2 Mendelian Genetics

parental phenotypes do not blend

• eg. if a parent who has dwarfism & a parent of regular height have a child, the child's height won't be in between it’ll be either regular OR dwarf

genes occur in pairs; only one member of the pair is transmitted

• or 2 members of a pair of genes segregate & pass to DIFFERENT gametes

genes at different loci are transmitted independently

there's a random recombination of maternal & paternal chromosomes in gametes

• • only 1 mutated copy is necessary for expression
• • vertical transmission (people of every generation are affected)
• • there's male to male transmission
• • males & females are equally affected
• • if you don't HAVE the gene then you won't pass it on (unaffected individuals have unaffected children)
• • disorder may arise as a de novo mutation

Achondroplasia

most common form of short-limbed dwarfism

• 1. ACHONDROPLASIA
• 2. Marfan Syndrome

• • short arms & legs, large head, characteristic facial features
• • intelligence/lifespan are usually normal
• • 99% of cases due to 1 of 2 common mutations
• • 1:26-28,000 live births
• • mutated gene = FGFR3
• • 80% of cases are caused by de novo mutations (neither of the parents are dwarfs)

1. Variable Penetrance [you have symptoms or you don’t]

2. Variable Expressivity [different people have different presentations]

the proportion of people who carry a mutated gene of an AD disorder who present with any of the known phenotype/symptoms of the gene

• the frequency of the phenotype is less than 100% in known heterozygotes, aka not everyone who has the AD mutation has symptoms
• eg. BRCA mutation

a person has a gene mutation that is inherited in an autosomal dominant fashion & shows clinical expression

a person has a gene mutation that is inherited in an autosomal dominant fashion but doesn't show any clinical expression

eg. for a male with the BRCA mutation, the penetrance of BRCA gene mutation is lower than for a woman (no ovaries)

[BRCA is a disease that has both variable penetrance & expressivity]

• family members may express symptoms of an autosomal dominant disorder to different degrees
• eg. Marfan syndrome

• features of a disorder vary between affected individuals, even in the same family (different features that can show up in different ways in different family members)

• connective tissue disorder with a high degree of clinical variability
• prevalence: 1:5-10,000

1. Ocular

2. Skeletal: bone overgrowth, joint laxity

3. Cardiovascular: major cause of death = dilatation of the aorta → rupture

increases the risk for de novo mutations (because of the increased number of divisions required to produce sperm throughout a lifetime)

• • 2 mutated copies needed for expression
• • usually only 1 generation is affected
• • both carrier parents are generally normal
• • family history may be negative
• • EQUAL number of males & females affected
• • consanguinity may be present
• • may see ethnic predisposition
• • less clinical variability than autosomal dominant disorders
• • penetrance is usually complete

Pulmonary disease

95%

36.5 years

• Sickle Cell Anemia - most common inherited blood disorder in the US
• • 1/8 of african americans are carriers
• • characterized by intermittent pain crises & organ damage because of vaso-occlusion + chronic hemolytic anemia
• • median life expectancy: 42-48 years
• 

• • if you know somebody who has a sibling that HAS an autosomal recessive condition, both their parents MUST be carriers (they’re obligate carriers)
• • this person by default does not have the “aa” genotype
• • therefore there’s a 67% (2/3) likelihood that they’re a carrier & 33% (1/3) chance they have an “AA” genotype

1. Cystic Fibrosis (1/25 caucasians are carriers)

2. Sickle Cell Anemia (ethnic predisposition)

• • NO male to male transmission [important way to differentiate between X-linked & autosomal dominant*]
• • higher incidence in males than females
• • multiple generations may be affected
• • all daughters of an affected male are carriers
• • carrier females may show variable expression due to lyonization
• 

• • bleeding disorder caused by deficiency in Factor VIII (type A) or Factor IX (type B)
• • most bleeding occurs internally into the joints, muscles
• • reduces life expectancy by ~10 years
• • affects 1:4-5,000 MALES

• • in somatic cells of female mammals, only one X chromosomes is active
• • inactivation occurs at the 32 cell stage in each cell
• • it’s random but FIXED: all daughter cells have the same X active or inactive
• • can be random or skewed (when 1 X chromosome is preferentially active or inactive)

• • can result when skewed X-inactivation occurs in some or all tissues
• • symptomatic females tend to be less severely affected than males
• • eg. men with Duschenne Muscular Dystrophy (DMD) generally don’t make it to reproductive age but some female carriers of DMD have dilated cardiomyopathy indicating there might be slightly skewed inactivation of heart cells

• progressive disease of the skeletal muscle that usually presents in early childhood with delayed motor milestones, waddling gait, & calf pseudohypertrophy
• • dilated cardiomyopathy typically occurs after 18 years old
• • life expectancy = ~27y
• • prevalence: 1:4-5,000 MALES

• 1. cells with unaffected X are inactivated in disproportionate numbers
• 2. she has 45,X karyotype (Turner's, XO) & inherits the mutation containing X chromosome
• 3. she has an X-chromosome rearrangement which results in skewed X-inactivation
• 4. she has an affected father & a carrier mother [rare]
• 5. disorder is genetically heterogeneous (really AR, or not necessarily only x-linked recessive)

1. Hemophilia

2. Duschenne Muscular Dystrophy (DMD)

• all the daughters are carriers, none of the sons are affected
• 

• • more females affected than males
• • sometimes lethal in males
• • affected males have daughters that are ALWAYS affected, but no affected sons
• • no male to male transmission
• • affected females have 50% chance of passing gene on with each pregnancy
• • much less common than X-linked recessive disorders

Incontinentia Pigmenti (lethal in males)

• • disorder of the skin, hair, teeth, nails, eyes & CNS
• • characteristic skin lesions evolve through 4 stages
• • alopecia, hypodontia, abnormal tooth shape & dystrophic nails are observed
• • cognitive delays, intellectual disability sometimes seen
• • RARE: 900-1,200 affected individuals
• 

any pattern of inheritance in which traits do not segregate in accordance with Mendel’s laws

• includes Mitochondrial, trinucleotide repeats, Mosaicism, Genomic Imprinting (uniparental disomy), Multifactorial, Chromosomal

• energy source in cell; location of oxidative phosphorylation

• has it’s own DNA: 16.5 kb circular dsDNA

37

• 2 rRNAs, 22 tRNAs & 13 subunits for ox.phos (although most ox.phos subunits are encoded by nuclear DNA & follow autosomal recessive inheritance)

• • sperm mitochondria degenerate upon penetration of the ovum
• • ovum contributes more cytoplasm to zygote than the sperm
• • mitochondria in offspring are exclusively maternal in origin
• • only mitochondria from oocyte contribute to zygote

• • when a father's affected, none of his children are affected
• • when a mother is affected, ALL her children are affected to some degree
• • some subunits are encoded by mitochondrial genes: these are inherited maternally & can lead to energy failure
• • most proteins functioning in mitochondria are encoded by nuclear genes; when these genes are disrupted, the resulting condition is usually inherited in an autosomal recessive fashion

• • common features = hearing loss, diabetes, seizures, intellectual disability, cardiomyopathy
• • caused by a HETEROPLASMIC point mutation with mtDNA
• • prevalence not well defined: 0.1-2.5/1,000

mixture of normal & abnormal mtDNA within a cell or individual

all mtDNA is the same (either normal or abnormal)

RANDOM - for both mitosis & meiosis

• • a certain percentage of abnormal mtDNA will be tolerated without symptoms until a critical threshold is reached, then symptoms will appear
• • clinical phenotype can vary according to the percentage of abnormal mtDNA
• • threshold can differ among individuals, even among different tissues in same individual
• • over time, more organ systems can be affected, as more tissues exceed the threshold
• 

• mitochondria are partitioned along with the cytoplasm during cell division; distribution of mutant & normal molecules in the daughter cells of heteroplasmic cell may be unequal

• in course of development & differentiation, different parts of the body may have different proportion of mutant molecules

• - selective advantage
• - random genetic drift

a smaller mtDNA might arise because of a deletion, replicate faster than a normal, full length mtDNA, therefore gradually increase its load over time

mitochondrial function DECREASES with age

• may result from damage to mtDNA from free radicals due to ox.phos or increased mutation rate because mtDNA doesn’t have the same repair mechanisms that nuclear DNA has

• reduction in functioning may contribute to worsening of mitochondrial disease with age & loss of mitochondrial function may contribute to the aging process in general

tissues with high energy requirements, eg. brain, skeletal muscle, heart muscle, smooth muscle

a muscle biopsy is performed to measure enzyme function and analyze mtDNA

it is theoretically possible but prognosis is difficult to predict because of heteroplasmy

• Nuclear Transfer
• • mom’s eggs extracted using IVF
• • her nucleus is removed & put into DONOR’S egg (other egg’s nucleus removed prior as well)
• • mother passes on genetics, just not mitochondrial DNA to children!
•