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/*
* Copyright (C) 2014-2021 Brian L. Browning
*
* This file is part of Beagle
*
* Beagle is free software: you can redistribute it and/or modify
* it under the terms of the GNU General Public License as published by
* the Free Software Foundation, either version 3 of the License, or
* (at your option) any later version.
*
* Beagle is distributed in the hope that it will be useful,
* but WITHOUT ANY WARRANTY; without even the implied warranty of
* MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the
* GNU General Public License for more details.
*
* You should have received a copy of the GNU General Public License
* along with this program. If not, see <http://www.gnu.org/licenses/>.
*/
package phase;
import blbutil.BitArray;
import java.util.Random;
import java.util.stream.IntStream;
import vcf.GT;
/**
* <p>Class {@code RevPbwtPhaser} phases input genotype data and imputes
* missing alleles using the Positional Burrows-Wheeler Transform (PBWT).
* The PBWT processes markers in order of decreasing marker index. Any
* heterozygote genotypes that cannot by phased using the PBWT are randomly
* phased, and any alleles that cannot be imputed using the PBWT are randomly
* imputed using the allele frequencies in the combined reference and target
* input genotype data.</p>
*
* <p>Instances of class {@code RevPbwtPhaser} are immutable.</p>
*
* <p>Reference: Richard Durbin. (2014) Efficient haplotype matching and storage
* using the Positional Burrows-Wheeler Transform (PBWT). Bioinformatics
* 30(9):1266-72.</p>
*
* <p>Reference: Olivier Delaneau, Jean-Francois Zagury, Matthew R Robinson,
* Jonathan Marchini, Emmanouil Dermitzakis. (2019) Accurate, scalable and
* integrative haplotype estimation. Nature Communications 10(1):5436.</p>
*
* @author Brian L. Browning {@code <browning@uw.edu>}
*/
public class RevPbwtPhaser {
private final GT targGT;
private final int start;
private final int end;
private final int[] bitsPerAllele;
private final BitArray[] markerToBits;
/**
* Creates a new {@code RevPbwtPhaser} for the specified data.
* @param fpd the input genotype data for phasing
* @param start the index of the first marker (inclusive) to be phased
* @param end the index of the last marker (exclusive) to be phased
* @param seed seed for random number generation
* @throws IllegalArgumentException if
* {@code start < 0 || end > fpd.stage1TargGt().nMarkers() || start >= end}
* @throws NullPointerException if {@code fpd == null}
*/
public RevPbwtPhaser(FixedPhaseData fpd, int start, int end, long seed) {
if (start<0 || end>fpd.stage1TargGT().nMarkers() || start>=end) {
throw new IllegalArgumentException(String.valueOf(start));
}
this.targGT = fpd.stage1TargGT();
this.start = start;
this.end = end;
this.bitsPerAllele = IntStream.range(start, end)
.map(m -> targGT.markers().marker(m).bitsPerAllele())
.toArray();
this.markerToBits = phase(fpd, start, end, seed);
}
private static BitArray[] phase(FixedPhaseData fpd, int start, int end,
long seed) {
Random rand = new Random(seed);
int overlap = fpd.stage1Overlap();
GT targGT = fpd.stage1TargGT();
PbwtRecPhaser recPhaser = new PbwtRecPhaser(fpd);
boolean[] missingGT = new boolean[targGT.nSamples()];
boolean[] unphHet = new boolean[targGT.nSamples()];
int[] alleles = new int[fpd.nHaps()];
BitArray[] markerToBits = new BitArray[end-start];
int lastM = -1;
for (int m=(end-1); m>=start; --m) {
int[] alleleCDF = recPhaser.phase(lastM, alleles, m, missingGT,
unphHet);
if (m>=overlap) {
finishPhasing(alleles, unphHet, alleleCDF, rand);
}
markerToBits[m-start] = storePhasing(targGT, m, alleles);
lastM = m;
}
return markerToBits;
}
private static void finishPhasing(int[] alleles, boolean[] unphHet,
int[] alleleCDF, Random rand) {
for (int s=0; s<unphHet.length; ++s) {
int h1 = s<<1;
int h2 = h1 | 0b1;
if (unphHet[s]) {
int a1 = alleles[h1];
int a2 = alleles[h2];
if (rand.nextBoolean()) {
alleles[h1] = a2;
alleles[h2] = a1;
}
unphHet[s] = false;
}
else {
if (alleles[h1] == -1) {
alleles[h1] = imputeAllele(alleleCDF, rand);
}
if (alleles[h2] == -1) {
alleles[h2] = imputeAllele(alleleCDF, rand);
}
}
}
}
private static int imputeAllele(int[] alleleCDF, Random rand) {
int bound = alleleCDF[alleleCDF.length-1];
if (bound==0) {
return 0;
}
else {
int r = rand.nextInt(alleleCDF[alleleCDF.length-1]);
int allele = 0;
while (r>=alleleCDF[allele]) {
++allele;
}
return allele;
}
}
private static BitArray storePhasing(GT targGT, int m, int[] alleles) {
int nTargHaps = targGT.nHaps();
int bitsPerAllele = targGT.markers().marker(m).bitsPerAllele();
BitArray bits = new BitArray(nTargHaps*bitsPerAllele);
int bit=0;
for (int h=0; h<nTargHaps; ++h) {
int mask = 1;
for (int j=0; j<bitsPerAllele; ++j, ++bit) {
if ((alleles[h] & mask)==mask) {
bits.set(bit);
}
mask <<= 1;
}
}
return bits;
}
/**
* Returns the input target genotypes.
* @return the input target genotypes
*/
public GT targGT() {
return targGT;
}
/**
* Return the inclusive start marker index.
* @return the inclusive start marker index
*/
public int start() {
return start;
}
/**
* Return the exclusive end marker index.
* @return the exclusive end marker index
*/
public int end() {
return end;
}
/**
* Returns the minimum number of bits required to store a non-missing
* allele for the specified marker
* @param marker a marker index
* @return the minimum number of bits required to store a non-missing
* allele for the specified marker
* @throws IndexOutOfBoundsException if
* {@code marker < this.start() || marker >= this.end()}
*/
public int bitsPerAllele(int marker) {
return bitsPerAllele[marker-start];
}
/**
* Returns the specified allele
* @param marker a marker index
* @param hap a haplotype index
* @return the specified allele
* @throws IndexOutOfBoundsException if
* {@code marker < this.start() || marker >= this.end()}
* @throws IndexOutOfBoundsException if
* {@code hap < 0 || hap >= this.targGT().nHaps()}
*/
public int allele(int marker, int hap) {
int nBitsPerAllele = this.bitsPerAllele[marker-start];
int bStart = hap*nBitsPerAllele;
BitArray bits = markerToBits[marker-start];
if (nBitsPerAllele==1) {
return bits.get(bStart) ? 1 : 0;
}
int allele = 0;
int mask = 1;
int bEnd = bStart + nBitsPerAllele;
for (int j=bStart; j<bEnd; ++j) {
if (bits.get(j)) {
allele |= mask;
}
mask <<= 1;
}
return allele;
}
}
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