

		return consensusSequence;

	}

	/**

	 * @see #getConsensusSequence()

	 */

	public void setConsensusSequence(SequenceString sequenceString) {

		if (sequenceString == null){

			sequenceString = SequenceString.NewInstance();

		}

		this.consensusSequence = sequenceString;

	}

	/**

	 * The isBarcode flag should be set to true if this (consensus) sequence is or includes

	 * a barcoding sequence. If the barcoding sequence is only a part of the consensus sequence

	 * this part shall be stored as {@link #getBarcodeSequencePart() barcoding sequence part}.

	 * A isBarcode value of <code>null</code> indicates that we do have no knowledge

	 * whether the sequence is a barcoding sequence or not.

	 *

	 * @see #getBarcodeSequencePart()

	 * @see #getSequenceString()

	 * @returns the isBarcode flag value (tri-state)

	 *

	 */

	public Boolean getIsBarcode() {

		return isBarcode;

	}

	/**

	 * @see #getIsBarcode()

	 * @see #getBarcodeSequencePart()

	 */

	public void setIsBarcode(Boolean isBarcode) {

		this.isBarcode = isBarcode;

	}

	/**

	 * If the barcode sequence string does not include 100% of the (consensus) sequence

	 * the part used as barcode is provided here. However, the barcode part

	 * should be kept empty if consensus sequence string and barcode sequence string are equal.

	 *

	 * @see #getIsBarcode()

	 */

	public SequenceString getBarcodeSequencePart() {

		return barcodeSequencePart;

	}

	/**

	 * @see #getBarcodeSequencePart()

	 */

	public void setBarcodeSequencePart(SequenceString barcodeSequencePart) {

		if (barcodeSequencePart == null){

			barcodeSequencePart = SequenceString.NewInstance();

		}

		this.barcodeSequencePart = barcodeSequencePart;

	}

	/**

	 * Sets the {@link TermType#DnaMarker DNA marker} examined and described by this sequencing.

	 * The marker should usually be similar to the one used in the according {@link Amplification

	 * amplification process}. However, it may slightly differ, or, if multiple amplifications where

	 * used to build this consensus sequence it may be the super set of the markers used in amplification.

	 *

	 * @return

	 */

	public DefinedTerm getDnaMarker(){

		return this.dnaMarker;

	}

	/**

	 * @see #getDnaMarker()

	 * @param marker

	 */

	public void setDnaMarker(DefinedTerm dnaMarker){

		this.dnaMarker = dnaMarker;

	}

	/**

	 * The accession number used in GenBank, EMBL and DDBJ.

	 * @return

	 */

	public String getGeneticAccessionNumber() {

		return geneticAccessionNumber;

	}

	/**

	 * Sets the genetic accession number.

	 * @see #getGeneticAccessionNumber()

	 */

	public void setGeneticAccessionNumber(String geneticAccessionNumber) {

		this.geneticAccessionNumber = geneticAccessionNumber;

	}

	/**

	 * The identifier used by the Barcode of Life Data Systems (BOLD, http://www.boldsystems.org/).

	 */

	public String getBoldProcessId() {

		return boldProcessId;

	}

	public void setBoldProcessId(String boldProcessId) {

		this.boldProcessId = boldProcessId;

	}

	/**

	 * Returns the name of the haplotype.

	 * A haplotype (haploide genotype) is a variant of nucleotide sequences on the same chromosome.

	 * A certain haplotype may be specific for an individual, a population or a species.

	 * @return

	 */

	public String getHaplotype() {

		return haplotype;

	}

	/**

	 * @see #getHaplotype()

	 */

	public void setHaplotype(String haplotype) {

		this.haplotype = haplotype;

	}

	/**

	 * The contigFile containing all data and data processing for this sequencing.

	 *

	 * @see #getConsensusSequence()

	 * @see #getSingleReads()

	 */

	public Media getContigFile() {

		return contigFile;

	}

	/**

	 * @see #getContigFile()

	 */

	public void setContigFile(Media contigFile) {

		this.contigFile = contigFile;

	}

	/**

	 * Citations are the set of references in which this sequence was published.

	 * Unlike taxonomic names the first publication of a sequence

	 * is not so important (maybe because it is required by publishers

	 * that they are all registered at Genbank) therefore we do not have something like an

	 * "original reference" attribute.<BR>

	 * Links to these references are to be stored within the reference itself.

	 * @return the set of references in which this sequence was published.

	 */

	public Set<Reference> getCitations() {

		return citations;

	}

	/**

	 * @see #getCitations()

	 */

	protected void setCitations(Set<Reference> citations) {

		this.citations = citations;

	}

	/**

	 * @see #getCitations()

	 */

	public void addCitation(Reference citation) {

		this.citations.add(citation);

	}

	/**

	 * @see #getCitations()

	 */

	public void removeCitation(Reference citation) {

		this.citations.remove(citation);

	}

	/**

	 * The {@link SingleRead single reads} that were used to build this consensus sequence.

	 *

	 * @see #getConsensusSequence()

	 * @see #getContigFile()

	 */

	public Set<SingleReadAlignment> getSingleReadAlignments() {

		return singleReadAlignments;

	}

	/**

	 * @see #getSingleReads()

	 */

	public void addSingleReadAlignment(SingleReadAlignment singleReadAlignment) {

		this.singleReadAlignments.add(singleReadAlignment);

		if (! this.equals(singleReadAlignment.getConsensusSequence())){

			singleReadAlignment.setConsensusAlignment(this);

		};

	}

	/**

	 * @see #getSingleReads()

	 */

	public void removeSingleReadAlignment(SingleReadAlignment singleReadAlignment) {

		this.singleReadAlignments.remove(singleReadAlignment);

		if (this.equals(singleReadAlignment.getConsensusSequence())){

			singleReadAlignment.setConsensusAlignment(null);

			singleReadAlignment.setSingleRead(null);

		}

	}

//	/**

//	 * @see #getSingleReads()

//	 */

//	//TODO private as long it is unclear how bidirectionality is handled

//	@SuppressWarnings("unused")

//	private void setSingleReadAlignments(Set<SingleReadAlignment> singleReadAlignments) {

//		this.singleReadAlignments = singleReadAlignments;

//	}

// *********************** CONVENIENCE ***********************************/

	/**

	 * Convenience method to add a single read to a consensus sequence

	 * by creating a {@link SingleReadAlignment}.

	 * @param singleRead the {@link SingleRead} to add

	 * @return the created SingleReadAlignment

	 */

	public SingleReadAlignment addSingleRead(SingleRead singleRead) {

		SingleReadAlignment alignment = SingleReadAlignment.NewInstance(this, singleRead);

		return alignment;

	}

	public void removeSingleRead(SingleRead singleRead) {

		Set<SingleReadAlignment> toRemove = new HashSet<SingleReadAlignment>();

		for (SingleReadAlignment align : this.singleReadAlignments){

			if (align.getSingleRead() != null && align.getSingleRead().equals(singleRead)){

				toRemove.add(align);

			}

		}

		for (SingleReadAlignment align : toRemove){

			removeSingleReadAlignment(align);

		}

		return;

	}

	/**

	 * Convenience method that returns all single reads this consensus sequence

	 * is based on via {@link SingleReadAlignment}s.

	 * @return set of related single reads

	 */

	@XmlTransient

	@Transient

	public Set<SingleRead> getSingleReads(){

		Set<SingleRead> singleReads = new HashSet<SingleRead>();

		for (SingleReadAlignment align : this.singleReadAlignments){

			if (align.getSingleRead() != null){  // == null should not happen

				singleReads.add(align.getSingleRead());

			}

		}

		return singleReads;

	}

	//*************************** Transient GETTER /SETTER *****************************/

	/**

	 * Delegate method to get the text representation of the consensus sequence

	 * @see #setSequenceString(String)

	 */

	@Transient

	public String getSequenceString() {

		return consensusSequence.getString();

	}

	/**

	 * Delegate method to set the text representation of the {@link #getConsensusSequence()

	 * consensus sequence}.

	 */

	@Transient

	public void setSequenceString(String sequence) {

		consensusSequence.setString(sequence);

	}

	/**

	 * Convenience method which computes the set of all related pherograms

	 * @return the set of pherograms.

	 */

	@Transient

	public Set<Media> getPherograms(){

		Set<Media> result = new HashSet<Media>();

		for (SingleReadAlignment singleReadAlign : singleReadAlignments){

			if (singleReadAlign.getSingleRead() != null &&  singleReadAlign.getSingleRead().getPherogram() != null){

				result.add(singleReadAlign.getSingleRead().getPherogram());

			}

		}

		return result;

	}

	//***** Registrations ************/

	/**

	 * Returns the computed genBank uri.

	 * @return the uri composed of {@link #GENBANK_BASE_URI} and {@link #geneticAccessionNumber}

	 * @throws URISyntaxException when URI could not be created with {@link #geneticAccessionNumber}

	 */

	@Transient

	public URI getGenBankUri() throws URISyntaxException {

		return createExternalUri(GENBANK_BASE_URI, geneticAccessionNumber);

	}

	/**

	 * Returns the computed EMBL uri.

	 * @return the uri composed of {@link #EMBL_BASE_URI} and {@link #geneticAccessionNumber}

	 * @throws URISyntaxException when URI could not be created with {@link #geneticAccessionNumber}

	 */

	@Transient

	public URI getEmblUri() throws URISyntaxException {

		return createExternalUri(EMBL_BASE_URI, geneticAccessionNumber);

	}

	/**

	 * Returns the computed DDBJ uri.

	 * @return the uri composed of {@link #DDBJ_BASE_URI} and {@link #geneticAccessionNumber}

	 * @throws URISyntaxException when URI could not be created with {@link #geneticAccessionNumber}

	 */

	@Transient

	public URI getDdbjUri() throws URISyntaxException {

		return createExternalUri(DDBJ_BASE_URI, geneticAccessionNumber);

	}

	/**

	 * Returns the URI for the BOLD entry.

	 * @return the uri composed of {@link #BOLD_BASE_URI} and {@link #boldProcessId}

	 * @throws URISyntaxException when URI could not be created with {@link #boldProcessId}

	 * @see #getBoldProcessId()

	 */

	@Transient

	public URI getBoldUri() throws URISyntaxException {

		return createExternalUri(BOLD_BASE_URI, boldProcessId);

	}

	private URI createExternalUri(String baseUri, String id) throws URISyntaxException{

		if (CdmUtils.isNotBlank(id)){

			return new URI(String.format(baseUri, id.trim()));

		}else{

			return null;

		}

	}

	//*********************** CLONE ********************************************************/

	/**

	 * Clones <i>this</i> sequence. This is a shortcut that enables to create

	 * a new instance that differs only slightly from <i>this</i> sequencing by

	 * modifying only some of the attributes.<BR><BR>

	 *

	 *

	 * @see eu.etaxonomy.cdm.model.media.IdentifiableEntity#clone()

	 * @see java.lang.Object#clone()

	 */

	@Override

	public Object clone()  {

		try{

		Sequence result = (Sequence)super.clone();

		//sequences

		result.consensusSequence = (SequenceString)this.consensusSequence.clone();

		result.barcodeSequencePart = (SequenceString)this.barcodeSequencePart.clone();

		//single sequences

		result.singleReadAlignments = new HashSet<SingleReadAlignment>();

		for (SingleReadAlignment singleReadAlign: this.singleReadAlignments){

			SingleReadAlignment newAlignment = (SingleReadAlignment)singleReadAlign.clone();

			result.singleReadAlignments.add(newAlignment);

		}

		//citations  //TODO do we really want to copy these ??

		result.citations = new HashSet<Reference>();

		for (Reference ref: this.citations){

			result.citations.add(ref);

		}

		return result;

		}catch (CloneNotSupportedException e) {

			logger.warn("Object does not implement cloneable");

			e.printStackTrace();

			return null;

		}

	}

}