Commit bac6e6b2 authored by Guillaume Poirier-Morency's avatar Guillaume Poirier-Morency
Browse files

Let kf be variable based on seed mismatches (fix #60)

Incorporate results from Salomon et al. 2015 who measured an impairment
to the arrival rate of the complex due to seed mismatches.

Fix no longer valid assumptions in unit tests.

Use the distributed seed and supplementary score tables in tests.
parent 356054a1
......@@ -239,6 +239,41 @@ compute_score (MirbookingScoreTable *score_table,
SEED_OFFSET,
SEED_LENGTH);
// Seed mismatches penalty to the arrival rate (Salomon et al. 2015)
//
// The two weights are obtained by considering dinucleotide mismatches in
// the leading 4mer box (0.16, 0.14, 0.10) and trailing 3mer box (0.81,
// 0.82) as two separate kind of impairment.
//
// that there are two kind of
// mismatches: within the leading 4mer of the seed and in the ending 3mer.
//
// Since two di-nucleotide mismatches incured a penalty of ~0.81, we assume
// that each individual mismatches result in a multiplicative penalty of
// 0.9.
gdouble w[7] = {0.36, 0.36, 0.36, 0.36, 0.9, 0.9, 0.9};
const guint8 *_seed = mirbooking_sequence_get_subsequence (MIRBOOKING_SEQUENCE (mirna),
SEED_OFFSET,
SEED_LENGTH);
guint8 seed[7];
memcpy (seed, _seed, 7);
const guint8 *target_seed_rc = mirbooking_sequence_get_subsequence_rc (MIRBOOKING_SEQUENCE (target),
position ,
SEED_LENGTH);
//
guint i;
for (i = 0; i < 7; i++)
{
if ((toupper (seed[i]) == 'U' ? 'T' : toupper (seed[i])) != target_seed_rc[i])
{
ret.kf *= w[i];
}
}
if (is_g_bulge (target, position))
{
gsize i, j;
......
#include "mirbooking-sequence.h"
#include <ctype.h>
#include <string.h>
#include <glib-object.h>
......@@ -288,6 +289,43 @@ mirbooking_sequence_get_subsequence (MirbookingSequence *self, gsize subsequence
}
}
static gchar
rc (gchar c)
{
switch (toupper (c))
{
case 'A':
return 'T';
case 'C':
return 'G';
case 'G':
return 'C';
case 'T':
case 'U':
return 'A';
default:
g_assert_not_reached ();
}
}
const guint8*
mirbooking_sequence_get_subsequence_rc (MirbookingSequence *self, gsize subsequence_offset, gsize subsequence_len)
{
static __thread guint8 subsequence_rc_buffer[64];
const guint8 *subsequence_buffer = mirbooking_sequence_get_subsequence (self,
subsequence_offset,
subsequence_len);
gsize i;
for (i = 0; i < subsequence_len; i++)
{
subsequence_rc_buffer[i] = rc (subsequence_buffer[subsequence_len - i - 1]);
}
return subsequence_rc_buffer;
}
static gssize
sequence_index (const guint8 *seq, gsize seq_len)
{
......
......@@ -25,6 +25,9 @@ gsize mirbooking_sequence_get_sequence_length (MirbookingSequence *sel
const guint8 * mirbooking_sequence_get_subsequence (MirbookingSequence *self,
gsize subsequence_offset,
gsize subsequence_len);
const guint8 * mirbooking_sequence_get_subsequence_rc (MirbookingSequence *self,
gsize subsequence_offset,
gsize subsequence_len);
gssize mirbooking_sequence_get_subsequence_index (MirbookingSequence *self,
gsize offset,
......
......@@ -4,7 +4,8 @@ mirbooking_tests = [
'mirbooking']
foreach name : mirbooking_tests
test(name, executable(name + '-test', name + '-test.c',
dependencies: [glib_dep, gobject_dep, mirbooking_dep, m_dep]))
dependencies: [glib_dep, gobject_dep, mirbooking_dep, m_dep]),
env: ['G_TEST_SRCDIR=@0@'.format( meson.current_source_dir())])
endforeach
mirbooking_integration_tests = [
......
......@@ -282,14 +282,11 @@ test_mirbooking_numerical_integration ()
/* duplex concentration should steadily increase toward equilibrium */
gint i;
gfloat last_error_ratio = 1.0/0.0;
gdouble step_size = 1;
for (i = 0; i < 10; i++)
{
g_assert (mirbooking_broker_evaluate (broker, &error_ratio, &error));
g_assert_null (error);
g_assert_cmpfloat (error_ratio, <, last_error_ratio);
last_error_ratio = error_ratio;
g_assert (mirbooking_broker_step (broker, MIRBOOKING_BROKER_STEP_MODE_INTEGRATE, step_size, &error));
g_assert_null (error);
......@@ -364,7 +361,7 @@ test_mirbooking_solve_and_integrate ()
gdouble kother = mirbooking_broker_get_target_site_kother (broker, target_site);
g_assert_cmpfloat (kother, >, 0);
gdouble Stp = mirbooking_broker_get_target_site_quantity (broker, target_site);
g_assert_cmpfloat_with_epsilon ((E * Stp) / ES, MIRBOOKING_SCORE_KM (occupant->score) + kother / occupant->score.kf, 1e-6);
g_assert_cmpfloat_with_epsilon ((E * Stp) / ES, MIRBOOKING_SCORE_KM (occupant->score) + kother / occupant->score.kf, 1e-3);
// steady-state is maintained
gdouble ktr = mirbooking_broker_get_target_transcription_rate (broker, target);
......@@ -595,7 +592,7 @@ test_mirbooking_target_knock_out ()
// stop target transcription
mirbooking_broker_set_target_transcription_rate (broker, target, 0);
mirbooking_broker_step (broker, MIRBOOKING_BROKER_STEP_MODE_INTEGRATE, 2 * 3600.0, NULL);
mirbooking_broker_step (broker, MIRBOOKING_BROKER_STEP_MODE_INTEGRATE, 100 * 3600.0, NULL);
mirbooking_broker_evaluate (broker, &error_ratio, NULL);
g_assert_cmpfloat_with_epsilon (mirbooking_broker_get_sequence_quantity (broker, MIRBOOKING_SEQUENCE (target)), 0, 1e-3);
......
......@@ -334,49 +334,107 @@ test_score_table_wee_et_al_2012 ()
* (July 2, 2015): 84–95, https://doi.org/10.1016/j.cell.2015.06.029.
*/
static void
test_score_table_solomon_et_al_2016 ()
test_score_table_salomon_et_al_2016 ()
{
MirbookingScore score;
g_autoptr (MirbookingMirna) mirna = mirbooking_mirna_new ("let-7b");
g_autoptr (MirbookingTarget) target = mirbooking_target_new ("reporter");
g_autoptr (GBytes) default_table = g_bytes_new_static (&SEED_SCORES, sizeof (SEED_SCORES));
g_autoptr (GBytes) supplementary_scores = g_bytes_new_static (&SUPPLEMENTARY_SCORES_4, sizeof (SUPPLEMENTARY_SCORES_4));
g_autoptr (GMappedFile) mapped_seed_scores = g_mapped_file_new (g_test_get_filename (G_TEST_DIST, "..", "data", "scores-7mer-3mismatch-ending", NULL), FALSE, NULL);
g_autoptr (GBytes) default_table = g_mapped_file_get_bytes (mapped_seed_scores);
g_autoptr (GMappedFile) mapped_supplementary_scores = g_mapped_file_new (g_test_get_filename (G_TEST_DIST, "..", "data", "scores-4mer", NULL), FALSE, NULL);
g_autoptr (GBytes) supplementary_scores = g_mapped_file_get_bytes (mapped_supplementary_scores);
g_autoptr (MirbookingScoreTable) score_table = MIRBOOKING_SCORE_TABLE (mirbooking_default_score_table_new (default_table,
MIRBOOKING_DEFAULT_SCORE_TABLE_SUPPLEMENTARY_MODEL_WEE_ET_AL_2012,
supplementary_scores));
// Complete
mirbooking_sequence_set_sequence (MIRBOOKING_SEQUENCE (mirna), "UGAGGUAGUAGGUUGUAUAGU");
mirbooking_sequence_set_sequence (MIRBOOKING_SEQUENCE (target), "ACUAUACAACCUACUACCUCA");
// Complete
mirbooking_sequence_set_sequence (MIRBOOKING_SEQUENCE (target), "ACUAUACAACCUACUACCUCA");
mirbooking_score_table_compute_score (score_table, mirna, target, 13, &score, NULL);
g_assert_cmpfloat (MIRBOOKING_SCORE_KD (score), ==, 1e12 * exp ((-0.56f - 9.37f - 0.83f - 5.43f) / (R * T)));
g_assert_cmpfloat (score.kcat, >=, 3.6e-2 - 0.2e-2);
g_assert_cmpfloat (score.kcat, <=, 3.6e-2 + 0.2e-2);
// Seed plus 3'UTR
mirbooking_sequence_set_sequence (MIRBOOKING_SEQUENCE (target), "UGAUAACAAGGAUCUACCUCA");
mirbooking_score_table_compute_score (score_table, mirna, target, 13, &score, NULL);
g_assert_cmpfloat (MIRBOOKING_SCORE_KD (score), ==, 1e12 * exp ((-0.56f - 9.37f - 0.83f - 5.43f) / (R * T)));
// TODO: g_assert_cmpfloat (MIRBOOKING_SCORE_KD (score), >=, 11 - 2);
g_assert_cmpfloat (MIRBOOKING_SCORE_KD (score), <=, 11 + 2);
// g_assert_cmpfloat (score.kr, >=, 3e-3 - 0.4e-3);
g_assert_cmpfloat (score.kr, <=, 3e-3 + 0.4e-3);
// AAAAA...AAA
mirbooking_sequence_set_sequence (MIRBOOKING_SEQUENCE (target), "ACUAUACAACCAAAAAAAAAA");
mirbooking_score_table_compute_score (score_table, mirna, target, 13, &score, NULL);
g_assert_cmpfloat (score.kr, >=, 0.79 - 0.08);
// g_assert_cmpfloat (score.kr, <=, 0.79 + 0.08);
// Seed only
mirbooking_sequence_set_sequence (MIRBOOKING_SEQUENCE (target), "UGAUAUGUUGGAUCUACCUCA");
mirbooking_score_table_compute_score (score_table, mirna, target, 13, &score, NULL);
g_assert_cmpfloat (score.kf, >=, 2.4e-4 - 0.1e-4);
g_assert_cmpfloat (score.kf, <=, 2.4e-4 + 0.1e-4);
g_assert_cmpfloat (score.kcat, >=, 3.6e-2 - 0.2e-2);
g_assert_cmpfloat (score.kcat, <=, 3.6e-2 + 0.2e-2);
mirbooking_score_table_compute_score (score_table, mirna, target, 13, &score, NULL);
g_assert_cmpfloat (score.kr, >=, 3.6e-3 - 0.3e-3);
g_assert_cmpfloat (score.kr, <=, 3.6e-3 + 0.3e-3);
g_assert_cmpfloat (MIRBOOKING_SCORE_KD (score), ==, 1e12 * exp ((-0.56f - 9.37f - 5.43f) / (R * T)));
// g_assert_cmpfloat (MIRBOOKING_SCORE_KD (score), >=, 15 - 2);
g_assert_cmpfloat (MIRBOOKING_SCORE_KD (score), <=, 15 + 2);
// Seed plus 3'UTR
mirbooking_sequence_set_sequence (MIRBOOKING_SEQUENCE (target), "UGAUAACAAGGAUCUACCUCA");
// g2g3
mirbooking_sequence_set_sequence (MIRBOOKING_SEQUENCE (target), "UGAUAUGUUGGAUCUACCAGA");
mirbooking_score_table_compute_score (score_table, mirna, target, 13, &score, NULL);
// TODO: g_assert_cmpfloat (score.kf, >=, 3.8e-5 - 0.1e-5);
g_assert_cmpfloat (score.kf, <=, 3.8e-5 + 0.1e-5);
g_assert_cmpfloat (score.kr, ==, INFINITY);
// g3g4
mirbooking_sequence_set_sequence (MIRBOOKING_SEQUENCE (target), "UGAUAUGUUGGAUCUACGACA");
mirbooking_score_table_compute_score (score_table, mirna, target, 13, &score, NULL);
// TODO: g_assert_cmpfloat (score.kf, >=, 3.4e-5 - 0.2e-5);
g_assert_cmpfloat (score.kr, ==, INFINITY);
g_assert_cmpfloat (MIRBOOKING_SCORE_KD (score), ==, 1e12 * exp ((-0.56f - 9.37f - 0.83f - 5.43f) / (R * T)));
// FIXME: g_assert_cmpfloat (MIRBOOKING_SCORE_KD (score), >=, 11 - 2);
g_assert_cmpfloat (MIRBOOKING_SCORE_KD (score), <=, 11 + 2);
// g4g5
mirbooking_sequence_set_sequence (MIRBOOKING_SEQUENCE (target), "UGAUAUGUUGGAUCUAAAUCA");
mirbooking_score_table_compute_score (score_table, mirna, target, 13, &score, NULL);
g_assert_cmpfloat (score.kf, >=, 2.4e-5 - 0.1e-5);
// TODO: g_assert_cmpfloat (score.kf, <=, 2.4e-5 + 0.1e-5);
g_assert_cmpfloat (score.kr, ==, INFINITY);
// g5g6
mirbooking_sequence_set_sequence (MIRBOOKING_SEQUENCE (target), "UGAUAUGUUGGAUCUUGCUCA");
mirbooking_score_table_compute_score (score_table, mirna, target, 13, &score, NULL);
g_assert_cmpfloat (score.kf, >=, 3.9e-5 - 0.1e-5);
// TODO: g_assert_cmpfloat (score.kf, <=, 3.9e-5 + 0.1e-5);
g_assert_cmpfloat (score.kr, ==, INFINITY);
// g6g7
mirbooking_sequence_set_sequence (MIRBOOKING_SEQUENCE (target), "UGAUAUGUUGGAUCAUCCUCA");
mirbooking_score_table_compute_score (score_table, mirna, target, 13, &score, NULL);
g_assert_cmpfloat (score.kf, >=, 2.0e-4 - 0.1e-4);
g_assert_cmpfloat (score.kf, <=, 2.0e-4 + 0.1e-4);
g_assert_cmpfloat (score.kr, >=, 3.5 - 0.1);
// TODO: g_assert_cmpfloat (score.kr, <=, 3.5 + 0.1);
// g7g8
mirbooking_sequence_set_sequence (MIRBOOKING_SEQUENCE (target), "UGAUAUGUUGGAUGAACCUCA");
mirbooking_score_table_compute_score (score_table, mirna, target, 13, &score, NULL);
g_assert_cmpfloat (score.kf, >=, 2.0e-4 - 0.1e-4);
g_assert_cmpfloat (score.kf, <=, 2.0e-4 + 0.1e-4);
g_assert_cmpfloat (score.kr, >=, 0.24 - 0.01);
// TODO: g_assert_cmpfloat (score.kr, <=, 0.24 + 0.01);
// g8
mirbooking_sequence_set_sequence (MIRBOOKING_SEQUENCE (target), "UGAUAUGUUGGAUGUACCUCA");
mirbooking_score_table_compute_score (score_table, mirna, target, 13, &score, NULL);
g_assert_cmpfloat (score.kf, >=, 1.8e-4 - 0.1e-4);
// TODO: g_assert_cmpfloat (score.kf, <=, 1.8e-4 + 0.1e-4);
// TODO: g_assert_cmpfloat (score.kr, >=, 0.086 - 0.002);
g_assert_cmpfloat (score.kr, <=, 0.086 + 0.002);
}
static void
......@@ -388,7 +446,8 @@ test_score_table_schirle_et_al_2015 ()
g_autoptr (MirbookingMirna) mirna = mirbooking_mirna_new ("");
mirbooking_sequence_set_sequence (MIRBOOKING_SEQUENCE (mirna), "UUCACAUUGCCCAAGUCUCUU");
g_autoptr (GBytes) default_table = g_bytes_new_static (&SEED_SCORES, sizeof (SEED_SCORES));
g_autoptr (GMappedFile) mapped_seed_scores = g_mapped_file_new (g_test_get_filename (G_TEST_DIST, "..", "data", "scores-7mer-3mismatch-ending", NULL), FALSE, NULL);
g_autoptr (GBytes) default_table = g_mapped_file_get_bytes (mapped_seed_scores);
g_autoptr (GBytes) supplementary_scores = g_bytes_new_static (&SUPPLEMENTARY_SCORES_4, sizeof (SUPPLEMENTARY_SCORES_4));
g_autoptr (MirbookingScoreTable) score_table = MIRBOOKING_SCORE_TABLE (mirbooking_default_score_table_new (default_table,
MIRBOOKING_DEFAULT_SCORE_TABLE_SUPPLEMENTARY_MODEL_WEE_ET_AL_2012,
......@@ -434,7 +493,8 @@ test_score_table_yan_et_al_2018 ()
g_autoptr (MirbookingMirna) mirna = mirbooking_mirna_new ("miB");
g_autoptr (MirbookingTarget) target = mirbooking_target_new ("FR-tat");
g_autoptr (GBytes) default_table = g_bytes_new_static (&SEED_SCORES, sizeof (SEED_SCORES));
g_autoptr (GMappedFile) mapped_seed_scores = g_mapped_file_new (g_test_get_filename (G_TEST_DIST, "..", "data", "scores-7mer-3mismatch-ending", NULL), FALSE, NULL);
g_autoptr (GBytes) default_table = g_mapped_file_get_bytes (mapped_seed_scores);
g_autoptr (GBytes) supplementary_scores = g_bytes_new_static (&SUPPLEMENTARY_SCORES, sizeof (SUPPLEMENTARY_SCORES));
g_autoptr (MirbookingScoreTable) score_table = MIRBOOKING_SCORE_TABLE (mirbooking_default_score_table_new (default_table,
MIRBOOKING_DEFAULT_SCORE_TABLE_SUPPLEMENTARY_MODEL_YAN_ET_AL_2018,
......@@ -537,7 +597,8 @@ test_score_table_yan_et_al_2018 ()
static void
test_score_table_jo_et_al_2015 ()
{
g_autoptr (GBytes) default_table = g_bytes_new_static (&SEED_SCORES, sizeof (SEED_SCORES));
g_autoptr (GMappedFile) mapped_seed_scores = g_mapped_file_new (g_test_get_filename (G_TEST_DIST, "..", "data", "scores-7mer-3mismatch-ending", NULL), FALSE, NULL);
g_autoptr (GBytes) default_table = g_mapped_file_get_bytes (mapped_seed_scores);
g_autoptr (GBytes) supplementary_scores = g_bytes_new_static (&SUPPLEMENTARY_SCORES, sizeof (SUPPLEMENTARY_SCORES));
g_autoptr (MirbookingScoreTable) score_table = MIRBOOKING_SCORE_TABLE (mirbooking_default_score_table_new (default_table,
MIRBOOKING_DEFAULT_SCORE_TABLE_SUPPLEMENTARY_MODEL_YAN_ET_AL_2018,
......@@ -587,7 +648,7 @@ int main (int argc, gchar **argv)
g_test_add_func ("/score-table/compute-seed-scores", test_score_table_compute_seed_scores);
g_test_add_func ("/score-table/mcff", test_score_table_mcff);
g_test_add_func ("/score-table/wee-et-al-2012", test_score_table_wee_et_al_2012);
g_test_add_func ("/score-table/solomon-et-al-2016", test_score_table_solomon_et_al_2016);
g_test_add_func ("/score-table/salomon-et-al-2016", test_score_table_salomon_et_al_2016);
g_test_add_func ("/score-table/schirle-et-al-2015", test_score_table_schirle_et_al_2015);
g_test_add_func ("/score-table/yan-et-al-2018", test_score_table_yan_et_al_2018);
g_test_add_func ("/score-table/jo-et-al-2015", test_score_table_jo_et_al_2015);
......
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