Non-Mendelian Inheritance and Multifactorial Inheritance Flashcards
what are the deviations from mendelian inheritance patterns?
- mitochondrial inheritance
- X inactivation
- multifactorial traits
what factors influence phenotypic expression of single gene disorders?
- mosaicism
- incomplete penetrance
- variable expression
- allelic and locus heterogeneity
- pleiotropy
- epigenetics and genomic imprinting/chromatin remodeling
- uniparental disomy
- anticipation and repeat exansion
what is mosaicism?
presence of 2 or more cell lines in an organism
what can lead to mosaicism?
nondisjunction during mitosis or X inactivation
2 types of mosaicism
- chromosomal mosaicism – xinactivation
2. gene variant mosaicism – mutations during embryogenesis
expressitivity of mosaicism
depending on what percentage of and what types of cells harbor the pathogenic variant, a mosaic individual may only exhibit some of the features associated with the condition
what causes trisomy 21 mosaicism? (47, +21/46)
nondisjunction of chromosome 21 occurs during MITOSIS in one of the early cell divisions
phenotype of trisomy 21 mosaicism?
- less extreme phenotype
2. 3% of Downs Syndrome
2 populations in trisomy 21 mosaicism?
- normal cell line with 46 chromosomes
2. a second cell line with 47 chromosomes (trisomy 21)
significance of early occurrence of trisomy 21 mosaicism
if the mutations occur later in development, there are fewer cells affected and less severe.
if mutations occur early in development, there are 50/50 normal/trisomy cells since the inactivated/mutated alleles are passed down more
what would karyotype be for trisomy 21 due to nondisjunction during meiosis
47,XY+21
what would be karyotype for trisomy 21 due to Robertsonian Translocation?
46,XY,-14,+(14q;21q)
what would karyotype be for trisomy 21 due to mosaicism?
key difference is 47 versus 46 chromosomes in the individual with Down Syndrome
what is penetrance?
percentage of individuals with the disease genotype who display the disease phenotype
complete penetrance
every individual with a mutation will have phenotype/symptoms of disorder
incomplete or reduced penetrance
some individuals with disease causing mutation do not show signs of the disorder
what factors affect penetrance?
- modifier genes
- heteroplasmy
- sex
- age
- environment
penetrance of mitochondrial diseases?
penetrance of mitochondrial diseases that are caused by pathogenic variants in the mtDNA is mainly dependent on percentage of heteroplasmy in individuals
examples of incomplete penetrance
- hereditary breast and ovarian cancer syndrome (BRCA1 or BRCA2) - increased risk, but not every person develops cancer
- hemochromatosis - men early age 30yo, women menopause
- xeroderma pigmentosum
- FRAGILE X SYNDROME
explain penetrance in fragile x syndrome
penetrance varies between number of repeats and between males and females (symptoms milder in females)
what causes Fragile X syndrome
EXPANSION of CGG sequence in the 5’ untranslated region (UTR) in FMR1 gene, leading to silence of gene through DNA methylation
what does FMR1 gene do?
regulating translation of certain proteins in neurons
symptoms of Fragile X syndrome
- macrosomia and macrocephaly at birth
- prominent forehead and jaw, large ears, long thin face, flat feet
- intellectual disability ranging from mild to severe
- ADHD and hyperactivity
- shy, anxiety, unstable mood, little social interaction
- AFTER PUBERTY abnormally large testicles
what is expressivity?
phenotypic variation between individuals with the same genotype
what factors affect expression of a genetic disease?
- age
- diet
- exercise
- exposure to harmful chemicals
- smoking
- UV light
examples of variable expressivity
- individuals in the same family with the same pathogenic mtDNA variant display different phenotypic features of the condition
- neurofibromatosis 1 – cafe-au-lait spots and axillary freckling vs subcutaneous neurofibromas, cafeaulait spots and optic glioma
- hereditary hemochromatosis (HFE)
examples of variable expression and incomplete penetrance?
- hereditary hemochromatosis
2. neurofibromatosis type 1
what is allelic heterogeneity
different mutations in the SAME gene/allele leading to the SAME phenotype
examples of allelic heterogeneity
- Marfan syndrome – nearly 2000 different disease causing mutations in FBN1 gene
- PKU – more than 100 gene mutations
- CF – mutations in CFTR gene causing complete absence or partial activation
what is locus heterogeneity?
specific/same phenotype caused by alterations in more than one gene/locus
aka one disorder can be caused by mutations in genes at different chromosomal loci
example of locus heterogeneity?
osteogenesis imperfecta
describe mutations for osteogenesis imperfecta
- pathogenic varients in EITHER COL1A1 or COL1A2 genes result in poor quality collagen or insufficient quantities of collagen
- subunits of procollagen triple helix encoded by 2 genes located on chromosomes 17 and 7
- mutation in CRTAP or P3H1 also (besides collagen)
what is pleiotropy
a single gene causing more than one phenotypic trait that may seem unrelated
example of pleiotropy
Marfan syndrome
what is example of pleiotropy and allelic heterogeneity
Marfan syndrome
what is epigenetics?
heritable alterations/factors that are NOT due to changes in the DNA sequence, and therefore DO NOT disrupt the genetic code
what do epigenetic factors/mechanisms alter?
gene expression – therefore, these alterations can cause persons with the same DNA sequences to have different disease profiles
what are epigenetic alterations regulated by?
- ENVIRONMENTAL FACTORS which can be transferred through generations
- behavioral circumstances
how do epigenetic mechanisms alter gene expression?
by altering DNA accessibility and chromatin structure
examples of epigenetic mechanisms
- DNA methylation
- post-translational modification of histone
- ATP dependent chromatin remodeling (remodeling nucleosomes)
- microRNAs effecting the translation of mRNAs
what happens in DNA methylation?
addition of methyl group to cytosine residues of CpG dinucelotides TURNS OFF gene expression
what is post-translational modification of histones?
acetylation of arginine and lysine residues (+ charged) takes away + charge and loosens histones (euchromatin)
deacetylation of arginine and lysine residues reestabilishes + charge, tightening histones (heterochromatin)
examples of epigenetic regulations
- X inactivation
- alteration of expression of cancer associated genes (oncogenes)
- monoallelic expression of a gene that is dependent on that gene’s parent of origin (genetic imprinting)
what epigenetic regulations are used for X inactivation?
- DNA methylation
2. histone modification
what epigenetic regulations are applied to oncogenes?
oncogenes are hypomethylated, increasing their activity and expression
what epigenetic regulations are applied to tumor suppressor genes/
tumor suppressors are usually hypermethylated in their promoter region, decreasing their activity and expression
how do drugs target epigenetic modifications in cancer therapy?
- 5-azocytidine demethylates genes to treat leukemia and myelodysplastic syndrome
- histone deacetylase inhibitors are used in the treatment of Tcell lymphoma
what is genetic imprinting?
one copy of a gene is turned off by either maternal or paternal imprinting, leading to monoallelic expression of a gene, which is dependent on that gene’s parent of origin
what is imprinting????????
certain genes are active only in paternal genes and imprinted aka methylated in materal genes; some genes are active only in maternal genes and imprinted aka inactive aka methylated in paternal genes
2 major clusters of imprinted genes in human genome
- short arm of chromosome 11 (11p15)
2. long arm of chromosome 15 (15q11 to 15q13)
describe what occurs in embryogenesis with imprinting
paternal copy of UBA3A gene is methylated, making it inactive. therefore, UBA3A gene is only expressed from maternal copy.
maternal copy of SNR PN (PWS) is methylated, making it inactive. therefore SNR PN (PWS) gene is only expressed from paternal copy
diseases due to deletions or mutations in transcriptionally active genes
- prader-willi syndrome
2. angelman syndrome
what occurs if there is a deletion in the paternal chromosome 15?
prader willi syndrome will develop, because the maternal SNR PN copy is methylated
what occurs if there is a deletion in the maternal chromosome 15?
angelman syndrome will develop, because the paternal UBA3A copy is methylated (and don’t have normal copy from mom)
pathology of prader willi syndrome
SNR PN gene is deleted from paternal chromosome, so there is no active SNR PN gene (mother’s is imprinted)
symptoms of prader willi
- neonatal hypotonia
- poor feeding in neonatal period
- hyperphagia and obesity by 2-4yo
- behavioral problems
- moderate intellectual disability
- moderate developmental delays
- hypogonadism and small hands and feet
pathology of angelman syndrome
UBA3A gene is deleted from maternal chromosome, so no active UBA3A gene since dad’s is imprinted
symptoms of angelman syndrome
- SEVERE intellectual disability
- seizures
- ataxia
- puppet like posture
- usually happy disposition
what is uniparental disomy?
inheritance of 2 copies of the same chromosome from ONE parent, and NO copy from the other parent
why does uniparental disomy occur?
nondisjunction usually results in 3 copies of a chromosome in 1 cell. therefore, trisomy rescue occurs where cell removes 1 copy so that the correct diploid number of chromosomes is then present.
what is unique about uniparental disomy ?
can occur without having an effect on the health of the patient, since the patient still inherits 2 copies of a gene
how can uniparental disomy cause genetic disorders?
if individual inherits 2 copies of an imprinted gene and NO copy of an active gene
what percentage of prader willi syndrome cases are due to UDP?
25%
what percentage of angelman syndrome cases are due to UDP?
5%
what 2 occurrences could happen to cause prader willi or angelman syndrome?
- deletions or mutations in the chromosomes
2. uniparental disomy (since trisomy rescue deletes one chromosome, could delete an active one)
what is anticipation?
a genetic disorder may appear at a younger age and more severity in subsequent generations (than earlier generations) due to the gradual expansion of a trinucleotide repeat polymorphism within or near a coding gene
what causes trinucleotide repeats
slipping of polymerase during DNA replication
what is a good example of anticipation
huntington disease
what is paternal anticipation
seen in huntington disease, where the CAG trinucleotide repeats in a male’s HD gene can expand when passed on to their offspring
what is juvenile huntington disease
significant expansion in CAG repeats as compared with previous generation causes early onset of disease symptoms before the age of 21yo
what is maternal anticipation
seen in fragile X syndrome, women who are carriers of fragile X syndrome premutation (CGG repeats larger than normal but below pathogenic variant) in FMR1 gene can bear children who inherit larger number of CGG repeats due to expansion
a seemingly unaffected parent can have an affected child due to trinucleotide repeat expansion
what are the triple repeat expansion diseases?
- Huntington Disease – auto dominant – CAG
- Fragile X syndrome – x linked dominant – CGG 5’UTR
- myotonic dystrophy – auto dominant – CTG 3’UTR
- Friedreich Ataxia – auto recessive – CAA intron
which expansion is associated with huntington disease
CAG coding
which expansion is associated with Fragile X syndrome
CGG in the 5’UTR
which expansion is associated with myotonic dystrophy
CTG in 3’UTR
which expansion is associated with Friedreich ataxia
CAA intron
what is polygenic
one trait or disease is controlled by more than 1 gene
what is multifactorial inheritance?
trait or disease is influenced by interaction of multiple genes AND environmental factors
which human diseases are caused by combination of genetic and environmental factors (diet, lifestyle)
cancer, heart disease, stroke, HTN, obesity, diabetes, alzheimers, alcoholism, schizophrenia, autism, depression, Crohns disease, neural tube defects, cleft lip, cleft palate
how can we determine recurrence risk for multifactorial diseases?
using empiric risk, statistic data from family history, diagnosis, medical records
what is empiric risk?
statistic data that is collected from family history, diagnosis and medical records, but doesn’t provide info about specific genes. predicts PROBABILITY that a trait will occur in observed population
limitations of empiric risk collection
- if data collected on only one population, it may not be transferrable to other populations
- if genetic and environmental components are different, the incidence will be different
traditional ways to study multifactorial traits
- adoption studies
- twin studies
- genome wide association studies (GWAS)
what do adoption studies look at?
comparing individuals who have the same genetic traits but are raised in different environments
what is concordance rate
presence of same trait in both members of a pair of twins
how are twins studied?
- concordance rate
2. heritability
how is concordance rate compared?
in monozygotic twins vs dizygotic twins.
what if concordance rate is 100% in monozygotic twins and 50% in dizygotic twins?
trait is most likely/strictly genetic
height
what if concordance rate is equal in MZ and DZ?
strictly environmental (measles)
what if concordance rate is higher in MZ than DZ?
trait has genetic component and is heritable (MS, MI, schizo, DM2)
what is used to calculate heritability
?
data of concordance rate from MZ and DZ twins
what if heritability score is close to 1?
trait mostly determined by genes
what if heritability score is close to 0?
trait is mostly determined by environment
what do empiric risk and heritability data NOT provide?
information about which genes are involved specifically or how many genes interact to influence specific trait
what are genome-wide association studies?
studies focusing on single nucleotide polymorphisms, aka single nucleotide changes that vary in at least 1% of the population
what do GWAS help identify?
“risk genes” of complex diseases – aka if the SNP is present, you are at risk
how could GWAS impact medicine?
identifying specific SNP and genes that are involved in increased disease risk could help develop medical care/preventative medicine
