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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
- 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
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.
- Double mutants in redundant/ compensating genes
- Interference with a haploinsufficiency
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.
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
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
Traits that are continuous & can be measured, e.g.:
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
- Spinal defects
• Spina bifida
• USA Incidence: 0.2%
• Can occur isolated or as part of a syndrome or
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.
• 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)
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
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
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.
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.
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,
- tremor, seizures
- 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)
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]
1) No genetic drift (infinite population)
2) No natural selection
3) No mutation
4) No gene flow
5) Random mating
The phenomenon in which different mutations at the same locus causes a similar phenotype.
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.
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)
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
• Failure to thrive
• Hepatic insufficiency
• 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)
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
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)
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)
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
Softening and weaking of the bones; primarily caused by lack of vitamin D and/or lack of calcium or phosphate (hint: X-Linked Dominant)
Unusual patterns of discolored skin. Males are more severely affected than females; Caused by excessive deposits of melanin (hint: X-Linked Dominant)
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)
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)
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)
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.)
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
- 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
- light sensitivity in some cases
- neurological abnormalities
- premature aging of some tissues
- facial and limb abnormalities
- 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
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
1) Removal of mutation by a nuclease
2) Gap filling by DNA polymerase
3) Sealing of nick by DNA ligase
- 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
XPC, XPE and XPA
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
7) DNA ligase seals the nicks (Excision of about 28 bp)
• 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
"Inborn Errors of Metabolism"
- genetic diseases that result in disorders of metabolism
* usually involve inactive enzyme
* build-up of enzyme substrate
- most are autosomal recessive
- carrier state is usually unaffected
- sometimes haploinsufficiency seen
- dried blood for enzyme activity
*chrionic villus sampling (8-12 weeks gestation)
& amniocentesis (>13 weeks gestation)
* newborn screening
- carrier testing/mutation analysis
- 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
* failure to thrive/poor growth
* hepatic insufficiency
* mental retardation/developmental delay
* ovarian failure
- Newborn screening performed routinely
- Treatment: Lifelong elimination of dietary galactose
* 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
- 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
- autosomal recessive
- Elevated levels of phenylalanine
- can result in severe mental retardation
* 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
- autosomal recessive
- build-up of fatty acid intermediates
- unable to produce ketones
* vomiting and lethargy after periods of diminished oral intake (e.g. minor illness)
* hypoglycemia- cerebral edema, encephalopathy, and death
- Tx: glucose
* 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
- autosomal recessive
- deficiency of DHCR7
- favorable heterozygous state
* reduced cholesterol
* increased 7-dehydrocholesterol
*congenital anomalies: brain, heart, genitalia, and hands
- Tx: supplemental cholesterol
- 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
- 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)
- 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
- autosomal recessive
- 1 in30 Ashkenazi Jews is a carrier
- deficiency of B-HexosaminidaseA (Hex A)
- neurodegenerative disease
* loss of motor skills
*macular cherry red spot
*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
* 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.
Fill it in
-Do this to a shape if the individual is affected with the trait of interest (i.e. HGPS).
-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.
-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.
-This kind of trait will only affect males.
-An affected fathers will have all affected sons.
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
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
When a small group of individuals becomes separated from the larger parent populations
Rare ________________ diseases don't skip generations and affects males and females equally.
two examples of rare autosomal dominant diseases are _______________ and ______________
Achrondroplasia, Huntington's Disease
Rare ________________ diseases can skip generations and affects male and females equally.
two examples of rare autosomal recessive diseases are ________________ and ______________
sickle cell anemia, cystic fibrosis
two examples of rare x-linked recessive diseases are ______________ and ________________
red-green colorblindness, hemophilia
when non-disjunction occurs in metaphase I ____________ don't separate properly; results in ___ messed up gametes.
when non-disjunction occurs in metaphase II ____________ don't separate properly; results in ____ messed up gametes.
sister chromatids, 2
a sperm or egg carries only one allele for each inherited character becasuse allele pairs (homologous chromosomes) separate from each other during meiosis.
law of segregation
Bardet Biedl Syndrome
Most well known oligogenic disease. includes retinal dystrophy, mental retardation etc
sign/symptom that is so characteristic for a specific disease that it makes a definite diagnosis: not useful for chromosomal abnormalities
mental retardation, upslanting of palpebral fissues, increased skin on back of neck, hearing loss/short stature, increased chance of leukemi and aging, hypotonia, death by cardiac malformation <1 year, hearing loss/cardiac malformations later in life
45 X, webbed neck, gonadal dysgenesis (streak gonads) Turners = donald neck, puffy feet, heart defect
almond-shaped eyes, compulsion to eat later, small hands/feet, hypopigmentation, mentalretardation
John Williams = musician and LOTR. Music, elfin, elves are bony --> hypercalcemia, outgoing. Chromosome 7
King George had syphillis --> infections (no thymus,), conotruncal problems (b/c STD=no sex), no calcium b/c no boes there, cleft/cardia
Velocardiofacial/Sphrintzen syndrom (Also CATCH22)
Discovered by sphrintzen, nasal speech/cleft palate, palatal abnormalities
Mendelian inheritance describes inheritance patterns that obey what two laws?
Law of segregation and law of independent assortment.
Simple Mendelian inheritance involves what?
A single gene with two different alleles where one is dominant over the other.
Describe simple Mendelian inheritance patterns.
This term is commonly applied to the inheritance of alleles that obey Mendel's laws and follow a strict dominant/recessive relationship. 50% of the protein encoded by two copies of the dominant (functional) allele is sufficient to produce the dominant trait.
Describe incomplete dominance.
This pattern of inheritance occurs when the heterozygote has a phenotyope that is intermediate between either corresponding homozygote (e.g. - pink flowers). 50% of the protein encoded by two copies of the functional allele is not sufficient to produce the same trait as the homozygote making 100%.
Describe incomplete penetrance.
This pattern occurs when a dominant phenotype is not expressed even though an individual carries a dominant allele. (e.g. - polydactyly). Can be due to environmental influences or other counteracting genes.
This pattern occurs when the heterozygote has a trait that is more beneficial than either homozygote. Heterozygotes may benefits in at least one of three ways: 1) disease resistance, 2) homodimer formation, or 3) variation in functional activity,
This pattern occurs when the heterozygote expresses both alleles simultaneously (e.g. - blood typing). The codominant alleles encode proteins that function slightly differently from each other, and the function of each protein in the heterozygote affects the phenotype uniquely.
Describe X-linked inheritance.
This pattern involves the inheritance of genes that are located on the X chromosome. In mammals and fruit flies, males are hemizygous for X-linked genes, while females have two copies. If a pair of X-linked alleles shows a simple dominant/recessive relationship, 50% of the protein encoded by two copies of the dominant allele is sufficient to produce the dominant trait (in the female)
Describe sex-influenced inheritance.
This pattern refers to the impact of sex on the phenotype of the individual. Some alleles are recessive in one sex and dominant in the opposite sex (e.g. - pattern baldness). Sex influence is a phenomenon of heterozygotes; most are autosomal.
Describe sex-limited inheritance.
This refers to traits that occur in only one of the two sexes (e.g. - breast development in mammals, beard growth, male bird plumage). sex hormones that are primarily produced in only one sex are essential to produce a particular phenotype.
Describe lethal alleles.
An allele that has the potential of causing the death of an organism. lethal alleles are most commonly loss-of-function alleles (recessive) that encode proteins necessary for survival. In rare cases, the allele may be due to a mutation in a nonessential gene that changes a protein to function with abnormal and detrimental consequences.
Prevalent alleles in a population are termed _____.
wild-type; these typically encode proteins that function normally and are made in the right amounts
What is genetic polymorphism?
The occurrence of more than one wild-type allele in large populations.
Alleles that have been altered by mutation are termed _____.
mutant alleles; these tend to be rare in natural population, are likely to cause a reduction in the amount or function of the encoded protein, and are often inherited in a recessive fashion
Genetic diseases are caused by what?
Mutant alleles. In many human genetic diseases, the recessive allele contains a mutation (often preventing the allele from producing a fully functioning protein).
In a simple dominant/recessive relationship, the recessive allele does not affect the phenotype of the heterozygote. What are two possible explanations for this?
1) 50% of the normal protein is enough to accomplish the protein's cellular function, and 2) the heterozygote may actually produce more than 50% of the functional protein
Whether a trait is dominant or incompletely dominant may depend on what?
How closely the trait is examined. For example, despite Mendel's visual conclusions, a microscopic examination of round peas reveals that not all round peas are "created equal."
In some instances, a dominant allele is not expressed in a heterozygote individual. This is known as _____.
The measure of penetrance of an allele is described at what level?
Population level. If 60% of heterozygotes carrying a dominant allele exhibit the trait allele, the trait is 60% penetran. However, individuals are either penetrant or not.
This is the degree to which a trait is expressed.
Expressivity. In the case of polydactyly, the number of digits can vary. A person with several extra digits has high expressivity of this trait. A person with a single extra digit has low expressivity.
The molecular explanation of expressivity and incomplete penetrance may not always be understood, but in most cases, the range of phenotypes is thought to be due to influences of what?
Environment (e.g. - temperature, PKU) and/or other genes.
Due to the effects of the environment on phenotypes, it is more appropriate to look at _____ rather than _____.
the range of conditions; one or two
What is the norm of reaction? How do you determine it?
Refers to the effects of environmental variation on a phenotype. Specifically, it is the phenotypic range seen in individuals with a particular genotype. To determine it, you subject true breeding strains to different environmental conditions (e.g. - facet numbers in fruit flies).
What is heterozygote advantage?
The phenomenon in which a heterozygote has greater reproductive success compared to either of the corresponding homozygotes. Also referred to as overdominance (e.g. - sickle cell anemia)
How is malaria contracted?
The protozoan _Plasmodium_ spends part of its life cycle within the _Anopheles_ mosquito and another part within the red blood cells of humans who have been bitten by an infected mosquito.
Why is sickle cell inheritance considered an advantage?
Even though homozygous condition is detrimental, the greater survival of the heterozygote has selected for the presence of the sickle-cell allele within populations where malaria is prevalent (red blood cells of heterozygotes are likely to rupture when infected by _Plasmodium sp_, preventing propagation of the parasite).
Explain disease resistance as it applies to a possible explanation for overdominance.
A microorganism will infect a cell if certain cellular proteins function optimally. Heterozygotes have one altered copy of the gene, reducing protein function. The reduced function is not enough to cause serious side effects but is enough to prevent infections (e.g. - sickle-cell anemia, malaria, Tay-Sachs disease [TB])
Explain homodimer formation as it applies to a possible explanation for overdominance.
A1A2 heterozygotes make A1A1, A2A2, and A1A2 homodimers. For some proteins, the A1A2 homodimer may have better functional activity giving the heterozygote superior characteristics.
Explain variation in functional activity as it applies to a possible explanation for overdominance.
E1E2 heterozygotes produce both E1 and E2 enzymes (each with different optimum temperature ranges); therefore they have an advantage under a wider temperature range than both E1E1 and E2E2 homozygotes
How is overdominance related to a common mating strategy used by animal and plant breeders?
Two different highly inbred strains are crossed to display traits superior to both parents. This phenomenon is termed hybrid vigor, or heterosis.
How is heterosis different from overdominance?
Heterosis is used to improve quantitative traits such as size, weight, and growth rate. It is different from overdominance, however, because it typically involves many genes (though its beneficial effects may be attributed to overdominance in one or more heterozygous genes)
Many genes exist in multiple alleles of how many versions of a gene?
Three or more. For example, blood type is controlled by a single gene but there are three alleles that control what type of blood someone has (therefore, four blood types).
The ABO group of antigens, which determine blood types in humans, is an example of multiple alleles and illustrates the allelic relationship called _____.
The carbohydrate tree on the surface of RBCs is composed of three sugars. A fourth can be added by the enzyme _____.
glycosyl transferase; the A and B antigens are different enough to be recognized by different antibodies.
A pedigree for an X-linked disease shows what? How is this demonstrated?
Mostly males are affected with their mothers as carriers. This is easily demonstrated by reciprocal crosses.
When discussing X-linked muscular dystrophy, an affected male and unaffected female have how many affected offspring? How many are carriers?
No affected offspring, females are carriers.
When discussing X-linked muscular dystrophy, an affected female and unaffected male have how many affected offspring? How many are carriers?
All male offspring are affected and females are all carriers.
Define holandric genes.
Genes located only on the Y chromosome (e.g. - the _Sry_ gene found in mammals; its expression is necessary for proper male development).
What is pseudoautosomal inheritance?
Has the same inheritance pattern of a gene located on an autosome even though gene is actually located on the sex chromosomes.
The inheritance pattern of certain traits is governed by the sex of the individual. These traits are of what two main types?
Sex-influenced and sex-limited
Feather plumage in chicken is caused by an autosomal gene; hen-feathering is controlled by a dominant allele expressed in both sexes while cock-feathering is controlled by a recessive allele only expressed in males. The pattern of hen-feathering depends on what?
Production of sex hormones. If the single ovary is surgically removed from a newly hatched _hh_ female, she will develop cock-feathering and look indistinguishable from a male.
Summarize sex-linked, -influenced, and -limited traits.
Sex-linked (on a sex chomosome); sex-influenced (allele is dominant in one sex but recessive in another - pay attention to heterozygotes); and sex-limited (trait only seen in 1 of the 2 sexes)
What are essential genes? How many genes are essential?
Those that are absolutely required for survival; the absence of their protein product leads to a lethal phenotype. It is estimated that about 1/3 of all genes are essential for survival.
Under what circumstance does a lethal allele kill an organism at an early age?
When it prevents cell division.
Huntington disease is cause by what?
A dominant (not typical) lethal allele. It is characterized by progressive degeneration of the nervous system, dementia and early death. Age of onset is usually between 30 and 50.
What are conditional lethal alleles?
May kill an organism only when certain environmental conditions prevail. Temperature-sensitive (ts) lethal alleles exist in developing Drosophila larva; they may be killed at 30°C but will survive if grown at 22°C
What are semilethal alleles?
Nn allele that kills some of the individuals in a population and not others; often the mechanism isnt well understood
A lethal allele may produce ratios that seemingly deviate from Mendelian ratios. Why?
Some animals that are homozygous for the dominant lethal allele (e.g. - Manx allele in cats) die an early embryonic death (1:2:1 ratio is observed as 1:2 ratio).
What is pleiotropy? What are its causes?
Multiple effects of a single gene on the phenotype of an organism. Causes include 1) the gene product can have different effects (e.g. - cystic fibrosis), 2) the gene may be expressed in different cell types, and 3) the gene may be expressed at different stages of development
A normal allele encodes the cystic fibrosis transmembrane conductance regulator (CFTR) which regulates ionic balance by transporting Cl- ions. The mutant does not transport chloride effectively, having multiple effects in the body including thick mucus in lungs, salty sweat on skin, and sterility in men. What is the broad term for these mutliple effects??
What is epistasis?
An inheritance pattern (involving two genes) in which the alleles of one gene mask the phenotypic effects of the alleles of a different gene. Epistasis is considered relative to a particular phenotype. Although phenotypes are masked, the 9:3:3:1 ratio of genotypes is still present.
What is complementation?
A phenomenon (involving two genes) in which two different parents that express the same or similar recessive phenotypes produce offspring with a wild-type phenotype.
What are modifying genes?
A phenomenon (involving two genes) in which the allele of one gene modifies the phenotypic outcome of the alleles of a different gene.
What is gene redundancy?
A pattern (involving two genes) in which the loss of function in a single gene has no phenotypic effect, but the loss of function of two genes has an effect. Functionality only one of the two genes is necessary for a normal phenotype; the genes are functionally redundant.
What are intergenic suppressors?
An inheritance pattern (involving two genes) in which the phenotypic effects of one mutation are reversed by a suppressor mutation in another gene.
Lots of morphological traits are affected by many different genes in combination with environmental factors (e.g. - height, weight, pigmentation). These are known as what?
In terms of comb morphology in chickens, two genes result in four phenotypes. How did Bateson and Punnett describe this?
They reasoned that comb morphology (a single trait) is determined by two different genes (dominant/recessive relationships, codominance, and new comb morphology were all involved).
A cross between two different white varieties of the sweet pea (CCpp and ccPP) produces purple offspring (CcPp). This phenomenon, in which offspring with a wild-type phenotype are produced from parents that both display the same or similar recessive phenotype, is called what?
Complementation. This phenomenon indicates that the recessive alleles are due to homozygosity at two different genes. A plant that is homozygous for either recessive white allele develops a white flower, regardless of whether or not the other gene contains a purple-producing allele.
In a cross between two different white varieties of the sweet pea (CCpp and ccPP), the F2 generation displays a white phenotype when there is homozygosity for the recessive allele of either gene - and masking of the purple (wild-type) phenotype. This is an example of what?
Why does epistatis typically occur?
Two or more different proteins participate in a common function. For example, two or more proteins may be part of an enzymatic pathway leading to the formation of a single product.
How can a cross involving a two-gene interaction produce three distinct phenotypes?
Epistasis. An example is inheritance of coat color in rodents in which two F1 agouti animals are crossed to produce a 9:3:4 radio (agouti, black, and albino)
What is the gene modifier effect?
The alleles of one gene modify the phenotypic effect of the alleles of a different gene. From this alternative viewpoint, pigmentation of the the agouti rats are modified to black. rather than masked (epistasis).
What is gene knockout?
Techniques to directly generate loss-of-function alleles. It allows scientists to understand the effects of the gene on structure or function of the organism.
Many gene knockouts have no obvious phenotypes. Why?
This many be due to gene redundancy where one gene can compensate for the loss of function of another. May be due to gene duplication (paralogs; not identical because of accumulated mutations).
Inheritance of capsule shape in shepherd's purse gives a 15:1 ratio. Either dominant T or V allele is sufficient to give a triangular seed. What explains this?
What is a suppressor mutation? Why are they important for study?
A second mutation that reverses the phenotypic effect of a first mutation. When it is in a different gene it is called an intergenic or extragenic suppressor. Suppressor mutations often reveal information about how proteins work (An example could be that two proteins physically interact)
Insertion or deletion of one or several, NOT a multiple of 3 BPs, causes shift of reading frame
Phenotypic Changes as a Result of DNA Mutations
1. Missense: Alters codon -Changes amino acid
2. Nonsense: Alters codon -Premature stop codon
3. Silent: Alters codon - Same amino acid
Associated with tandem repeated CAG, 100% penetrance, Autosomal Dominant, progressive neurodegenerative genetic disorder, late onset
Spontaneous Mutation: Interconversion of isomers by proton rearrangements; Causes Transition - Can cause erroneous base pairing: C-A Tautomer pairing instead of C-G
Spontaneous Deamination of 5-Methylcytosine to Thymine
C becomes T Causes transversion G to T
Methylated Cytosine's tautomer is the same structure as Thymine, therefore is not recognized by repair mechanisms, this is why CG islands are hotspots for mutations
Removal of a purine base by hydrolysis of glycosidic bond- Makes AP (apurinic) site
Depurination can cause several types of mutations:
• Transitions & Transversions
• Base pair deletions
• DNA strand breaks
Deamination by HNO2
Produced by nitrates and nitrites
-Cytosine deaminated to become U, then pairs with A
-A deaminated to become Hypoxanthine, which then pairs with C, instead of the T with which original A would have paired
Covalent modifications by addition of methyl or ethyl groups
+ AP Site
Examples: Dimethylsulfoxide (DMS), Aflatoxins
Effects of Ionizing Radiation on DNA
Formation of Free Radicals
1.Causes strand breaks
2.Transversions by pairing G with A after methylating G
Direct Reversal of DNA Damage
DNA Repair in which damage is simply fixed directly, for example:
-a methylated guanine fixed by O6 methylguanine methyltransferase back to a regular G
-Ligase joining the two internal ends of a broken DNA double strand (an error prone repair b/c damaged or lost dNTPs are not replaced/repaired before ligation).
Mismatched Base Repair
1) MutS (in prokaryotes; hMSH2 in humans) recognizes problem in daughter strand. MutS can tell the difference b/w the two strands b/c the parent strand is methylated.
2) MutL (hMLH1 in humans) activates MutH (? human)
3) MutH cleaves daughter strand in vicinity of problem, directs MutS, helicase, & exonuclease to remove oligonucleotide
4) DNA Poly I (DNA Poly Beta in humans) fills in gap
5) Ligase seals strand
Base Excision Repair
recognition & repair of damaged or mutated bases
1) Glycosylase: recognizes and cleaves out the nitrogenous base (not the whole nucleotide)
2) Endonuclease: breaks the phosphodiester bond
3) Deoxyribosephosphodiesterase: removes deoxyribose and creates a free 3'-OH and 5'-P
4) DNA Poly Beta: fills gap
5) Ligase seals strand
Nucleotide Excision Repair
recognition & repair damage or "lesions" that distort DNA structure (ex: Thymine Dimers, distortion by intercalating agents, add'n of bulky chemical groups)
1) Excinuclease Complex activity: a) recognizes damage, b) Helicase unwinds, c) 5' & 3' Endonucleases excise oligo nucleotide including the damaged DNA
2) DNA Polymerase Beta fills in oligonucleotide gap
3) Ligase reseals phosopodiester bonds
repair of DNA strand breaks by use of homologous chromosomes (ex: replication blocked by T-dimer in parent strand 'A')
1) reinitiation of DNA Polymerase causes gap downstream of parent strand A's lesion
2) homologous region of undamaged parent strand ('B', (already replicated) excised out to repair daughter 'A'
3) excised gap in parent B filled by DNA polymerase Beta using daughter B as template
4) original T-dimer repaired (nucleotide excision repair mechanism)
Repair of Double Strand Breaks
Double strand broken (ex: by ionizing radiotion)
1) unbroken homologous chromosome recombines with broken-strand chromosome
2) DNA polymerase fills gaps using unbroken chromosome as template
3) Ligase rejoins strands to form Holliday Junctions
Hereditary Nonpolyposis Colorectal Cancer
Disease caused by mutations in genes that regulate Mismatch Repair
-affects 1/200 people (accounts for 15% of colon cancer)
-50% of people with this particular hereditary disease have defective hMSH2 protein
Mutated genes involved in Nucleotide Excision Repair, particularly the excinuclease complex (Helicase & endonucleases)
-2000x increase in risk of sunlight induced cancers (melanoma)
ATM gene mutated (protein kinase involved in damage control during cell cycle)
-ATM can't detect DNA double strand breaks, thus p53 tumor suppressor levels don't increase and stop cell cycle
-causes severe neurological disorders
-carriers have increases sensitivity to Xrays and high rate of radiation-induced breast cancer
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