Single Gene Inheritance I Flashcards
Single-gene traits are often called what?
Mendelian traits
Mendel had two relationships he explained; what are these?
- segregation
- independent assortment
What is segregation?
the two alleles for each trait separate during gamete formation, and then unite at random, one from each parent, at fertilization
Independent assortment
during gamete formation, different pairs of alleles segregate independently of each other
exception: if the two genes are on same chromosome
locus
the position of a gene on a chormosome
alleles
alternative forms of a gene found at the same locus on homologous chromosomes
*these segregate at meiosis so one is given to an individual from each parent
Normal alleles are usually referred to as what?
wild type alleles
Abnormal alleles are usually referred to as what?
mutant alleles
genotype
the genetic constitution
*usually described according to the alleles present at a particular locus (homozygotes, heterozygotes, hemizygotes)
phenotype
observable trait(s) or characteristic(s)
homozygotes
have 2 identical alleles at a locus
heterozygotes
have 2 different alleles at a locus
hemizygotes
have only 1 allele at a locus
*used primarily for X-linked traits in males
Phenotypic traits may be of what two distinctions?
- dominant (seen in both heterozygotes and homozygotes)
- recessive (seen in homozygotes for autosomal traits and hemizygotes for X-linked recessive traits)
Autosomal
non-sex chromosome
proband
the individual through whom the genetic disorder is first ascertained (starting point for study)
consanguineous
couples who are related
genetic heterogeneity
term used to describe the phenomenon where the same phenotype is caused by different genotypic abnormalities
allelic heterogeneity
occurs when the abnormal phenotype is caused by different mutations at the same locus
ex: cystic fibrosis, where hundreds of mutations of the CFTR protein have been described, all leading to the CF phenotype
Locus, or nonallelic heterogeneity
used to describe the situation where a particular phenotype can be the result of mutations at 2 or more separate loci
ex: congenital sensorineural deafness, in which dominant, recessive, and X-linked forms have all been described
What is autosomal dominant inheritance?
- all affected people have an affected parent
- half of offspring of affected person are affected (any child of affected parent has a 50% chance of inheriting the trait)
- no gender bias
- the phenoytpe appears in every generation
- phenotypically normal family members do not transmit the trait to their children
*male to male transmission is the cardinal distinguishing feature of autosomal dominant traits
Autosomal dominant inheritance : punnett square
One affected parent (Dd) One normal parent (dd) Children: Dd (affected) Dd dd (normal) dd
autosomal dominant disorders or traits
those expressed in either the heterozygote or the homozygote
What three features are often most striking for autosomal dominant disorders?
- pleiotropy
- variable expression
- reduced penetrance
*although almost all genetic disorders display these three features, they are often most striking for autosomal dominant disorders
pleiotropy
mutant genes usually produce their effects on multiple organ systems and functions, and are therefore said to exhibit pleiotropy
ex: Marfan’s syndrome; defect in fibrilli –> cardiac defects, ocular defects, skeletal defects (mostly known for skeletal)
variable expression
occurs when individuals with the same genotype have different phenotypes
ex: neurofibromatosis, type I (within a family, market variation in number and location of pigmented skin lesions, benign peripheral nerve sheath tumors, learning disability, and/or intracranial (brain) tumors that can be life-threatening — some variation is age-related (Age-related penetrance))
reduced penetrance
- penetrance is an all-or-none phenomenon (one either shows some features of genotype or none at all)
ex: having a deleterious BRCA1 mutation confers a lifetime risk of cancer of approximately 80%; 20% of people with the same mutation will never develop cancer. The penetrance of the mutation is ~80%
Give an example of each of the following: 1 - pleiotropy 2 - variable expression 3 - reduced penetrance 4 - allelic heterogeneity
1 - Marfan’s syndrome
2 - neurofibromatosis, type I (NF)
3 - BRCA1
4 - cystic fibrosis (CF) - different mutations in CFTR
What is the mathematical relationship for penetrance?
penetrance = # of individuals of a particular genotype who have the disorder / total # of individuals with the genotype
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fitness
the fitness of a condition is measured by the number of affected persons who are able to survive to reproductive age and to have offspring
- if a disorder has a fitness of 0, then all cases represent new mutations
- if a disorder has a fitness of 1, then new mutation is presumed to be very uncommon
Give an example of each:
1 - disease with fitness = 0
2 - disease with fitness = 1
1 - thanatrophoric dysplasia, a skeletal dysplasia that is invariably lethal in the newborn period
2 - Huntington’s disease
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autosomal recessive phenotypes
- less common than autosomal dominant conditions
- only expressed in homozygotes who have inherited one mutant allele from each parent
- an AR trait generally appears only in the sibship of the proband (horizontal inheritance)
- the recurrence for siblings of affected individuals is 1 in 4 (if a sibling is unaffected, then the sibling has a 2 out of 3 chance of being a carrier/heterozygous)
- parents of affected individuals may sometimes be consanguineous (this is especially true for rare recessive disorders)
- parents of an affected person are asymptomatic carriers of mutant alleles (parents may be unaffected carriers)
- males and females are equally likely to be affected for most AR conditions
- no gender biase
autosomal recessive inheritance: punnett square
Two carrier parents (Rr, Rr) Children: RR (normal) Rr (carrier) Rr rr (affected)
- R is wild type allele (normal)
- r is mutant allele
The chance that the parents are consanguineous is increased with what disorders?
rare autosomal recessive disorders
The increased risk to offspring of consanguineous matings is the result of what?
homozygosity by descent: when one is homozygous by descent, the mutant alleles present in the affected [homozygous] individual are both derived from a single common ancestor (this phenomenon is also referred to as a founder effect)
What is the founder effect?
when one is homozygous by descent, the mutant alleles present in the affected [homozygous] individual are both derived from a single common ancestor
Penetrance
- all or none pehenomenon
- person with abnormal genotype does not manifest
- penetrance = # of persons with disorder / # of persons with abnormal genotype
- age-dependent genotype (i.e. PKD)
- subtle manifestations (i.e. skeletal abnormalities, not visible on clinical examination)
What are some factors influencing penetrance?
- modifier genes
- carcinogens
- responses to DNA damage
- hormonal/reproductive factors (i.e. estrogen)
Age related penetrance
- as a person ages, they are more likely to develop manifestations of a disease
ex: renal cysts
some people develop dozens of cysts that take up parenchyma of kidney and make it non-functional
Autosomal recessive is very unlikely, but can possibly be seen more often in what communities/marriages?
perhaps between a couple who is not completely unrelated
ex: in a closed off community, like the Amish
Penetrance vs. Expressivity
Penetrance
- results from a combination of genetic, environmental, and lifestyle factors, many of which are unknown
- all-or-nothing
- ex: 85% of women with a BRCA1 mutation will develop breast cancer, 15% of carriers will not –> thus, BRCA1 has reduced penetrance
Expressivity:
- the range of signs and symptoms that can occur in different people with the same genetic condition
- everyone is affected, but some have different symptoms
- ex: some people with Marfan syndrome have mild manifestations (being tall and thin with long, slender fingers)
Is level of expressivity ever indicated in pedigree?
no
Some AR disorders are concentrated within genetic isolates. What is this? Give an example
genetic mutation variations are of different types in different populations, also increased rate in these populations
ex: Tay-Sachs disease (Jewish population has higher rate, so do French Canadians, but different type of mutation)
Tay Sachs disease is an example of what?
an AR disorder that is concentrated within genetic isolates (i.e. Jews, French Canadians)
Founder Effect
take a group of people, pull out a small number of them, they form as a basis of founding another community; the disease frequency in the newly formed community may differ greatly from the original community (depends on sample you take out)
Locus heterogeniety
ex: autosome recessive deafness
their deafness is caused by two different genes (two different loci) between the parents; so they could have children that are carriers of both types of deafness, but have normal hearing
X-linked disorders
- conditions for which the locus is on the X chromosome
- recessive or dominant
- inheritance and the clinical expression of these disorders are different between males and females (this is primarily the result of the fact that males have only one allele/hemizygous for X-linked genes whereas females have 2 alleles)
X-linked recessive
- no male-male transmission
- carrier females unaffected
- 1/2 of sons of female carriers affected
- daughters of female carriers have 50% chance of being carriers
- mutant gene is transmitted from father to all his daughters, they are all therefore carriers (assuming mother does not have mutant gene)
- affected males in a kindred are related through females
- incidence in males much higher than females
- heterozygous females are usually unaffected but may show variable expression of the condition
X-linked dominant
- no male-male transmission
- carrier females variably affected
- 1/2 of offspring of female carriers affected
Dosage compensation
X-linked genes are expressed at the same level in females (with 2 X chromosomes) as in males (with 1 X chromosome)
basically, females express only one allele/dose of their
X-linked genes, although they have two alleles/doses. This ensures that females do not produce twice the gene product of their male counterparts, who have only one allele for X-linked genes
This results form X-inactivation (described by Mary Lyon):
- leaves one active X in each cell
- occurs early in embryogenesis and is random
- on average, half a woman’s active X’s are paternal and half maternal
- may result in variable expression
Lyonization
the principle of X-inactivation and of gene expression:
- in female somatic cells only one X is active. The second X is condensed and is represented as the Barr body in interphase cells
2 - inactivation is an early embryonic event
3 - the inactive X may be either the paternal or maternal X. Once a particular X is inactivated, all the clonal descendants of that cell will have the same inactive X
4 - the Lyon hypothesis explains dosage compensation and variable expression in female heterozygotes
X-linked recessive inheritance
Mother is not carrier (XX)
Affected father that has X chromosome that has disease (xY)
Girls are always carriers (Xx, 50%)
Boys are not (XY, 50%)
Carrier Mother: Xx
Normal Father: xY
Girls: XX (normal) or Xx (carrier)
Boys: XY (normal) or xY (affected)
*could be that girl and mother had some mild manifestations of disease due to being carrier
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Variable expression
- variable expression in female heterozygotes may also be the result of Lyonization
- because X-inactivation is a random event most females will have the paternally-derived X as the active X in about half their cells and the maternally-derived X as the active X in about half
- depending on this variability between paternal/maternal proportions, the female will have a milder or more sever phenotype
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X-linked recessive pedigree: general features
- skipped a generation
- seeing multiple times (generations) on pedigree
- male-dominant
- can’t necessarily rule out it’s not dominant when this small of pedigree, but just think it through I guess and look at other details
X-linked recessive pedigree:
Normal father, Carrier mother
Normal father (XY), Carrier mother (Xx) Children: XX (normal) XY (normal) Xx (carrier) xY (affected)
X-linked recessive pedigree:
Affected father, Normal mother
Affected father (xY), Normal mother (XX) Children: xX (carrier) xX YX (normal) YX
Hemophilia A
- aka factor VIII deficiency
- characteristic X-linked disorder
- carrier female has 50% chance her sons will have hemophilia, 50% chance that a daughter will be a carrier
- Lyonization: carrier females have approximately 50% the factor VIII activity of non-carrier females and normal males
- all of affected male’s sons will be normal, all his daughters will be carriers
- because of increased survival (and therefore increased genetic fitness) of affected males, it is not uncommon that hemophiliacs have children
DMD pedigree
- might see grandfather affected with carrier daughters (maybe mild manifestations)
- these daughters might have son that is affected, daughter that is carrier, or normal son/daughter
- -> daughter carrier can have affected son
Duchenne’s Muscular Dystrophy
- X-linked recessive disorder
- caused by mutations of muscle protein, dystrophin
- many carrier mothers will have moderately elevated creatinine kinase levels and risks for cardiomyopathy
- affected males do not reproduce, so DMD can be termed a genetic lethal, with a genetic fitness of 0
- since 1/3 of all DMD genes are carried in males and since these males do not reproduce, then 1/3 of all cases of DMD must be result of a new mutation
(the same can be said of any [genetically] lethal X-linked disorder
What are two examples of X-linked recessive disorders?
- Hemphilia A
- Duchenne’s Muscular Dystrophy
X-linked dominant inheritance
- those traits which are regularly expressed in heterozygotes
- affected males have no affected sons and only affected daughters (no normal daughters)
- both male and female offspring of heterozygous females have a 50% chance of being affected
- for rare phenotypes, affected females are twice as common as affected males and usually have milder expression of the phenotype
- for conditions which are prenatal lethals in hemizygous males, the sex ratio of offspring of heterozygous mothers is 2:1 female to male, since all affected male conceptuses are spontaneously aborted
*phenotype is more sever for affected male child, while it is milder in females because of Lyonization (half her X’s express mutation, half express normal allele)
X-linked dominant punnet square:
Normal Mother, Affected Father
Normal Mother (xx), Affected Father (Xy) Children: xX (affected) xy (normal) xX xy
X-linked dominant punnet square:
Affected mother, Normal father
Affected mother (Xx), Normal father (xy) Children: Xx (affected) Xy (affected) xx (normal) xy (normal)
Incontentia Pigmenti
- X-linked dominant
- lethal for males in fetal period
- pedigrees show only affected females
- sex ratio of offspring of affected females is 2:1 female to male
X-linked hypophosphatemic rickets
- X-linked dominant
- vitamin D-resistant rickets
- kidney tubules do not reabsorb phosphate
- females less severely affected than males
Mother with IP will have
- unaffected daughters
- unaffected sons
- affected daughters
- never have affected sons, perinatal lethal for boys
(but you might have a boy born Xxy (kleinfelter’s) that could be born with IP, but Xxy boys doesn’t really happen)
