4. Single-Gene Disorders: Inheritance Patterns Flashcards
Pedigrees
Graphical representation of a family tree that uses the standard symbols
1 gen (1^0) - parent and child; sibs - 50% of shared DNA
2 gen (2^0) - grandparent and grandchild, uncle/aunt and nephew/niece; half sibs - 25% DNA shared
3 gen (3^0) first cousins 12.5% DNA shared
Sib (sibling)
Brother or sister
Series of brothers and sisters is known as a sibship
Proband
First member in a family to be evaluated by a health care provider for pedigree analysis
Dominant vs recessive
Dominant: human monogenetic disorder (or trait) is determined by a nuclear gene if it manifests in a heterozygote
Recessive: must have 2 defective alleles to present
5 basic Mendelian inheritance patterns
- Autosomal dominant: 1 mutant allele, heterozygote
- Autosomal recessive: 2 mutant alleles, homozygous
- X-linked dominant
- X-linked recessive
- Y-linked
4 rules of inheritance
- Dominant conditions: 50% chance each kid gets disease
- Recessive condition: 25% chance each kid gets disease
- Carrier status: in recessive diseases only
- No male to male transmission in X-linked diseases (father gives Y)
Autosomal dominant
One abnormal gene copy is required for individual to be affected
Both sexes are affected and may transmit the gene to offspring of ether sex - no sex chromosome relation
When affected person has children with an unaffected person = each child has 50% chance of developing disease
Autosomal recessive
Two mutant alleles required (one from each parent) at the disease locus
Person affected can be of either sex and is usually born to unaffected parents (heterozygote - asymptomatic carriers)
The chance that each future child is also affected is 25%
Consanguinity
Incest marriages
Couples who have one or more recent ancestors in common
A fracture of many autosomal recessive disorders, especially in rare conditions
Seen in many people with same ethnicity
X-linked inheritance
Loss or gain of just one of our 46 chromosomes is lethal except for 45,X (Turner syndrome), trisomy 21 (Down syndrome) - problems with gene dosage
Most of the very few genes on Y chromosome have male specific functions or have equivalent copy on X
X-inactivation
Mechanism to compensate for having different numbers of X chromosomes in males and females
Initiated after a cellular mechanism counts the number of X chromosomes in each cell of the early embryo
If the number of X chromosomes is two (or more) all except one is randomly inactivated (only in somatic cells) - induced to form transcriptionally inactive - Barr Body
Barr body
Inactive due and condensed X chromosome seen in somatic cells only
X-linked Dominant inheritance
Affected individuals can be of either sex and at least One parent is affected
Significantly more affected females than affected males - NO male to male transmission of disorder
affected females typically have a milder (but more variable) expression than affected males
All children born to an affected mother and unaffected father have 50% chance of being affected
Affected father with single X chromosome will consistently have unaffected sons - they do not inherit his defective X but daughters always at risk
X-linked recessive
Affected individuals mostly male and affected males are usually born to asymptomatic carrier parents
- male cannot be carrier for X-linked recessive diseases -
- mother has 2 X and normal X will silence defective X
A distinguishing feature is that there is no male-to-male transmission because males pass a Y chromosome to sons
Matrilineal inheritance
Tissues that have a high energy requirement - muscle and brain- are primarily affected in mtDNA disorders
Sperm does contribute mtDNA to zygote, but the patrilineal mtDNA is destroyed in early embryo - inheritance occurs exclusively through the mother
Individuals with mitochondrial DNA disorder can be of either sex - affected males do not transmit the conditions to any of their children
Forces leading to variation between populations
Purifying (negative) selection - selective removal of alleles that are deleterious (dangerous)
Associative/ non-random mating: humans mate and prefer phenotypes like themselves
Genetic drift: if person is affected by genetic disease is not likely to reproduce
New mutations: causing new disease alleles and causing genes to lose their function
Influx of migrants: if population absorbs a large influx of migrants with different allele frequencies - gene pool changes
Non-penetrance/ age-related penetrance
Penetrance- probability that a person who has mutant allele will express the disease phenotype
Dominantly inherited disorder = 100% inheritance (Huntington’s disease)
Some disorder have late age onset - severity of disease increases with age as harmful products slowly build up
Locus heterogeneity
Production of identical phenotypes by mutations at two or more different loci/genes
Explains how parents who are both affected with a recessive disorder that has common phenotype produce multiple unaffected children
Different mutations - same disease manifestation
Compound heterozygote
Presence of two different mutant alleles at a particular gene locus, one on each chromosome pair
EX: HFE gene - patients who inherit one C282Y mutation from one parent to another H63D mutation from another parent
Type of mutation is different but in the same gene = manifest disease
Anticipation
Some disorders show consistent generational differences in phenotype
EX: fragile X mental retardation syndrome, myotonic dystrophy, and Huntington disease
Can be expressed at an earlier age and become increasingly severe with each new generation of affected individuals
Disease manifests earlier and earlier through generations
Neurofibromatosis type 1
Autosomal dominant
Increased propensity to develop a variety of beginner and malignant tumors
Caused by mutations in gene nuerofibromin at chromosome location 12q11.2
Neurofibromas - originate from nonmeyelinating Schwann cells - tumor suppressive gene mutation
Scolesis, neurofibromas (tumors), aggregated nodules on eye (lisch nodules)
Duchenne muscular dystrophy
X-linked recessive
Caused by mutations in dystrophin gene located on X chromosome
Dystrophin - maintain integrity of muscle membrane protein
Boys with this condition show a progressive degeneration of muscle that leads to weakness - problems with ambulation, then respiration and death (by late teens disease manifests by age 3)
Marked elevation in serum enzyme creating phosphokinase (CPK or CK) - correlate with degree of muscle deterioration
