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Foundations Week 7 > Single Gene Inheritance I > Flashcards

Single Gene Inheritance I Flashcards

1
Q

Single-gene traits are often called what?

A

Mendelian traits

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2
Q

Mendel had two relationships he explained; what are these?

A
  • segregation

- independent assortment

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3
Q

What is segregation?

A

the two alleles for each trait separate during gamete formation, and then unite at random, one from each parent, at fertilization

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4
Q

Independent assortment

A

during gamete formation, different pairs of alleles segregate independently of each other
exception: if the two genes are on same chromosome

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5
Q

locus

A

the position of a gene on a chormosome

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6
Q

alleles

A

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

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7
Q

Normal alleles are usually referred to as what?

A

wild type alleles

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8
Q

Abnormal alleles are usually referred to as what?

A

mutant alleles

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9
Q

genotype

A

the genetic constitution

*usually described according to the alleles present at a particular locus (homozygotes, heterozygotes, hemizygotes)

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10
Q

phenotype

A

observable trait(s) or characteristic(s)

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11
Q

homozygotes

A

have 2 identical alleles at a locus

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12
Q

heterozygotes

A

have 2 different alleles at a locus

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13
Q

hemizygotes

A

have only 1 allele at a locus

*used primarily for X-linked traits in males

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14
Q

Phenotypic traits may be of what two distinctions?

A
  • dominant (seen in both heterozygotes and homozygotes)

- recessive (seen in homozygotes for autosomal traits and hemizygotes for X-linked recessive traits)

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15
Q

Autosomal

A

non-sex chromosome

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16
Q

proband

A

the individual through whom the genetic disorder is first ascertained (starting point for study)

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17
Q

consanguineous

A

couples who are related

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18
Q

genetic heterogeneity

A

term used to describe the phenomenon where the same phenotype is caused by different genotypic abnormalities

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19
Q

allelic heterogeneity

A

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

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20
Q

Locus, or nonallelic heterogeneity

A

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

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21
Q

What is autosomal dominant inheritance?

A
  • 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

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22
Q

Autosomal dominant inheritance : punnett square

A 
One affected parent (Dd)
One normal parent (dd)
Children:
Dd (affected)
Dd
dd (normal)
dd
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23
Q

autosomal dominant disorders or traits

A

those expressed in either the heterozygote or the homozygote

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24
Q

What three features are often most striking for autosomal dominant disorders?

A
  • pleiotropy
  • variable expression
  • reduced penetrance

*although almost all genetic disorders display these three features, they are often most striking for autosomal dominant disorders

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25
Q

pleiotropy

A

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)

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26
Q

variable expression

A

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))

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27
Q

reduced penetrance

A
  • 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%
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28
Q 
Give an example of each of the following:
1 - pleiotropy
2 - variable expression
3 - reduced penetrance
4 - allelic heterogeneity
A

1 - Marfan’s syndrome
2 - neurofibromatosis, type I (NF)
3 - BRCA1
4 - cystic fibrosis (CF) - different mutations in CFTR

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29
Q

What is the mathematical relationship for penetrance?

A

penetrance = # of individuals of a particular genotype who have the disorder / total # of individuals with the genotype

29
Q

f

A

f

31
Q

fitness

A

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
32
Q

Give an example of each:
1 - disease with fitness = 0
2 - disease with fitness = 1

A

1 - thanatrophoric dysplasia, a skeletal dysplasia that is invariably lethal in the newborn period
2 - Huntington’s disease

32
Q

f

A

f

34
Q

autosomal recessive phenotypes

A
  • 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
35
Q

autosomal recessive inheritance: punnett square

A 
Two carrier parents (Rr, Rr)
Children:
RR (normal)
Rr (carrier)
Rr
rr (affected)
  • R is wild type allele (normal)
  • r is mutant allele
36
Q

The chance that the parents are consanguineous is increased with what disorders?

A

rare autosomal recessive disorders

37
Q

The increased risk to offspring of consanguineous matings is the result of what?

A

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)

38
Q

What is the founder effect?

A

when one is homozygous by descent, the mutant alleles present in the affected [homozygous] individual are both derived from a single common ancestor

39
Q

Penetrance

A
  • 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)
40
Q

What are some factors influencing penetrance?

A
  • modifier genes
  • carcinogens
  • responses to DNA damage
  • hormonal/reproductive factors (i.e. estrogen)
41
Q

Age related penetrance

A
  • 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
42
Q

Autosomal recessive is very unlikely, but can possibly be seen more often in what communities/marriages?

A

perhaps between a couple who is not completely unrelated

ex: in a closed off community, like the Amish

43
Q

Penetrance vs. Expressivity

A

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)
44
Q

Is level of expressivity ever indicated in pedigree?

A

no

45
Q

Some AR disorders are concentrated within genetic isolates. What is this? Give an example

A

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)

46
Q

Tay Sachs disease is an example of what?

A

an AR disorder that is concentrated within genetic isolates (i.e. Jews, French Canadians)

47
Q

Founder Effect

A

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)

48
Q

Locus heterogeniety

A

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

49
Q

X-linked disorders

A
  • 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)
50
Q

X-linked recessive

A
  • 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
51
Q

X-linked dominant

A
  • no male-male transmission
  • carrier females variably affected
  • 1/2 of offspring of female carriers affected
52
Q

Dosage compensation

A

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
53
Q

Lyonization

A

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

54
Q

X-linked recessive inheritance

A

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

54
Q

f

A

f

55
Q

Variable expression

A
  • 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
56
Q

f

A

f

57
Q

f

A

f

59
Q

X-linked recessive pedigree: general features

A
  • 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
60
Q

X-linked recessive pedigree:

Normal father, Carrier mother

A 
Normal father (XY), Carrier mother (Xx)
Children:
XX (normal)
XY (normal)
Xx (carrier)
xY (affected)
61
Q

X-linked recessive pedigree:

Affected father, Normal mother

A 
Affected father (xY), Normal mother (XX)
Children:
xX (carrier)
xX
YX (normal)
YX
62
Q

Hemophilia A

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
62
Q

DMD pedigree

A
  • 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
63
Q

Duchenne’s Muscular Dystrophy

A
  • 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
65
Q

What are two examples of X-linked recessive disorders?

A
  • Hemphilia A

- Duchenne’s Muscular Dystrophy

66
Q

X-linked dominant inheritance

A
  • 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)

67
Q

X-linked dominant punnet square:

Normal Mother, Affected Father

A 
Normal Mother (xx), Affected Father (Xy)
Children:
xX (affected)
xy (normal)
xX
xy
68
Q

X-linked dominant punnet square:

Affected mother, Normal father

A 
Affected mother (Xx), Normal father (xy)
Children:
Xx (affected)
Xy (affected)
xx (normal)
xy (normal)
68
Q

Incontentia Pigmenti

A
  • 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
69
Q

X-linked hypophosphatemic rickets

A
  • X-linked dominant
  • vitamin D-resistant rickets
  • kidney tubules do not reabsorb phosphate
  • females less severely affected than males
71
Q

Mother with IP will have

A
  • 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)

Foundations Week 7 (10 decks)

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