Principles of Genetic Inheritance Flashcards
LO #1 Principles of Genetic Inheritance
- To understand and explain the genetic inheritance of disease states, you should be able to:
a. Analyze human pedigrees to appropriately identify the mode of genetic inheritance associated with:
i. Recessive traits
ii. Dominant traits
iii. X-linked diseases
iv. Mitochondrial inheritance - Compare and contrast most common mtDNA-related diseases
Pedigrees 101 (1 of 2)
Pedigrees 101 (2 of 2)
What is a proband?
Proband (propositus):
First diagnosed person in the pedigree
Describe Autosomal Dominant Inheritance
- Only 1 allele of a gene is needed for expression
- Affected offspring only needs 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 Dominant Inheritance
–Combinations of alleles from the fertilization of egg by sperm
–Recurrent risk is 50%
Describe Autosomal Recessive Inheritance
- 2 copies of a mutant allele (gene) is needed to influence phenotype
- One mutant allele present: the individual is a carrier of the mutation but will not display phenotype
- Females and males are affected equally
- If two carriers of the mutation procreate, the child will have a 25% chance of being unaffected, 25% of being affected and a 50% of being an unaffected carrier
- Autosomal Recessive Inheritance
- Two carriers mating
- Resulting combinations of alleles from the fertilization of egg by sperm
–25% chance of being unaffected, 25% of being affected and a 50% of being an unaffected carrier
ex.
- Oculocutaneous albinism type 1A (OCA1A)
- 1/40,000
- 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 to 4 months of life.
- Visual acuity ranges from 20/100 and 20/400 and an alternating strabismus is often present.
- Sun-exposed skin becomes rough, coarse, thickened and can have solar keratoses.
- Patients have an increased risk of developing basal and squamous cell carcinomas (melanoma rare)
Describe X-linked Recessive Inheritance
Recall: males (XY) ; females (XX)
- Disease allele on X in males is termed “hemizygous”
- Females can be heterozygous or homozygous
- Rarely affected but can be if they are homozygous and lyonization occurs in development
- Always expressed in male carriers
- Unaffected males don’t transmit the trait (not carriers)
- Female carriers transmit the disease allele to 50% of sons and 50% of daughters
- All daughters of affected males are heterozygous carriers
- Never father-to-son transmission (X-linked)
ex.
Duchenne Muscular Dystrophy
1/5000 males at birth
Usually fatal by mid-20’s
Absence or defect in dystrophin
- Males are hemizygous for genes on sex chromosomes, having only one X and one Y chromosome
- Absence in or defect of dystrophin
- Muscle weakness usually occurs around age of 4 in boys and then progressively worsens
- Females are often termed “manifesting carriers” (lyonization – X-inactivation) [Am. J. Hum. Genet. 46:672-681, 1990]
- Skewed X-inactivation during embryonic stage (where there are limited number of cells giving rise to the different germ layers) [https://www.nature.com/articles/s41431-018-0291-3]
- 2/3 of cases are genetic in origin (mother), 1/3 are random mutations
- observed clinically from the moment he takes his first steps.
- It becomes harder and harder to walk
- ability to walk usually completely disintegrates between 9 to 12 years of age
- Most men essentially “paralyzed from the neck down” by the age of 21.
- Muscle wasting begins in the legs and pelvis, then progresses to the muscles of the shoulders and neck, followed by loss of arm muscles and respiratory muscles.
- Cardiomyopathy is common
What is Mitochondrial DNA (mtDNA)?
- Several copies of 16,569 bp, double-stranded, circular mtDNA molecule per mitochondria
- Encodes rRNA, tRNA, and 13 polypeptides involved in oxidative phosphorylation
- Transcription takes place in the mitochondrion, independently of the nucleus
- Contain no introns
- Inherited exclusively through the maternal line
- Mutation rate is ~10x higher than nDNA
–No DNA repair mechanisms
–Damage from free oxygen radicals from OXPHOS
Pedigree Hallmarks:
All offspring of an affected woman will be affected
Affected female offspring will pass to all offspring
Affected males will not pass on to offspring
MELAS and Mitochondrial heteroplasmy
mutations graphic
Heteroplasmy of mitochondria graphic
What is Leber’s hereditary optic neuropathy (LHON)?
•Leber’s hereditary optic neuropathy (LHON)
–Degeneration of retinal ganglion cells
–Caused by one of three pathogenic mtDNA point mutations affecting NADH dehydrogenase
•Starves RGCs of energy, making them unable to transmit signals to the brain.
–Acute or subacute loss of central vision
- Typically early teens or 20’s
- Inter-eye delay of 8 weeks
–Really exciting gene therapy research ensuing
- Leber heredity optic neuropathy (LHON): due to mutations in genes that encode the subunits of complex I. This results in less active complex I, which presents as acute loss of vision in early adulthood.
- impaired glutamate transport and increased ROS causing apoptosis of retinal ganglion cells (RGC).
What is Myoclonic epilepsy and ragged red fibers (MERRF)?
•Myoclonic epilepsy and ragged red fibers (MERRF)
–Caused by a mutation in the gene encoding for tRNA for lysine, which disrupts the synthesis of cytochrome-c oxidase
–Patients present with myoclonus dinated muscle movement*, ataxia, seizures, dementia
–Particularly affects the muscles and nerves
–Large variability of presentation due to heteroplasmy
- Myoclonic epilepsy and ragged red fibers (MERRF): caused by a mutation in the gene or the tRNA for lysine, which disrupts the synthesis of cytochrome-c oxidase
- Patients with this conditions display sudden, brief involuntary twitching or jerking, ataxia, seizures, eventual dementia
What is Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)?
•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, migraine
- Mitochondrial encephalopathy, lactic acidosis and stroke-like activity (MELAS): there is a mutation in the tRNA gene for leucine, which disrupts the synthesis of complex I and cytochrome-c oxidase. This affects the nervous system and muscle function. Patients present with a host of symptoms including severe headaches, seizures, vomiting, and hemiparesis.
- Most common is point mutation
- Dysfunctional mitochondria due not utilize pyruvate which is converted to lactic acid (accumulation
Describe X-linked Dominant Inheritance.
•Males with the disease allele transmit the trait:
–Only to females
–100% transmission to females
•Females with the disease allele transmit the trait:
–To both males and females, equally
–50% transmission to offspring
- Vitamin D resistant rickets: hypophosphatemia
- Alport syndrome
- Incontinentia pigmenti
- Fragile X syndrome
- Rett syndrome*
- 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 abnormal
- Short stature
- Incidence: 1/60,000
- Treatment: oral phosphate & vitamin D
•
- 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, and seizures occur in about 10%.
- expansion of the CGG triplet repeat within the FMR1 (fragile X mental retardation 1) gene on the X chromosome
- This results in silencing and a deficiency of the FMRP (required for the normal development of connections between neurons
LO #2 Principles of Genetic Inheritance
- To understand the chromosomal basis of human disease, you should be able to:
a. Explain nondisjunction, polyploidy, aneuploidy, uniparental disomy and genomic imprinting
b. Compare and contrast these chromosomal abnormalities:
i. Prader-Willi syndrome
ii. Klinefelter syndrome
iii. Trisomies 13, 18, and 21
c. Understand from the correlation boxes:
i. Uniparental disomy (orange; p. 319)
ii. Genomic imprinting (orange; p. 320)
iii. Chromosomal mutations (blue; p. 328)
iv. Karyotyping (blue; p. 385)
Describe Meiotic Errors.
•Euploid: cells with a normal number of chromosomes
–Ex. Haploid gametes and diploid somatic cells
- Nondisjunction: abnormal separation of one or more pairs of homologous chromosomes or sister chromatids
- Polyploidy: cells contain a complete set of extra chromosomes in a cells
–Multiple of 23, incompatible with human life
–Often seen in plants
•Aneuploidy: cells contain a missing or additional individual chromosomes
–Monosomy, trisomy
(Left) nondisjunction at Meiosis I (failure of homologous chromosomes to separate)
(RIght) nondisjunction at Meiosis II (failure of sister chromatids to separate)
What is nondisjunction?
- 1:1 ratio of daughter cells with an extra chromosome (2n+1) to those with a loss of a chromosome (2n-1)
- Germline mutation if occurs during meiosis (in spermatocyte or oocyte)
–Transmissible to the next generation
•If occurs during mitosis (after fusion of ovum and sperm) individual will exhibit mosaicism
–Only some of the cells with be aneuploid
–The earlier the mutation occurs in embryogenesis, the greater the number of aneuploid fetal cells
The most common cause of aneuploidy
Nondisjunction: the failure of chromosomes to separate normally during meiosis
Can occur during meiosis I or II
(Left) nondisjunction at Meiosis I
(RIght) nondisjunction at Meiosis II
The resulting gamete either lacks a chromosome (monosomic) or has two copies (trisomic)
Separate the homologues during meiosis I and separate the sister chromatids during meiosis II
Meiosis I: gamete with an extra chromosome or gamete lacking chromosome
Result is Offspring with too many or too few chromosomes
Meiosis II: separation of the homologues occurs, but nondisjunction in the separation of the chromatids
The most common cause of aneuploidy
Nondisjunction: the failure of chromosomes to disjoin normally during meiosis
Can occur during meiosis I or II
The resulting gamete either lacks a chromosome (monosomic) or has two copies (trisomic)
Why does nondisjunction increase with maternal age? These originate with gametes and these gametes start developing when they’re a fetus, so the female gametes are 40-years old as well. Lots of opportunity for errors and mutations.
What is genomic imprinting?
[ORANGE BOX]
Genomic Imprinting (pg. 320): Mendelian inheritance dictates that we receive an active copy of each gene from each of our parents.
- However, in genomic imprinting certain genes are expressed only from the mother or the father.
- Imprinted alleles are silenced such that the gene is expressed only from the non-imprinted allele of the mother or father.
- Imprinting is an epigenetic process that involves the methylation and histone modification of egg or sperm cells during their formation while the genetic sequence is unchanged.
- Imprinting pattern is duplicated in all somatic cells.
- Very few genes are imprinted, but dysfunction of these genes leads to genetic defects such as Prader-Willi syndrome.
What is uniparental disomy?
[ORANGE BOX]
Uniparental disomy (pg. 319): UPD is a phenomenon when an individual receives two copies of a chromosome or part of a chromosome from one parent and no copes from the other parent.
- Can occur as random error in meiosis during the formation of egg and sperm cells
- Could also occur in early fetal development
- Often is asymptomatic because the individual still has at least one copy of each gene
- If UPD occurs in imprinted genes, there may be delayed development, mental retardation, and other medical issues
- Prader-Willi syndrome occurs from UPD, which involves imprinting gene on the long arm of chromosome 15
- Dysfunction of these gene leads to uncontrolled eating and obesity
- Both chromosomes are inherited from the one parent
–Along with the parent-specific imprinting
–UPD likely has no effect on health or development
– Since most genes are not imprinted, it doesn’t matter if a person inherits both copies from one parent
–UPD may result in a lack of active copies of essential genes
Related to nondisjunction and genomic imprinting
Loss of gene function can lead to delayed development, intellectual disability, or other health problems
What are Prader-Willi and Angelman Syndromes?
•UPD or deletion in chromosome 15
–Phenotype depends on if deletion is on paternal or maternal chromosome
–Paternal = Prader-Willi Syndrome
•Short stature, hypotonia, small hands/feet, obesity, mild to moderate intellectual disability, uncontrolled eating
–Maternal= Angelman Syndrome
- Severe intellectual disability, seizures, ataxic gait
- Angelman Syndrome:
–UPD chromosome #15 (paternal)
–Non-UPD if section of the mother’s chromosome #15 is deleted
•Prader-Willi Syndrome:
–UPD chromosome #15 (maternal)
–Non-UPD if section of father’s chromosome #15 deleted
Graphic- gene imprinting in Prader-Willi and Angelman Syndromes
What is genomic imprinting?
•For some human genes, one of the alleles is transcriptionally inactive (no mRNA produced)
–Depending on the parent from whom the allele was received
- An allele transmitted by the mother would be inactive, and the same allele transmitted by the father would be active
- A phenotypically normal individual would only have one transcriptionally active copy of the gene
Mendel’s work established that in peas, phenotype is the same whether a given allele is inherited from the mother or father
•Imprinting is essentially gene silencing
–Through methylation of 5’ region of gene
–Chromatin condensation
•At least 100 human genes known to be imprinted
–Most in genomic regions containing clusters of imprinted genes
- Epigenetic imprints remain throughout the lifespan of the individual in somatic cells
- In germ cells, epigenetic imprints are reset at each generation
–In meiosis, imprints are erased and new ones are set
epigenetic phenomenon that causes genes to be expressed in a parent-of-origin-specific manner.
What are Chromosomal mutations?
[BLUE BOX]
Chromosomal mutations (pg. 328): Mutations involve large segments of DNA, often encompassing millions of base pairs.
- Inversion: segment of chromosomal DNA is present in its reverse orientation
- Deletion: a segment is lost
- Duplication: segment is copied, resulting in amplification of genes contained in that region
- Translocation: to different chromosomes exchange segments of their DNA. Translocation can either be balanced (where the resultant hybrid chromosomes are similar length to their normal counterparts) or unbalanced (where they are dissimilar in length).
What are translocations?
•Non-homologous chromosomes exchange genetic material
–Reciprocal
•Exchange of material between nonhomologous chromosomes
•
–Robertsonian
•Long arm of two acrocentric chromosomes combined, short arm typically is lost
What is karyotyping?
[BLUE BOX]
Karyotyping (pg. 385): a technique that allows the determination of he number, size and gross structures of metaphase chromosomes.
- Karyotyping is the traditional gold standard cytogenic method used in identifying several chromosomal abnormalities associated with genetic disorders
- Does not provide information at the molecular level
What is 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
–~30% webbed neck
–Low hairline on neck
–CV defects
–No cognitive defects
(coarctation of aorta, bicuspid aortic valve)
What is Klinefelter Syndrome?
•Karyotype: 47, XXY
–Varying presentation
–Varying degrees of cognitive, social, behavioral, 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)
What is Trisomy 21?
•Downs Syndrome (47, XX +21)
–Most common (1 in 700 pregnancies)
–Strongly associated with increased maternal age
–Results most commonly from maternal meiotic nondisjunction (in the ovum)
–Also due to unbalanced translocation 46, XX der(14:21)(q10;q10)+21 (only 4% occurrences)
–Varying degrees of cognitive impairment
–Structural abnormalities: increased nuchal translucency, cardiac defects, duodenal atresia, ventriculomegaly, absent nasal bone, short limbs
Duodenal atresia: duodenum not fully formed and intestines are blocked
Ventriculomegaly: dilatation of the lateral cerebral ventricles
Nuchal translucency: maximum thickness of the subcutaneous translucency between the skin and the soft tissue overlying the cervical spine
There are three types of Down syndrome: trisomy 21 (nondisjunction), translocation and mosaicism.
Trisomy 21, the most common type of Down syndrome, occurs when there are three, rather than two, number 21 chromosomes present in every cell of the body. Instead of the usual 46 chromosomes, a person with Down syndrome has 47. It is this additional genetic material that alters the course of development and causes the characteristics associated with the syndrome. Trisomy 21 accounts for 95% of cases.
Translocation accounts for 4% of all cases of Down syndrome. In translocation, part of chromosome 21 breaks off during cell division and attaches to another chromosome, typically chromosome 14. While the total number of chromosomes in the cells remain 46, the presence of an extra part of chromosome 21 causes the characteristics of Down syndrome.
Mosaicism occurs when nondisjunction of chromosome 21 takes place in one – but not all – of the initial cell divisions after fertilization.When this occurs, there is a mixture of two types of cells, some containing the usual 46 chromosomes and others containing 47. Mosaicism accounts for about 1% of all cases of Down syndrome.
Duodenal atresia: duodenum not fully formed and intestines are blocked
Ventriculomegaly: dilatation of the lateral cerebral ventricles
Nuchal translucency: maximum thickness of the subcutaneous translucency between the skin and the soft tissue overlying the cervical spine
What is Trisomy 18?
•Edwards Syndrome (47, XX +18)
–1 out of every 6000 births
–Often IUGR
–95% die in utero
–<10% of live births survive to 1 year
–Microencephaly, prominent occiput, malformed and low-set ears, small mouth and jaw, cleft lip/palate, rocker bottom feet, overlapped fingers
What is Trisomy 13
•Patau Syndrome (47, XX +13)
–Severe developmental abnormalities
–1 out of every 12,500 births
–Most die before birth
–Most perinatal death within 1 week (13% of live births survive to 10 y.o.)
–Heart abnormalities, kidney malformations, CNS dysfunction
–Microcephaly, malformed ears, closely spaced/absent eyes, clenched hands and polydactyl, cleft lip/palate
Free trisomy of chromosome 13 (75% of cases), and trisomy from Robertsonian translocations (25% of cases)
CNS anomalies (45%–55%): holoprosencephaly, agenesis of the corpus callosum, and cerebellar malformations., Craniofacial anomalies (80%): bilateral cleft lip and palate, micro and anophthalmia, and micrognathia., Congenital heart disease (40%–50%):septation defects and absent pulmonary venous return., Urinary tract anomalies (30%–35%): cystic renal dysplasia., Skeletal anomalies (20%–30%): postaxial polydactyly and clenched hands [6]., Abdominal wall anomalies (30%): exomphalos etc. Trisomy 13 or Patau syndrome is a lethal condition in most cases, and 95% of the survivors die within 6 months. Very rare cases without severe malformations have survived for several years. With epilepsy, severe psychomotor delay and blindness can also be associated.
LO #3 Principles of Genetic Inheritance
- To understand the occurrence of retinoblastoma, neurofibromatosis, Marfan syndrome and other clinical manifestations, you should be able to (Medical Genetics, p. 67-74):
a. Explain factors affecting the variability in the expression of disease-causing genes, including de novo mutations, reduced penetrance, locus heterogeneity, pleiotropy, mosaicism and lyonization (X-inactivation).
These factors usually affect disorders that have an autosomal dominant pattern of inheritance, although they are occasionally seen in disorders with an autosomal recessive inheritance pattern.
What is Reduced/Incomplete Penetrance?
- The frequency a gene manifests itself is called penetrance
- Proportion of individuals in a population who carry a disease-causing allele and express the disease phenotype
- Reduced penetrance often occurs with familial cancer syndromes.
- Retinoblastoma is a cancer of the retina that primarily affects children and is caused by mutations in the Rb gene. Interestingly, not all people who carry this mutation suffer from retinoblastoma.
- For example, many people with a mutation in the BRCA1 or BRCA2 gene will develop cancer during their lifetime, but some people will not.
- Reduced penetrance probably results from a combination of genetic, environmental, and lifestyle factors, many of which are unknown.
- Huntington’s disease also presents with incomplete penetrance
Retinoblastoma
- Autosomal dominant inheritance
- Phenotype occurs in 90% of individuals inheriting gene defect; so 90% penetrance
A dominant trait seemingly skipping generations
False conclusion that a trait is recessive
What is Variable Expressivity?
•Describes the range of phenotypes that vary between individuals with a specific genotype
Expressivity measures the extent to which a given genotype is expressed at the phenotypic level.
Different degrees of expression in different individuals may be due to variation in the allelic constitution of the rest of the genome or to environmental factors
Expressivity measures the extent to which a given genotype is expressed at the phenotypic level.
Different degrees of expression in different individuals may be due to variation in the allelic constitution of the rest of the genome or to environmental factors
Dislocated lens (ectopialentis)
sudden tearing of the layers in the aorta wall
Defects in fibrillin
1 in 3000-10,000 live births
Marfan Syndrome
Affects the connective tissue, subsequently many different systems
Ectopia lentis, weakened and stretched aorta
May lead to an aneurysm and aortic dissection
Penetrance vs. Expressivity
What is Locus Heterogeneity?
•Single disorder, trait, or pattern of traits caused by mutations in genes at different chromosomal loci
–Only one mutant locus is needed for the phenotype to manifest.
–Mutations in COL1A1, COL1A2, CRTA, and P3H1
bones that break easily, often from mild trauma or with no apparent cause.
Types I-VIII (I being least severe and II being most severe)
Mutations in COL1A1, COL1A2 represent 90% of all cases
CRTA, and P3H1 more severe phenotypes
blue sclerae, short stature, hearing loss, respiratory problems, and a disorder of tooth development called dentinogenesis imperfecta. The most severe forms can result in abnormally small, fragile rib cage and underdeveloped lungs. Infants with these abnormalities have life-threatening problems with breathing and often die shortly after birth.
Perinatally fatal Type II OI
Osteogenesis Imperfecta
Brittle-bone disease (7/100,000)
Mutations in collagen genes (two loci: chromosome 7 and 17), either mutation exhibits similar phenotypes (varying severity
LO #4 Principles of Genetic Inheritance
- To understand trends in population health and important clinical manifestations associated with topics in population genetics, you should be able to:
a. Apply the Hardy-Weinberg equilibrium in predicting incidences of genetic disease in populations
b. Describe the impact of consanguinity of the inheritance of genetic diseases
c. Apply the basics of quantitative genetics to determine gene and genotype prevalence in populations
d. Describe the criteria for determining recurrent risks of diseases in multifactorial inheritance
Basic Concepts of Probability (genetics)
- Independence: the occurrence of one does not affect the probability of occurrence of the other
- Multiplication Rule: probability of a given outcome in multiple trials is the product of the probabilities of each trial outcome
- Addition Rule: probability of either one outcome or another is the sum of the two probabilities
Describe Gene/Genotype Frequency.
- Measure and understand population variation in the incidence of genetic disease
- Gene frequencies specify
- The proportions of each allele in a population
- The proportions of each genotype in a population
- Under simple conditions and assumptions, these frequencies can be estimated by direct counting
Recall that a genotype is one’s genetic make-up (i.e. allele pair) at a given locus
Gene/Genotype Frequency: Example
MN blood group (locus on chromosome 4), 200 subjects (and therefore 400 alleles)
- There are two major alleles, labeled M and N
- Afpenetrancefter blood typing the subjects:
Genotype # Genotypes Genotype Frequency
MM: 64 64/200 = 0.32
MN: 120 120/200 = 0.60
NN: 16 16/200 = 0.08
Allele # Alleles Allele Frequency
M: (64x2)+120=248 248/400 = 0.62
N: (16x2)+120=152 152/400 = 0.38
Describe Hardy-Weinberg Principle.
- Specifies the relationship between gene frequency and genotype frequency
- Useful in estimating gene frequency from Disease Prevalence Data
-To estimate the incidence of heterozygous carriers of recessive disease gene
•In the MN blood group example, due to co-dominance, the three genotypes can be easily distinguished, blood-typed and counted
p^2 + 2pq + q^2 = 1
•
- Locus that has two alleles: A and a
- Only know the frequency of allele A (p) and deduce a (q) [0.7 and 0.3, respectively]
- Want to determine the population frequencies of each genotype: AA, Aa, and aa
- Assuming random mating, use the rules (i.e. multiplication and addition) to obtain genotype frequencies:
AA: p2 = 0.49 {multiplication rule}
aa: q2 = 0.09 {multiplication rule}
Aa: 2pq = 2(0.21) = 0.42 {addition rule}
Hardy-Weinberg Principle example
What is cystic fibrosis?
•Recessive inheritance of disease
–Only the affected homzygotes (i.e. aa), are distinguishable
- H-W tells us that the frequency of aa should be q2
- The incidence of cystic fibrosis (in European population), q2 = 1/2500
Suggests many recessive disease alleles are effectively “hidden”
The thick and sticky mucus associated with cystic fibrosis clogs the tubes that carry air in and out of your lungs. This can cause signs and symptoms such as:
A persistent cough that produces thick mucus (sputum)
Wheezing
Breathlessness
Exercise intolerance
Repeated lung infections
Inflamed nasal passages or a stuffy nose
Describe Autosomal Inheritance Patterns
- Autosomal Dominant:
- Vertical transmission of the disease phenotype
- Lack of skipped generations
- Roughly equal numbers of affected males and females
- Father-to-son transmission may be observed
•
- Autosomal Recessive:
- Clustering of the disease phenotype among siblings
- Disease is not usually seen among parents or other ancestors
- Equal numbers of affected males and females
- Consanguinity may be present
What is Consanguinity?
- Consanguineous mating’s are more likely to produce offspring affected by rare autosomal recessive disorders
- Studies show that mortality rates
among the offspring of first-cousin
mating’s are up to 9% higher than
those of the general population
Each person potentially carries one to five recessive mutations lethal to offspring if matched with another copy of the mutation (homozygosity)
LO #5 Principles of Genetic Inheritance
- To understand how variations in clinical manifestations can arise from multifactorial inheritance, you should be able to (Medical Genetics, p. 239-246):
a. Describe the translational threshold model
b. Understand from the correlation box:
i. Heteroplasmy (orange; p. 320)
Describe Multifactorial Inheritance
- Polygenic: traits in which variations are thought to be caused by the combined effects of multiple genes
- Multifactorial: when environmental factors cause variation in the trait
- These traits are caused by the additive effects of many genetic and environmental factors
–They tend to follow a normal, or bell-shaped distribution in populations
–Particularly quantitative traits (measurable)
The distribution of height in a population
“Many genes”
Previous discussion has focused mutations in single genes or by abnormalities of single chromosomes.
A much larger component of disease burden is composed of congenital malformations and common adult diseases (cancer, heart disease, and diabetes).
Complex interplay of multiple genetic and environmental factors.
Assume Height is determined by a single gene with two alleles, A and a. Allele A tends to make people tall, and allele a tends to make them short.
If there is no dominance at this locus, then the three possible genotypes, AA, Aa, and aa, will produce three phenotypes: tall, intermediate, and short.
Assume that the allele frequencies of A and a are each 0.50. If we assemble a population of individuals, we will observe the height distribution
Assume that height is determined by two loci instead of one. The second locus also has two alleles, B (tall) and b (short), and they affect height in exactly the same way as alleles A and a do. There are now nine possible genotypes in our population: aabb, aaBb, aaBB, Aabb, AaBb, AaBB, AAbb, AABb, and AABB. Because an individual might have zero, one, two, three, or four “tall” alleles, there are now five distinct phenotypes
Extend = example so that many genes and environmental factors influence height. Then there are many possible phenotypes, each differing slightly, and the height distribution approaches the bell-shaped curve. Identified more than 200 loci associated with human height (polygenic, multifactorial trait).
- For diseases that do not follow the bell-curve distribution there is an underlying liability distribution
- For multifactorial diseases that are either present or absent, it is thought that a threshold of liability must be crossed before the disease is expressed
–Below the threshold, the person appears normal
–Above the threshold, the person is affected by the disease
What is Pyloric Stenosis?
•Pyloric Stenosis: muscular hypertrophy between stomach and duodenum
–Leads to vomiting and obstruction
–Five times more common in males than females
–Males need less risk genes to show disease; females need more risk genes
•Least affected sex has a higher risk threshold and transmits the condition more often to the most frequently affected sex
–Children of women with pyloric stenosis are more likely to be born with condition (especially males)
–Children of affected males with pyloric stenosis are less likely to be born with condition
Describe Multifactorial Inheritance: Recurrence Risks and Transmission Patterns
•Recurrence risks for multifactorial diseases can change substantially from one population to another
–Gene frequencies as well as environmental factors can differ among populations
- Recurrence risk is higher if more than one family member is affected
- If expression of disease in the proband is more severe, the recurrence risk is higher
- Recurrence risk is higher if the proband is of the less commonly affected sex
- The recurrence risk for the disease usually decreases rapidly in more remotely related relatives
- Simultaneous influence of multiple genetic and environmental factors
- Trait may be influenced by the combination of a single gene with large effects and a multifactorial background
–Additional genes and environmental factors might have small individual effects
The distribution of height, assuming the presence of a major gene (genotypes AA, Aa, and aa ) combined with a multifactorial background
