8.19.16 Lecture Flashcards
Genetic variation originates from ___.
Heritable DNA mutations
What are the four general patterns of inheritance?
- Sex-linked (encoded on X or Y chromosome)
- Autosomal (encoded on numeric chromosomes)
- Recessive (both alleles must be affected for the phenotype to be conferred)
- Dominant (a single mutant allele confers a phenotype)
Draw the following pedigree symbols:
- Male
- Female
- Unspecified sex
- # of children of a certain sex
- Affected
- Nonpenetrant carrier (may manifest disease)
- Obligate carrier (will not manifest disease)
- Proband
- Deceased
- Marriage/union
- Divorced
- Consanguinity
- Monozygotic twins
- Dizygotic twins
- Twins, unknown zygosity
- Pedigree with generations and individuals numbered
- Still birth
- Adopted into family
- Adopted out of family
- Consultand
- Spontaneous abortion
- Miscarriage
- No offspring
- Multiple unions
- Pregnancy (with information)
- Termination of pregnancy
What is the genetic constitution of an individual or locus?
Genotype
What is the outward characteristics of an individual or gene product?
Phenotype
What is one of the alternative versions of a gene or DNA sequence at a given locus?
Allele
What is the position occupied by a gene on a chromosome?
Locus
What is a genotype with identical alleles at a given locus?
Homozygote
What is a genotype with different alleles at a given locus?
Heterozygote
What is a genotype with a single allele for a given chromosome segment?
Hemizygous
What is a genotype with two different mutant alleles at one locus?
Compound heterozygote
What is an alternate genotype present in a population at >1% frequency?
Polymorphism
What is the proportion of individuals manifesting disease?
Penetrance
What is the extent to which a mutation exhibits a phenotype?
Expressivity
What results from different mutations at one locus?
Allelic heterogeneity
What results from mutations at different loci?
Locus heterogeneity
What occurs when the same mutations manifest differently among individuals?
Phenotypic heterogeneity
What type of inheritance manifests only when there is no healthy allele present (for single gene disorders)?
Recessive inheritance
Individuals carry ___ recessive alleles that are lethal in homozygotes.
1-5
What is an example of a recessive disease?
Sickle cell anemia
What are the major characteristics of autosomal recessive inheritance?
- Only displayed in homozygotes
- Appears in more than one sibling of the proband, but not in parents, offspring, or other relatives (in other words, there is clustering among siblings and absence in ancestors)
- Males and females are affected equally
- Parents are asymptomatic carriers
- Parents may be consanguineous
- The recurrence risk for siblings = 1/4
- Carrier risk of unaffected siblings of proband = 2/3
What is a relationship resulting from common ancestry which increases the chance that both parents carry the same mutant allele?
Consanguinity
Risk of recessive genetic disease is affected by ___, ___, and ___.
Consanguinity; inbreeding; population carrier frequency
How is the degree of relationship to the proband calculated?
Degree of relationship = n = # of uninterrupted lines between proband and target
What is the coefficient of inbreeding of a child and what does it equal?
F = 1/2(proportion of alleles in common); this is the probability a child will receive both alleles for a particular gene from the same ancestor (one from mother, one from father); the proportion of loci at which a person is homozygous or identical by descent
What is the proportion of alleles in common?
(1/2)^n
If a person is inbred through more than one line of descent, how is F calculated?
Sum F
___ disorders exhibit a phenotype despite presence of a healthy allele.
Dominant
What are the features of autosomal dominant inheritance?
- For single gene disorders, a pheontype is dominant if it manifests in the heterozygote.
- If not lethal, the phenotype is found in every generation.
- The child of an affected parents has 1/2 risk of inheriting the disease trait.
- Unaffected family members are unlikely to transmit the disease to offspring.
- Males and females are usually equally affected.
A mutant allele is dominant in what 5 instances?
- Haploinsufficieny: the single normal copy produces an insufficient quantity of the normal gene product for the requirements of the organism.
- Dominant negative effect: the product of the inactive mutant interferes with the function of the normal gene product
- Simple gain of function: the product of the mutant gene acquires a new or enhanced function
- Affected gene is a tumor suppressor, resulting in a predisposition to cancer that is inherited as a dominant trait because even a single cell losing the function of the other allele is enough to cause cancer.
- Codominance: a trait is defined by two alleles that each exhibit a phenotype
What is incomplete dominance?
The phenotype of the heterozygote is distinct from and often intermediate to the phenotypes of the homozygous phenotypes.
What is an example of a dominant disorder resulting from haploinsufficiency?
Familial hypercholesterolemia; heterogyotes have a normal allele producing a functional LDL receptor, so the receptor level is 50% less than normal
What is an example of an autosomal dominant disorder with reduced penetrance?
Ectrodactylyl; the phenotype does not always present, despite the existence of the genotype
Describe the characteristics of an X-linked recessive inheritance pattern.
- Incidence of trait is much higher in males than in females
- Heterozyogus females are usually unaffected; males are - they do not have the extra X to compensate for the mutations.
- Affected fathers transmit the disease to their grandsons through their daughters, but not to or through their sons.
- All daughters of affected fathers are carriers and have a 50% chance of transmitting the gene to their children. The affected females are carriers and affected males express disease.
- Males never transmit the disease directly to their sons.
Describe the characteristics of an X-linked dominant inheritance pattern.
- Very rare
- Affected mothers have a 50% chance of transmitting the disorder to sons and daughters
- Affected fathers always have affected daughters but not affected sons
- Affected females may have a milder expression of the phenotype
What are 4 non-Mendelian inheritance patterns that exist for some single gene disorders?
- Mosaicism
- Genomic Imprinting/Parent of origin effects
- Repeat Disorders
- Mitochondrial inheritance
What is mosaicism?
A mutation occurring during cell proliferation leads to a proportion of the cells carrying the mutation.
What is the difference between somatic and germline mosaicism?
Somatic: mutation occurs during development; only the part of the body derived from the mutant cell may be affected.
Germline: mutation affects germ cells; parents may be negligibly affected, but multiple offspring may exhibit severe/uniform disease.
What is genomic imprinting?
The disease expression is dependent on the parent transmitting the disease because of the inherited expressivity of the gene copy in question.
Prader-Willi and Angelman Syndromes result from…
…a microdeletion in the q arm of chromosome 15.
In genomic imprinting, different phenotypes depend on…
…the parental origin of deletion.
For defective genes imprinted active in females during oogenesis, affected and carrier females should always produce children of which ___ are affected. Affected and carrier males should always produce children of which ___ are carrier.
Half; half.
What happens in repeat disorders?
Some genes contain several repeats of 3 nucleotides. The number of triplet repeats in a given gene can sometimes increase from generation to generation. Beyond a certain threshold, abnormalities can worsen in later generations. This is known as anticipation.
The more repeats someone has in a repeat disorder, the ___ the onset of the disease.
Earlier
Mitochondrial DNA is ___ inherited. A small and random sample is included during ___.
Maternally; oogenesis
Mitochondrial DNA can be ___, which means that more than one type of mitochondrial DNA may be present in cells from one individual.
Heteroplasmic
Because mitochondrial DNA undergoes random segregation through multiple rounds of mitosis during embryogeneis, mitochondrial diseases are passed on if…
…a proportion of diseased mitochondria exceeds a threshold.
What is an example of a mitochondrial disease?
Leber hereditary optic neuropathy
What are 6 possible complications to pedigree patterns to watch out for?
- New mutations
- Genomic imprinting (different phenotypes depending on parental sources)
- Reduced penetrance (the genotype doesn’t necessarily give the phenotype)
- Phenotypic variability (disorders that affect multiple organs can produce different symptoms in related family members - pleiotropy - due to effects of environment or other genes)
- Delayed onset (triplet repeat expansion disorders)
- Small family size (limited pedigree information)
