Medical Genetics Exam 1

Sickle Cell (gene mutation, pathogenesis, clinical features, factors affecting degree of sickling)

Gene mutation:

Autosomal recessive point mutation (glutamate turns to valine) of the beta subunit of hemoglobin (fetal hemoglobin doesn't have the beta subunit so babies are asymptomatic)

Pathogenesis:

Mutation causes crystallization of hemoglobin in low O2 environments (like when it delivers O2 to the tissues), giving the cells a sickled shape and causing them to get stuck in the small vessels which can lead to tissue damage from ischemia. Chronic hemolysis is also common.

Degree of sickling depends on 1. how much hemoglobin the RBCs have (more=more sickling) 2. intracellular pH 3. how fast the blood is moving (slower=more likely to get stuck)

Clinical Features:

- hemolytic anemia

- vaso-occlusive crisis leading to pain

- autosplenectomy (general altered splenic function)

- chronic hypoxia (leading to general lack of organ development and damage)

Progeria (gene mutation, age of diagnosis, pathogenesis, clinical features)

Gene mutation:

Sporadic autosomal dominant mutation (VERY RARE)

Age of diagnosis: Around age 2

Pathogenesis:

Lamin A proteins form the nuclear envelope with the guidance of farnysl molecules that attach to the lamin A and guide them into place. In healthy individuals, the farnysl then detaches to allow the nuclear envelope to form. In progeria, the farnysl cannot detach from the altered lamin A (called progerin) so the envelope cannot properly form leading to DNA damage and early aging.

Clinical Features:

- All the conditions associated with old age, but at a very young age

- Skin and skeletal deformities

- Arteriosclerosis and cardiovascular abnormalities (usually life threatening causing death in teens)

Cystic Fibrosis (gene mutation, pathogenesis, clinical features)

Gene mutation:

Autosomal recessive mutation on the CFTR gene (the most common lethal inherited disease in caucasians)

Pathogenesis:

The mutation in CFTR causes an accumulation of misfolded proteins and decreases chloride transport out of the cell. This causes Na+ and H2O reabsorption which causes secretions from the cells to be very thick. (the opposite happens in sweat glands where they cannot take the Cl- back in so Na+ and H2O stay out of the cell and they end up losing a lot of water and ions through their skin)

Clinical Features:

Primarily lung issues but also affects GI, pancreas, genitourinary. Frequent, severe lung infections are common since the thick mucus traps bacteria and prevents them from clearing pathogens (typically infection or lung damage is the cause of death)

MODY (gene mutation, pathogenesis, clinical features, treatment)

Gene mutation:

An autosomal dominant mutation to the HNF4A gene

Pathogenesis: The mutation causes mRNA transcripts of the gene to be degraded, but gene products are required to maintain pancreatic beta cells (less protein=less pancreatic function=decreased insulin production)

Clinical Features:

- Often misdiagnosed as type II diabetes

- Usually diagnosed before the age of the 30 (type II diabetes typically sets in after age 40)

Treatment:

Sulphonylureas are used to stimulate the production and release of insulin by pancreatic beta cells

Leukemia (gene mutation, pathogenesis)

Gene mutation:

miR-17-92 overexpression in B-cell lymphomas, acute lymphoid and myeloid leukemias

Pathogenesis:

miR-17-92 is a miRNA that regulates cell cycle associated genes, so when it is overactive, it causes rapid division of stem cells

Hemophilia (gene mutation, other similar conditions)

Gene mutation:

Sex-linked recessive disorder caused by the insertion of a transposon into the factor VIII gene (a clotting factor gene) making it dysfunctional

Other transposon conditions:

- BRCA2 gene causing neurofibromatosis and breast/ovarian cancer

Charcot-Marie-Tooth Disease (gene mutation, pathogenesis, clinical features)

Gene mutation:

Inherited peripheral neuropathy caused by a mitochondrial tRNA mutation that can be autosomal dominant, autosomal recessive, or X-linked

Pathogenesis:

Dysfunctional tRNA leads to defects in nerve cell proteins that cause damage to the myelin sheath or axon. This leads to loss of sensation and motor function everywhere the affected nerves innervate (deinervation atrophy).

Clinical Features:

- loss of muscle bulk (especially in lower legs and feet)

- curled toes (hammer toes)

- decreased ability to run

- foot drop/gait change

- frequent tripping/falling

- decreased/lost sensation in your legs and feet

How I like to remember it:

C - curled toes

M - muscle weakness and mass loss

T - tRNA mutation

Huntington's Disease (gene mutation, pathogenesis, clinical features)

Gene mutation:

Autosomal dominant neurodegenerative condition caused by CAG repeats in the Huntingtin gene on the p arm of chromosome 4

Pathogenesis:

- Excess CAG repeats cause dysfunction of the resulting protein leading to degeneration of the basal ganglia that control personality, cognition, and physical skills

- The number of CAG repeats can indicate onset and severity of the disease (<27 repeats is healthy, 27-35 repeats you are at risk of passing it on but you won't have it (anticipation), >35 repeats is pathologic). The more repeats there are, the earlier and more severe the symptoms will be

Clinical Features:

- onset ~35-45 years old (dependent on number of CAG repeats)

- Early symptoms: subtle changes in personality, cognition, and movement

- progressive neurologic symptoms including Huntington's chorea (jerky, uncontrolled movements)

- Cause of death is usually suicide, fall injury, or infection

Diamond-Blackfan Anemia (gene mutation, pathogenesis, clinical features, penetrance)

Gene mutation:

(Sometimes) sporadic autosomal dominant mutation of the RPS19 gene leading to ribosomopathy

Pathogenesis:

Mutation of the RPS19 impairs pre-rRNA processing of the 18s rRNA (part of the small subunit of the ribosome). Defective ribosome function causes poor red blood cell production. The bone marrow responds with stress hematopoiesis, leading to persistent fetal hemoglobin (HbF) expression past the typical age. In an attempt to increase O2 levels in the blood, they also have elevated erythropoietin (EPO) and elevated erythrocyte adenosine deaminase (ADA) that can be used as a biomarker.

Clinical Features:

- Hypoproductive anemia with macrocytosis in the first year of life (almost from birth, they have very few but abnormally large RBC due to decreased production by the bone marrow)

- Short stature, short forehead, wide eyes, flat bridge of nose, microcephaly, skeletal and urogenital anomalies

- Increased incidence of AML and osteogenic sarcoma

Penetrance:

- it has variable penetrance meaning that just because someone has the mutation they may not have the disease

- if a disease has 100% penetrance then anyone with the mutation will have the disease

5q Minus Syndrome (gene mutation, pathogenesis, clinical features, treatment)

Gene mutation:

Sporadic, somatic mutation (occurs after embryogenesis) resulting in the deletion of a portion of the q arm of chromosome 5 (typically just occurs in stem cells in the bone marrow)

Pathogenesis:

Deletion of the RPS14 gene causes a decrease in ribosomes (ribosomopathy), leading to decreased levels of erythropoiesis and erythroid differentiation (since it mostly occurs in the bone marrow stem cells, this means that there are fewer RBCs being produced)

Clinical Features:

- Doesn't usually occur until later in life (60s or 70s)

- Severe macrolytic anemia (blood cells are really big, but there are fewer of them)

- Normal/elevated platelet count but with hypolobulated micromegakaryocytes (platelets are small and have fewer lobes than usual)

- Low rate of progression to AML

Treatment:

Lenalidomide can be used to increase erythropoiesis by selectively killing the 5q minus cells and allowing healthy bone marrow stem cells to repopulate

corticosteroids are not useful in treatment

Xeroderma Pigmentosum (gene mutation, pathogenesis, clinical features)

Gene Mutation:

Autosomal recessive disorder that causes defective nucleotide excision repair (NER)

Pathogenesis:

Mutation to NER pathway means you can't repair damage to DNA caused by UV rays (sunlight) that make thymine dimers. Thymine dimers prevent proper DNA replication. Mutations in DNA accumulate causing increased risk of cancer.

Clinical Features:

- Typically see cancer (basal cell carcinoma and other skin cancers) before the age of 10

- Corneal clouding

- Freckles

- Keratitis (skin inflam.)

- 30% of cases have severe progressive neurologic disorder

Hereditary Non-Polyposis Colorectal Cancer (gene mutation, pathogenesis, clinical features)

Gene Mutation:

Autosomal dominant mutation to MMR proteins that control DNA mismatch repair

Pathogenesis:

Mutations accumulate in unrepaired DNA causing increased risk of cancer development

Clinical Features:

- MOST COMMON FORM OF HEREDITARY COLORECTAL CANCER

- Develop polyps at the same rate as the general population but they are more likely to develop into cancer

- 50-70% increased risk of developing colorectal and other cancers

- Predominantly right sided, flat adenomas at a young age

Severe Combined Immunodeficiency - SCID (gene mutation, pathogenesis, clinical features)

Gene Mutation:

X-linked OR autosomal recessive mutation

Pathogenesis:

Common cases -> mutation in the common gamma chain of receptors for interleukins (IgG, IgA, IgE, etc.) causing deficiency in B and T cells, ILR2 does not work to send messages from outside to inside the cells

Severe cases -> mutation prevents non-homologous DNA end joining so cells can't repair double strand breaks leading to receptor malfunction

Clinical Features:

- Lack of almost any immune response makes them VERY sensitive to infections

- Requires a bone marrow transplant before 3 months old in order to survive past the age of 2

- Frequent, severe infections and failure to thrive are common

Bloom Syndrome (gene mutation, pathogenesis, clinical features)

Gene Mutation:

Autosomal recessive mutation in the BLM gene

Pathogenesis:

Mutation in the BLM gene causes defective RecQ helicases that prevents unwinding of DNA needed for homologous recombination mediated DNA repair (certain DNA damage can't be repaired)

Clinical Features:

- Short stature

- Butterfly rash on the face

- Long, narrow face with prominant ears and nose and a small lower jaw

- High-pitched voice

- Lack of DNA repair also increases the risk of cancer so they typically only live 20-30 years

Neurofibromatosis Type-1 (gene mutation, pathogenesis, clinical features)

Gene Mutation:

Autosomal dominant mutation to the neurofibromin gene at location 17q11.2 (a tumor suppressor gene)

Pathogenesis:

Mutation of the tumor suppressor gene greatly increases the risk of developing benign and malignant tumors especially neurofibromas (tumor from nonmyelinating Schwann cells)

Clinical Features:

- Neurofibromas

- Cafe au lait spots

- Bone defects (scoliosis)

- Optic nerve gliomas

Duchenne Muscular Dystrophy (gene mutation, pathogenesis, clinical features)

Gene Mutation:

X-linked recessive mutation to the dystrophin gene

Pathogenesis:

Mutation to the dystrophin (muscle membrane protein) gene causes reduced ability to repair microtears in muscles which leads to muscle cell apoptosis or necrosis and muscle degradation over time.

Clinical Features:

- More common in males since it's X-linked

- Progressive muscle weakness leading to problems with movement and then problems with breathing

- Drastically reduced life span

- Marked elevation of the serum enzyme creatine phosphokinase (CPK) - proportional to the degree of muscle deterioration (high CPK=faster degeneration)

list what a primary care provider should know in genetics

medical paradigm is changing

genetic disorders may be treatable

children with geneitic disorders become adults with genetic disorders

clinical decisicons will increasingly rely on the results of genetics tests

family hisotry can be a clue to risk

describe some of the misconception about genetics

genetics deals with only rare disorders

children should not be tested for genetic disorders

insurance does not pay for genetic testing

genetic testing leads to discrimmination

genetic disorders are not treatable

monogenic disorders 

definition: 

caused by a mutation in a single gene 

inheritance pattern:

usually follow mendelian inheritance (autosomal dominant, autosomal rescessive, x-linked)

onset: 

often early in life 

examples:

sickle cell anemia (beta-globin gene), cystic fibrosis (CFTR gene), huntingtons disease (HTT gene), phenylketonuria (PAH gene)

environmental role: 

minimal (gene mutation is primary cause)

risk predicition: 

more straightforward (can test for the single gene) 

polygeneic disorders

definition: Caused by combined effect of multiple genes (often with environmental influence)

inheritance pattern: Do not follow simple Mendelian patterns; complex inheritance

onset: Often later in life

examples Type 2 diabetes - Hypertension - Coronary artery disease - Schizophrenia - Asthma

envvironemnt: Major role (environment interacts with genetic predisposition)

risk prediction More difficult (many genes + lifestyle factors)

o   Human genome

§  Nuclear genome is about 22,000 genes

·      Genes and related sequences (25%)

o   Coding DNA (codes for protein, mRNA, transcription, translation, CODES FOR 1.25% of protein 5% of 25%

o   Non-coding DNA (codes for functional RNA molecule, transcription only)

·      Other DNA (junk/we don’t understand, criminal investigation, paternity) (75%)

o   Single or low copy number (60%)

o   Middle to highly repetitive (40%)

§  Tandemly repeated

§  Dispersed repeats

§  Mitochondrial genome is about 37 genes

·      rDNA = 2 genes

·      tRNA = 22 genes (no junk and everything has a job)

·      protein coding = 13 genes

Nucleic acids:

• provides the basic genetic material of cells and viruses

• Consist of a sugar, a nitrogenous base, and phosphate group

• Have a sugar-phosphate backbone with bases projecting from the sugars

  • Adenine (A), guanine (G), cytosine (C), and either thymine (T) in RNA or uracil (U) in RNA

genes

o   DNA segments that carry the genetic information to make proteins or functional RNA molecules within the cells

100,000 genes from 23,000- 25,000 proteins by splicing

genome

o   collective term for all the different DNA molecules within a cells or organism – distributed between the nucleus and the mitochondria

Transcriptome

o   : total set of transcripts in an organism – expressions of the genes modified by external influences (phosphorylation)

Proteome

o   protein variation & function expressed by a genome, cell, tissue or organism

Metabolome

o   complete set of small-molecule metabolites (such as metabolic intermediated, hormones and other signaling molecules)

Microbiome (human):

o   refers to the constellation of viruses, bacteria, and fungi that colonize various human tissues

Ribose Sugar (in RNA)

• Type: Pentose sugar (5 carbon atoms)

• Chemical Formula: C₅H₁₀O₅

• Structure:

  • Has five carbon atoms arranged in a ring (furanose form).

  • Each carbon is numbered from 1′ (prime) to 5′.

  • Hydroxyl group (–OH) is attached to the 2′ carbon.

  • Found in: RNA (Ribonucleic Acid)

Deoxyribose Sugar (in DNA)

• Type: Pentose sugar

• Chemical Formula: C₅H₁₀O₄

• Structure:

  •  Similar to ribose, but missing one oxygen atom.

  • On the 2′ carbon, it has just a hydrogen atom (–H) instead of a hydroxyl group.

  • Found in: DNA (Deoxyribonucleic Acid)

purines 

Two rings (double)

Larger

Adenine (A), Guanine(G)

DNA & RNA

Pyrimidines

One ring (single)

Smaller

Cytosine (C), Thymine (T), Uracil (U)

DNA & RNA (except T in DNA, U in RNA)

Differentiate between the nitrogenous base composition of DNA and RNA.

Feature	DNA	RNA
Sugar	Deoxyribose	Ribose
Nitrogenous Bases	A, T, G, C	A, U, G, C
Unique Base	Thymine (T)	Uracil (U)
Base Pairing	A–T, G–C	A–U, G–C

Describe the rule of base pairing.

Nucleic Acid	Base Pairing
DNA	A = T, G ≡ C
RNA	A = U, G ≡ C

calculate the number of bases based on the given information

o   Chargaff’s rule: n(G)=n(C); n(A)=n(T)

DNA replication (semi-conservative):

o   two strands of the double helix are unwound, and each strand is used to make a new complementary DNA copy – occurs in S phase of cell cycle

§  DNA Polymerase III (enzyme attaches new nucleotides, doesn’t make mistakes and fixes them when needed) -> attach new DNA nucleotides

§  Makes DNA copies that are transmitted from cell to cell and from parents to offspring

Transcription

genes are used to make a single-stranded RNA copy that is complementary in sequence to one of the DNA strands

Translation

o   coding sequence of mRNA are used to make polypeptides chain of a protein

§  Messenger RNA: a temporary copy of a gene that contains information to make a polypeptide

§  Polypeptide: becomes part of a functional protein that contributes to an organisms traits

Messenger RNA:

§  a temporary copy of a gene that contains information to make a polypeptide

Polypeptide

§  becomes part of a functional protein that contributes to an organisms traits

Recall the central dogma of molecular biology.

o   DNA -> transcription with RNA polymerase which causing splicing -> RNA -> translation with ribosomes where chemical modification, folding, cleavage, transport, and binding of multiple polypeptide chains -> proteins

Step	Process	Product
DNA → RNA	Transcription	mRNA
RNA → Protein	Translation	Polypeptide (Protein)

 

Identify the key players in DNA replication.

Molecule	Function
Helicase	Unzips the DNA double helix by breaking hydrogen bonds between base pairs.
Single-Stranded Binding Proteins (SSBs)	Bind to and stabilize single-stranded DNA, preventing it from reannealing.
Topoisomerase (e.g. DNA gyrase)	Relieves the tension caused by unwinding the DNA (prevents supercoiling).
Primase	Synthesizes short RNA primers that provide a starting point for DNA synthesis.
DNA Polymerase	Adds new DNA nucleotides to the growing strand in the 5' → 3' direction.
Sliding Clamp	Holds DNA polymerase in place during replication.
RNase H (or DNA Polymerase I in prokaryotes)	Removes RNA primers after DNA synthesis.
DNA Ligase	Joins DNA fragments (e.g., Okazaki fragments) on the lagging strand by forming phosphodiester bonds.

 

 

Term	Description
Leading Strand	Synthesized continuously in the 5′ → 3′ direction.
Lagging Strand	Synthesized discontinuously as Okazaki fragments.
Replication Fork	Y-shaped structure formed during DNA unwinding.
Origin of Replication	Specific sequence where replication begins.

Promoter Region

§  Located upstream (before) the coding region.

§  Site where RNA polymerase binds to start transcription.

§  Contains regulatory elements (e.g., TATA box).

Exons

§  Coding sequences of the gene.

§  These are expressed and translated into proteins.

§  After transcription, exons are spliced together to form mature mRNA.

Introns

§  Non-coding sequences found between exons.

§  Removed from pre-mRNA during RNA splicing.

§  Not translated into protein.

Terminator Region

§  Signals the end of transcription

RNA splicing:

o   primary RNA transcript undergoes a form of processing

§  Involves cleaving the RNA transcript at the junctions between transcribed exons and introns

§  The transcribed exon sequences are then covalently linked (spliced) in turn to make a mature RNA

§  RNA splicing is the process by which introns (non-coding sequences) are removed from pre-mRNA, and exons (coding sequences) are joined together to form mature mRNA that can be translated into a protein.

Spliceosomes

o   performs slicing within the nucleus

Alternative splicing:

o   an additional source of complexity comes from using different combinations of exons to make alternative transcripts from the same gene

purose of RNA splicing

§  To remove non-coding introns from the RNA transcript.

§  To connect exons in the correct order.

§  To produce functional mRNA that can be used in protein synthesis.

§   To allow for alternative splicing, increasing protein diversity

step by step process of RNA splicing 

§  Recognition of Splice Sites

·      The spliceosome identifies:

o   5′ splice site (beginning of intron)

o   3′ splice site (end of intron)

o   A branch point within the intron (usually an adenine "A"

·      Cutting the Intron

o   The 5′ end of the intron is cut.

o   This cut end forms a loop (called a lariat) by binding to the branch point A

·      Exon Joining

o   The 3′ end of the intron is cut.

o   The exons are ligated (joined) together

·      Release of Intron

o   The lariat-shaped intron is released and degraded.

o   The mature mRNA (only exons) is ready for translation.

Describe the role of posttranslational modification in protein synthesis and give some examples.

Type	Function	Example
Phosphorylation	Regulates activity (on/off switch for enzymes)	Activation of insulin receptor
Glycosylation	Adds sugar molecules; affects folding, stability, and recognition	Antibodies (IgG), cell surface proteins
Ubiquitination	Tags protein for degradation by the proteasome	p53 regulation, damaged proteins
Methylation	Alters gene expression; common in histone proteins	Histone methylation (epigenetics)
Acetylation	Affects protein function and DNA binding	Histone acetylation → gene activation
Proteolytic Cleavage	Removes parts of a protein to activate it	Activation of insulin from proinsulin

Phosphorylation

Regulates activity (on/off switch for enzymes)

Activation of insulin receptor

Glycosylation

Adds sugar molecules; affects folding, stability, and recognition	Antibodies (IgG), cell surface proteins

Ubiquitination

Tags protein for degradation by the proteasome

p53 regulation, damaged proteins

Methylation

Alters gene expression; common in histone proteins	Histone methylation (epigenetics)

Acetylation

Affects protein function and DNA binding	Histone acetylation → gene activation

Proteolytic Cleavage

Removes parts of a protein to activate it	Activation of insulin from proinsulin

Lipidation

Adds lipid groups to anchor proteins to membranes	Ras protein (involved in signaling)

Disulfide Bond Formation

Stabilizes 3D structure, especially in secreted proteins	Antibodies, insulin

recall the number of base pairs and protien coding genes in the human genome

only 2% of the human genmone is protien coding

all mitochondrial DNA is used for protiens of functonal RNA

Define RNA genes 

they code for functional noncoding RNA (ncRNA) 

all the RNA expect mRNA

tRNA, vRNA, microRNA, longncRNA, siRNA, piRNA, snoRNA, snRNA, exRNA

there now evidence that mutations in ncRNA can cause disease 

microRNA with example

small (21-23 neuclotide) RNA molelcues that interfere with mRNA to regulate genes

binds to mRNA to degrade it or prevent translation (gene silencing)

pri-miRNA (transcribed whole) —> pre-miRN (Cleaved to for 2 stranded RNA -(dicer separates the strands)→ mature miRNA (single stranded RNA)

long ncRNA

> 200 nucleotides

regulation of:

• allelic expression → x chromosome inactivation, imprinting (one copy of a gene is silent → sometimes maternal, sometimes paternal)

• deleopment (lineage commutment (telling stem cells what to become), myogenesis)

  • disease states (cancer, muscular dystrophy, heart failure)

significance of human genome project 

first complete sequencing of the human nuclear genome 

took 13 years 

priortized euchromatin (transcriptonally active DNA) → 93% of the genome (transcribed but only about 2% translated)

didnt focus on neterochromation 

describe tandem repeats

repetitive sequences of RNA

1. functional multicope genes like → actin, tubulin

2. sequences with uncertain functions like → minisatellites 12-100 or mircosatellities 6-12

transposons

pieces of DNA that can move from one location in the genome to another

associates with disease is very raret

tandem repeats associated diseases

huntingtons, fragile x syndrome, myotonic dystrophy, spinocderebellar axtia and friedrion atoxia (happens because of excessive number of repeats) 

define haploinsufficiency and its effect on ribosome assembly

when less ribosomal protien A is produced the unbound protien b binds to MDM2 (p53 repressor) leaving p53 active

causes cell cycle arrest and apoptisis

recognize the significance of ribosomopathies and the included disorders

increased risk of cancer

skeletal defects

congenital or acquried bone marrow failure (its constantly diving and needs protien)

recall the possible mechanisms of ribosomopathies 

ribosomal haploinsufficiency

• disrupted ribosome biogensis leads to an accumulation of free ribosomal protiens 

• these bind to MDM2 (a repressor of p53) makng them inactive

• p53 becomes more active leading to all cycle arrest and apoptosis 

excess of heme

• no ribosome = no globin = excess unbound heme

  • the excess heme causes oxidative stress and damages the membrane 

describe the relationship between miRNA dysregulation and leukemia with specfic examples

relationship

• miRNA is overexpressed this dysregulates cell cycle accoicated genes

• leads to overgrowth of WBCs

example:

• miR-17-92 → primary role in cell is proliferation and stem cell differentitation

• this gene is overexpressed in B-cell lymphomas, actute lympoid leukemia and myeliod leukemia

  • Erg2 tells stem cells to differentiate via 10-92 gene when miR-17-92 is overexpressed it inhibits Erg2 so cells just divide rapidly

discuss how intertional mutagenesis by transposons can cause hemophilia

when transposons are inserted into an active gene it can disrupt proper functioning

hemophilia a

• transposon inserted in clotting factor 8 gene leading to its inactivation

• decrease clotting facor = hemophilia = excessive bleeding

identify the probability of a couple getting a child with hemophilia with on of the parents having the disease

hemophilia is most commonly x-linked recessive so there is a 25% chance 

50% chance if mom has it → all sons will have it but no daughters 

0% chance if dad has it → daughters will be carriers and sons will not 

recognize how the probability changes when the father is having hemophilia vs, when the mother has the disease

mom will give it to all her sons

dad will make daughters carriers but no diease

recognize the differences in the probability of inheriting hemophilia based on childs gender

if only 1 parent has it → daughters will always be carrier but never have it

sons will have it if mom does and will be healthy if dad doesgiv

give examples of other transposon related conditions 

BRAC2 gene mutation leading to breast/ovarian cancer and neurofibromatosis 

neurofibromatosis

a genetic disorder that affects the nervous system, causing the growth of non-cancerous (benign) tumors on nerves

recall how lenalidomide can change the disease process in 5q minus syndrome

stimulates bone marrow to increase erthropoiesis

modulates cytokine production → to regulate inflammation

inhibts phosphatases

essentailly it selectively kills cancer cells to prevent Acute Myeloid Leukemia (AML) progression

recognize the first line of treatment for 5q minus syndrome 

lenalidomide!!!!!

corticosteriods are not useful in treatment → for first line in diamond blackfan anemia 

phenotype

observable characteristics

genotype

the combo of alleles you have

disease phenotype

specific manifestations of a gene or group of genes expressed in a harmful way

character/trait 

the observable manifestation of a gene that aren’t disease associated → blood type, eye color, hair color 

genetic variation

change in the sequences of DNA (the alleles), change in phenotype (why we aren’t all clones)

recognize the contribution of enviromental and epigenetics factors to the disease development

sometimes the enviroment or epigenetics can affect phenotype → freckles/tanning in the sun

changing the phenotype but without changing the genotype → DNA stays the same

define mutations

change in the DNA sequence that is not corrected by cellular DNA repair system 

• neutral change → change in hair color or height

• could cause disease phenotype

• silent mutation → no obvious effect

  • beneficial effect → very rare

recognize the source that contribures to a majority of mutation 

result of change in the DNA that is NOT CORRECTED by repair mechanisms 

occasionally caused by radiation or chemicals but most occur naturally (endogenously)

to be expressed: 

dna repair → silent mutation → embryonic lethality → live birth with diease 

descrive genetic varitation and its types with examples

1. no change in the DNA

   1. point mutation → small # of nucleotides often silent or neutral mutation

   2. SNPS → single base is changed

2. net loss/gain of DNA sequence → almost always harmful and can cause spontaneous abortion or disease

   1. trisomy → whole extra chromosome

   2. deletion → loss of whole or portion of a chromosome

recognize the most common DNA changes and its effect on phenotype

SNPs are the most common DNA change

• 75% of DNA changes is from SNPs → 1 SNP per 1000 base pairs

  • most variation is neutral but a SMALL FRACTION is harmful

differentiate between rare variants and polymorphism 

1. polymorphisms: greater then or equal to 1% of people have the variant → SNPs

2. rare variants: less than 1% of people have them → can still be neutral, beneficial, or harmful like the BRCA1 gene 

state the signficance of a single nucleotide polymorphisms (SNPs)

the most common type of genetic variation, accounting for about 75% of DNA changes

even identical twins don’t have same SNP pattern

discuss ABO blood group and somatic rearrangement in the immune system as examples of functional genetic variation

ABO blood group

• inactivation of some genes give rise to A, B, AB, and O blood types

• a blood type = RBCs have the A antigen only so we have B antiboides

immune system:

• genes of the immune system are polymorphic (constantly changing or going through somatic rearrangment) so we can make new antibodues

  • constant positive selection to increase antigen recognition protiens to maximize diversity in the protiens involved in antigen recognition

list the origns of DNA sequence variation

1. recombination

   1. more common in the subtelomeric regions

   2. happens during meiosis so no 2 sperm or egg are identical

2. independent assortment

   1. homologous pairs separate independently in meiosis

3. various mutation events

   1. endogenous chemical damage to DNA

   2. chemical damage to DNA caused by external factors

   3. DNA replication errors 

   4. chromosome segregation and recombination errors

hydrolytic damage and the mechanism of how it causes damage to the DNA

disrupt covalent bonds that hold bases to sugars, cleaving the base from the sugar to produce and abasic site → loss of purine bases (depurination)

abasic site

a location in a DNA or RNA molecule where a nucleotide has lost its nitrogenous base. This creates a gap in the strand's sequence, disrupting its normal structure

oxidative damage and the mechanism of how it causes damage to the DNA

ROS damage the DNA

• superoxide anions (O2-)

• hydrogen peroxide (H2O2)

  • hydroxyl radical (OH-)

aberrant DNA methylation and the mechanism of how it causes damage to the DNA

s-adenosyl methionine (SAM) is used by cells to methylate stuff

sometimes it accidentally methylates DNA which can silent genes and produce harmful bases

list the external mutagens that can cause DNA damage to the DNA and identify the mechanism

these are disrupt transcription and replication

1. UV raditation → pyrimifine (T or C) dimers (2 covalently bonded pyrimidine in the SAME STRAND)

2. high energy irradiation (x-rays) → generate ROSs that break the DNA strands

   1. mutagenic chemicals (cigarette smoke, car fumes) → bulky DNA takes (covalent bond BTWN strands) distort the double helix making it harder to read

summarize the purpose of DNA repair and the consequences of a repair fails to occur

DNA crosslinking can prevent DNA from being read so its important to fix → UV raditation or mutageneic chemicals 

is DNA is not repaired is usually leads to apoptosis or disease 

minor DNA damage → altered base 

DNA damage → apoptosis or DNA repair → single strand breaks or double strand breaks 

single strand breaks: base excision repair, nucleotide excison repair, mismatch repair 

double strand breaks: non-homologous end joining, homologous recombination