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hmm_lib.c
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hmm_lib.c
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#include "util_lib.h"
void viterbi(HMM *hmm_ptr, const char *O, char *output_buffer, char *aa_buffer,
char *dna_buffer, char *sequence_head, bool whole_genome,
int len_seq, char *dna, char *dna_rc,
char *protein, int *insertions, int *deletions, char *temp_str_ptr) {
int *vpath; // optimal path after backtracking
int **path; // viterbi path array
double **alpha; // viterbi prob array
int i, j, t, kk;
Nucleotide from, from0, to; /*from0: i-2 position, from: i-1 position */
int from2; /* The dinucleotide combining `from` and `from0` */
int num_d; /* the number of delete */
double h_kd, r_kd, p_kd;
double temp_alpha, prob;
double start_freq;
Strand strand = UNKNOWN_STRAND;
unsigned int dna_seq_len = len_seq + (len_seq / 10);
/* Length of dynamic dna_seq (add 10% for inserting placeholders for missing nucleotides) */
Nucleotide dna_seq_array[dna_seq_len];
Nucleotide *dna_seq = (Nucleotide*) &dna_seq_array;
/* For performance, initially use storage on the stack. */
/* (If necessary, replace it later with dynamically-allocated storage.) */
int dna_id = 0;
int out_nt;
int start_t = -1, end_t = -1;
int prev_match = 0;
int start_orf;
int frame;
int nr_insertions = 0, nr_deletions = 0;
int temp_i[6] = {0,0,0,0,0,0};
int temp_i_1[6] = {1,1,1,1,1,1};
int num_N = 0;
/* Parse the sequence */
Nucleotide sequence[len_seq];
for (i = 0; i < len_seq; i++)
sequence[i] = nucleotide_parse(O[i]);
/***************************************************************/
/* initialize */
/***************************************************************/
int gene_len = (whole_genome)? 120 : 60;
alpha = (double **)dmatrix(len_seq);
path = (int **)imatrix(len_seq);
vpath = (int *)ivector(len_seq);
for (i = 0; i < NUM_STATE; i++) {
alpha[i][0] = -1 * (hmm_ptr->pi[i]);
}
/* stop state */
if ((sequence[0] == NUCL_T) && (((sequence[1] == NUCL_A) && (sequence[2] == NUCL_A)) ||
((sequence[1] == NUCL_A) && (sequence[2] == NUCL_G)) ||
((sequence[1] == NUCL_G) && (sequence[2] == NUCL_A)))) {
alpha[E_STATE][0] = DBL_MAX;
alpha[E_STATE][1] = DBL_MAX;
path[E_STATE][1] = E_STATE;
path[E_STATE][2] = E_STATE;
alpha[M6_STATE][2] = DBL_MAX;
alpha[M5_STATE][1] = DBL_MAX;
alpha[M4_STATE][0] = DBL_MAX;
alpha[M3_STATE][2] = DBL_MAX;
alpha[M2_STATE][1] = DBL_MAX;
alpha[M1_STATE][0] = DBL_MAX;
if ((sequence[1] == NUCL_A) && (sequence[2] == NUCL_A)) {
alpha[E_STATE][2] = alpha[E_STATE][2] - LOG_53;
} else if ((sequence[1] == NUCL_A) && (sequence[2] == NUCL_G)) {
alpha[E_STATE][2] = alpha[E_STATE][2] - LOG_16;
} else if ((sequence[1] == NUCL_G) && (sequence[2] == NUCL_A)) {
alpha[E_STATE][2] = alpha[E_STATE][2] - LOG_30;
}
}
if ((sequence[2] == NUCL_A) &&
(((sequence[0] == NUCL_T) && (sequence[1] == NUCL_T)) ||
((sequence[0] == NUCL_C) && (sequence[1] == NUCL_T)) ||
((sequence[0] == NUCL_T) && (sequence[1] == NUCL_C)))) {
alpha[S_STATE_1][0] = DBL_MAX;
alpha[S_STATE_1][1] = DBL_MAX;
alpha[S_STATE_1][2] = alpha[S_STATE][0];
path[S_STATE_1][1] = S_STATE_1;
path[S_STATE_1][2] = S_STATE_1;
alpha[M3_STATE_1][2] = DBL_MAX;
alpha[M6_STATE_1][2] = DBL_MAX;
if ((sequence[0] == NUCL_T) && (sequence[1] == NUCL_T)) {
alpha[S_STATE_1][2] = alpha[S_STATE_1][2] - LOG_53;
} else if ((sequence[0] == NUCL_C) && (sequence[1] == NUCL_T)) {
alpha[S_STATE_1][2] = alpha[S_STATE_1][2] - LOG_16;
} else if ((sequence[0] == NUCL_T) && (sequence[1] == NUCL_C)) {
alpha[S_STATE_1][2] = alpha[S_STATE_1][2] - LOG_30;
}
}
int multiple=0;
/******************************************************************/
/* fill out the rest of the columns */
/******************************************************************/
for (t = 1; t < len_seq; t++) {
from = sequence[t-1];
from0 = (t > 1)? sequence[t-2] : NUCL_G;
to = sequence[t];
/* if DNA is other than ACGT, do it later */
if (from == NUCL_INVALID)
from = NUCL_G;
if (from0 == NUCL_INVALID)
from0 = NUCL_G;
if (to == NUCL_INVALID) {
to = NUCL_G;
num_N += 1;
} else {
num_N = 0;
}
from2 = from0 * 4 + from;
/******************/
/* M state */
/******************/
for (i = M1_STATE; i <= M6_STATE; i++) {
if (alpha[i][t]<DBL_MAX) {
if (t==0) {
} else {
if (i==M1_STATE) {
/* from M state */
j = M6_STATE;
alpha[i][t] = alpha[j][t-1] - (hmm_ptr->tr[TR_GG]) - (hmm_ptr->tr[TR_MM]) - (hmm_ptr->e_M[0][from2][to]);
path[i][t] = j;
/* from D state */
if (!whole_genome) {
for (j = M5_STATE; j >= M1_STATE; j--) {
if (j >= i ) {
num_d = i-j+6;
} else if (j+1<i) {
num_d = i-j;
} else {
num_d = -10;
}
if (num_d>0) {
temp_alpha = alpha[j][t-1] - (hmm_ptr->tr[TR_MD]) -
(hmm_ptr->e_M[0][from2][to])
- LOG_25*(num_d-1) - (hmm_ptr->tr[TR_DD])*(num_d-2) -
(hmm_ptr->tr[TR_DM]);
if ( temp_alpha < alpha[i][t]) {
alpha[i][t] = temp_alpha;
path[i][t] = j;
}
}
}
}
/* from Start state */
temp_alpha = alpha[S_STATE][t-1] - (hmm_ptr->e_M[0][from2][to]);
if ( temp_alpha < alpha[i][t] ) {
alpha[i][t] = temp_alpha;
path[i][t] = S_STATE;
}
} else { /*i ==M2-M6*/
/* from M state */
j = i - 1;
alpha[i][t] = alpha[j][t-1] - (hmm_ptr->tr[TR_MM]) -
(hmm_ptr->e_M[i-M1_STATE][from2][to]);
path[i][t] = j;
/* from D state */
if (!whole_genome) {
for (j = M6_STATE; j >= M1_STATE; j--) {
if (j >= i) {
num_d = i-j+6;
} else if (j+1 < i) {
num_d = i-j;
} else {
num_d = -10;
}
if (num_d > 0) {
temp_alpha = alpha[j][t-1] - (hmm_ptr->tr[TR_MD]) -
(hmm_ptr->e_M[i-M1_STATE][from2][to])
- LOG_25*(num_d-1) - (hmm_ptr->tr[TR_DD])*(num_d-2) -
(hmm_ptr->tr[TR_DM]);
if ( temp_alpha < alpha[i][t]) {
alpha[i][t] = temp_alpha;
path[i][t] = j;
}
}
}
}
}
/* from I state */
if (i == M1_STATE) {
j = I6_STATE;
} else {
j = I1_STATE + (i - M1_STATE -1);
}
/* to avoid stop codon */
if (t<2) {
} else if ((i==M2_STATE || i==M5_STATE) && (sequence[temp_i[j-I1_STATE]] == NUCL_T) &&
(((sequence[t] == NUCL_A) && (sequence[t+1] ==NUCL_A)) ||
((sequence[t] == NUCL_A) && (sequence[t+1] ==NUCL_G)) ||
((sequence[t] == NUCL_G) && (sequence[t+1] ==NUCL_A)))) {
} else if (((j-I1_STATE > 0) && (temp_i[j-I1_STATE]>0)) && ((i==M3_STATE || i==M6_STATE) && (sequence[temp_i[j-I1_STATE]-1] == NUCL_T) &&
(((sequence[temp_i[j-I1_STATE]] == NUCL_A) && (sequence[t] ==NUCL_A)) ||
((sequence[temp_i[j-I1_STATE]] == NUCL_A) && (sequence[t] ==NUCL_G)) ||
((sequence[temp_i[j-I1_STATE]] == NUCL_G) && (sequence[t] ==NUCL_A))))) {
} else {
temp_alpha = alpha[j][t-1] - (hmm_ptr->tr[TR_IM]) - LOG_25;
if ( temp_alpha < alpha[i][t]) {
alpha[i][t] = temp_alpha;
path[i][t] = j;
}
}
}
}
}
/******************/
/* I state */
/******************/
for (i = I1_STATE; i <= I6_STATE; i++) {
if (t != 0) {
/* from I state */
j = i;
alpha[i][t] = alpha[j][t-1] - (hmm_ptr->tr[TR_II]) -
(hmm_ptr->tr_I_I[from][to]);
path[i][t] = j;
/* from M state */
j = i - I1_STATE + M1_STATE ;
if (i == I6_STATE) {
temp_alpha = alpha[j][t-1] - (hmm_ptr->tr[TR_GG]) -
(hmm_ptr->tr[TR_MI]) -(hmm_ptr->tr_M_I[from][to]);
} else {
temp_alpha = alpha[j][t-1] -
(hmm_ptr->tr[TR_MI]) -(hmm_ptr->tr_M_I[from][to]);
}
if (temp_alpha < alpha[i][t]) {
alpha[i][t] = temp_alpha;
path[i][t] = j;
temp_i[i-I1_STATE] = t-1;
}
}
}
/******************/
/* M' state */
/******************/
for (i = M1_STATE_1; i <= M6_STATE_1; i++) {
if ((i==M1_STATE_1 || i==M4_STATE_1)&& t>=3 &&
(((sequence[t-3] == NUCL_T) && (sequence[t-2] == NUCL_T) && (sequence[t-1] == NUCL_A)) ||
((sequence[t-3] == NUCL_C) && (sequence[t-2] == NUCL_T) && (sequence[t-1] == NUCL_A)) ||
((sequence[t-3] == NUCL_T) && (sequence[t-2] == NUCL_C) && (sequence[t-1] == NUCL_A)))) {
/* from Start state since this is actually stop codon in minus strand */
alpha[i][t] = alpha[S_STATE_1][t-1] -
(hmm_ptr->e_M_1[i-M1_STATE_1][from2][to]);
path[i][t] = S_STATE_1;
} else {
if (t != 0) {
if (i == M1_STATE_1 ) {
/* from M state */
j = M6_STATE_1;
alpha[i][t] = alpha[j][t-1] - (hmm_ptr->tr[TR_GG]) -
(hmm_ptr->tr[TR_MM]) - (hmm_ptr->e_M_1[0][from2][to]);
path[i][t] = j;
/* from D state */
if (!whole_genome) {
for (j = M5_STATE_1; j >= M1_STATE_1; j--) {
if (j >= i) {
num_d = i-j+6;
} else if (j+1 <i) {
num_d = i-j;
} else {
num_d = -10;
}
if (num_d > 0) {
temp_alpha = alpha[j][t-1] - (hmm_ptr->tr[TR_MD]) -
(hmm_ptr->e_M_1[0][from2][to])
- LOG_25*(num_d-1) - (hmm_ptr->tr[TR_DD])*(num_d-2) -
(hmm_ptr->tr[TR_DM]);
if ( temp_alpha < alpha[i][t]) {
alpha[i][t] = temp_alpha;
path[i][t] = j;
}
}
}
}
} else {
/* from M state */
j = i - 1;
alpha[i][t] = alpha[j][t-1] - (hmm_ptr->tr[TR_MM]) -
(hmm_ptr->e_M_1[i-M1_STATE_1][from2][to]);
path[i][t] = j;
/* from D state */
if (!whole_genome) {
for (j = M6_STATE_1; j>=M1_STATE_1; j--) {
if (j >= i ) {
num_d = i-j+6;
} else if (j+1 < i) {
num_d = i-j;
} else {
num_d = -10;
}
if (num_d>0) {
temp_alpha = alpha[j][t-1] - (hmm_ptr->tr[TR_MD]) -
(hmm_ptr->e_M_1[i-M1_STATE_1][from2][to])
- LOG_25*(num_d-1) - (hmm_ptr->tr[TR_DD])*(num_d-2) -
(hmm_ptr->tr[TR_DM]);
if ( temp_alpha < alpha[i][t]) {
alpha[i][t] = temp_alpha;
path[i][t] = j;
}
}
}
}
}
/* from I state */
if (i == M1_STATE_1) {
j = I6_STATE_1;
} else {
j = I1_STATE_1 + (i - M1_STATE_1 -1);
}
//!! 11 --> 16
//!! What is the actual point of -1
/* to avoid stop codon */
if (t<2) {
} else if ((i==M2_STATE_1 ||
i==M5_STATE_1) &&
(sequence[t+1] == NUCL_A ) &&
(((sequence[temp_i_1[j-I1_STATE_1]] == NUCL_T) && (sequence[t] ==NUCL_T)) ||
((sequence[temp_i_1[j-I1_STATE_1]] == NUCL_C) && (sequence[t] ==NUCL_T)) ||
((sequence[temp_i_1[j-I1_STATE_1]] == NUCL_T) && (sequence[t] ==NUCL_C)))) {
} else if ((i==M3_STATE_1 ||
i==M6_STATE_1) &&
(sequence[t] == NUCL_A ) &&
(((sequence[temp_i_1[j-I1_STATE_1]-1] == NUCL_T) && (sequence[temp_i_1[j-I1_STATE_1]] ==NUCL_T)) ||
((sequence[temp_i_1[j-I1_STATE_1]-1] == NUCL_C) && (sequence[temp_i_1[j-I1_STATE_1]] ==NUCL_T)) ||
((sequence[temp_i_1[j-I1_STATE_1]-1] == NUCL_T) && (sequence[temp_i_1[j-I1_STATE_1]] ==NUCL_C)))) {
} else {
temp_alpha = alpha[j][t-1] - (hmm_ptr->tr[TR_IM]) - LOG_25;
if ( temp_alpha < alpha[i][t]) {
alpha[i][t] = temp_alpha;
path[i][t] = j;
}
}
}
}
}
/******************/
/* I' state */
/******************/
for (i = I1_STATE_1; i <= I6_STATE_1; i++) {
if (t != 0) {
/* from I state */
j = i;
alpha[i][t] = alpha[j][t-1] - (hmm_ptr->tr[TR_II]) -
(hmm_ptr->tr_I_I[from][to]);
path[i][t] = j;
if (t<5) continue;
/* from M state */
if (path[S_STATE_1][t-3]!= R_STATE && path[S_STATE_1][t-4] !=R_STATE &&
path[S_STATE_1][t-5] !=R_STATE) {
j = i - I1_STATE_1 + M1_STATE_1;
if (i==I6_STATE_1) {
temp_alpha = alpha[j][t-1] - (hmm_ptr->tr[TR_GG]) -
(hmm_ptr->tr[TR_MI]) -(hmm_ptr->tr_M_I[from][to]);
} else {
temp_alpha = alpha[j][t-1] -
(hmm_ptr->tr[TR_MI]) -(hmm_ptr->tr_M_I[from][to]);
}
if (temp_alpha < alpha[i][t]) {
alpha[i][t] = temp_alpha;
path[i][t] = j;
//!! We are addressing the character array with this.
temp_i_1[i-I1_STATE_1] = t-1;
}
}
}
}
/***********************/
/* Non_coding state */
/***********************/
if (t != 0) {
alpha[R_STATE][t] = alpha[R_STATE][t-1] - (hmm_ptr->tr_R_R[from][to]) - (hmm_ptr->tr[TR_RR]);
path[R_STATE][t] = R_STATE;
temp_alpha = alpha[E_STATE][t-1] - (hmm_ptr->tr[TR_ER]) ;
if (temp_alpha < alpha[R_STATE][t] ) {
alpha[R_STATE][t] = temp_alpha;
path[R_STATE][t] = E_STATE;
}
temp_alpha = alpha[E_STATE_1][t-1] - (hmm_ptr->tr[TR_ER]) ;
if (temp_alpha < alpha[R_STATE][t] ) {
alpha[R_STATE][t] = temp_alpha;
path[R_STATE][t] = E_STATE_1;
}
alpha[R_STATE][t] -= LOG_95;
}
/******************/
/* END state */
/******************/
if (alpha[E_STATE][t] == 0) {
alpha[E_STATE][t] = DBL_MAX;
path[E_STATE][t] = NOSTATE;
if (t < len_seq -2 && (sequence[t] == NUCL_T) &&
(((sequence[t+1] == NUCL_A) && (sequence[t+2] == NUCL_A)) ||
((sequence[t+1] == NUCL_A) && (sequence[t+2] == NUCL_G)) ||
((sequence[t+1] == NUCL_G) && (sequence[t+2] == NUCL_A)))) {
alpha[E_STATE][t+2] = DBL_MAX;
/* transition from frame4,frame5,and frame6 */
temp_alpha = alpha[M6_STATE][t-1] - (hmm_ptr->tr[TR_GE]);
if (temp_alpha < alpha[E_STATE][t+2]) {
alpha[E_STATE][t+2] = temp_alpha;
path[E_STATE][t] = M6_STATE;
}
/* transition from frame1,frame2,and frame3 */
temp_alpha = alpha[M3_STATE][t-1] - (hmm_ptr->tr[TR_GE]);
if (temp_alpha < alpha[E_STATE][t+2]) {
alpha[E_STATE][t+2] = temp_alpha;
path[E_STATE][t] = M3_STATE;
}
alpha[E_STATE][t] = DBL_MAX;
alpha[E_STATE][t+1] = DBL_MAX;
path[E_STATE][t+1] = E_STATE;
path[E_STATE][t+2] = E_STATE;
alpha[M6_STATE][t+2] = DBL_MAX;
alpha[M5_STATE][t+1] = DBL_MAX;
alpha[M4_STATE][t] = DBL_MAX;
alpha[M3_STATE][t+2] = DBL_MAX;
alpha[M2_STATE][t+1] = DBL_MAX;
alpha[M1_STATE][t] = DBL_MAX;
if ((sequence[t+1] == NUCL_A) && (sequence[t+2] == NUCL_A)) {
alpha[E_STATE][t+2] = alpha[E_STATE][t+2] - (0.54);
} else if ((sequence[t+1] == NUCL_A) && (sequence[t+2] == NUCL_G)) {
alpha[E_STATE][t+2] = alpha[E_STATE][t+2] - LOG_16;
} else if ((sequence[t+1] == NUCL_G) && (sequence[t+2] == NUCL_A)) {
alpha[E_STATE][t+2] = alpha[E_STATE][t+2] - LOG_30;
}
/* adjustment based on probability distribution */
start_freq=0;
double sub_sum = 0;
if (t>=60) { /* bug reported by Yu-Wei */
for (i = -60; i <= -3; i++) {
if (t+i+2 < len_seq) {
start_freq -= (hmm_ptr->tr_E[i+60][trinucleotide(sequence[t+i], sequence[t+i+1], sequence[t+i+2])]);
}
}
} else {
for (i = (-1*t); i <= -3; i++) {
if (t+i+2 < len_seq) {
sub_sum += (hmm_ptr->tr_E[i+60][trinucleotide(sequence[t+i], sequence[t+i+1], sequence[t+i+2])]);
}
}
sub_sum = sub_sum * 58 / (-3 + t + 1);
start_freq -= sub_sum;
}
h_kd = hmm_ptr->E_dist[2] * exp(-1*pow(start_freq-hmm_ptr->E_dist[1],2)/(2*pow(hmm_ptr->E_dist[0],2)));
r_kd = hmm_ptr->E_dist[5] * exp(-1*pow(start_freq-hmm_ptr->E_dist[4],2)/(2*pow(hmm_ptr->E_dist[3],2)));
p_kd = h_kd / (h_kd + r_kd);
if (p_kd<0.01) {
p_kd=0.01;
} else if (p_kd>0.99) {
p_kd=0.99;
}
alpha[E_STATE][t+2] = alpha[E_STATE][t+2] - log(p_kd);
}
}
/*************************************************/
/* START' state */
/* originally stop codon of genes in - strand */
/*************************************************/
if (alpha[S_STATE_1][t] == 0) {
alpha[S_STATE_1][t] = DBL_MAX;
path[S_STATE_1][t] = NOSTATE;
if (t<len_seq-2 && (sequence[t+2] == NUCL_A) &&
(((sequence[t] == NUCL_T) && (sequence[t+1] == NUCL_T)) ||
((sequence[t] == NUCL_C) && (sequence[t+1] == NUCL_T)) ||
((sequence[t] == NUCL_T) && (sequence[t+1] == NUCL_C)))) {
alpha[S_STATE_1][t] = DBL_MAX;
path[S_STATE_1][t] = R_STATE;
alpha[S_STATE_1][t+1] = DBL_MAX;
alpha[S_STATE_1][t+2] = alpha[R_STATE][t-1] - (hmm_ptr->tr[TR_RS]);
path[S_STATE_1][t+1] = S_STATE_1;
path[S_STATE_1][t+2] = S_STATE_1;
temp_alpha = alpha[E_STATE_1][t-1] - (hmm_ptr->tr[TR_ES]);
if (temp_alpha < alpha[S_STATE_1][t+2]) {
alpha[S_STATE_1][t+2] = temp_alpha;
path[S_STATE_1][t] = E_STATE_1;
}
temp_alpha = alpha[E_STATE][t-1] - (hmm_ptr->tr[TR_ES1]);
if (temp_alpha < alpha[S_STATE_1][t+2]) {
alpha[S_STATE_1][t+2] = temp_alpha;
path[S_STATE_1][t] = E_STATE;
}
alpha[M3_STATE_1][t+2] = DBL_MAX;
alpha[M6_STATE_1][t+2] = DBL_MAX;
if ((sequence[t] == NUCL_T) && (sequence[t+1] == NUCL_T)) {
alpha[S_STATE_1][t+2] = alpha[S_STATE_1][t+2] - (0.54);
} else if ((sequence[t] == NUCL_C) && (sequence[t+1] == NUCL_T)) {
alpha[S_STATE_1][t+2] = alpha[S_STATE_1][t+2] - LOG_16;
} else if ((sequence[t] == NUCL_T) && (sequence[t+1] == NUCL_C)) {
alpha[S_STATE_1][t+2] = alpha[S_STATE_1][t+2] - LOG_30;
}
/* adjustment based on probability distribution */
start_freq=0;
for (i = 3; i <= 60; i++) {
if (t+i+2 < len_seq) {
start_freq -= (hmm_ptr->tr_S_1[i-3][trinucleotide(sequence[t+i], sequence[t+i+1], sequence[t+i+2])]);
}
}
h_kd = hmm_ptr->S1_dist[2] * exp(-1*pow(start_freq-hmm_ptr->S1_dist[1],2)/(2*pow(hmm_ptr->S1_dist[0],2)));
r_kd = hmm_ptr->S1_dist[5] * exp(-1*pow(start_freq-hmm_ptr->S1_dist[4],2)/(2*pow(hmm_ptr->S1_dist[3],2)));
p_kd = h_kd / (h_kd + r_kd);
if (p_kd<0.01) {
p_kd=0.01;
} else if (p_kd>0.99) {
p_kd=0.99;
}
alpha[S_STATE_1][t+2] = alpha[S_STATE_1][t+2] - log(p_kd);
}
}
/************************/
/* START state */
/************************/
if (alpha[S_STATE][t] == 0) {
alpha[S_STATE][t] = DBL_MAX;
path[S_STATE][t] = NOSTATE;
if (t<len_seq-2 && (sequence[t+1] == NUCL_T) && (sequence[t+2] == NUCL_G)&&
((sequence[t] == NUCL_A) || (sequence[t] == NUCL_G) || (sequence[t] == NUCL_T))) {
alpha[S_STATE][t] = DBL_MAX;
alpha[S_STATE][t+1] = DBL_MAX;
alpha[S_STATE][t+2] = alpha[R_STATE][t-1] - (hmm_ptr->tr[TR_RS]);
path[S_STATE][t] = R_STATE;
path[S_STATE][t+1] = S_STATE;
path[S_STATE][t+2] = S_STATE;
temp_alpha = alpha[E_STATE][t-1] - (hmm_ptr->tr[TR_ES]);
if (temp_alpha < alpha[S_STATE][t+2]) {
alpha[S_STATE][t+2] = temp_alpha;
path[S_STATE][t] = E_STATE;
}
temp_alpha = alpha[E_STATE_1][t-1] - (hmm_ptr->tr[TR_ES1]);
if (temp_alpha < alpha[S_STATE][t+2]) {
alpha[S_STATE][t+2] = temp_alpha;
path[S_STATE][t] = E_STATE_1;
}
if (sequence[t] == NUCL_A) {
alpha[S_STATE][t+2] = alpha[S_STATE][t+2] - LOG_83;
} else if (sequence[t] == NUCL_G) {
alpha[S_STATE][t+2] = alpha[S_STATE][t+2] - LOG_10;
} else if (sequence[t] == NUCL_T) {
alpha[S_STATE][t+2] = alpha[S_STATE][t+2] - LOG_07;
}
/* adjustment based on probability distribution */
start_freq=0;
double sub_sum = 0;
if (t>=30) {
for (i = -30; i <= 30; i++) {
if (t+i+2 < len_seq) {
start_freq -= (hmm_ptr->tr_S[i+30][trinucleotide(sequence[t+i], sequence[t+i+1], sequence[t+i+2])]);
}
}
} else {
for (i = (-1*t); i <= 30; i++) {
if (t+i+2 < len_seq) {
sub_sum += (hmm_ptr->tr_S[i+30][trinucleotide(sequence[t+i], sequence[t+i+1], sequence[t+i+2])]);
}
}
sub_sum = sub_sum * 61 / (30 + t + 1);
start_freq -= sub_sum;
}
h_kd = hmm_ptr->S_dist[2] * exp(-1*pow(start_freq-hmm_ptr->S_dist[1],2)/(2*pow(hmm_ptr->S_dist[0],2)));
r_kd = hmm_ptr->S_dist[5] * exp(-1*pow(start_freq-hmm_ptr->S_dist[4],2)/(2*pow(hmm_ptr->S_dist[3],2)));
p_kd = h_kd / (h_kd + r_kd);
if (p_kd<0.01) {
p_kd=0.01;
} else if (p_kd>0.99) {
p_kd=0.99;
}
alpha[S_STATE][t+2] = alpha[S_STATE][t+2] - log(p_kd);
}
}
/**********************************************/
/* END' state */
/* originally start codon of genes in - strand */
/**********************************************/
if (alpha[E_STATE_1][t] == 0) {
alpha[E_STATE_1][t] = DBL_MAX;
path[E_STATE_1][t] = NOSTATE;
if (t < len_seq - 2 && (sequence[t] == NUCL_C) && (sequence[t+1] == NUCL_A) &&
((sequence[t+2] == NUCL_T) || (sequence[t+2] == NUCL_C) || (sequence[t+2] == NUCL_A))) {
/* transition from frame6 */
alpha[E_STATE_1][t+2] = alpha[M6_STATE_1][t-1] - (hmm_ptr->tr[TR_GE]);
path[E_STATE_1][t] = M6_STATE_1;
alpha[E_STATE_1][t] = DBL_MAX;
alpha[E_STATE_1][t+1] = DBL_MAX;
path[E_STATE_1][t+1] = E_STATE_1;
path[E_STATE_1][t+2] = E_STATE_1;
if (sequence[t+2] == NUCL_T) {
alpha[E_STATE_1][t+2] = alpha[E_STATE_1][t+2] - LOG_83;
} else if (sequence[t+2] == NUCL_C ) {
alpha[E_STATE_1][t+2] = alpha[E_STATE_1][t+2] - LOG_10;
} else if (sequence[t+2] == NUCL_A ) {
alpha[E_STATE_1][t+2] = alpha[E_STATE_1][t+2] - LOG_07;
}
/* adjustment based on probability distribution */
start_freq=0;
double sub_sum = 0;
if (t>=30) {
for (i = -30; i <= 30; i++) {
if (t+i+2 < len_seq) {
start_freq -= (hmm_ptr->tr_E_1[i+30][trinucleotide(sequence[t+i], sequence[t+i+1], sequence[t+i+2])]);
}
}
} else {
for (i = (-1*t); i <= 30; i++) {
if (t+i+2 < len_seq) {
sub_sum += (hmm_ptr->tr_E_1[i+30][trinucleotide(sequence[t+i], sequence[t+i+1], sequence[t+i+2])]);
}
}
sub_sum = sub_sum * 61 / (30 + t + 1);
start_freq -= sub_sum;
}
h_kd = hmm_ptr->E1_dist[2] *
exp(-1*pow(start_freq-hmm_ptr->E1_dist[1],2)/(2*pow(hmm_ptr->E1_dist[0],2)))
;
r_kd = hmm_ptr->E1_dist[5] *
exp(-1*pow(start_freq-hmm_ptr->E1_dist[4],2)/(2*pow(hmm_ptr->E1_dist[3],2)))
;
p_kd = h_kd / (h_kd + r_kd);
if (p_kd<0.01) {
p_kd=0.01;
} else if (p_kd>0.99) {
p_kd=0.99;
}
alpha[E_STATE_1][t+2] = alpha[E_STATE_1][t+2] - log(p_kd);
}
}
if (num_N>9) {
for (i = 0; i < NUM_STATE; i++) {
if (i!=R_STATE) {
alpha[i][t] = DBL_MAX;
path[i][t] = R_STATE;
}
}
}
}
/***********************************************************/
/* backtrack array to find the optimal path */
/***********************************************************/
sprintf(output_buffer, "%s\n", sequence_head);
/* find the state for sequence[N] with the highest probability */
prob = DBL_MAX;
for (i = 0; i < NUM_STATE; i++) {
if (alpha[i][len_seq-1] < prob) {
prob = alpha[i][len_seq-1];
vpath[len_seq-1] = i;
}
}
/* backtrack the optimal path */
for (t = len_seq-2; t >= 0; t--) {
if (t+1 < 0 || vpath[t+1] < 0) continue;
vpath[t] = path[vpath[t+1]][t+1];
}
for (t = 0; t < len_seq; t++) {
if (strand == UNKNOWN_STRAND && start_t < 0 &&
((vpath[t]>=M1_STATE && vpath[t]<=M6_STATE) ||
(vpath[t]>=M1_STATE_1 && vpath[t]<=M6_STATE_1) ||
vpath[t] == S_STATE || vpath[t] == S_STATE_1 )) {
start_t=t+1;
}
if (strand == UNKNOWN_STRAND &&
(vpath[t]==M1_STATE || vpath[t]==M4_STATE ||
vpath[t]==M1_STATE_1 || vpath[t]==M4_STATE_1)) {
dna[0] = '\0';
dna_rc[0] = '\0';
protein[0] = '\0';
nr_insertions = 0;
nr_deletions = 0;
dna_id = 0;
dna[dna_id] = O[t];
dna_seq[dna_id] = sequence[t];
start_orf = t+1;
prev_match = vpath[t];
if (vpath[t] < M6_STATE) {
strand = FORWARD_STRAND;
} else {
strand = REVERSE_STRAND;
}
} else if (strand != UNKNOWN_STRAND && (vpath[t] == E_STATE || vpath[t] == E_STATE_1 || t == len_seq-1)) {
if (vpath[t] == E_STATE || vpath[t] == E_STATE_1) {
end_t = t+3;
} else {
end_t = t+1;
/* FGS1.12 start: remove incomplete codon */
int temp_t = t;
while (vpath[temp_t] != M1_STATE && vpath[temp_t] != M4_STATE &&
vpath[temp_t] != M1_STATE_1 && vpath[temp_t] != M4_STATE_1) {
dna[dna_id] = '\0';
dna_id--;
temp_t--;
}
/* FGS1.12 end: remove incomplete codon */
}
frame = start_orf%3;
if (frame==0) {
frame=3;
}
//!! Transfer all of the output buffer writing code to another function. Modularize this.
if (dna_id > gene_len) {
print_gene(strand, start_t, end_t, frame, output_buffer, aa_buffer, dna_buffer, sequence_head,
dna, dna_id + 1, dna_seq, dna_rc, protein, insertions, deletions, nr_insertions, nr_deletions, temp_str_ptr,multiple);
multiple++;
}
strand = UNKNOWN_STRAND;
start_t = -1;
end_t = -1;
dna_id = 0;
} else if (strand != UNKNOWN_STRAND &&
((vpath[t] >= M1_STATE && vpath[t] <= M6_STATE) ||
(vpath[t] >= M1_STATE_1 && vpath[t] <= M6_STATE_1)) &&
vpath[t] - prev_match < 6) {
out_nt = vpath[t]-prev_match;
if (vpath[t] < prev_match) {
out_nt += 6;
}
for (kk = 0; kk < out_nt; kk++) { /* for deleted nt in reads */
dna_id++;
if (dna_id >= dna_seq_len) {
/* About to write past the end of the referenced storage, so allocate a */
/* bigger block of memory to replace it and copy the existing contents. */
printf("[Debug] %s (line %d): >>> Reallocating dna_seq: t=%d, dna_id=%d, dna_seq_len=%d\n",
__FILE__, __LINE__, t, dna_id, dna_seq_len);
dna_seq_len += (dna_seq_len / 10); /* Length of dynamic dna_seq (grow by 10%) */
Nucleotide *new_dna_seq = calloc(dna_seq_len, sizeof(Nucleotide));
memcpy(new_dna_seq, dna_seq, (dna_id + 1) * sizeof(Nucleotide));
if (dna_seq != (Nucleotide*) &dna_seq_array) {
// dna_seq references a dynamically allocated block, which must be freed.
free(dna_seq);
}
dna_seq = new_dna_seq;
}
dna[dna_id] = 'N';
dna_seq[dna_id] = NUCL_INVALID;
if (kk>0) {
deletions[nr_deletions] = t+1;
nr_deletions++;
}
}
dna[dna_id] = O[t];
dna_seq[dna_id] = sequence[t];
prev_match = vpath[t];
} else if (strand != UNKNOWN_STRAND &&
((vpath[t] >= I1_STATE && vpath[t] <= I6_STATE) ||
(vpath[t] >= I1_STATE_1 && vpath[t] <= I6_STATE_1))) {
insertions[nr_insertions] = t+1;
nr_insertions++;
} else if (strand != UNKNOWN_STRAND && vpath[t] == R_STATE) {
/* for long NNNNNNNNN, pretend R state */
strand = UNKNOWN_STRAND;
start_t = -1;
end_t = -1;
dna_id = 0;
}
}
free_dmatrix(alpha);
free_imatrix(path);
free(vpath);
vpath = NULL;
if (dna_seq != (Nucleotide*) &dna_seq_array) {
// dna_seq references a dynamically allocated block, which must be freed.
free(dna_seq);
}
dna = 0;
dna_rc = 0;
protein = 0;
}
void get_prob_from_cg(HMM *hmm_ptr, TRAIN *train_ptr, const char *O, int len_seq) {
int cg_count = 0;
int i;
for (i = 0; i < len_seq; i++) {
if ((O[i] == 'C'||O[i] =='c') || (O[i] == 'G'||O[i] == 'g') ) {
cg_count++;
}
}
cg_count = floor((cg_count*1.0/len_seq)*100)-26;
if (cg_count < 0) {
cg_count = 0;
} else if (cg_count > 43) {
cg_count = 43;
}
memcpy(hmm_ptr->e_M, train_ptr->trans[cg_count], sizeof(hmm_ptr->e_M));
memcpy(hmm_ptr->e_M_1, train_ptr->rtrans[cg_count], sizeof(hmm_ptr->e_M_1));
memcpy(hmm_ptr->tr_R_R, train_ptr->noncoding[cg_count], sizeof(hmm_ptr->tr_R_R));
memcpy(hmm_ptr->tr_S, train_ptr->start[cg_count], sizeof(hmm_ptr->tr_S));
memcpy(hmm_ptr->tr_E, train_ptr->stop[cg_count], sizeof(hmm_ptr->tr_E));
memcpy(hmm_ptr->tr_S_1, train_ptr->start1[cg_count], sizeof(hmm_ptr->tr_S_1));
memcpy(hmm_ptr->tr_E_1, train_ptr->stop1[cg_count], sizeof(hmm_ptr->tr_E_1));
memcpy(hmm_ptr->S_dist, train_ptr->S_dist[cg_count], sizeof(hmm_ptr->S_dist));
memcpy(hmm_ptr->E_dist, train_ptr->E_dist[cg_count], sizeof(hmm_ptr->E_dist));
memcpy(hmm_ptr->S1_dist, train_ptr->S1_dist[cg_count], sizeof(hmm_ptr->S1_dist));
memcpy(hmm_ptr->E1_dist, train_ptr->E1_dist[cg_count], sizeof(hmm_ptr->E1_dist));
}
//!! This function is for some strange reason definitely leaking memory. Need to find out why.
void get_train_from_file(char *filename, HMM *hmm_ptr, char *mfilename,
char *mfilename1, char *nfilename, char *sfilename, char *pfilename,
char *s1filename, char *p1filename, char *dfilename, TRAIN *train_ptr) {
int i, j, k, p;
double prob;
FILE *fp, *fpm, *fpm1, *fpn, *fps, *fpp, *fps1, *fpp1, *fpd;
char name[10];
char head[20];
char start[10];
char end[10];
/****************************************************/
/* transition */
/****************************************************/
fp = fopen (filename , "r");
/* Transition */
fscanf(fp, "%s", head);
for (i = 0; i < NUM_TRANSITIONS; i++) {
//!! This causes a memory leak for unknown reasons.
fscanf(fp, "%s %lf", name, &prob);
hmm_ptr->tr[hmm_state_transition_parse(name)] = log(prob);
}
/* TransitionMI */
fscanf(fp, "%s", head);
for (i = 0; i < 16; i++) {
fscanf(fp, "%s %s %lf\n", start, end, &prob);
hmm_ptr->tr_M_I[nucleotide_parse(start[0])][nucleotide_parse(end[0])] = log(prob);
}
/* TransitionII */
fscanf(fp, "%s", head);
for (i = 0; i < 16; i++) {
fscanf(fp, "%s %s %lf", start, end, &prob);
hmm_ptr->tr_I_I[nucleotide_parse(start[0])][nucleotide_parse(end[0])] = log(prob);
}
/* PI */
fscanf(fp, "%s", head);
for (i = 0; i < NUM_STATE; i++) {
fscanf(fp, "%s %lf", name, &prob);
hmm_ptr->pi[i] = log(prob);
}
fclose(fp);
/****************************************************/
/* M state transition */
/****************************************************/
fpm = fopen (mfilename , "r");
for (p = 0; p < 44; p++) { /* cg */
fscanf(fpm, "%s", head);
for (i = 0; i < 6; i++) { /* period */
for (j = 0; j < 16; j++) { /* condition */
for (k = 0; k < 4; k++) { /* emission */
fscanf(fpm, "%lf", &prob);
train_ptr->trans[p][i][j][k] = log(prob);
}
}
}
}
fclose(fpm);
/****************************************************/
/* M state_1 transition */
/****************************************************/
fpm1 = fopen (mfilename1 , "r");
for (p = 0; p < 44; p++) {
fscanf(fpm1, "%s", head);
for (i = 0; i < 6; i++) {
for (j = 0; j < 16; j++) {
for (k = 0; k < 4; k++) {
fscanf(fpm1, "%lf", &prob);