#!/usr/bin/env python

# This software is Copyright 2017 The Regents of the University of California. All Rights Reserved. Permission to copy, modify, and distribute this software and its documentation for educational, research and non-profit purposes, without fee, and without a written agreement is hereby granted, provided that the above copyright notice, this paragraph and the following three paragraphs appear in all copies. Permission to make commercial use of this software may be obtained by contacting:
#
# Office of Innovation and Commercialization
#
# University of California
#
# La Jolla, CA 92093-0910
#
# (858) 534-5815
#
# invent@ucsd.edu
#
# This software program and documentation are copyrighted by The Regents of the University of California. The software program and documentation are supplied "as is", without any accompanying services from The Regents. The Regents does not warrant that the operation of the program will be uninterrupted or error-free. The end-user understands that the program was developed for research purposes and is advised not to rely exclusively on the program for any reason.
#
# IN NO EVENT SHALL THE UNIVERSITY OF CALIFORNIA BE LIABLE TO ANY PARTY FOR DIRECT, INDIRECT, SPECIAL, INCIDENTAL, OR CONSEQUENTIAL DAMAGES, INCLUDING LOST PROFITS, ARISING OUT OF THE USE OF THIS SOFTWARE AND ITS DOCUMENTATION, EVEN IF THE UNIVERSITY OF CALIFORNIA HAS BEEN ADVISED OF THE POSSIBILITY OF SUCH DAMAGE. THE UNIVERSITY OF CALIFORNIA SPECIFICALLY DISCLAIMS ANY WARRANTIES, INCLUDING, BUT NOT LIMITED TO, THE IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE. THE SOFTWARE PROVIDED HEREUNDER IS ON AN "AS IS" BASIS, AND THE UNIVERSITY OF CALIFORNIA HAS NO OBLIGATIONS TO PROVIDE MAINTENANCE, SUPPORT, UPDATES, ENHANCEMENTS, OR MODIFICATIONS.

# Author: Viraj Deshpande
# Contact: virajbdeshpande@gmail.com
# Maintained by Jens Luebeck jluebeck@ucsd.edu

import copy
from collections import defaultdict
import sys
import numpy as np
import re

sys.setrecursionlimit(10000)
import argparse
import os
import pysam
import global_names

GAIN = 4.5
CNSIZE_MIN = 50000


parser = argparse. \
    ArgumentParser(description="Filter and merge amplified intervals")
parser.add_argument('--bed', dest='bed',
                    help="Input bed file with list of amplified intervals", metavar='FILE',
                    action='store', type=str, required=True)
parser.add_argument('--out', dest='out',
                    help="OPTIONAL: Prefix filename for output bed file. Default: <INPUT_BED_BASENAME>_amplified.bed",
                    metavar='FILE',
                    action='store', type=str, default='')
parser.add_argument('--bam', dest='bam',
                    help="OPTIONAL: Bamfile, used to avoid large aneuploidies", metavar='FILE',
                    action='store', type=str, default='')
parser.add_argument('--gain', dest='gain',
                    help="OPTIONAL: CN gain threshold for interval to be considered as a seed. Default: 5",
                    action='store', type=float, default=GAIN)
parser.add_argument('--cnsize_min', dest='cnsize_min',
                    help="OPTIONAL: Minimum size (in bp) for interval to be considered as a seed. Default: 100000",
                    action='store', type=int, default=CNSIZE_MIN)
parser.add_argument('--ref', dest='ref',
                    help="Values: [hg19, GRCh37, GRCh38, GRCh38_viral, mm10, GRCm38]. \"hg19\", \"GRCh38\", \"mm10\" : chr1, .. chrM etc / \"GRCh37\", \"GRCm38\" : '1', '2', .. 'MT' etc/ \"None\" : Do not use any annotations. AA can tolerate additional chromosomes not stated but accuracy and annotations may be affected.", metavar='STR',
                    action='store', type=str, choices=["hg19", "GRCh37", "GRCh38", "GRCh38_viral", "mm10", "GRCm38"], required=True)
parser.add_argument('--no_cstats', dest='no_cstats', help="Do not re-use coverage statistics from coverage.stats.",
                    action='store_true', default=False)

args = parser.parse_args()

global_names.REF = args.ref
import ref_util as hg

if args.bed != '':
    rdAlts = args.bed

if args.out != '':
    outname = args.out + ".bed"
else:
    outname = os.path.splitext(rdAlts)[0] + "_amplified.bed"

GAIN, CNSIZE_MIN = args.gain, args.cnsize_min

rdList0 = hg.interval_list(rdAlts, 'bed')
if rdList0:
    try:
        if len(rdList0[0].info) == 0:
            sys.stderr.write("ERROR: CNV estimate bed file had too few columns.\n"
                             "Must contain: chr  pos1  pos2  cnv_estimate\n")
            sys.exit(1)
        _ = float(rdList0[0].info[-1])

    except ValueError:
        sys.stderr.write("ERROR: CNV estimates must be in last column of bed file.\n")
        sys.exit(1)

tempL = []
for r in rdList0:
    if args.ref == "GRCh38_viral" and not r.chrom.endswith("chr"):
        tempL.append(r)

    elif float(r.info[-1]) > GAIN:
        tempL.append(r)

rdList = hg.interval_list(tempL)

# rdList = hg.interval_list([r for r in rdList0 if float(r.info[-1]) > GAIN or (args.ref == "GRCh38_viral" and not r.chrom.endswith("chr"))])

if args.bam != "":
    import bam_to_breakpoint as b2b
    if os.path.splitext(args.bam)[-1] == '.cram':
        bamFile = pysam.Samfile(args.bam, 'rc')
    else:
        bamFile = pysam.Samfile(args.bam, 'rb')

    cstats = None
    cb = bamFile
    if os.path.exists(os.path.join(hg.DATA_REPO, "coverage.stats")) and not args.no_cstats:
        coverage_stats_file = open(os.path.join(hg.DATA_REPO, "coverage.stats"))
        for l in coverage_stats_file:
            ll = l.strip().split()
            bamfile_pathname = str(cb.filename.decode())
            bamfile_filesize = os.path.getsize(bamfile_pathname)
            if ll[0] == os.path.abspath(bamfile_pathname):
                cstats = tuple(map(float, ll[1:]))
                if len(cstats) < 15 or cstats[13] != 3 or bamfile_filesize != int(cstats[14]) or any(np.isnan(cstats)):
                    cstats = None

        coverage_stats_file.close()


    bamFileb2b = b2b.bam_to_breakpoint(bamFile, coverage_stats=cstats)
    pre_int_list = []
    for r in rdList:
        try:
            chrom_cov_ratio = bamFileb2b.median_coverage(refi=r)[0] / bamFileb2b.median_coverage()[0]
            # print("chrom ratio " + r.chrom + " " + str(chrom_cov_ratio))
            if float(r.info[-1]) > GAIN + 2 * max(1.0, bamFileb2b.median_coverage(refi=r)[0] / bamFileb2b.median_coverage()[0]) - 2 and \
                    bamFileb2b.median_coverage(refi=r)[0] / bamFileb2b.median_coverage()[0] > 0:
                if r.size() < 10000000 or float(r.info[-1]) > 1.5*GAIN:
                    pre_int_list.append(r)

            elif float(r.info[-1]) > 1 and args.ref == "GRCh38_viral" and not r.chrom.startswith("chr"):
                pre_int_list.append(r)

        except ZeroDivisionError:
            print(r.chrom, args.ref, float(r.info[-1]))
            # if float(r.info[-1]) > 1 and args.ref == "GRCh38_viral" and not r.chrom.startswith("chr"):
            #     pre_int_list.append(r)
            #
            continue

    rdList = hg.interval_list(pre_int_list)

amplicon_listl = rdList

cr = hg.conserved_regions
uc_list = hg.interval_list([])
for a in amplicon_listl:
    if (len(hg.interval_list([a]).intersection(cr)) == 0 or
            a.size() > max(1000000,
                           10 * sum([a.intersection(ci[1]).size() for ci in hg.interval_list([a]).intersection(cr)])) or
            a.size() - sum([a.intersection(ci[1]).size() for ci in hg.interval_list([a]).intersection(cr)]) > 2000000):
        if (len(hg.interval_list([a]).intersection(cr))) == 0:
            uc_list.append(a)
        else:
            cra = hg.interval_list([a]).intersection(cr)
            cpos = a.start
            for crai in cra:
                if cpos < crai[1].start - 1000000:
                    uc_list.append(hg.interval(a.chrom, cpos, crai[1].start - 1000000, info=a.info))
                cpos = crai[1].end + 1000000
            if a.end > cpos:
                uc_list.append(hg.interval(a.chrom, cpos, a.end, info=a.info))

new_uc_list = []
for a in uc_list:
    if args.ref == "GRCh38_viral" and not a.chrom.startswith("chr"):
        if a.rep_content() < 2.5:
            new_uc_list.append(a)
    else:
        if float(a.info[-1]) * a.segdup_uniqueness() > GAIN and a.rep_content() < 2.5:
            new_uc_list.append(a)

uc_merge = hg.interval_list(new_uc_list).merge_clusters(extend=300000)

with open(outname, "w") as outfile:
    for a in uc_merge:
        is_viral = False
        if args.ref == "GRCh38_viral" and not a[0].chrom.startswith("chr"):
            is_viral = True

        if sum([ai.size() for ai in a[1]]) > CNSIZE_MIN or is_viral:
            outfile.write('\t'.join(
                [str(a[0]), str(sum([ai.size() * float(ai.info[-1]) for ai in a[1]]) / sum([ai.size() for ai in a[1]])),
                 rdAlts]) + '\n')
