Tay-Sachs Disease

Chromosome Disorders

- autosomal recessive,
- progressive neurodegenerative disorder
- developmental retardation, followed by
paralysis, dementia and blindness, with death in
the second or third year of life
- The basic enzyme defect concerns one of the
two components of hexosaminidase. Component
Hex-A is absent.
- Lack of active hexosaminidase tesults in
accumulation of GM2-gangliosides in cells

Huntington's Disease

Chromosome Disorders

- autosomal dominant
- progressive neurodegenerative disorder
- Physical symptoms can begin at any age from
infancy to old age, but usually begin between 35
and 44 years of age.
- phenotype characterized by chorea, dystonia,
incoordination, cognitive decline, and behavioral
difficulties.
- There is progressive, selective neural cell loss
and atrophy in the caudate and putamen
- associated with CAG repeats
- The function of protein (huntingtin) is unclear.
It is essential for development

Phenylketonuria (PKU)

Chromosome Disorders

- autosomal recessive
- resulting from deficiency of phenylalanine
hydroxylase, enzyme that catalyzes the
hydroxylation of phenylalanine to tyrosine
- undiagnosed and untreated, phenylketonuria can
result in impaired postnatal cognitive development
resulting from a neurotoxic effect of
hyperphenylalaninemia
- Other symptoms include a 'mousy' odor; light
pigmentation; peculiarities of gait, stance, and
sitting posture; eczema; and epilepsy
- treatable by dietary means

Juvenile Diabetes

Chromosome Disorders

• disorder of glucose homeostasis that is
characterized by susceptibility to ketoacidosis in
the absence of insulin therapy
• genetically heterogeneous autoimmune disease
• Appearance of the IDDM phenotype is thought to
require a predisposing genetic background and
interaction with other environmental factors.
• enteroviruses possible trigger

Neural Tube Defects

Chromosome Disorders

• ~1/4000 fetuses
• most common forms: spina bifida or anencephaly
• spina bifida : fetal spinal column doesn't close
completely during the first month of pregnancy.
usually nerve damage causing at least some
paralysis of the legs.
• Anencephaly: much of the brain does not develop.
Babies are either stillborn or die shortly after
birth.
• Risk of early death = 10% in US
• Survival to age 30 = 50-68% in surgically repaired
• Relative risk decreased by 50% or more with folic
acid supplementation
• Variation at numerous single loci associated with
increased risk
• Many associated with folate metabolism

Fetal Alcohol Spectrum Disorder

Chromosome Disorders

• Poor growth while the baby is in the womb and
after birth
• Decreased muscle tone and poor coordination
• Delayed development and significant functional
problems in three or more major areas: thinking,
speech, movement, or social skills (as expected
for the baby's age)
• Heart defects
• Structural problems with the face
• Possible genetic predisposition

• Even single dose can cause deformity in embryo
• May be useful for treatment of viral diseases
• HIV
• Herpes Simplex V
• But risk of birth defect
• 1998 - approved for treatment of severe skin lesions
associated with Hansen’s disease (leprosy)
• Also approved for multiple myeloma

1) Limited Family sizes --> small number of offspring is statistically problematic

2) Mendelian Ratios --> proband only affected individual within pedigree and any families with carriers but non infected are often not studied

3) Limited Number of Affected Families --> small sample sizes and rare trait with few family pedigrees

4) Cannot Predetermine Mating --> hard to determine genotypes, non-informative mating

5) Inaccurate Information --> info on proband but not on relatives

- autosomal dominant

- autosomal recessive

- X-linked recessive

- X-linked dominant

- Y-linked

- Heterogeneity (I-allelic and II-locus)

- Penetrance

- Variable Expressivity

- Pleiotropy

Cystic Fibrosis (CFTR) - Most Severe Phenotypes

7q31.2

Allelic Heterogeneity

• enhanced sodium ion absorption
• thick mucus builds up in the respiratory
system and in the pancreas
• Recurrent respiratory infections
• digestive disorders due to mucus that clogs
the pancreas
• congenital bilateral absence of the vas
deferens
• Delayed growth

Dystrophin Locus (Phenotypes)

Xp21.2

Allelic Heterogeneity

- Duchenne Muscular Dystrophy

- Becker Muscular Dystrophy (milder)

- X-linked Dilated Cardiomyopathy

Androgen Receptor Gene (Phenotypes and Receptor)

Xq11-q12

Allelic Heterogeneity

- Inactivation - Testicular Feminization Syndrome

- Partial Inactivation - Reifenstein Syndrome

- Expansion of glutamine - Spinobulbar Muscular Atrophy

- Receptor has 3 binding domains (N-terminal, DNA, and androgen)

Androgen Receptor Gene

Reifenstein Syndrome

Allelic Heterogeneity

• Sexual dysfunction in males and infertility
• Abnormal male genitals
• Undescended testes
• Small scrotum, with a line down the middle (bifid) or
incompletely closed
• small penis
• Hypospadias (the urethra exits the body on the side of the penis, not the tip)
• Breast development in males at time of puberty
• Decreased body hair and beard, but normal pubic and armpit hair

Androgen Receptor Gene

Spinobulbar Muscular Atrophy

Allelic Heterogeneity

• a form of motor neurone disease which occurs in adults and causes progressive muscle weakness and wasting
• Facial weakness
• Tongue weakness
• Dysphagia (difficulty swallowing)
• Dysarthria (speech impairment)
• Gynecomastia

Fibroblast Growth Factor Receptor 3 (FGFR3)

Phenotypes Caused by Defects

Allelic Heterogeneity

- Achondroplasia - 98% of mutations caused by G --> A at site 1138

- Thanatophoric Dysplasia - dwarfs die in first hours of life, ribs/bones of extremities are very short - Types I & II

- Hypochondroplasia - similar but milder achondroplasia

Lamin A/C Locus

1q21.2

Allelic Heterogeneity

- Lamins --> structural proteins of nuclear lamina

- Lamins A and C are distinct proteins produced by alternative splicing from same gene

Phenotypes

• Progeria (premature aging)
• A type of dilated cardiomyopathy
• Early-onset atrial fibrillation
• A form of Emery-Dreifuss muscular dystrophy
• Limb girdle muscular dystrophy type 1B
• Charcot-Marie-Tooth disease type 2B
• Familial lipodystrophy
• Mandibuloacral dysplasia
• Lipoatrophy with diabetes, hepatic steatosis, hypertrophic
cardiomyopathy, an leukomelanodermic papules

- Diseases/disorders associated with mutations at multiple loci (complementation)

- Associated with blindness, hearing loss, mental illnesses (schizophrenia, autism), and breast cancer

Inherited Hearing Loss (HL)

Locus Heterogeneity

- Most common birth defect

• Non-syndromic hearing loss is when there are no other
significant features besides the hearing loss.
• Syndromic hearing loss involves other medical or
physical findings in addition to the hearing loss.

Non-Syndromic Hereditary Deafness (NSHL)

Locus Heterogeneity

- Many different loci types involved: rec, dom, X-linked, polygenic, mito

- Encode proteins for: hair bundle morphogenesis, ion homeostasis, extracellular matrix proteins, transcription factors, others

Retinitis Pigmentosa

Locus Heterogeneity

- can be caused by autosomal dom RP, autosomal rec RP, X-linked RP, Unknown, Digenic RP

- characterized by constriction of the visual fields, night blindness, and fundus changes, including 'bone corpuscle' or ‘bone spicule’ lumps of pigment

Usher Disease

Locus Heterogeneity

- Autosomal recessive combo of hearing loss and retinitis pigmentosa

- probability that a genotype will yield the expected phenotype (all-or-nothing seen in NF1, Duchenne MD, CF, PKU)

- associated with variable age of onset

- associated with ability to recog the expression of the mutant allele

Wilson Disease

Penetrance

- Hepatic Copper Metabolism Disorder

- dramatic buildup of intracellular copper

- swelling of liver/spleen

- tremors

- muscle stiffness

- Kayser-Fleischer Rings --> copper deposits around iris

- refers to severity of the phenotype

- tnedency of some variable dominant conditions to become more sever in successive generations

Neurofibramatosis (NF1)

Variable Expressivity

- formation of neirofibromas and other formations s whcih predispose to certain cancers based on tissue types

- observe cafe-au-lait spots and fibromatous skin formations

Expanding Trinucleotide Repeats

Variable Expressivity

- Fragile-X Syndrome

- Myotonic Dystrophy

- Huntington's Disease

- Correlated with repeat size (larger repeat, increased age of onset, increase in severity)

- Single locus has effects on more than one phenotypic character

Marfan Syndrome

15q21.1

Pleiotropy

- disorder of fibrous connective tissue

- occurs in skeletal, ocular, and cardiovascular systems

- autosomal dominant

Symptoms

• Skeletal: tall stature, thinness, joint
hypermobility, limb elongation
• Ocular: lens dislocation (ectopia lentis)
• Cardiovascular: increased susceptibility
to heart disease and aortic aneurysms
• mitral valve prolapse, aortic root
dilatation, and aortic dissection
• Other: skin, lung, nervous system

Marfan Inheritance

Pleiotropy

- clear evidence of single pattern of inheritance --> confusing due to pleiotropy, variable expressivity, and allelic heterogeneity

- family evidence of complete recessive inheritance is rare

- inheriting mtDNA

- maternal inheritance (none from father due to sperm mito being selectivley eliminated quantitatively)

- Heteroplasmy - genetic drift within the cell

Leber's Hereditary Optic Myopathy

Mitochondrial Inheritance

Prader-Willi Syndrome

15q11-13

Parental Imprinting

- paternal inheritance of gene

- mental retadation, hypotonia, obesity, hypogenitalism

Angelman Syndrome

15q11-13

Parental Imprinting

- "happy puppet" syndrome

- maternal inheritance of gene

- mental retardation, growth retardation, hyperactivity

- Expression of gene based on parental origin

- methylation of CpG

- occurrence of new mutations during development (make it difficult to interpret pedigree)

- no prior family history of disorder

- mutation clustering can cause dominant mutations to mimic recessive inheritance phenotypically

- risk of recurrence

- occurrence of multiple lineages during devt

- caused by differential gene expression and fusion of multiple zygotes (chimerism)

Mosaic - one zygote mutates and continues division normally

Chimera - two different zygotes fuse and continue division normally

- Both result in the same phenotype but are referred to differently

X-Chromosome Inactivation

Mosaicism

- primary form of mosaicism

- Occur of abnormal phenotype in heterozygous female

Purpose of Pedigree Creation (4 reasons)

Inheritance Patterns

1) Aid to correct diagnosis

2) Determine accurate prognosis

3) Presymptomatic diagnosis

4) Preconception counseling

Autosomal Dominant

Inheritance Patterns

- Phenotype appears in every generation

- Sex indiscriminant

- Recurrence Risk --> each child has a 50% chance of inheriting the disease

- Achondroplasia, NF1

Autosomal Recessive

Inheritance Patterns

- Phenotype does not show every generation

- Requires homozygous condition

- Sex indiscriminant

- Recurrence risk is 25% for siblings

- Tay-Sachs, CF, PKU

- Risk is higher in consanguinous couplings

X-Linked

Inheritance Patterns

- Higher incidence in males than females

- Mother transmits to affected son or carrier daughter

- Affected father transmits to daughter

- Carrier females unaffected (with some variability)

- Duchenne MD, colorblindness

X-linked Dominant

Inheritance Patterns

- More affected females than males

- Females have 50% chance of transmission

- Males affect daughters but not sons

Sex-Limited Inheritance

Inheritance Patterns

- Expressed in only one sex but located on autosome (influence of sex hormones)

- Influenced by anatomy (Females cannot have testicular disorders)

Sex-Influenced

Inheritance Patterns

- Expressed in both sexes but with different degrees of expression (affect penetrance)

- Singing voice pitch, male pattern baldness

- BCRA-1

BCRA-1

Sex-Influenced Traits

- Normal expression protects against breast cancer

- Mutation creates null dominant phenotype and increases risk of breast cancer in women and prostate cancer in men

- Mutations also increase the risk of other forms of cancer

1) Are males or females affected?

2) Vertical Transmission?

3) Male-male-transmission

4) Non-penetrant carriers?

5a) Affected parent --> what children affected

5b) Unaffected parents --> what children affected

6) Age of onset

- Used to follow alternative expressions of a gene in studies

- Involve polymorphisms

- Presymptomatic/Prenatal diagnoses

- Detect heterozygous carriers

- Disease risk

- Linkage mapping

- Forensics

- Zygosity/Paternity Testing

- Direct/Indirect gene variation

- RFLPs --> DNA frags produced close to restriction sites

- Hypervariable Repeat Seqs (VNTRs and STRs)

- seen with PCR and gel - allows multiplexing (examine multiple loci)

- di > tri > tetra-nt repeats

- Fluorescently label mutiplexes

- Higher mutation rates/unequal crossing over

- Co-dominant inheritance

- Not enough STRs to map every disease gene

- SNP - random and co-dominant - more frequent than STRs --> automated detection (Affymetrix and Illumina)

- 1.8 million genetic markers

- ~ 1 mil SNPs

- 2 arrays cover 0.25 mil SNPs

- Larger than 1 kB

- Display copy number differences in comparison to reference

- Locaized variants in DNA which do not give rise to a phenotype or disease

Copy Number Variation

CNV

- In germline

- Inherited or de novo

Copy Number Alteration

CNV

Copy Number Polymorphism

CNV

- Common CNV

- Fixed Start/End position

Copy Number Difference

CNV

1) Single nt polymorphisms (SNPs)

2) Short Indels

3) Simple Seq Repeats

4) Copy Number Variants (CNV)

1) Allele frequencies

2) Genotype frequencies

- Populations changed by size, migration, nonrandom mating, reduced transmission

Allele Frequencies

Population Studies

- Observe linkage, segregation, genetic counseling, association

- Estimation - Count the number of alleles of different types

- Relationship b/t genotypes and allele freqs

1) No mutation

2) No natural selection

3) No migration

4) Infinite Population size

5) Random mating

- Any distribution w/ 2 alleles

- Expressed in allele freqs (ignore genotype freqs)

p² (AA) + 2pq (Aa) + q² (aa) = 1

p + q = 1

Congenital Adrenal Hyperplasia

H-W Equilibrium

- Mutations in the 6p21.3

- Excessive production of androgens and causes virilization

- All copies of disease allele will be present as heterozygotes

- Frequency of homozygotes = q²

- Mutation, Selection, non-random mating, genetic drift, mating choices

Rate Estimation

• recessive autosomal µ = s · q2
• dominant autosomal µ = s · q
• X-linked recessive µ = s · q/3

Mutation

Non-H-W Conditions

- Common and serious

- Propagation from replication errors (triplet repeat, HD, fragile-X)

Selection

Non-H-W Conditions

- Advantageous mutations

- Heterozygote advantage

- Late age of onset

Genetic Drift

Non-H-W Conditions

Mating Choices

Non-H-W Conditions

Non-random mating

- Inbreeding

- Mating by population (regional, national, racial factors)

- Mating by similar phenotypes (deafness, height, etc)

Consanguinity

Non-H-W Conditions

- Inbreeding - two individuals from common ancestor reproduce --> inc probability of recessive homozygosity --> results in increased incidence of an autosomal recessive disease due to consanguinous matings and isolated populations

- Non-random association b/t alleles at two loci

- Trait locus and Marker locus

- Recombination breaks down alleles affected by LD

Arise from:

- Mutation (on a unique chrome)

- Population Isolation/Expansion (follows bottleneck and leads to remote inbreeding)

- Population Mixing

- Selection by locus interaction

Linkage Disequilibrium Analysis

Linkage Disequilibrium

Haplotype analysis --> number of genotypes in population less than possible combos (not enough time) --> associations b/t SNPs and disease phenotypes --> allows gene mapping and personalized medicine

Genetic Association Studies

Linkage Disequilibrium

- detect associations b/t one or more genetic polymorphisms and a trait

- arise only b/c of common ancestry in humans

Genetic Association Causes

Linkage Disequilibrium

Direct

- Close linkage

- Chance

- Pleiotropy

- Population heterogeneity

Indirect

- SNPs or CNVs are surrogates for causal locus

Allelic Association vs Linkage

Linkage Disequilibrium

Allelic Association

- association at population level

- pinpoints alleles

- more powerful

- more tests required

- more sensitive to mistyping

- sensitive to population heterogeneity

Allelic Association vs Linkage

Linkage Disequilibrium

Linkage Associations

- intrafamilial associations

- pinpoints loci

 - less powerful

- fewer test required

- less sensitive to mistyping

- not sensitive to population heterogeneity

- study of genetic variation across entire human genome designeed to id associations with observable traits/disease

- involves many markers and many people to find genetic variation

- useful to find variations in common, complex diseases