Principles of Genetic Inheritance Flashcards
Autosomal dominant inheritance
- only one allele of a gene is needed for expression
- affected offspring only needs one affected parent
- unaffected individuals do not transmit trait (aa)
- males and females can transmit trait to both males and females - autosomal
- trait is expected in every generation
- recurrent risk is 50%
Autosomal recessive inheritance
- 2 copies of a mutant allele is needed to influence phenotype
- males and females affected equally
- if two heterozygous parents: 25:50:25
- pedigree may show affected individual with two phenotypically normal parents
Oculocutaneous albinism type 1A (OCA1A)
Autosomal recessive disease
Caused by a mutation in the TYR gene encoding tyrosinase, completely inactive or incomplete tyrosinase
melanin biosynthetic pathway is completely blocked
- white skin and hair at birth, irises are blue to pink and fully translucent, photophobia
nystagmus may be present at birth or it may develop in the first 3-4 months of life
sun-exposed skin becomes rough, coarse, thickened, and can have solar keratoses
X-Linked Recessive
disease allele on X in males is termed “hemizygous”, females can be heterozygous or homozygous
- always expressed in male “carriers”
- Female carriers transmit disease allele to 50% of sons and 50% of daughters
- all daughters of affected males are heterozygous carriers
Duchenne Muscular Dystrophy
X-linked disorder
- absence or defect in dystrophin
- muscle weakness usually occurs around teh age of 4 and progressively worsens, ability to walk completely disintigrates by age 9-12, most men essentially “paralyzed from the neck down” by age 21
Mitochondrial DNA (mtDNA)
- encodes rRNA, tRNA, and 13 polypeptides involved in oxidative phosphorylation
- txn takes place in mitochondrion, independently of the nucleus
- inherited exclusively through the maternal line
- pedigree would show all offspring of an affected woman will be affected. Affected males will not pass on to offspring
- severity depends on the percentage of dysfunctional mt.DNA (heteroplasmy)
Leber’s Hereditary optic neuropathy (LHON)
- mitochondrial DNA (maternally inherited)
- degeneration of retinal ganglion cells
- caused by one of three pathogenic mt. DNA point mutations affecting NADH dehydrogenase
- Starves RGCs of energy, making them unable to transmit signals to the brain
- acute or subacute loss of vision (typically in early teens or 20s, inter-eye delay of 8 weeks)
- impaired glutamate transport and increased ROS causing apoptosis of retinal ganglion cells (RGC)
Myoclonic epilepsy and ragged red ribers (MERRF)
- mitochondrial DNA (maternally inherited)
- mutation in the gene encoding tRNA for lysine, disrupts the synthesis of cytochrome-c oxidase
- patients with myclonus dinated muscle movement (twitching or jerking), ataxia, seizures, dementia
- particularly affects the muscles and nerves
- large variability of presentation due to heterplasmy
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)
most common maternally inherited mitochondrial disease
- affects many body systems, particularly brain, nervous system, and muscles
stroke and dementia, diabetes, deafness, cognitive impairment, short stature, migraines
X-Linked Dominant
only one copy is needed
- affected males transmit the disease to all females, but never to males
- females with the disease allele transmit the trait to both females and equally, with 50% transmission to offspring
Vitamin D resistant rickets: hypophosphatemia
- X linked dominant
- low phosphorus in blood due to defective reabsorption of phosphate in kidney
- Deficient absorption of calcium in intestines causes softening of bone (rickets)
- vitamin D metabolism is abnormal
short stature
treatment is oral phosphate and vitamin D
Fragile X syndrome
X-linked dominant
- mild-to-moderate intellectual disability, long and narrow face, large ears, flexible fingers, and large testicles
- features of autism such as problems with social interactions and delayed speech
- hyperactivity is common, seizures occur in about 10%
- expansion of the CGG triplet repeat within FMR1 gene on X chromosome, results in silencing and a deficiency of the FMRP, which is required for normal development of connections between neurons
Euploidy
cells with a normal number of chromosomes
Ex. haploid gametes and diploid somatic cells
Nondisjunction
meiotic error
- abnormal separation of one or more pairs of homologous chromosomes or sister chromatids
- germline error during meiosis in spermatocyte or oocyte is transmissible to the next generation
- if occurs during mitosis (after fusion of ovum and sperm) individual will exhibit mosaicism, only some of the cells will be with aneuploid
- nondisjunction increases with maternal age
Polyploidy
meiotic error
cells contain a complete set of extra chromosomes in a cell
- multiple of 23, incompatible with human life
- often seen in plants
Aneuploidy
meiotic error
cells contain a missing or additional individual chromosomes
- monosomy, trisomy
uniparental disomy
both chromosomes are inherited from one parent
- along with the parent-specific imprinting, but since most genes are not imprinted it usually has no effect on health or development
- loss of function genes in that chromosome will cause issue
Genomic imprinting
- we receive one copy of each gene from each parent, but genomic imprinting states that some genes are only expressed from the mother or the father
- imprinted alleles are silenced, so the non-imprinted allele is expressed (only from one parent)
- epigenetic process involving methylation and histone modification of egg or sperm cells during their formation while genetic sequence is unchanged - duplicated in all somatic cells
Prader-Willi and Angelman Syndromes
UPD or deletion in chromosome 15
- phenotype/disease depends on if deletion is on maternal or paternal chromosome
- paternal = Prader-Willi (short stature, hypotonia, small ahnds/feet, obesity, mild to moderate intellectual disability, uncontrolled eating)
- maternal = Angelman Syndrome (severe intellectual disability, seizures, ataxic gait)
Translocations
non-homologous chromosomes exchange genetic material
- reciprocal - exchange of material between nonhomologous chromosomes
- Robertsonian - long arm of two acrocentric chromosomes combined, short arm is typically lost
Karyotyping
technique that allows the determination of the number, size, and gross structures of metaphase chromosomes
- Traditional gold standard cytogenic method used in identifying several chromosomal abnormalities associated with genetic disorders, but does not provide information on the genetic level
Turner Syndrome
Karyotype: 45, XO
Monosomy (X), Female (no Y)
- short stature, ovarian hypofunction/premature ovarian failure, many do not undergo puberty, most are infertile
- webbed neck, low hairline on neck, CV defects (coarctition of aorta, bicuspid aortic valve), no cognitive defects
Klinefelter Syndrome
Karyotype 47, XXY
- Varying presentation, varying degrees of cognitive, social, behavioral, and learning difficulties
- primary hypogonadism (low T)
- small and/or undescended testes, gynecomastia, infertility, tall stature
- variability in X numbers can increase symptoms (48 XXXY, 49 XXXXY)
Downs Syndrome
Trisomy 21 (47, XX +21)
- most common trisomy, strongly associated with maternal age
- results most commonly from maternal meiotic nondisjunction (in the ovum)
- also due to unbalanced translocation
- varying degrees of cognitive impairment
- increased nuchal translucency, cardiac defects, duodenal atresia, ventriculomegaly, absent nasal bone, and short limbs
- Trisomy 21 (nondisjunction) is most common (95% of cases)
- translocation (usually piece of 21 onto chrom 14) 4% of cases
- mosaicism - nondisjunction occurs in one of the initial cell divisions after fertilization, causing some cells with 46 chromosomes and some with 47 (1% of cases)
