def setUp(self):
""" define a family and variant, and start the Allosomal class
"""
# generate a test family
child_gender = "F"
mom_aff = "1"
dad_aff = "1"
self.trio = self.create_family(child_gender, mom_aff, dad_aff)
# generate a test variant
child = create_snv(child_gender, "0/1")
mom = create_snv("F", "0/0")
dad = create_snv("M", "0/0")
var = TrioGenotypes(child.get_chrom(), child.get_position(), child,
mom, dad)
self.variants = [var]
# make sure we've got known genes data
self.known_gene = {
"inh": ["Monoallelic"],
"confirmed_status": ["confirmed dd gene"]
}
self.inh = Allosomal(self.variants, self.trio, self.known_gene, "1001")
self.inh.is_lof = var.child.is_lof()
def setUp(self):
""" define a family and variant, and start the Allosomal class
"""
# generate a test family
child_gender = "F"
mom_aff = "1"
dad_aff = "1"
self.trio = self.create_family(child_gender, mom_aff, dad_aff)
# generate a test variant
child_var = self.create_snv(child_gender, "0/1")
mom_var = self.create_snv("F", "0/0")
dad_var = self.create_snv("M", "0/0")
var = TrioGenotypes(child_var)
var.add_mother_variant(mom_var)
var.add_father_variant(dad_var)
self.variants = [var]
# make sure we've got known genes data
self.known_genes = {"TEST": {"inh": ["Monoallelic"], "confirmed_status": ["Confirmed DD Gene"]}}
self.inh = Allosomal(self.variants, self.trio, self.known_genes, "TEST")
self.inh.is_lof = var.child.is_lof()
def test_check_homozygous_male(self):
""" test that check_homozygous() works correctly for males
"""
# check for trio with de novo on male X chrom
var = TrioGenotypes('X', 100, create_snv('M', "1/1"),
create_snv('F', "0/0"), create_snv('M', "0/0"))
trio = self.create_family('male', '1', '1')
self.inh = Allosomal([var], trio, self.known_gene, "TEST")
self.inh.set_trio_genotypes(var)
self.assertEqual(self.inh.check_homozygous("X-linked dominant"),
"single_variant")
self.assertEqual(self.inh.log_string, "male X chrom de novo")
# check for trio = 210, with unaffected mother
var = TrioGenotypes('X', 100, create_snv('M', "1/1"),
create_snv('F', "1/0"), create_snv('M', "0/0"))
self.inh.set_trio_genotypes(var)
self.assertEqual(self.inh.check_homozygous("X-linked dominant"),
"single_variant")
self.assertEqual(
self.inh.log_string,
"male X chrom inherited from het mother or hom affected mother")
# check for trio = 210, with affected mother, which should also pass
self.inh.mother_affected = True
self.assertEqual(self.inh.check_homozygous("X-linked dominant"),
"single_variant")
self.assertEqual(
self.inh.log_string,
"male X chrom inherited from het mother or hom affected mother")
# check for trio = 220, with affected mother
var = TrioGenotypes('X', 100, create_snv('M', "1/1"),
create_snv('F', "1/1"), create_snv('M', "0/0"))
self.inh.set_trio_genotypes(var)
self.assertEqual(self.inh.check_homozygous("X-linked dominant"),
"single_variant")
self.assertEqual(
self.inh.log_string,
"male X chrom inherited from het mother or hom affected mother")
# check for trio = 220, with unaffected mother, which should not pass
self.inh.mother_affected = False
self.assertEqual(self.inh.check_homozygous("X-linked dominant"),
"nothing")
self.assertEqual(self.inh.log_string,
"variant not compatible with being causal")
# check that homozygous X-linked over-dominance doesn't pass
self.assertEqual(self.inh.check_homozygous("X-linked over-dominance"),
'nothing')
# check we raise errors with unknown inheritance modes
with self.assertRaises(ValueError):
self.inh.check_homozygous("Digenic")
def setUp(self):
""" define a family and variant, and start the Inheritance class
"""
# generate a test family
child_gender = "F"
mom_aff = "1"
dad_aff = "1"
self.trio = self.create_family(child_gender, mom_aff, dad_aff)
# generate list of variants
self.variants = [self.create_variant(child_gender)]
self.variants.append(self.create_variant(child_gender))
# make sure we've got known genes data
self.known_genes = {
"TEST": {
"inheritance": ["Monoallelic"],
"confirmed_status": ["Confirmed DD Gene"]
}
}
gene_inh = self.known_genes[self.variants[0].get_gene()]["inheritance"]
self.inh = Autosomal(self.variants, self.trio, gene_inh)
def find_variants(self, variants, gene):
""" finds variants that fit inheritance models
Args:
variants: list of TrioGenotype objects
gene: gene ID as string
Returns:
list of variants that pass inheritance checks
"""
# get the inheritance for the gene (monoalleleic, biallelic, hemizygous
# etc), but allow for times when we haven't specified a list of genes
# to use
gene_inh = None
if self.known_genes is not None and gene in self.known_genes:
gene_inh = self.known_genes[gene]["inh"]
# If we are looking for variants in a set of known genes, and the gene
# isn't part of that set, then we don't ant to examine the variant for
# that gene, UNLESS the variant is a CNV, since CNVs can be included
# purely from size thresholds, regardless of which gene they overlap.
if self.known_genes is not None and gene not in self.known_genes:
variants = [x for x in variants if x.is_cnv()]
# ignore intergenic variants
if gene is None:
for var in variants:
if var.get_chrom() == self.debug_chrom and var.get_position(
) == self.debug_pos:
print(var, "lacks HGNC/gene symbol")
return []
# Now that we are examining a single gene, check that the consequences
# for the gene are in the required functional categories.
variants = [
var for var in variants
if var.child.is_lof(gene) or var.child.is_missense(gene)
]
if variants == []:
return []
logging.debug("{} {} {} {}".format(self.family.child.get_id(), gene,
variants, gene_inh))
chrom_inheritance = variants[0].get_inheritance_type()
if chrom_inheritance == "autosomal":
finder = Autosomal(variants, self.family, self.known_genes, gene,
self.cnv_regions)
elif chrom_inheritance in ["XChrMale", "XChrFemale", "YChrMale"]:
finder = Allosomal(variants, self.family, self.known_genes, gene,
self.cnv_regions)
variants = finder.get_candidate_variants()
variants = [(x[0], list(x[1]), list(x[2]), [gene]) for x in variants]
return variants
def test_check_variant_without_parents_male(self):
""" test that check_variant_without_parents() works correctly for males
"""
var = TrioGenotypes('X', 100, create_snv('M', "1/1"), None, None)
trio = self.create_family('male', '1', '1')
self.inh = Allosomal([var], trio, self.known_gene, "TEST")
self.inh.set_trio_genotypes(var)
# check for X-linked dominant inheritance
self.assertEqual(
self.inh.check_variant_without_parents("X-linked dominant"),
"single_variant")
# and check for hemizygous inheritance
self.assertEqual(self.inh.check_variant_without_parents("Hemizygous"),
"single_variant")
def find_variants(self, variants, gene, family):
""" finds variants that fit inheritance models
Args:
variants: list of TrioGenotype objects
gene: gene ID as string
Returns:
list of variants that pass inheritance checks
"""
# get the inheritance for the gene (monoalleleic, biallelic, hemizygous
# etc), but allow for times when we haven't specified a list of genes
# to use
known_gene = None
gene_inh = None
if self.known_genes is not None and gene in self.known_genes:
known_gene = self.known_genes[gene]
gene_inh = known_gene['inh']
chrom_inheritance = variants[0].get_inheritance_type()
# If we are looking for variants in a set of known genes, and the gene
# isn't part of that set, then we don't ant to examine the variant for
# that gene, UNLESS the variant is a CNV, since CNVs can be included
# purely from size thresholds, regardless of which gene they overlap.
if self.known_genes is not None and gene not in self.known_genes:
variants = [ x for x in variants if x.is_cnv() ]
# ignore intergenic variants
if gene is None:
for var in variants:
if var.get_chrom() == self.debug_chrom and var.get_position() == self.debug_pos:
print(var, "lacks HGNC/gene symbol")
return []
# Now that we are examining a single gene, check that the consequences
# for the gene are in the required functional categories.
variants = [ var for var in variants if var.child.is_lof(gene) or var.child.is_missense(var.child.is_cnv(), gene) ]
if variants == []:
return []
for x in variants[0].child.info.symbols:
try:
symbol = x.get(gene, ['HGNC', 'SYMBOL', 'ENSG'])
break
except KeyError:
continue
logging.info("{}\t{}\tvariants: {}\trequired_mode: {}".format(
family.child.get_id(), symbol, [str(x) for x in variants], gene_inh))
if chrom_inheritance == "autosomal":
finder = Autosomal(variants, family, known_gene, gene, self.cnv_regions)
elif chrom_inheritance in ["XChrMale", "XChrFemale", "YChrMale"]:
finder = Allosomal(variants, family, known_gene, gene, self.cnv_regions)
return finder.get_candidate_variants()
def test_check_compound_hets_allosomal(self):
""" test that check_compound_hets() works correctly for allosomal vars
"""
# set some X chrom variants, so we can alter them later
var1 = self.create_variant("F", chrom="X", position="15000000")
var2 = self.create_variant("F", chrom="X", position="16000000")
# set the inheritance type, the compound het type ("hemizygous"
# for allosomal variants, and start allosomal inheritance)
inh = "Hemizygous"
compound = "hemizygous"
self.inh = Allosomal([var1, var2], self.trio, inh)
variants = ["", ""]
# check that de novo containing "110, 100" combos pass
variants[0] = self.set_compound_het_var(var1, "110", compound)
variants[1] = self.set_compound_het_var(var2, "100", compound)
if IS_PYTHON3:
self.assertCountEqual(self.inh.check_compound_hets(variants),
variants)
elif IS_PYTHON2:
self.assertEqual(sorted(self.inh.check_compound_hets(variants)),
sorted(variants))
# check that "110, 102" combo fails if the father is unaffected
variants[0] = self.set_compound_het_var(var1, "110", compound)
variants[1] = self.set_compound_het_var(var2, "102", compound)
self.assertEqual(self.inh.check_compound_hets(variants), [])
# check that "110, 102" combo passes if the father is affected
self.inh.father_affected = True
if IS_PYTHON3:
self.assertCountEqual(self.inh.check_compound_hets(variants),
variants)
elif IS_PYTHON2:
self.assertEqual(sorted(self.inh.check_compound_hets(variants)),
sorted(variants))
# make sure we can't set the father as het on the X chrom
with self.assertRaises(ValueError):
self.set_compound_het_var(var2, "101", compound)
def test_check_variant_without_parents_male(self):
""" test that check_variant_without_parents() works correctly for males
"""
var = TrioGenotypes('X', 100, create_snv('M', "1/1"), None, None)
trio = self.create_family('male', '1', '1')
self.inh = Allosomal([var], trio, self.known_gene, "TEST")
self.inh.set_trio_genotypes(var)
# check for X-linked dominant inheritance
self.assertEqual(self.inh.check_variant_without_parents("X-linked dominant"), "single_variant")
# and check for hemizygous inheritance
self.assertEqual(self.inh.check_variant_without_parents("Hemizygous"), "single_variant")
def test_check_homozygous_male(self):
""" test that check_homozygous() works correctly for males
"""
# check for trio with de novo on male X chrom
var = TrioGenotypes('X', 100, create_snv('M', "1/1"),
create_snv('F', "0/0"), create_snv('M', "0/0"))
trio = self.create_family('male', '1', '1')
self.inh = Allosomal([var], trio, self.known_gene, "TEST")
self.inh.set_trio_genotypes(var)
self.assertEqual(self.inh.check_homozygous("X-linked dominant"), "single_variant")
self.assertEqual(self.inh.log_string, "male X chrom de novo")
# check for trio = 210, with unaffected mother
var = TrioGenotypes('X', 100, create_snv('M', "1/1"),
create_snv('F', "1/0"), create_snv('M', "0/0"))
self.inh.set_trio_genotypes(var)
self.assertEqual(self.inh.check_homozygous("X-linked dominant"), "single_variant")
self.assertEqual(self.inh.log_string, "male X chrom inherited from het mother or hom affected mother")
# check for trio = 210, with affected mother, which should also pass
self.inh.mother_affected = True
self.assertEqual(self.inh.check_homozygous("X-linked dominant"), "single_variant")
self.assertEqual(self.inh.log_string, "male X chrom inherited from het mother or hom affected mother")
# check for trio = 220, with affected mother
var = TrioGenotypes('X', 100, create_snv('M', "1/1"),
create_snv('F', "1/1"), create_snv('M', "0/0"))
self.inh.set_trio_genotypes(var)
self.assertEqual(self.inh.check_homozygous("X-linked dominant"), "single_variant")
self.assertEqual(self.inh.log_string, "male X chrom inherited from het mother or hom affected mother")
# check for trio = 220, with unaffected mother, which should not pass
self.inh.mother_affected = False
self.assertEqual(self.inh.check_homozygous("X-linked dominant"), "nothing")
self.assertEqual(self.inh.log_string, "variant not compatible with being causal")
# check that homozygous X-linked over-dominance doesn't pass
self.assertEqual(self.inh.check_homozygous("X-linked over-dominance"), 'nothing')
# check we raise errors with unknown inheritance modes
with self.assertRaises(ValueError):
self.inh.check_homozygous("Digenic")
def find_variants(self, variants, gene):
""" finds variants that fit inheritance models
Args:
variants: list of TrioGenotype objects
gene: gene ID as string
Returns:
list of variants that pass inheritance checks
"""
# get the inheritance for the gene (monoalleleic, biallelic, hemizygous
# etc), but allow for times when we haven't specified a list of genes
# to use
gene_inh = None
if self.known_genes is not None and gene in self.known_genes:
gene_inh = self.known_genes[gene]["inh"]
# ignore intergenic variants
if gene is None:
for var in variants:
if var.get_chrom() == self.debug_chrom and var.get_position(
) == self.debug_pos:
print(var, "lacks HGNC/gene symbol")
return []
logging.debug(self.family.child.get_id() + " " + gene + " " + \
str(variants) + " " + str(gene_inh))
chrom_inheritance = variants[0].get_inheritance_type()
if chrom_inheritance == "autosomal":
finder = Autosomal(variants, self.family, self.known_genes,
gene_inh, self.cnv_regions)
elif chrom_inheritance in ["XChrMale", "XChrFemale", "YChrMale"]:
finder = Allosomal(variants, self.family, self.known_genes,
gene_inh, self.cnv_regions)
return finder.get_candidate_variants()
def setUp(self):
""" define a family and variant, and start the Allosomal class
"""
# generate a test family
child_gender = "F"
mom_aff = "1"
dad_aff = "1"
self.trio = self.create_family(child_gender, mom_aff, dad_aff)
# generate a test variant
child = create_snv(child_gender, "0/1")
mom = create_snv("F", "0/0")
dad = create_snv("M", "0/0")
var = TrioGenotypes(child.get_chrom(), child.get_position(), child, mom, dad)
self.variants = [var]
# make sure we've got known genes data
self.known_gene = {"inh": ["Monoallelic"], "confirmed_status": ["confirmed dd gene"]}
self.inh = Allosomal(self.variants, self.trio, self.known_gene, "1001")
self.inh.is_lof = var.child.is_lof()
class TestAllosomalPy(unittest.TestCase):
""" test the Allosomal class
"""
def setUp(self):
""" define a family and variant, and start the Allosomal class
"""
# generate a test family
child_gender = "F"
mom_aff = "1"
dad_aff = "1"
self.trio = self.create_family(child_gender, mom_aff, dad_aff)
# generate a test variant
child = create_snv(child_gender, "0/1")
mom = create_snv("F", "0/0")
dad = create_snv("M", "0/0")
var = TrioGenotypes(child.get_chrom(), child.get_position(), child, mom, dad)
self.variants = [var]
# make sure we've got known genes data
self.known_gene = {"inh": ["Monoallelic"], "confirmed_status": ["confirmed dd gene"]}
self.inh = Allosomal(self.variants, self.trio, self.known_gene, "1001")
self.inh.is_lof = var.child.is_lof()
def create_family(self, child_gender, mom_aff, dad_aff):
""" create a default family, with optional gender and parental statuses
"""
fam = Family('test')
fam.add_child('child', 'mother', 'father', child_gender, '2', 'child_vcf')
fam.add_mother('mother', '0', '0', 'female', mom_aff, 'mother_vcf')
fam.add_father('father', '0', '0', 'male', dad_aff, 'father_vcf')
fam.set_child()
return fam
def set_trio_genos(self, var, geno):
""" convenience function to set the trio genotypes for a variant
"""
genos = {"0": "0/0", "1": "0/1", "2": "1/1"}
# convert the geno codes to allele codes
child = genos[geno[0]]
mom = genos[geno[1]]
dad = genos[geno[2]]
# set the genotype field for each individual
var.child.format["GT"] = child
var.mother.format["GT"] = mom
var.father.format["GT"] = dad
# and set th genotype for each individual
var.child.set_genotype()
var.mother.set_genotype()
var.father.set_genotype()
# set the trio genotypes for the inheritance object
self.inh.set_trio_genotypes(var)
def test_check_variant_without_parents_female(self):
""" test that check_variant_without_parents() works correctly for female
"""
var = TrioGenotypes('X', 100, create_snv('F', "1/0"), None, None)
self.inh.set_trio_genotypes(var)
# check for X-linked dominant inheritance
self.assertEqual(self.inh.check_variant_without_parents("X-linked dominant"), "single_variant")
self.assertEqual(self.inh.log_string, "allosomal without parents")
var = TrioGenotypes('X', 100, create_snv('F', "1/1"),
create_snv('F', "0/0"), create_snv('M', "0/0"))
self.inh.set_trio_genotypes(var)
self.assertEqual(self.inh.check_variant_without_parents("X-linked dominant"), "single_variant")
# and check for hemizygous inheritance
var = TrioGenotypes('X', 100, create_snv('F', "1/0"),
create_snv('F', "0/0"), create_snv('M', "0/0"))
self.inh.set_trio_genotypes(var)
self.assertEqual(self.inh.check_variant_without_parents("Hemizygous"), "hemizygous")
var = TrioGenotypes('X', 100, create_snv('F', "1/1"),
create_snv('F', "0/0"), create_snv('M', "0/0"))
self.inh.set_trio_genotypes(var)
self.assertEqual(self.inh.check_variant_without_parents("Hemizygous"), "single_variant")
def test_check_variant_without_parents_male(self):
""" test that check_variant_without_parents() works correctly for males
"""
var = TrioGenotypes('X', 100, create_snv('M', "1/1"), None, None)
trio = self.create_family('male', '1', '1')
self.inh = Allosomal([var], trio, self.known_gene, "TEST")
self.inh.set_trio_genotypes(var)
# check for X-linked dominant inheritance
self.assertEqual(self.inh.check_variant_without_parents("X-linked dominant"), "single_variant")
# and check for hemizygous inheritance
self.assertEqual(self.inh.check_variant_without_parents("Hemizygous"), "single_variant")
def test_check_heterozygous_de_novo(self):
""" test that check_heterozygous() works correctly for de novos
"""
# all of these tests are run for female X chrom de novos, since male
# X chrom hets don't exist
var = TrioGenotypes('X', 100, create_snv('F', "1/0"),
create_snv('F', "0/0"), create_snv('M', "0/0"))
self.inh.set_trio_genotypes(var)
# check for X-linked dominant inheritance
self.assertEqual(self.inh.check_heterozygous("X-linked dominant"), "single_variant")
self.assertEqual(self.inh.log_string, "female x chrom de novo")
# check for biallelic inheritance
self.assertEqual(self.inh.check_heterozygous("Hemizygous"), "single_variant")
# check for X-linked over dominance
self.assertEqual(self.inh.check_heterozygous("X-linked over-dominance"), 'single_variant')
# check we raise errors with unknown inheritance modes
with self.assertRaises(ValueError):
self.inh.check_heterozygous("Digenic")
genos = {'0': '0/0', '1': '1/0', '2': '1/1'}
for (child, mom, dad) in ["102", "110", "112", "122"]:
var = TrioGenotypes('X', 100, create_snv('F', genos[child]),
create_snv('F', genos[mom]), create_snv('M', genos[dad]))
self.inh.set_trio_genotypes(var)
self.inh.check_heterozygous("X-linked dominant")
self.assertNotEqual(self.inh.log_string, "female x chrom de novo")
def test_check_heterozygous_affected_mother(self):
""" test that check_heterozygous() works correctly for affected mothers
"""
# check that trio with het affected mother is captured
var = TrioGenotypes('X', 100, create_snv('F', "1/0"),
create_snv('F', "1/0"), create_snv('M', "0/0"))
self.inh.set_trio_genotypes(var)
self.inh.mother_affected = True
self.assertEqual(self.inh.check_heterozygous("X-linked dominant"), "single_variant")
self.assertEqual(self.inh.log_string, "x chrom transmitted from aff, other parent non-carrier or aff")
# check that when the other parent is also non-ref, the variant is no
# longer captured, unless the parent is affected
var = TrioGenotypes('X', 100, create_snv('F', "1/0"),
create_snv('F', "1/0"), create_snv('M', "1/1"))
self.inh.set_trio_genotypes(var)
self.assertEqual(self.inh.check_heterozygous("X-linked dominant"), "nothing")
self.assertEqual(self.inh.log_string, "variant not compatible with being causal")
self.inh.father_affected = True
self.inh.check_heterozygous("X-linked dominant")
self.assertEqual(self.inh.log_string, "x chrom transmitted from aff, other parent non-carrier or aff")
# and check that hemizgygous vars return as "compound_het"
self.assertEqual(self.inh.check_heterozygous("Hemizygous"), "compound_het")
def test_check_heterozygous_affected_father(self):
""" test that check_heterozygous() works correctly for affected fathers
"""
# set the father as non-ref genotype and unaffected
var = TrioGenotypes('X', 100, create_snv('F', "1/0"),
create_snv('F', "0/0"), create_snv('M', "1/1"))
self.inh.set_trio_genotypes(var)
# check that the het proband, with het unaffected father is passes
self.assertEqual(self.inh.check_heterozygous("X-linked dominant"), "nothing")
self.assertEqual(self.inh.log_string, "variant not compatible with being causal")
# check that the het proband, with het affected father is captured
self.inh.father_affected = True
self.assertEqual(self.inh.check_heterozygous("X-linked dominant"), "single_variant")
self.assertEqual(self.inh.log_string, "x chrom transmitted from aff, other parent non-carrier or aff")
# check that when the other parent is also non-ref, the variant is no
# longer captured, unless the parent is affected
var = TrioGenotypes('X', 100, create_snv('F', "1/0"),
create_snv('F', "1/0"), create_snv('M', "1/1"))
self.inh.set_trio_genotypes(var)
self.assertEqual(self.inh.check_heterozygous("X-linked dominant"), "nothing")
self.assertEqual(self.inh.log_string, "variant not compatible with being causal")
self.inh.mother_affected = True
self.inh.check_heterozygous("X-linked dominant")
self.assertEqual(self.inh.log_string, "x chrom transmitted from aff, other parent non-carrier or aff")
def test_check_homozygous_male(self):
""" test that check_homozygous() works correctly for males
"""
# check for trio with de novo on male X chrom
var = TrioGenotypes('X', 100, create_snv('M', "1/1"),
create_snv('F', "0/0"), create_snv('M', "0/0"))
trio = self.create_family('male', '1', '1')
self.inh = Allosomal([var], trio, self.known_gene, "TEST")
self.inh.set_trio_genotypes(var)
self.assertEqual(self.inh.check_homozygous("X-linked dominant"), "single_variant")
self.assertEqual(self.inh.log_string, "male X chrom de novo")
# check for trio = 210, with unaffected mother
var = TrioGenotypes('X', 100, create_snv('M', "1/1"),
create_snv('F', "1/0"), create_snv('M', "0/0"))
self.inh.set_trio_genotypes(var)
self.assertEqual(self.inh.check_homozygous("X-linked dominant"), "single_variant")
self.assertEqual(self.inh.log_string, "male X chrom inherited from het mother or hom affected mother")
# check for trio = 210, with affected mother, which should also pass
self.inh.mother_affected = True
self.assertEqual(self.inh.check_homozygous("X-linked dominant"), "single_variant")
self.assertEqual(self.inh.log_string, "male X chrom inherited from het mother or hom affected mother")
# check for trio = 220, with affected mother
var = TrioGenotypes('X', 100, create_snv('M', "1/1"),
create_snv('F', "1/1"), create_snv('M', "0/0"))
self.inh.set_trio_genotypes(var)
self.assertEqual(self.inh.check_homozygous("X-linked dominant"), "single_variant")
self.assertEqual(self.inh.log_string, "male X chrom inherited from het mother or hom affected mother")
# check for trio = 220, with unaffected mother, which should not pass
self.inh.mother_affected = False
self.assertEqual(self.inh.check_homozygous("X-linked dominant"), "nothing")
self.assertEqual(self.inh.log_string, "variant not compatible with being causal")
# check that homozygous X-linked over-dominance doesn't pass
self.assertEqual(self.inh.check_homozygous("X-linked over-dominance"), 'nothing')
# check we raise errors with unknown inheritance modes
with self.assertRaises(ValueError):
self.inh.check_homozygous("Digenic")
def test_check_homozygous_female(self):
""" test that check_homozygous() works correctly for females
"""
var = self.variants[0]
# check for trio = 200, which is non-mendelian
self.set_trio_genos(var, "200")
self.assertEqual(self.inh.check_homozygous("Hemizygous"), "nothing")
self.assertEqual(self.inh.log_string, "non-mendelian trio")
# check for trio = 210, which is non-mendelian
self.set_trio_genos(var, "210")
self.assertEqual(self.inh.check_homozygous("Hemizygous"), "nothing")
self.assertEqual(self.inh.log_string, "non-mendelian trio")
# check for trio = 202, which is non-mendelian
self.set_trio_genos(var, "202")
self.assertEqual(self.inh.check_homozygous("Hemizygous"), "nothing")
self.assertEqual(self.inh.log_string, "non-mendelian trio")
# and check for trio = 212, without affected parents
self.set_trio_genos(var, "212")
self.assertEqual(self.inh.check_homozygous("Hemizygous"), "nothing")
self.assertEqual(self.inh.log_string, "variant not compatible with being causal")
# and check for trio = 212, with affected father
self.set_trio_genos(var, "212")
self.inh.father_affected = True
self.assertEqual(self.inh.check_homozygous("Hemizygous"), "single_variant")
self.assertEqual(self.inh.log_string, "testing")
# and check for trio = 212, with affected mother
self.set_trio_genos(var, "212")
self.inh.mother_affected = True
self.assertEqual(self.inh.check_homozygous("Hemizygous"), "single_variant")
self.assertEqual(self.inh.log_string, "testing")
# and check for trio = 222, with affected mother
self.set_trio_genos(var, "222")
self.assertEqual(self.inh.check_homozygous("Hemizygous"), "single_variant")
self.assertEqual(self.inh.log_string, "testing")
# and check for trio = 222, with affected mother
self.set_trio_genos(var, "222")
self.inh.mother_affected = False
self.assertEqual(self.inh.check_homozygous("Hemizygous"), "nothing")
self.assertEqual(self.inh.log_string, "variant not compatible with being causal")
def test_check_homozygous_with_cnv(self):
""" test that check_homozygous() works correctly for variant lists with CNVs
"""
# generate a test variant
chrom = "X"
pos = '160'
child = create_cnv('F', 'unknown', chrom=chrom, pos=pos)
mom = create_cnv('F', 'unknown', chrom=chrom, pos=pos)
dad = create_cnv('F', 'unknown', chrom=chrom, pos=pos)
cnv = TrioGenotypes(chrom, pos, child, mom, dad)
var = self.variants[0]
# check for trio = 200, which is non-mendelian
self.set_trio_genos(var, "200")
self.assertEqual(self.inh.check_homozygous("Hemizygous"), "nothing")
self.assertEqual(self.inh.log_string, "non-mendelian trio")
# check when a CNV is in the variants list
self.inh.variants.append(cnv)
self.assertEqual(self.inh.check_homozygous("Hemizygous"), "compound_het")
self.assertEqual(self.inh.log_string, "non-mendelian, but CNV might affect call")
class TestAllosomalPy(unittest.TestCase):
""" test the Allosomal class
"""
def setUp(self):
""" define a family and variant, and start the Allosomal class
"""
# generate a test family
child_gender = "F"
mom_aff = "1"
dad_aff = "1"
self.trio = self.create_family(child_gender, mom_aff, dad_aff)
# generate a test variant
child = create_snv(child_gender, "0/1")
mom = create_snv("F", "0/0")
dad = create_snv("M", "0/0")
var = TrioGenotypes(child.get_chrom(), child.get_position(), child,
mom, dad)
self.variants = [var]
# make sure we've got known genes data
self.known_gene = {
"inh": ["Monoallelic"],
"confirmed_status": ["confirmed dd gene"]
}
self.inh = Allosomal(self.variants, self.trio, self.known_gene, "1001")
self.inh.is_lof = var.child.is_lof()
def create_family(self, child_gender, mom_aff, dad_aff):
""" create a default family, with optional gender and parental statuses
"""
fam = Family('test')
fam.add_child('child', 'mother', 'father', child_gender, '2',
'child_vcf')
fam.add_mother('mother', '0', '0', 'female', mom_aff, 'mother_vcf')
fam.add_father('father', '0', '0', 'male', dad_aff, 'father_vcf')
fam.set_child()
return fam
def set_trio_genos(self, var, geno):
""" convenience function to set the trio genotypes for a variant
"""
genos = {"0": "0/0", "1": "0/1", "2": "1/1"}
# convert the geno codes to allele codes
child = genos[geno[0]]
mom = genos[geno[1]]
dad = genos[geno[2]]
# set the genotype field for each individual
var.child.format["GT"] = child
var.mother.format["GT"] = mom
var.father.format["GT"] = dad
# and set th genotype for each individual
var.child.set_genotype()
var.mother.set_genotype()
var.father.set_genotype()
# set the trio genotypes for the inheritance object
self.inh.set_trio_genotypes(var)
def test_check_variant_without_parents_female(self):
""" test that check_variant_without_parents() works correctly for female
"""
var = TrioGenotypes('X', 100, create_snv('F', "1/0"), None, None)
self.inh.set_trio_genotypes(var)
# check for X-linked dominant inheritance
self.assertEqual(
self.inh.check_variant_without_parents("X-linked dominant"),
"single_variant")
self.assertEqual(self.inh.log_string, "allosomal without parents")
var = TrioGenotypes('X', 100, create_snv('F', "1/1"),
create_snv('F', "0/0"), create_snv('M', "0/0"))
self.inh.set_trio_genotypes(var)
self.assertEqual(
self.inh.check_variant_without_parents("X-linked dominant"),
"single_variant")
# and check for hemizygous inheritance
var = TrioGenotypes('X', 100, create_snv('F', "1/0"),
create_snv('F', "0/0"), create_snv('M', "0/0"))
self.inh.set_trio_genotypes(var)
self.assertEqual(self.inh.check_variant_without_parents("Hemizygous"),
"hemizygous")
var = TrioGenotypes('X', 100, create_snv('F', "1/1"),
create_snv('F', "0/0"), create_snv('M', "0/0"))
self.inh.set_trio_genotypes(var)
self.assertEqual(self.inh.check_variant_without_parents("Hemizygous"),
"single_variant")
def test_check_variant_without_parents_male(self):
""" test that check_variant_without_parents() works correctly for males
"""
var = TrioGenotypes('X', 100, create_snv('M', "1/1"), None, None)
trio = self.create_family('male', '1', '1')
self.inh = Allosomal([var], trio, self.known_gene, "TEST")
self.inh.set_trio_genotypes(var)
# check for X-linked dominant inheritance
self.assertEqual(
self.inh.check_variant_without_parents("X-linked dominant"),
"single_variant")
# and check for hemizygous inheritance
self.assertEqual(self.inh.check_variant_without_parents("Hemizygous"),
"single_variant")
def test_check_heterozygous_de_novo(self):
""" test that check_heterozygous() works correctly for de novos
"""
# all of these tests are run for female X chrom de novos, since male
# X chrom hets don't exist
var = TrioGenotypes('X', 100, create_snv('F', "1/0"),
create_snv('F', "0/0"), create_snv('M', "0/0"))
self.inh.set_trio_genotypes(var)
# check for X-linked dominant inheritance
self.assertEqual(self.inh.check_heterozygous("X-linked dominant"),
"single_variant")
self.assertEqual(self.inh.log_string, "female x chrom de novo")
# check for biallelic inheritance
self.assertEqual(self.inh.check_heterozygous("Hemizygous"),
"single_variant")
# check for X-linked over dominance
self.assertEqual(
self.inh.check_heterozygous("X-linked over-dominance"),
'single_variant')
# check we raise errors with unknown inheritance modes
with self.assertRaises(ValueError):
self.inh.check_heterozygous("Digenic")
genos = {'0': '0/0', '1': '1/0', '2': '1/1'}
for (child, mom, dad) in ["102", "110", "112", "122"]:
var = TrioGenotypes('X', 100, create_snv('F', genos[child]),
create_snv('F', genos[mom]),
create_snv('M', genos[dad]))
self.inh.set_trio_genotypes(var)
self.inh.check_heterozygous("X-linked dominant")
self.assertNotEqual(self.inh.log_string, "female x chrom de novo")
def test_check_heterozygous_affected_mother(self):
""" test that check_heterozygous() works correctly for affected mothers
"""
# check that trio with het affected mother is captured
var = TrioGenotypes('X', 100, create_snv('F', "1/0"),
create_snv('F', "1/0"), create_snv('M', "0/0"))
self.inh.set_trio_genotypes(var)
self.inh.mother_affected = True
self.assertEqual(self.inh.check_heterozygous("X-linked dominant"),
"single_variant")
self.assertEqual(
self.inh.log_string,
"x chrom transmitted from aff, other parent non-carrier or aff")
# check that when the other parent is also non-ref, the variant is no
# longer captured, unless the parent is affected
var = TrioGenotypes('X', 100, create_snv('F', "1/0"),
create_snv('F', "1/0"), create_snv('M', "1/1"))
self.inh.set_trio_genotypes(var)
self.assertEqual(self.inh.check_heterozygous("X-linked dominant"),
"nothing")
self.assertEqual(self.inh.log_string,
"variant not compatible with being causal")
self.inh.father_affected = True
self.inh.check_heterozygous("X-linked dominant")
self.assertEqual(
self.inh.log_string,
"x chrom transmitted from aff, other parent non-carrier or aff")
# and check that hemizgygous vars return as "compound_het"
self.assertEqual(self.inh.check_heterozygous("Hemizygous"),
"compound_het")
def test_check_heterozygous_affected_father(self):
""" test that check_heterozygous() works correctly for affected fathers
"""
# set the father as non-ref genotype and unaffected
var = TrioGenotypes('X', 100, create_snv('F', "1/0"),
create_snv('F', "0/0"), create_snv('M', "1/1"))
self.inh.set_trio_genotypes(var)
# check that the het proband, with het unaffected father is passes
self.assertEqual(self.inh.check_heterozygous("X-linked dominant"),
"nothing")
self.assertEqual(self.inh.log_string,
"variant not compatible with being causal")
# check that the het proband, with het affected father is captured
self.inh.father_affected = True
self.assertEqual(self.inh.check_heterozygous("X-linked dominant"),
"single_variant")
self.assertEqual(
self.inh.log_string,
"x chrom transmitted from aff, other parent non-carrier or aff")
# check that when the other parent is also non-ref, the variant is no
# longer captured, unless the parent is affected
var = TrioGenotypes('X', 100, create_snv('F', "1/0"),
create_snv('F', "1/0"), create_snv('M', "1/1"))
self.inh.set_trio_genotypes(var)
self.assertEqual(self.inh.check_heterozygous("X-linked dominant"),
"nothing")
self.assertEqual(self.inh.log_string,
"variant not compatible with being causal")
self.inh.mother_affected = True
self.inh.check_heterozygous("X-linked dominant")
self.assertEqual(
self.inh.log_string,
"x chrom transmitted from aff, other parent non-carrier or aff")
def test_check_homozygous_male(self):
""" test that check_homozygous() works correctly for males
"""
# check for trio with de novo on male X chrom
var = TrioGenotypes('X', 100, create_snv('M', "1/1"),
create_snv('F', "0/0"), create_snv('M', "0/0"))
trio = self.create_family('male', '1', '1')
self.inh = Allosomal([var], trio, self.known_gene, "TEST")
self.inh.set_trio_genotypes(var)
self.assertEqual(self.inh.check_homozygous("X-linked dominant"),
"single_variant")
self.assertEqual(self.inh.log_string, "male X chrom de novo")
# check for trio = 210, with unaffected mother
var = TrioGenotypes('X', 100, create_snv('M', "1/1"),
create_snv('F', "1/0"), create_snv('M', "0/0"))
self.inh.set_trio_genotypes(var)
self.assertEqual(self.inh.check_homozygous("X-linked dominant"),
"single_variant")
self.assertEqual(
self.inh.log_string,
"male X chrom inherited from het mother or hom affected mother")
# check for trio = 210, with affected mother, which should also pass
self.inh.mother_affected = True
self.assertEqual(self.inh.check_homozygous("X-linked dominant"),
"single_variant")
self.assertEqual(
self.inh.log_string,
"male X chrom inherited from het mother or hom affected mother")
# check for trio = 220, with affected mother
var = TrioGenotypes('X', 100, create_snv('M', "1/1"),
create_snv('F', "1/1"), create_snv('M', "0/0"))
self.inh.set_trio_genotypes(var)
self.assertEqual(self.inh.check_homozygous("X-linked dominant"),
"single_variant")
self.assertEqual(
self.inh.log_string,
"male X chrom inherited from het mother or hom affected mother")
# check for trio = 220, with unaffected mother, which should not pass
self.inh.mother_affected = False
self.assertEqual(self.inh.check_homozygous("X-linked dominant"),
"nothing")
self.assertEqual(self.inh.log_string,
"variant not compatible with being causal")
# check that homozygous X-linked over-dominance doesn't pass
self.assertEqual(self.inh.check_homozygous("X-linked over-dominance"),
'nothing')
# check we raise errors with unknown inheritance modes
with self.assertRaises(ValueError):
self.inh.check_homozygous("Digenic")
def test_check_homozygous_female(self):
""" test that check_homozygous() works correctly for females
"""
var = self.variants[0]
# check for trio = 200, which is non-mendelian
self.set_trio_genos(var, "200")
self.assertEqual(self.inh.check_homozygous("Hemizygous"), "nothing")
self.assertEqual(self.inh.log_string, "non-mendelian trio")
# check for trio = 210, which is non-mendelian
self.set_trio_genos(var, "210")
self.assertEqual(self.inh.check_homozygous("Hemizygous"), "nothing")
self.assertEqual(self.inh.log_string, "non-mendelian trio")
# check for trio = 202, which is non-mendelian
self.set_trio_genos(var, "202")
self.assertEqual(self.inh.check_homozygous("Hemizygous"), "nothing")
self.assertEqual(self.inh.log_string, "non-mendelian trio")
# and check for trio = 212, without affected parents
self.set_trio_genos(var, "212")
self.assertEqual(self.inh.check_homozygous("Hemizygous"), "nothing")
self.assertEqual(self.inh.log_string,
"variant not compatible with being causal")
# and check for trio = 212, with affected father
self.set_trio_genos(var, "212")
self.inh.father_affected = True
self.assertEqual(self.inh.check_homozygous("Hemizygous"),
"single_variant")
self.assertEqual(self.inh.log_string, "testing")
# and check for trio = 212, with affected mother
self.set_trio_genos(var, "212")
self.inh.mother_affected = True
self.assertEqual(self.inh.check_homozygous("Hemizygous"),
"single_variant")
self.assertEqual(self.inh.log_string, "testing")
# and check for trio = 222, with affected mother
self.set_trio_genos(var, "222")
self.assertEqual(self.inh.check_homozygous("Hemizygous"),
"single_variant")
self.assertEqual(self.inh.log_string, "testing")
# and check for trio = 222, with affected mother
self.set_trio_genos(var, "222")
self.inh.mother_affected = False
self.assertEqual(self.inh.check_homozygous("Hemizygous"), "nothing")
self.assertEqual(self.inh.log_string,
"variant not compatible with being causal")
def test_check_homozygous_with_cnv(self):
""" test that check_homozygous() works correctly for variant lists with CNVs
"""
# generate a test variant
chrom = "X"
pos = '160'
child = create_cnv('F', 'unknown', chrom=chrom, pos=pos)
mom = create_cnv('F', 'unknown', chrom=chrom, pos=pos)
dad = create_cnv('F', 'unknown', chrom=chrom, pos=pos)
cnv = TrioGenotypes(chrom, pos, child, mom, dad)
var = self.variants[0]
# check for trio = 200, which is non-mendelian
self.set_trio_genos(var, "200")
self.assertEqual(self.inh.check_homozygous("Hemizygous"), "nothing")
self.assertEqual(self.inh.log_string, "non-mendelian trio")
# check when a CNV is in the variants list
self.inh.variants.append(cnv)
self.assertEqual(self.inh.check_homozygous("Hemizygous"),
"compound_het")
self.assertEqual(self.inh.log_string,
"non-mendelian, but CNV might affect call")
class TestAllosomalPy(unittest.TestCase):
""" test the Allosomal class
"""
def setUp(self):
""" define a family and variant, and start the Allosomal class
"""
# generate a test family
child_gender = "F"
mom_aff = "1"
dad_aff = "1"
self.trio = self.create_family(child_gender, mom_aff, dad_aff)
# generate a test variant
child_var = self.create_snv(child_gender, "0/1")
mom_var = self.create_snv("F", "0/0")
dad_var = self.create_snv("M", "0/0")
var = TrioGenotypes(child_var)
var.add_mother_variant(mom_var)
var.add_father_variant(dad_var)
self.variants = [var]
# make sure we've got known genes data
self.known_genes = {"TEST": {"inh": ["Monoallelic"], "confirmed_status": ["Confirmed DD Gene"]}}
self.inh = Allosomal(self.variants, self.trio, self.known_genes, "TEST")
self.inh.is_lof = var.child.is_lof()
def create_snv(self, gender, genotype):
""" create a default variant
"""
chrom = "X"
pos = "15000000"
snp_id = "."
ref = "A"
alt = "G"
filt = "PASS"
# set up a SNV object, since SNV inherits VcfInfo
var = SNV(chrom, pos, snp_id, ref, alt, filt)
info = "HGNC=TEST;CQ=missense_variant;random_tag"
format_keys = "GT:DP"
sample_values = genotype + ":50"
var.add_info(info)
var.add_format(format_keys, sample_values)
var.set_gender(gender)
var.set_genotype()
return var
def create_cnv(self, gender, inh, chrom, pos):
""" create a default variant
"""
snp_id = "."
ref = "A"
alt = "<DUP>"
filt = "PASS"
# set up a SNV object, since SNV inherits VcfInfo
var = CNV(chrom, pos, snp_id, ref, alt, filt)
info = "HGNC=TEST;HGNC_ALL=TEST;END=16000000;SVLEN=5000"
format_keys = "INHERITANCE:DP"
sample_values = inh + ":50"
var.add_info(info)
var.add_format(format_keys, sample_values)
var.set_gender(gender)
var.set_genotype()
return var
def create_family(self, child_gender, mom_aff, dad_aff):
""" create a default family, with optional gender and parental statuses
"""
fam = Family("test")
fam.add_child("child", "child_vcf", "2", child_gender)
fam.add_mother("mother", "mother_vcf", mom_aff, "2")
fam.add_father("father", "father_vcf", dad_aff, "1")
fam.set_child()
return fam
def set_trio_genos(self, var, geno):
""" convenience function to set the trio genotypes for a variant
"""
genos = {"0": "0/0", "1": "0/1", "2": "1/1"}
# convert the geno codes to allele codes
child = genos[geno[0]]
mom = genos[geno[1]]
dad = genos[geno[2]]
# set the genotype field for each individual
var.child.format["GT"] = child
var.mother.format["GT"] = mom
var.father.format["GT"] = dad
# and set th genotype for each individual
var.child.set_genotype()
var.mother.set_genotype()
var.father.set_genotype()
# set the trio genotypes for the inheritance object
self.inh.set_trio_genotypes(var)
def test_check_variant_without_parents_female(self):
""" test that check_variant_without_parents() works correctly for female
"""
var = self.variants[0]
var.child.set_gender("F")
self.set_trio_genos(var, "100")
# remove the parents, so it appears the var lacks parental information
self.inh.trio.mother = None
self.inh.trio.father = None
# check for X-linked dominant inheritance
self.assertEqual(self.inh.check_variant_without_parents("X-linked dominant"), "single_variant")
self.assertEqual(self.inh.log_string, "allosomal without parents")
self.set_trio_genos(var, "200")
self.assertEqual(self.inh.check_variant_without_parents("X-linked dominant"), "single_variant")
# and check for hemizygous inheritance
self.set_trio_genos(var, "100")
self.assertEqual(self.inh.check_variant_without_parents("Hemizygous"), "hemizygous")
self.set_trio_genos(var, "200")
self.assertEqual(self.inh.check_variant_without_parents("Hemizygous"), "single_variant")
def test_check_variant_without_parents_male(self):
""" test that check_variant_without_parents() works correctly for males
"""
var = self.variants[0]
var.child.set_gender("M")
self.set_trio_genos(var, "200")
# remove the parents, so it appears the var lacks parental information
self.inh.trio.mother = None
self.inh.trio.father = None
# check for X-linked dominant inheritance
self.assertEqual(self.inh.check_variant_without_parents("X-linked dominant"), "single_variant")
# and check for hemizygous inheritance
self.assertEqual(self.inh.check_variant_without_parents("Hemizygous"), "single_variant")
def test_check_heterozygous_de_novo(self):
""" test that check_heterozygous() works correctly for de novos
"""
# all of these tests are run for female X chrom de novos, since male
# X chrom hets don't exist
var = self.variants[0]
self.set_trio_genos(var, "100")
# check for X-linked dominant inheritance
self.assertEqual(self.inh.check_heterozygous("X-linked dominant"), "single_variant")
self.assertEqual(self.inh.log_string, "female x chrom de novo")
# check for biallelic inheritance
self.assertEqual(self.inh.check_heterozygous("Hemizygous"), "single_variant")
with self.assertRaises(ValueError):
self.inh.check_heterozygous("X-linked over-dominance")
for geno in ["102", "110", "112", "122"]:
self.set_trio_genos(var, geno)
self.inh.check_heterozygous("X-linked dominant")
self.assertNotEqual(self.inh.log_string, "female x chrom de novo")
def test_check_heterozygous_affected_mother(self):
""" test that check_heterozygous() works correctly for affected mothers
"""
var = self.variants[0]
# check that trio = 110, with het affected mother is captured
self.set_trio_genos(var, "110")
self.inh.mother_affected = True
self.assertEqual(self.inh.check_heterozygous("X-linked dominant"), "single_variant")
self.assertEqual(self.inh.log_string, "x chrom transmitted from aff, other parent non-carrier or aff")
# check that when the other parent is also non-ref, the variant is no
# longer captured, unless the parent is affected
self.set_trio_genos(var, "112")
self.assertEqual(self.inh.check_heterozygous("X-linked dominant"), "nothing")
self.assertEqual(self.inh.log_string, "variant not compatible with being causal")
self.inh.father_affected = True
self.inh.check_heterozygous("X-linked dominant")
self.assertEqual(self.inh.log_string, "x chrom transmitted from aff, other parent non-carrier or aff")
# and check that hemizgygous vars return as "compound_het"
self.assertEqual(self.inh.check_heterozygous("Hemizygous"), "compound_het")
def test_check_heterozygous_affected_father(self):
""" test that check_heterozygous() works correctly for affected fathers
"""
var = self.variants[0]
# set the father as non-ref genotype and affected
self.set_trio_genos(var, "102")
# check that the het proband, with het unaffected father is passes
self.assertEqual(self.inh.check_heterozygous("X-linked dominant"), "nothing")
self.assertEqual(self.inh.log_string, "variant not compatible with being causal")
# check that the het proband, with het affected father is captured
self.inh.father_affected = True
self.assertEqual(self.inh.check_heterozygous("X-linked dominant"), "single_variant")
self.assertEqual(self.inh.log_string, "x chrom transmitted from aff, other parent non-carrier or aff")
# check that when the other parent is also non-ref, the variant is no
# longer captured, unless the parent is affected
self.set_trio_genos(var, "112")
self.assertEqual(self.inh.check_heterozygous("X-linked dominant"), "nothing")
self.assertEqual(self.inh.log_string, "variant not compatible with being causal")
self.inh.mother_affected = True
self.inh.check_heterozygous("X-linked dominant")
self.assertEqual(self.inh.log_string, "x chrom transmitted from aff, other parent non-carrier or aff")
def test_check_homozygous_male(self):
""" test that check_homozygous() works correctly for males
"""
var = self.variants[0]
self.trio.child.gender = "M"
# check for trio = 200, which is de novo on male X chrom
self.set_trio_genos(var, "200")
self.assertEqual(self.inh.check_homozygous("X-linked dominant"), "single_variant")
self.assertEqual(self.inh.log_string, "male X chrom de novo")
# check for trio = 210, with unaffected mother
self.set_trio_genos(var, "210")
self.assertEqual(self.inh.check_homozygous("X-linked dominant"), "single_variant")
self.assertEqual(self.inh.log_string, "male X chrom inherited from het mother or hom affected mother")
# check for trio = 210, with affected mother, which should not pass
self.inh.mother_affected = True
self.assertEqual(self.inh.check_homozygous("X-linked dominant"), "nothing")
self.assertEqual(self.inh.log_string, "variant not compatible with being causal")
# check for trio = 220, with affected mother
self.set_trio_genos(var, "220")
self.assertEqual(self.inh.check_homozygous("X-linked dominant"), "single_variant")
self.assertEqual(self.inh.log_string, "male X chrom inherited from het mother or hom affected mother")
# check for trio = 220, with unaffected mother, which should not pass
self.set_trio_genos(var, "220")
self.inh.mother_affected = False
self.assertEqual(self.inh.check_homozygous("X-linked dominant"), "nothing")
self.assertEqual(self.inh.log_string, "variant not compatible with being causal")
# check that non-standard inheritance modes raise errors
with self.assertRaises(ValueError):
self.inh.check_homozygous("X-linked over-dominance")
def test_check_homozygous_female(self):
""" test that check_homozygous() works correctly for females
"""
var = self.variants[0]
# check for trio = 200, which is non-mendelian
self.set_trio_genos(var, "200")
self.assertEqual(self.inh.check_homozygous("Hemizygous"), "nothing")
self.assertEqual(self.inh.log_string, "non-mendelian trio")
# check for trio = 210, which is non-mendelian
self.set_trio_genos(var, "210")
self.assertEqual(self.inh.check_homozygous("Hemizygous"), "nothing")
self.assertEqual(self.inh.log_string, "non-mendelian trio")
# check for trio = 202, which is non-mendelian
self.set_trio_genos(var, "202")
self.assertEqual(self.inh.check_homozygous("Hemizygous"), "nothing")
self.assertEqual(self.inh.log_string, "non-mendelian trio")
# and check for trio = 212, without affected parents
self.set_trio_genos(var, "212")
self.assertEqual(self.inh.check_homozygous("Hemizygous"), "nothing")
self.assertEqual(self.inh.log_string, "variant not compatible with being causal")
# and check for trio = 212, with affected father
self.set_trio_genos(var, "212")
self.inh.father_affected = True
self.assertEqual(self.inh.check_homozygous("Hemizygous"), "single_variant")
self.assertEqual(self.inh.log_string, "testing")
# and check for trio = 212, with affected mother
self.set_trio_genos(var, "212")
self.inh.mother_affected = True
self.assertEqual(self.inh.check_homozygous("Hemizygous"), "single_variant")
self.assertEqual(self.inh.log_string, "testing")
# and check for trio = 222, with affected mother
self.set_trio_genos(var, "222")
self.assertEqual(self.inh.check_homozygous("Hemizygous"), "single_variant")
self.assertEqual(self.inh.log_string, "testing")
# and check for trio = 222, with affected mother
self.set_trio_genos(var, "222")
self.inh.mother_affected = False
self.assertEqual(self.inh.check_homozygous("Hemizygous"), "nothing")
self.assertEqual(self.inh.log_string, "variant not compatible with being causal")
def test_check_homozygous_with_cnv(self):
""" test that check_homozygous() works correctly for variant lists with CNVs
"""
# generate a test variant
chrom = "X"
position = "60000"
child_var = self.create_cnv("F", "unknown", chrom, position)
mom_var = self.create_cnv("F", "unknown", chrom, position)
dad_var = self.create_cnv("M", "unknown", chrom, position)
cnv_var = TrioGenotypes(child_var)
cnv_var.add_mother_variant(mom_var)
cnv_var.add_father_variant(dad_var)
var = self.variants[0]
# check for trio = 200, which is non-mendelian
self.set_trio_genos(var, "200")
self.assertEqual(self.inh.check_homozygous("Hemizygous"), "nothing")
self.assertEqual(self.inh.log_string, "non-mendelian trio")
# check when a CNV is in the variants list
self.inh.variants.append(cnv_var)
self.assertEqual(self.inh.check_homozygous("Hemizygous"), "compound_het")
self.assertEqual(self.inh.log_string, "non-mendelian, but CNV might affect call")
def test_check_compound_hets_autosomal(self):
""" test that check_compound_hets() works correctly for autosomal vars
"""
# set some variants, so we can alter them later
var1 = self.create_variant("F", chrom="1", position="15000000")
var2 = self.create_variant("F", chrom="1", position="16000000")
var3 = self.create_variant("F", chrom="1", position="17000000")
# set the inheritance type, the compound het type ("compound_het"
# for autosomal variants, and start autosomal inheritance)
inh = "Biallelic"
compound = "compound_het"
self.inh = Autosomal([var1, var2, var3], self.trio, inh)
variants = ["", ""]
# check the expected "110, 101" combo passes
variants[0] = self.set_compound_het_var(var1, "110", compound)
variants[1] = self.set_compound_het_var(var2, "101", compound)
if IS_PYTHON3:
self.assertCountEqual(self.inh.check_compound_hets(variants),
variants)
elif IS_PYTHON2:
self.assertEqual(sorted(self.inh.check_compound_hets(variants)),
sorted(variants))
# check that "110, 110" combo fails
variants[0] = self.set_compound_het_var(var1, "110", compound)
variants[1] = self.set_compound_het_var(var2, "110", compound)
self.assertEqual(self.inh.check_compound_hets(variants), [])
# check that "101, 101" combo fails
variants[0] = self.set_compound_het_var(var1, "101", compound)
variants[1] = self.set_compound_het_var(var2, "101", compound)
self.assertEqual(self.inh.check_compound_hets(variants), [])
# check that > 2 valid compound hets passes all variants
variants = ["", "", ""]
variants[0] = self.set_compound_het_var(var1, "110", compound)
variants[1] = self.set_compound_het_var(var2, "101", compound)
variants[2] = self.set_compound_het_var(var3, "110", compound)
if IS_PYTHON3:
self.assertCountEqual(self.inh.check_compound_hets(variants),
variants)
elif IS_PYTHON2:
self.assertEqual(sorted(self.inh.check_compound_hets(variants)),
sorted(variants))
# check that a single var fails to give compound hets
single_var = variants[:1]
self.assertEqual(self.inh.check_compound_hets(single_var), [])
# check that zero length list gives no compound hets
no_vars = []
self.assertEqual(self.inh.check_compound_hets(no_vars), [])
# check that de novo containing "110, 100" combos give compound hets
variants = ["", ""]
variants[0] = self.set_compound_het_var(var1, "110", compound)
variants[1] = self.set_compound_het_var(var2, "100", compound)
if IS_PYTHON3:
self.assertCountEqual(self.inh.check_compound_hets(variants),
variants)
elif IS_PYTHON2:
self.assertEqual(sorted(self.inh.check_compound_hets(variants)),
sorted(variants))
# check that de novo "100, 100" combos give compound hets
variants[0] = self.set_compound_het_var(var1, "100", compound)
variants[1] = self.set_compound_het_var(var2, "100", compound)
if IS_PYTHON3:
self.assertCountEqual(self.inh.check_compound_hets(variants),
variants)
elif IS_PYTHON2:
self.assertEqual(sorted(self.inh.check_compound_hets(variants)),
sorted(variants))
# check that "111, 111" combos require affected parents
variants[0] = self.set_compound_het_var(var1, "111", compound)
variants[1] = self.set_compound_het_var(var2, "111", compound)
self.assertEqual(self.inh.check_compound_hets(variants), [])
# check "111, 111" combo with a single affected parent
self.inh.mother_affected = True
self.assertEqual(self.inh.check_compound_hets(variants), [])
# check "111, 111" combo with both parents affected
self.inh.father_affected = True
if IS_PYTHON3:
self.assertCountEqual(self.inh.check_compound_hets(variants),
variants)
elif IS_PYTHON2:
self.assertEqual(sorted(self.inh.check_compound_hets(variants)),
sorted(variants))
# check that without parents, all variants are included, even if they
# wouldn't pass normally
self.inh.trio.mother = None
self.inh.trio.father = None
variants[0] = self.set_compound_het_var(var1, "101", compound)
variants[1] = self.set_compound_het_var(var2, "101", compound)
if IS_PYTHON3:
self.assertCountEqual(self.inh.check_compound_hets(variants),
variants)
elif IS_PYTHON2:
self.assertEqual(sorted(self.inh.check_compound_hets(variants)),
sorted(variants))
class TestInheritancePy(unittest.TestCase):
""" test the Inheritance class
"""
def setUp(self):
""" define a family and variant, and start the Inheritance class
"""
# generate a test family
child_gender = "F"
mom_aff = "1"
dad_aff = "1"
self.trio = self.create_family(child_gender, mom_aff, dad_aff)
# generate list of variants
self.variants = [self.create_variant(child_gender)]
self.variants.append(self.create_variant(child_gender))
# make sure we've got known genes data
self.known_genes = {
"TEST": {
"inheritance": ["Monoallelic"],
"confirmed_status": ["Confirmed DD Gene"]
}
}
gene_inh = self.known_genes[self.variants[0].get_gene()]["inheritance"]
self.inh = Autosomal(self.variants, self.trio, gene_inh)
def create_snv(self, gender, genotype, chrom, pos):
""" create a default variant
"""
snp_id = "."
ref = "A"
alt = "G"
filt = "PASS"
# set up a SNV object, since SNV inherits VcfInfo
var = SNV(chrom, pos, snp_id, ref, alt, filt)
info = "HGNC=TEST;CQ=missense_variant;random_tag"
format_keys = "GT:DP"
sample_values = genotype + ":50"
var.add_info(info)
var.add_format(format_keys, sample_values)
var.set_gender(gender)
var.set_genotype()
return var
def create_cnv(self, gender, inh, chrom, pos):
""" create a default variant
"""
snp_id = "."
ref = "A"
alt = "<DUP>"
filt = "PASS"
# set up a SNV object, since SNV inherits VcfInfo
var = CNV(chrom, pos, snp_id, ref, alt, filt)
info = "HGNC=TEST;HGNC_ALL=TEST;END=16000000;SVLEN=5000"
format_keys = "INHERITANCE:DP"
sample_values = inh + ":50"
var.add_info(info)
var.add_format(format_keys, sample_values)
var.set_gender(gender)
var.set_genotype()
return var
def create_variant(self, child_gender, chrom="1", position="15000000"):
""" creates a TrioGenotypes variant
"""
# generate a test variant
child_var = self.create_snv(child_gender, "0/1", chrom, position)
mom_var = self.create_snv("F", "0/0", chrom, position)
dad_var = self.create_snv("M", "0/0", chrom, position)
var = TrioGenotypes(child_var)
var.add_mother_variant(mom_var)
var.add_father_variant(dad_var)
return var
def create_family(self, child_gender, mom_aff, dad_aff):
""" create a default family, with optional gender and parental statuses
"""
fam = Family("test")
fam.add_child("child", "child_vcf", "2", child_gender)
fam.add_mother("mother", "mother_vcf", mom_aff, "2")
fam.add_father("father", "father_vcf", dad_aff, "1")
fam.set_child()
return fam
def test_check_inheritance_mode_matches_gene_mode(self):
""" test that check_inheritance_mode_matches_gene_mode() works correctly
"""
# check that the default inheritance types have been set up correctly
self.assertEqual(self.inh.inheritance_modes,
{"Monoallelic", "Biallelic", "Both"})
# make sure that the default var and gene inheritance work
self.assertTrue(self.inh.check_inheritance_mode_matches_gene_mode())
# check that no gene inheritance overlap fails
self.inh.gene_inheritance = {"Mosaic"}
self.inh.inheritance_modes = {"Monoallelic", "Biallelic", "Both"}
self.assertFalse(self.inh.check_inheritance_mode_matches_gene_mode())
# check that a single inheritance type still works
self.inh.gene_inheritance = {"Monoallelic"}
self.assertTrue(self.inh.check_inheritance_mode_matches_gene_mode())
# check that multiple inheritance types for a gene still work
self.inh.gene_inheritance = {"Monoallelic", "Biallelic"}
self.assertTrue(self.inh.check_inheritance_mode_matches_gene_mode())
# check that extra inheritance modes are included still work
self.inh.gene_inheritance = {"Monoallelic", "Biallelic", "Mosaic"}
self.assertTrue(self.inh.check_inheritance_mode_matches_gene_mode())
def test_set_trio_genotypes(self):
""" test that set_trio_genotypes() works correctly
"""
# set the genotypes using the default variant
var = self.variants[0]
self.inh.set_trio_genotypes(var)
# the genotypes for the inh object should match the vars genotypes
self.assertEqual(self.inh.child, var.child)
self.assertEqual(self.inh.mom, var.mother)
self.assertEqual(self.inh.dad, var.father)
# now remove the parents before re-setting the genotypes
del var.mother
del var.father
self.inh.trio.father = None
self.inh.trio.mother = None
self.inh.set_trio_genotypes(var)
# the child should match the vars genotypes, but the parent's
# genotypes should be None
self.assertEqual(self.inh.child, var.child)
self.assertIsNone(self.inh.mom)
self.assertIsNone(self.inh.dad)
def test_add_variant_to_appropriate_list(self):
""" test that add_variant_to_appropriate_list() works correctly
"""
var = self.variants[0]
inheritance = "Monoallelic"
check = "compound_het"
# check that compound_het vars are only added to the compound_het list
self.inh.compound_hets = []
self.inh.candidates = []
self.inh.add_variant_to_appropriate_list(var, check, inheritance)
self.assertEqual(self.inh.candidates, [])
self.assertEqual(self.inh.compound_hets, [(var, check, inheritance)])
# check that single_variant vars are only added to the candidates list
self.inh.compound_hets = []
self.inh.candidates = []
check = "single_variant"
self.inh.add_variant_to_appropriate_list(var, check, inheritance)
self.assertEqual(self.inh.candidates, [(var, check, inheritance)])
self.assertEqual(self.inh.compound_hets, [])
# check that other vars aren't added either list
self.inh.compound_hets = []
self.inh.candidates = []
check = "nothing"
self.inh.add_variant_to_appropriate_list(var, check, inheritance)
self.assertEqual(self.inh.candidates, [])
self.assertEqual(self.inh.compound_hets, [])
def test_check_if_any_variant_is_cnv(self):
""" test if check_if_any_variant_is_cnv() works correctly
"""
# generate a test variant
chrom = "1"
position = "60000"
child_var = self.create_cnv("F", "unknown", chrom, position)
mom_var = self.create_cnv("F", "unknown", chrom, position)
dad_var = self.create_cnv("M", "unknown", chrom, position)
cnv_var = TrioGenotypes(child_var)
cnv_var.add_mother_variant(mom_var)
cnv_var.add_father_variant(dad_var)
# check that all variants=SNV returns False
self.assertFalse(self.inh.check_if_any_variant_is_cnv())
# add a CNV to the variants, then check that we find a CNV
self.inh.variants.append(cnv_var)
self.assertTrue(self.inh.check_if_any_variant_is_cnv())
def set_compound_het_var(self, var, geno, compound_type):
""" convenience function to set the trio genotypes for a variant
"""
genos = {"0": "0/0", "1": "0/1", "2": "1/1"}
# convert the geno codes to allele codes
child = genos[geno[0]]
mom = genos[geno[1]]
dad = genos[geno[2]]
# set the genotype field for each individual
var.child.format["GT"] = child
var.mother.format["GT"] = mom
var.father.format["GT"] = dad
# and set th genotype for each individual
var.child.set_genotype()
var.mother.set_genotype()
var.father.set_genotype()
# set the trio genotypes for the inheritance object
return (var, compound_type, "Biallelic")
def test_check_compound_hets_autosomal(self):
""" test that check_compound_hets() works correctly for autosomal vars
"""
# set some variants, so we can alter them later
var1 = self.create_variant("F", chrom="1", position="15000000")
var2 = self.create_variant("F", chrom="1", position="16000000")
var3 = self.create_variant("F", chrom="1", position="17000000")
# set the inheritance type, the compound het type ("compound_het"
# for autosomal variants, and start autosomal inheritance)
inh = "Biallelic"
compound = "compound_het"
self.inh = Autosomal([var1, var2, var3], self.trio, inh)
variants = ["", ""]
# check the expected "110, 101" combo passes
variants[0] = self.set_compound_het_var(var1, "110", compound)
variants[1] = self.set_compound_het_var(var2, "101", compound)
if IS_PYTHON3:
self.assertCountEqual(self.inh.check_compound_hets(variants),
variants)
elif IS_PYTHON2:
self.assertEqual(sorted(self.inh.check_compound_hets(variants)),
sorted(variants))
# check that "110, 110" combo fails
variants[0] = self.set_compound_het_var(var1, "110", compound)
variants[1] = self.set_compound_het_var(var2, "110", compound)
self.assertEqual(self.inh.check_compound_hets(variants), [])
# check that "101, 101" combo fails
variants[0] = self.set_compound_het_var(var1, "101", compound)
variants[1] = self.set_compound_het_var(var2, "101", compound)
self.assertEqual(self.inh.check_compound_hets(variants), [])
# check that > 2 valid compound hets passes all variants
variants = ["", "", ""]
variants[0] = self.set_compound_het_var(var1, "110", compound)
variants[1] = self.set_compound_het_var(var2, "101", compound)
variants[2] = self.set_compound_het_var(var3, "110", compound)
if IS_PYTHON3:
self.assertCountEqual(self.inh.check_compound_hets(variants),
variants)
elif IS_PYTHON2:
self.assertEqual(sorted(self.inh.check_compound_hets(variants)),
sorted(variants))
# check that a single var fails to give compound hets
single_var = variants[:1]
self.assertEqual(self.inh.check_compound_hets(single_var), [])
# check that zero length list gives no compound hets
no_vars = []
self.assertEqual(self.inh.check_compound_hets(no_vars), [])
# check that de novo containing "110, 100" combos give compound hets
variants = ["", ""]
variants[0] = self.set_compound_het_var(var1, "110", compound)
variants[1] = self.set_compound_het_var(var2, "100", compound)
if IS_PYTHON3:
self.assertCountEqual(self.inh.check_compound_hets(variants),
variants)
elif IS_PYTHON2:
self.assertEqual(sorted(self.inh.check_compound_hets(variants)),
sorted(variants))
# check that de novo "100, 100" combos give compound hets
variants[0] = self.set_compound_het_var(var1, "100", compound)
variants[1] = self.set_compound_het_var(var2, "100", compound)
if IS_PYTHON3:
self.assertCountEqual(self.inh.check_compound_hets(variants),
variants)
elif IS_PYTHON2:
self.assertEqual(sorted(self.inh.check_compound_hets(variants)),
sorted(variants))
# check that "111, 111" combos require affected parents
variants[0] = self.set_compound_het_var(var1, "111", compound)
variants[1] = self.set_compound_het_var(var2, "111", compound)
self.assertEqual(self.inh.check_compound_hets(variants), [])
# check "111, 111" combo with a single affected parent
self.inh.mother_affected = True
self.assertEqual(self.inh.check_compound_hets(variants), [])
# check "111, 111" combo with both parents affected
self.inh.father_affected = True
if IS_PYTHON3:
self.assertCountEqual(self.inh.check_compound_hets(variants),
variants)
elif IS_PYTHON2:
self.assertEqual(sorted(self.inh.check_compound_hets(variants)),
sorted(variants))
# check that without parents, all variants are included, even if they
# wouldn't pass normally
self.inh.trio.mother = None
self.inh.trio.father = None
variants[0] = self.set_compound_het_var(var1, "101", compound)
variants[1] = self.set_compound_het_var(var2, "101", compound)
if IS_PYTHON3:
self.assertCountEqual(self.inh.check_compound_hets(variants),
variants)
elif IS_PYTHON2:
self.assertEqual(sorted(self.inh.check_compound_hets(variants)),
sorted(variants))
def test_check_compound_hets_allosomal(self):
""" test that check_compound_hets() works correctly for allosomal vars
"""
# set some X chrom variants, so we can alter them later
var1 = self.create_variant("F", chrom="X", position="15000000")
var2 = self.create_variant("F", chrom="X", position="16000000")
# set the inheritance type, the compound het type ("hemizygous"
# for allosomal variants, and start allosomal inheritance)
inh = "Hemizygous"
compound = "hemizygous"
self.inh = Allosomal([var1, var2], self.trio, inh)
variants = ["", ""]
# check that de novo containing "110, 100" combos pass
variants[0] = self.set_compound_het_var(var1, "110", compound)
variants[1] = self.set_compound_het_var(var2, "100", compound)
if IS_PYTHON3:
self.assertCountEqual(self.inh.check_compound_hets(variants),
variants)
elif IS_PYTHON2:
self.assertEqual(sorted(self.inh.check_compound_hets(variants)),
sorted(variants))
# check that "110, 102" combo fails if the father is unaffected
variants[0] = self.set_compound_het_var(var1, "110", compound)
variants[1] = self.set_compound_het_var(var2, "102", compound)
self.assertEqual(self.inh.check_compound_hets(variants), [])
# check that "110, 102" combo passes if the father is affected
self.inh.father_affected = True
if IS_PYTHON3:
self.assertCountEqual(self.inh.check_compound_hets(variants),
variants)
elif IS_PYTHON2:
self.assertEqual(sorted(self.inh.check_compound_hets(variants)),
sorted(variants))
# make sure we can't set the father as het on the X chrom
with self.assertRaises(ValueError):
self.set_compound_het_var(var2, "101", compound)
