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Fanconi Anemia (FA)

- Diagnosis critically depends on a positive result from a chromosomal breakage test in which cells are exposed to a cross-linking agent such as mitomycin C
- Mainly affects the bone marrow. It results in decreased production of all types of blood cells
- 13 Complementation groups
- Genes involved in DNA repair and
Genomic instability.
- Mutations also increase risk for childhood cancer and BC
- Complementation analysis can determine if two mutations causing a similar phenotype are alleles of the same gene

Synthetic Lethality

Each single mutation is viable but when intercrossed the resulting double mutants are lethal; Two mutations fail to complement and yet do not map to the same locus.

***A genetic interaction of two non-allelic and non-lethal genes that when mutated simultaneously results in cell death.

Happens With:
- Double mutants in redundant/ compensating genes
- Interference with a haploinsufficiency

Additive Alleles

Two or more gene loci account for the hereditary influence on the phenotype in an additive way; Each locus is occupied by _________ that contributes a constant amount to the phenotype. (That amount is often small).

The more _____________, the more phenotypic variation.

Discontinuous Traits

Traits occur in distinct categories; Trait is there or it is not.
(Examples: Albinism, Cystic Fibrosis, Huntington's Disease) - Mendelian Inheritance,
Single Genes, Dominance, Recessiveness

Continuous Traits

Distribution of phenotypes in the population varies along a continuum. Individuals differ by small degrees.
(Examples include Height, Blood Pressure, Reaction time, Learning Ability) - Polygenic Quantitative or Multifactorial Inheritance. (Genes act additively)


The proportion of total phenotypic variation in a population due to genetic factors.

It does not indicate how much of a trait is genetically determined or the extent to which an individual's phenotype is due to genotype

Signs of Complex Genetic Disease

- Imprecise phenotype
- Incomplete penetrance
- Multiple phenocopies
- Locus heterogeneity
- Allelic heterogeneity
- Polygenic effects
- Large numbers of isolated cases
- Increased risk to relatives
- Risk to relatives declines with decreasing kinship to the proband
- No recognizable pattern of inheritance

Quantitative Traits

Traits that are continuous & can be measured, e.g.:
• Atherosclerosis
• Obesity

Qualitative Traits

Traits that are discontinuous/discrete, e.g.:
• Cleft Palate
• Neural Tube Defects

Neural Tube Defects

Around the 3rd or 4th weeks of pregnancy, specialized cells on the dorsal side of the fetus begin to fuse and form the neural tube; an opening in the spinal cord or brain that occurs very early in human development

One of the most common birth defects,
occurring in approximately one in 1,000 live births in the US.

- Cranial defects
• Ancencephaly
- Spinal defects
• Spina bifida
• Meningocele
• Meningomyelocele
• USA Incidence: 0.2%
• Can occur isolated or as part of a syndrome or
teratogenic effect

Recurrence Risks

If the prevalence of the disease in the population is f, the risk for offspring and siblings of the proband is ABOUT f^(0.5); based on observations of large numbers of families with a disease

Higher if one family member is affected
- Higher if the expression of the disease in the proband is more severe
- Higher if the proband is of the less commonly affected sex
- Decreases rapidly in more remote relatives
- Recurrence risks can change rapidly from one population to another.

Twin Studies

• Disease concordance <100% indicates both
genetic and environmental contributions
- In pairs of MZ twins, if one has cystic fibrosis, the
other one will have it too. (100% concordance)
- In pairs of MZ twins, if one has diabetes type I,
the other twin is likely to have diabetes type I
40% of the time. (40% concordance)

Adoption Studies

Twins raised apart - Kids of affected parents raised by unaffected parents
Example: Kids born to parents with schizophrenia and raised by unaffected parents have an 8 - 10% chance of disease. Compare to kids born to parents without disease - have only 1% chance of disease.

Difference between Suppression & Epistasis

A suppressor cancels the expression of the mutant allele and restores the corresponding wild type phenotype

Difference between X-Linked Dominant & X-Linked Recessive

X-Linked Dominant = Affected Father + Normal Mother = Normal Sons & All Affected Daughters

X-Linked Recessive =

X-Linked Recessive = Affected Father + Normal Mother


wild type arising from reversal of a mutation in the same gene

Suppressor (Suppressor Genes)

a mutant allele of a gene that reverse the
effect of a mutation of another gene, resulting in a wild type or near wild type phenotype

Complementation Groups

Groups with the ability to complement and restore the normal activity of a gene; Arises because loss of function in genes responsible for different steps in the same metabolic pathway can give rise to the same phenotype

X-inactivation & Dosage Compensation

demonstrates mosaicism in heterozygote carriers. Half of the cells lack pigment, the other half express the normal allele.

Germline or Somatic Mosaicism (Mosaics)

The presence of two populations of cells with different genotypes in one individual who has developed from a single fertilized egg.


the presence of a new mutation during early embryogenesis in a germline stem cell of an unaffected individual.

Depending on when during the development of the germline the mutation occurred, multiple siblings can be affected.

*Can make a dominant mutation look like a recessive.

Rett Syndrome

a debilitating neurological disorder diagnosed almost exclusively in females with no cure; appear to develop normally until 6 to 18 months of age when they enter a period of regression, losing speech and motor skills.

Fewer than 1% cases are familial

Most develop repetitive hand movements, irregular breathing patterns, seizures and extreme motor control problems.

Reye Syndrome

a phenocopy of urea cycle defect; occurs in children that had a viral infection (Flu or chicken pox) and were given Aspirin.

Children get sick very suddenly with severe encephalopathy.

The hallmark of encephalopathy is an altered mental state:
- loss of cognitive function,
- personality changes,
- inability to concentrate,
- lethargy,
- depression
- tremor, seizures

Mitochondrial Inheritance

- transmited through ova.
- male gametes DO NOT contribute their cytoplasm to the zygote
- Traits pass from mother to child
- No male with the disease can transmit it to his children
- Disorders involve combinations of CNS, eye, & muscle tissue abnormalities
- Genes code mainly for RNA genes for oxidative phosphorylation (to generate ATP)


All mitochondrial DNA (mDNA) are identical


Many mitochondrial DNA, not all the same


a single chromosome from one parent is duplicated (a later stage meiosis II error in non-disjunction)


a pair of non-identical chromosomes are inherited from one parent (an earlier stage meiosis I error in non-disjunction)

Blood Typing & Multi-allelic system

3 alleles in the population (A, B, & O); Two alleles A and B are co-dominant antigen alleles;
i = is null allele and recessive to A & B (6 Genotypes & 4 Blood Types) [CO-DOMINANCE]

Hardy-Weinberg Assumptions

1) No genetic drift (infinite population)
2) No natural selection
3) No mutation
4) No gene flow
5) Random mating

Allelic heterogeneity

The phenomenon in which different mutations at the same locus causes a similar phenotype.

Locus heterogeneity

A single disorder, trait, or pattern of traits caused by mutations in genes at different chromosomal loci.

Sickle Cell Anemia & Incomplete Dominance

The 2 alleles produce 3 genotypes
with different phenotypes:
HbA/HbA Normal RBC
HbS/HbS Sickle Shape of RBC AND Sickle Cell Anemia
HbA/ HbS No Anemia, RBC Sickle in low oxygen also called Sickle Cell Trait

The genetic defect that causes sickle-cell disease also protects against malaria.

Clinical Heterogeneity

Different mutations within the same gene can cause; Different conditions
e.g. HPRT Gene (Hypoxanthine-guanine phosphoribosyltransferase) --- GOUT (Uric acid builds up in the joint) or LESCH NYHAN (Uric acid build up in body fluids; Affects Muscle Tone Behaviour; Mental Retardation)

Anticipation & Trinucleotide Repeats

The tendency of dominant conditions to become more severe or have earlier onset in successive generations.

Common in Trinucleotide Repeat Disorders :
Number of repeats tend to grow as the gene is transmitted down the generations. (Possibly, during DNA replication sections of the DNA showing repeats within the gene are over-duplicated by accident.)

In Huntington's expansion occurs preferentially during male gametogenesis.

In Fragile X expansion occurs preferentially in female gametogenesis.


Expressivity = The degree to which an allele expresses the phenotype (i.e. the strength of the trait)
- Variable among individuals
Affected by various factors
- Genetic background (suppression and position of genes)
- Temperature
*Himalayan rabbits
- Nutrition
*Lactose Intolerance
Onset of gene expression may differ among individuals
*Tay-Sachs, Huntington Disease

Waardenburg Syndrome & Variable Expressivity

Difference in Expression of Gene

- Hearing Loss
- Different Colored Eyes
- White Forelock
- Premature Graying of Hair


Major symptoms:
• Failure to thrive
• Hepatic insufficiency
• Cataracts
• Developmental delay
• Poor growth
• Mental retardation
- Ovarian failure in females
- Treatment: Dietary restriction of Galactose (Milk)

CFTR gene & Cystic Fibrosis

Cystic Fibrosis Transmembrane Conductance Regulator gene; Function = regulates the flow of chloride ions across the cell membrane.

POSSIBLE MUTATIONS (Allelic Heterogeneity):
Class I: no synthesis of gene product (Most Severe)
Class II: defective protein, destroyed in proteosome
Class III: protein gets to the surface but is abnormally regulated
(R117H missense mutations. Ion channels proceed to the cell membrane but respond poorly to cyclic amp and do not stay open; milder phenotype and don't have pancreatic problems)
Class IV: defective chloride ion conductance
Class V: splice site mutations, result in reduced mRNA
(IV & V = less-severe pulmonary disease and lower mortality rates)

Marfan Syndrome

Autosomal Dominant Disorder: Connective tissue provides substance and support to tendons, ligaments, blood vessel walls, cartilage, heart valves and many other structures.

Mutations in the FBN-1 (Fibrilin) gene cause ocular, cardiovascular, skeletal defects

Law of Dominance

Interaction of the two alleles results in expression of only one of the alleles

Affected Patient of Autosomal Dominant

Heterozygote for the mutation

Affected Patient of Autosomal Recessive

Homozygote for the mutation

Non-Invasive & Invasive New-Born Screening

- Ultrasound
- Blood
- Urine
- Sweat
- Spit

Phenylketouria vs. Alkaptonuria

- Phenylketouria = mental retardation & other severe nervous system impairments; phenylalanine buildup (cause = DEFECTIVE ENZYME, PHENYLALANINE HYDROXYLASE)
- Alkaptonuria = black urine/nails & skin/joint cartilage; homogentisic acid buildup (cause = LOSS OF FUNCTION mutation)

Founder Effect

high frequency of a particular allele in a population because the population is derived from a small number of founders, one or more of whom carried the variant allele (e.g. Polydactyly in Amish community because of inbreeding)

Amino Acid Disorders (Aminoacidopathies)

Caused by body's inability to:
- breakdown or metabolize certain amino acids
- detoxify the by-product of amino acids (ammonia) through the urea cycle

Complications occur within days following firth OR after months following birth

Complications = mental retardation, developmental delays, failure to thrive, & death

3 Main Causes of Single Gene Disorders

- Enzyme Defect = Accumulation of Substrate, Lack of Product, Failure to Inactivate a Protein which Causes Damage (e.g. PKU)
- Receptor/Transport protein defect = Familial Hypercholesterolemia
- Structural protein defect = Structure, Function, & Quantity (e.g. Marfan Syndrome)

SRY Gene

Encodes for a transcription factor that plays a primary role in maleness (testis determining factor); part of the HMG family (High Mobility Group), male sterility may be caused by de-novo partial deletion of the Y-chromosome that contain the sperm-promoting genes essential for Y-Linked Traits

Familial Rickets

Softening and weaking of the bones; primarily caused by lack of vitamin D and/or lack of calcium or phosphate (hint: X-Linked Dominant)

Incontientia Pigmenti

Unusual patterns of discolored skin. Males are more severely affected than females; Caused by excessive deposits of melanin (hint: X-Linked Dominant)

Coffin-Lowry Syndrome

A rare genetic disorder characterized by head, facial, and skeletal abnormalities, mental retardation, short stature, and hypotonia

NO Cure; Treatment is symptomatic and supportive, and may include Physical & Speech therapy (hint: X-Linked Dominant)

Faulty Enamel Trait

The enamel coating of the teeth fails to develop properly (hint: X-Linked Dominant)

Mismatch Repair

Corrects errors that remain after proofreading, in the short window of time when newly synthesized DNA is hemi-methylated; Mistakes in deletions and insertions of repeat sequences are corrected by this.
Mutations in this predispose to
Hereditary Non Polyposis Colon Cancer (HNPCC)

Translesion Repair

In response to DNA damage, post-translational modifications on PCNA cause a change in DNA polymerase (fall off the processive DNA Pol and replacement with the translesion DNA Pol) allows to continue DNA replication at the site of mutation.


Extending across a lesion, often specifically a damaged section of DNA; Chemically altered bases or damage to the sugar-phosphodiester backbone

Repaired and the process of repair can convert lesion into a mutation (recall that mutations are any change to the DNA sequence)

Treatments that induce ___________cause mutations and cancer and are therefore referred to as mutagens or carcinogens.
Carcinogens fall into large chemical families of compounds such as aromatic amides, polycyclic hydrocarbons, nitrosamines, and some are natural plant metabolites (i.e. Aflatoxin B1).
In addition, some drugs used in cancer chemotherapy such as platinum derivatives form covalent DNA adducts and as such are also carcinogens

Base Excision Repair

• Removal of base first to make an apurinic site
- Involves recognition of erroneous base by DNA glycosylase
• Cleave DNA backbone by an endonuclease to remove deoxyribose sugar
• Synthesize DNA to fill-in missing nucleotide

Nucleotide Excision Repair

• Repairs bulky lesions
- Alkylations and other modifications to DNA
- Excision of a large segment of the DNA (catalyzed by the uvr genes in E. coli)

• Individuals with xeroderma pigmentosum have lost ability to undergo _____________.

Differences between Base Excision, Mismatch, & Nucleotide Excision Repair

BER = Base excision involves removing only the defective base from the DNA by cleavage of the N-glycosidic linkage of the base to deoxyribose. This leaves an apurinic or apyrimidinic site, which must then undergo additional repair processes.

NER = Nucleotide excision involves removing the defective base together with its deoxyribose and phosphate (as well as some neighboring nucleotides) by cleavage of phosphodiester bonds in the DNA chain.

MR = corrects errors of DNA replication and recombination that result in mispaired (but undamaged) nucleotides.

Non-Homologous End Joining

• End joining repairs double-stranded breaks but does not require a homologous region of DNA during repair
• Can lead to inversions and translocations

DNA Double Strand Breaks

The most deleterious damage to DNA
If remained un-repaired will lead to cell death or cancer

- Products of normal cellular metabolism:
(Meiotic Recombinations - V(D)J recombination in the immune system (B and T cells) - Processing of the replication fork (during S phase)
- Induced by environmental carcinogens:
(Ionizing radiation - Oxidative stress - Radioactive reagents - Chemotherapy)

Homologous Recombination

An error-free mechanism of DNA
Repair that rely on the presence of a
homologouse chromatid as a DNA template

Thus, in somatic cells HR can occur
only after DNA replication has completed
when two sister chromatids are present.

Mechism: Homologous Recombination Repair (HRR)

1) DNA damage cause DSBs.
2) Resection of broken ends by nucleases.
3) Binding of SS binding proteins to form nucleoprotein filament.
4) Strand invasion by the nucleoprotein
filament into the sister chromatid that will be used as a template.
5) DNA synthesis will form a D loop as mode of DNA synthesis is conservative (both strands are synthesized).

Sister Chromatid Exchange

Occurs in somatic cells between sister chromatids; after replication and during mitosis when condensed sister chromatids pair up.

The rate increases when DNA damaged by genotoxic agents.

(HINT: Executed by a "homologous recombination" DNA repair pathway.)

Bloom Syndrome

A rare inherited disorder characterized by a high frequency of chromosomes breaks and rearrangements
AFFECTED MEN usually do not produce sperm, and are sterile.
AFFECTED WOMEN experience early menopause.
- A high risk of early onset cancer
in affected individuals (~25 yrs old) .
- Mostly in people descendent from central and eastern Europe (Ashkenazi) Jewish background
(1/3 of patients) 1:50,000

Clinical Symptoms:
- Smaller than average
- Often have a high-pitched voice
- Characteristic facial features:
including: a long, narrow face
small lower jaw
prominent nose and ears.
- Sensitive to sunlight, little body fat, chronic lung problems, diabetes, and immune deficiency that leads to recurrent pneumonia and ear infections.

Xeroderma Pigmentosum (XP)

An autosomal recessive disorder of defective
excision DNA repair; Defects in multiple genes in the Nucleotide Excision repair are lead to this disorder

- Severe sensitivity to UV light:
- Sunburns may last for weeks
- Many freckles
- Irregular dark pigment spots
- Development of many skin cancers
- Premature aging of the skin
- Ocular and cutaneous neoplasms

Hetrokaryons/somatic cell hybridization :
- Growing in vitro skin fibroblasts from different
- Cell fusion generates hetrokaryon cells.
- The ability to complement
- And restore the normal activity of the
excision process defines the complementary

Cockayne's Syndrome

- light sensitivity in some cases
- neurological abnormalities
- premature aging of some tissues
- facial and limb abnormalities
- dwarfism
- early death due to neurodegeneration
- unlike other DNA repair diseases, this
syndrome is not linked to cancer

Prevention of Neural Tube Defects

The genotype can not be altered, but knowing about multifactorial disease, can help to modify the environment.

- Altering the environment can be focused on those at high risk to decrease susceptibility

- Altering the environment can be focused on those at high risk to decrease susceptibility

Mismatch Repair

Corrects errors that remain after proofreading:
- Bias to correcting newly made DNA (as opposed to original DNA strand)
- Original DNA strand recognized based on DNA methylation of parental strand
- Newly replicated DNA is hemi-methylated, with newly synthesized DNA as lacking methylation

Excision Repair

Three steps:
1) Removal of mutation by a nuclease
2) Gap filling by DNA polymerase
3) Sealing of nick by DNA ligase

Two types:
- Nucleotide excision repair
- Base excision repair

DNA Double Strand Breakage (DSB)

• Activated when both DNA strands are cleaved
• This mechanism is responsible for linking the two broken ends
• Two Types:
- Homologous recombination
- Non-homologous end joining

Homologous Recombination Repair

___________________ fixes a double-strand DNA break by using the undamaged homologous chromosome as information

Replication Block of NER

Replication block anywhere in the genome: (called global genomic repair, GGR)

Transcription Block of NER

Transcription block occurs at stalled transcription complex and called ________________.

Transcription Factor II H (TFIIH)

• One of several general transcription factors that make up the RNA polymerase II preinitiation complex.
• Consists of ten subunits, 7 of which (XPD, XPB, p62, p52, p44, p34 and TTDA) form the core complex.
• ERCC2/XPD and ERCC3/XPB, have helicase and ATPase activities and help create the transcription bubble.
• The cyclin activating kinase-subcomplex (CDK7, MAT1, and cyclin H) are needed to phosphorylate the CTD of RNA Pol II and is linked to the core via the XPD protein

Mechanism: Nucleotide Excision Repair

1) Recognition of the DNA damage by
2) The helicases XPB and XPD (TFIIH)
separate the DNA alleles
3) RPA single stranded DNA binding protein
Bind to DNA at the site DNA damage
4) Reminder of proteins are recruited:
5) XPF and XPG (nucleases) excise the DNA
6) Polymerase synthesizes new
complementary DNA
7) DNA ligase seals the nicks (Excision of about 28 bp)

Photoreactivation Repair

• Removes thymine dimers caused by UV light
- Process depends on activity of a protein called the photoreactivation enzyme (PRE), found only in bacteria
- Energy to break covalent bonds comes from UV light

Recombination-Based Post-Replication Repair

• Post-replication repair occurs when DNA replication skips over a lesion and requires homologous recombination to correct the damage
- DNA duplex is unwound and strand invasion (recall discussion of Holliday Junction structure)
- Non-damaged parental strand is copied, unwound and used to correct lesions and gaps on both sister chromatids


• Occurs when a diploid organism has only a single functional copy of a gene (with the other copy inactivated by mutation) and the single functional copy does not produce enough of a gene product (typically a protein) to bring about a wild-type condition, leading to an abnormal or diseased state.
• It is responsible for some but not all Autosomal Dominant disorders.


• a combination of alleles (DNA sequences) at adjacent locations (loci) on the chromosome that are transmitted together
• may be one locus, several loci, or an entire chromosome depending on the number of recombination events that have occurred between a given set of loci


• a set of single-nucleotide polymorphisms (SNPs) on a single chromosome of a chromosome pair that are statistically associated

Single Nucleotide Polymorphism (SNP)

• In order for a difference in nucleotide sequence to be considered as an __________, the less-frequent base must have a frequency of greater than about 5% in the human population.
• By this definition, the density of _________ in the human genome averages about one per 1300 bp


- a phenotype that resembles the phenotype produced by a specific gene but is caused instead by a different, typically non genetic, factor


- breakdown of complex chemicals into simpler ones, often produce waste products to be excreted


- the conversion of food molecules into living cells and tissue

"Inborn Errors of Metabolism"

- genetic diseases that result in disorders of metabolism
* usually involve inactive enzyme
* build-up of enzyme substrate

Inheritance Patterns

- most are autosomal recessive
- carrier state is usually unaffected
- sometimes haploinsufficiency seen

Genetic Testing

- dried blood for enzyme activity
*chrionic villus sampling (8-12 weeks gestation)
& amniocentesis (>13 weeks gestation)
* newborn screening
- carrier testing/mutation analysis

Affected Substrates

- carbohydrates
- proteins
- heavy metals
- lysosomal storage disorders


- monosaccharide (lactose=glucose + galactose)
- processed into glucose, glycogen, glycolipids or glycoproteins
- Deficiency in GA-I-Puridyl transferase causes:
* build-up of galactose-I-phosphate
* preference for alternative pathways of degradation of galactose


- autosomal recessive
- deficiency in GAL-I-Puridyl transferase
- 70% caused by single missense mutation in exon 6
- sign/sx
* failure to thrive/poor growth
* hepatic insufficiency
* cataracts
* mental retardation/developmental delay
* ovarian failure
- Newborn screening performed routinely
- Treatment: Lifelong elimination of dietary galactose
* milk
* organ meats (liver, kidney, heart)
* garbanzo beans
* fermented soy products (soy sauce, miso, tempe)


- disacchariade (lactose=galactose+glucose)
- produced in mammalian breast milk
*small intestine: milk absorbed and processed by lactase-phlorizin hydrolase (LPH)
* upon cessation of breast feeding LPH activity diminishes
* further exposure to lactose will cause lactose intolerance

Lactose Intolerance

- it is ABNORMAL to be able process lactose after cessation of breast feeding
- 5 to 90% (depending on geographic location) have Autosomal Recessive "disorder" (trait) for Persistence of LPH Activity
* able to process lactose
* highest incidence in NW Europe and Africa
* concordance w/ areas of high dairy intake
- difference between LPH persistence and non-persistence is NOT caused by mutation
* differences in STRPs points toward expression control
- common in tropical and subtropical countries
-SX: nausea, bloating, and diarrhea after dairy product ingestion
- partial metabolism (e.g. yogurt) helps prevent SX


- essential amino acid
- defects in phenylalanine hydroxylase cause build-up in phenylalanine --> Phenylketonuria

Phenylketonuria (PKU)

- autosomal recessive
- Elevated levels of phenylalanine
- can result in severe mental retardation
- TX:
* restrict phenylalanine intake (300-500mg/day)
*maintain blood phenylalanine levels between 2 & 10 mg/dL
* BUY essential amino acid, so can't eliminate
* Lifelong therapy recommended
- sources of phenylalanine
* turkey, tuna, beans, milk, soy milk, breast milk, gelatin, broccoli
* Aspartame- artificial sweetener, degraded into phenylalanine (50% by weight)

- How much phenylalanine is in a 20oz bottle of Diet Coke? 150 mg
How much phenylalanine is in a 2-3 oz serving of turkey 840 mg

Branched Chain Amino Acids

- 40% of performed amino acids used by mammals
- can be used as sources of energy with proper catabolism
- defects in catabolism cause build-up of BCAA and ketoacids -- MAPLE SYRUP URINE DISEASE

Maple Syrup Urine Disease (MSUD)

- autosomal recessive
- deficiency of BCKAD enzyme
- build-up in BCAA and ketoacids
- ketaocids cause urine to smell like maple syrup
- S/Sx: progressive neurodegeneration and death in first few months of life if left untreated
- Tx: dietary restriction of BCAA, Thiamine, gene therapy

Medium-Chain Fatty Acids

- converted to ketones which are used for
* lipid synthesis
* energy source during periods of fasting

MCAD Deficiency

- autosomal recessive
- build-up of fatty acid intermediates
- unable to produce ketones
- S/Sx
* vomiting and lethargy after periods of diminished oral intake (e.g. minor illness)
* hypoglycemia- cerebral edema, encephalopathy, and death
- Tx: glucose
- Testing
* genetic testing of ACADM gene
* MCAD enzyme activity assay


- precursor of cholesterol
- deficiency in DHCR-7 in causes build-up of 7-dehydrocholesterol and very low levels of cholesterol --> SMITH-LEMLI-OPITZ Syndrome

Smith-Lemli-Opitz Syndrome

- autosomal recessive
- deficiency of DHCR7
- favorable heterozygous state
- S/Sx
* reduced cholesterol
* increased 7-dehydrocholesterol
*congenital anomalies: brain, heart, genitalia, and hands
- Tx: supplemental cholesterol

Heavy Metals

- heavy metals used as cofactors in some enzymatic processes
- a proper balance of heavy metals must be maintained in the body
* too little and enzymes can not perform function
* too much --> toxic
- transport and storage proteins control balance of heavy metals
- mutations in genes that code for these proteins result in imbalance of heavy metals

Copper/Wilson Disease

- autosomal recessive
- caused by mutation in gene for ATP7B
* copper transport protein
- excessive Cu due to failed excretion by the liver into biliary tree
- S/Sx: progressive liver disease and neurological abnormalities, Kayser- neurological abnormalities, Kayser-Fleischer ring (pathognomonic)
- Tx: chelating agents (e.g. penicillamine)

Iron/ Hemachromatosis

- autosomal recessive
- gene HFE codes for cell-surface protein that plays role in iron stores regulation
- single missense mutation causes abnormal regulation and increased iron absorption
- S/Sx: onset in 40's-60's, fatigue, joint pain, hyperpigmentation, cardiomyopathy, liver damage
- Tx: phlebotomy and iron chelators
- Selective advantage for at least one copy of gene as iron-deficiency affects 1/3 of global population

Lysosomal Storage Disease

- lysosome= a cellular organelle that contains enzymes that break down proteins and certain carbohydrates
- most d/o caused by deficiency in degrading enzymes
- results in accumulation of substrate within lysosome and ultimately within the cell

Tay Sachs

- autosomal recessive
- 1 in30 Ashkenazi Jews is a carrier
- deficiency of B-HexosaminidaseA (Hex A)
- neurodegenerative disease
* macrocephaly
* loss of motor skills
*macular cherry red spot
- mortality
*infant onset: fatal by 3 or 4
* juvenile onset: death by 15 years old
* adult onset: poor motor control, declining intelligence, psychosis


- 1 in 100 in the U.S. are carriers
- Type I particularly high in Ashkenazi Jews
- deficiency of B-Glucosidase (causes an accumulation of glucosylceramide)
- Clinical features: splenomegaly, heptomegaly, bone marrow infiltration, multi-organ failure and debilitating skeletal disease
- Three types:
* Type I: most common; does not involve CNS
* Type II: most severe, often leading to death within the first 2 years of life
* Type III: Intermediate form
- Tx:
* Mostly supportive (e.g. splenectomy for hypersplenism, blood transfusions for anemia)
* enzyme replacement can reverse symptoms resulting from spleen and liver involvement (not as effective in neurological symptoms)
* some benefit from BMT, particularly with chronic neurological conditions

Hutchinson-Gilford progeria syndrome (HGPS)

-This genetic disease is characterized by young children showing signs of accelerated aging.
-Often they die by age 13.
-It is inherited as an autosomal dominant trait.
-It affects about 50 children worldwide.


-This is a pictoral representation of a human's family history. It is used to study how traits are passed on in humans.


-This shape represents a male in a pedigree.


-This shape represents a female in a pedigree.


-This shape represents an individual whose gender is not known.

Fill it in

-Do this to a shape if the individual is affected with the trait of interest (i.e. HGPS).

A dot

-Put this inside the shape to represent an individual that is a carrier.


-Put this through a shape to show that an individual is deceased.


-To indicate this in a pedigree, put brackets around the individual, draw a dotted line to the adoptive parents, and draw a solid line to the biological parents.


-This is the first person found by a geneticist to be affect by the trait. A pedigree is constructed around him or her.


-This is the mating of related parents (i.e. two first cousins).
-In pedigrees, it is often symbolized by two parallel lines between the parents.

Autosomal recessive trait

-Assuming it is fully penetrant, this trait will appear equally in males and females.
-It tends to skip generations because an individual must inherit two alleles together in order to be affected. Affected children can be born to unaffected, heterozygous parents.
-It is more likely to appear in the children of related parents.

Tay-Sachs disease

-This genetic disease is caused by an autosomal recessive trait.
-It causes lipids to accumulate in the brain leading to swelling of the head, blindness, deafness, other neurological systems, and eventually death by the age of 2-3.

Autosomal dominant trait

-Assuming it is fully penetrant, this trait will appear equally in males and females.
-It doesn't skip generations since only one allele is needed for the individual to be affected. Affected persons will have at least one affected parent.
-Unaffected parents will not have any affected offspring.

X-linked recessive trait

-This trait appears more in males than in females. This is because males only need a single copy of an allele in order to be affected. Females will need two.
-A carrier mother will pass the trait on to some of her sons. This causes the trait to skip generations.
-An affected male can not pass the trait on to his sons because all males inherit only the Y sex chromosome from their fathers.
-An affected male and unaffected female will produce carrier daughters.

X-linked dominant trait

-This trait often appears more in females than in males.
-It does not skip generations because each affected individual must have an affected parent.
-An affected male will pass the trait on to all his daughters (since they inherit his X chromosome) but none of his sons (since they inherit his Y chromosome).
-An affected male must have an affected mother.
-Heterozygous, affected females will pass on the trait to about half of her sons and about half of her daughters.

Y-linked traits

-This kind of trait will only affect males.
-An affected fathers will have all affected sons.

Natural Selection

The differential survival and reproduction of individuals in a population


the change in the genetic structure of populations over time


A group of organisms of the same species that occur in the same area and interbreed or share a common genepool

The Hardy Weinberg Theorem

The frequency of alleles in the population will remain the same from generation to generation

The Hardy Weinberg Theorem Equation

p + q = 1

Under what conditions is the Hardy Weinberg Theorem valid?

1.) The population is very large
2.) Matings are random
3.) There are no net change in the gene pool due to mutation
4.) There is no migration of individuals into and out of the population
5.) There is no selection

Gene Flow

Migration of individuals between two populations

Genetic Drift

The effects of small population size

Genetic Fixation

The lost of all but one possible allele at a gene locus in a population

Bottleneck Effect

A population undergoes a drastic reduction in size as a result of chance events

Founder Effect

When a small group of individuals becomes separated from the larger parent populations

Gene Pool

All the alleles at all gene loci of all individuals in the population

Allelic Frequency

the percentage of any specific allele in the gene pool

Genotypic Frequency

the proportion of a given genotype within a population.


the movement of persons from one country or locality to another

Which processes can alter allele frequencies in a population?

Natural Selection

cross an unknown genotype with a homozygous recessive and see what outcomes you get.


dominant trait is not completely dominant (results in a pink flower)

incomplete dominance

both alleles are visible (results in a red and white striped flower)


Rare ________________ diseases don't skip generations and affects males and females equally.

autosomal dominant

two examples of rare autosomal dominant diseases are _______________ and ______________

Achrondroplasia, Huntington's Disease

Rare ________________ diseases can skip generations and affects male and females equally.

autosomal recessive

two examples of rare autosomal recessive diseases are ________________ and ______________

sickle cell anemia, cystic fibrosis

Rare ______________ diseases skip generations and affect mostly men.

X-linked recessive

two examples of rare x-linked recessive diseases are ______________ and ________________

red-green colorblindness, hemophilia

faulty separation of chromosomes during meiosis


abnormal number of chromosomes


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